Myasthenia gravis

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Myasthenia gravis
DiplopiaMG1.jpg
Eye deviation and a drooping eyelid in a person with myasthenia gravis trying to open her eyes
Specialty Neurology
Symptoms Varying degrees muscle weakness, double vision, drooping eyelids, trouble talking, trouble walking [1]
Usual onsetWomen under 40, men over 60 [1]
DurationLong term [1]
Causes Autoimmune disease [1]
Diagnostic method Blood tests for specific antibodies, edrophonium test, nerve conduction studies [1]
Differential diagnosis Guillain–Barré syndrome, botulism, organophosphate poisoning, brainstem stroke, [2] metabolic myopathies
TreatmentMedications, surgical removal of the thymus, plasmapheresis [1]
Medication Acetylcholinesterase inhibitors (neostigmine, pyridostigmine), immunosuppressants [1]
Frequency50 to 200 per million [3] [4]

Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. [1] The most commonly affected muscles are those of the eyes, face, and swallowing. [1] [5] It can result in double vision, drooping eyelids, and difficulties in talking and walking. [1] Onset can be sudden. [1] Those affected often have a large thymus or develop a thymoma. [1]

Contents

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. [6] [7] [1] This prevents nerve impulses from triggering muscle contractions. [1] 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. [8] Rarely, an inherited genetic defect in the neuromuscular junction results in a similar condition known as congenital myasthenia. [9] [10] Babies of mothers with myasthenia may have symptoms during their first few months of life, known as neonatal myasthenia [1] or more specifically transient neonatal myasthenia gravis. [11] Diagnosis can be supported by blood tests for specific antibodies, the edrophonium test, electromyography (EMG), or a nerve conduction study. [1]

MG is generally treated with medications known as acetylcholinesterase inhibitors, such as neostigmine and pyridostigmine. [1] Immunosuppressants, such as prednisone or azathioprine, may also be used. [1] The surgical removal of the thymus may improve symptoms in certain cases. [1] Plasmapheresis and high-dose intravenous immunoglobulin may be used during sudden flares of the condition. [1] If the breathing muscles become significantly weak, mechanical ventilation may be required. [1] Once intubated acetylcholinesterase inhibitors may be temporarily held to reduce airway secretions. [12]

MG affects 50 to 200 people per million. [3] [4] It is newly diagnosed in 3 to 30 people per million each year. [13] Diagnosis has become more common due to increased awareness. [13] MG most commonly occurs in women under the age of 40 and in men over the age of 60. [1] [5] [14] It is uncommon in children. [1] With treatment, most live to an average life expectancy. [1] The word is from the Greek mys, "muscle" and asthenia "weakness", and the Latin gravis, "serious". [15]

Signs and symptoms

The initial, main symptom in MG is painless weakness of specific muscles, not fatigue. [16] 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. [17] MG 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. [18]

Eyes

In about two-thirds of individuals, the initial symptom of MG is related to the muscles around the eye. [16] Eyelid drooping (ptosis may occur due to weakness of m. levator palpebrae superioris) [19] and double vision (diplopia, [16] due to weakness of the extraocular muscles). [17] Eye symptoms tend to get worse when watching television, reading, or driving, particularly in bright conditions. [16] Consequently, some affected individuals choose to wear sunglasses. [16] The term "ocular myasthenia gravis" describes a subtype of MG where muscle weakness is confined to the eyes, i.e. extraocular muscles, m. levator palpebrae superioris, and m. orbicularis oculi. [19] Typically, this subtype evolves into generalized MG, usually after a few years. [19]

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, [20] or food and liquids may regurgitate into the nose rather than go down the throat (velopharyngeal insufficiency). [17] Weakness of the muscles that move the jaw (muscles of mastication) may cause difficulty chewing. In individuals with MG, chewing tends to become more tiring when chewing tough, fibrous foods. [16] Difficulty in swallowing, chewing, and speaking is the first symptom in about one-sixth of individuals. [16]

Speaking

Weakness of the muscles involved in speaking may lead to dysarthria and hypophonia. [16] Speech may be slow and slurred, [21] or have a nasal quality. [17] In some cases, a singing hobby or profession must be abandoned. [20]

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 [16] (the "hanging jaw sign") and as a snarling expression when attempting to smile. [17] With drooping eyelids, facial weakness may make the individual appear sleepy or sad. [16] Difficulty in holding the head upright may occur. [21]

Other

The muscles that control breathing and limb movements can also be affected; rarely do these present as the first symptoms of MG, but develop over months to years. [22] In a myasthenic crisis, a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain life. [23] Crises may be triggered by various biological stressors such as infection, fever, an adverse reaction to medication, or emotional stress. [23]

Cause

Medications that cause or worsen MG

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 MG. In the fluoroquinolone antibiotic family, ciprofloxacin, norfloxacin, ofloxacin, and moxifloxacin are reported to exacerbate MG. [24] And, In the aminoglycoside family of antibiotics, gentamicin, streptomycin, and neomycin are reported to exacerbate MG. [25] The aminoglycoside tobramycin has not been reported to exacerbate MG and may be used in patients that require aminoglycoside treatment. [24] Because of the rarity or absent reports on their exacerbation of MG, the following antibiotics are considered safe to use in MG patients: the cephalosporin class of drugs, sulfa drugs, the tetracycline group of drugs, clindamycin, polymyxin B, and nitrofurantoin. [24]

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 patients who received these drugs, 52 developed new onset MG and 11 had a flare of their preexisting MG. The symptoms of MG developed within 6 days to 16 weeks (median time 4 weeks). Their medicine-induced MG symptoms were often severe with 29 patients developing respiratory failure that required mechanical ventilation. [26] Other studies have reported that these checkpoint inhibitors cause respiratory failure in 45% and death in 25–40% of patients. [24] [27] These medications, it is suggested, are best avoided in MG patients, particularly in patients who previously had a life-threatening reaction to them. If these medications must be used in MG patients, it is recommended that the patients be pre-treated with a glucocorticoid, plasmapheresis, or intravenous immunoglobulin to reduce the chances of their developing severe symptoms. [24]

Statins: Statins are drugs that lower blood cholesterol levels. In a review of 169 patients who were reported to develop MG or had worsened MG symptoms while taking a statin (i.e., simvastatin, atorvastatin, rosuvastatin, pravastatin, lovastatin, or fluvastatin), 138 had developed generalized MG, 13 had developed ocular MG, and 18 had worsening of their MG. Following discontinuance of the statin and treatment of their MG, 63 patients fully recovered, 27 patients were recovering, 19 patients had not yet recovered, 5 patients recovered but had ongoing symptoms, 1 patient had died, and there was no follow-up data for 54 patients. Among these cases, 56% were considered to be serious. [28] Non-statin cholesterol-lowering drugs, (e.g., niacin and the bile acid sequestrants drugs cholestyramine, colestipol, colesevelam, alirocumab, and evolocumab) have been used in patients without causing or worsening MG. It is advised that a statin be discontinued and thereafter all statins be avoided in the rare cases where the statin caused the development or worsening of MG. [24]

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 MG patients who, prior to being treated with it, did not have respiratory symptoms. Furthermore, this drug has caused MG-like symptoms in patients who have kidney failure but do not have MG. And, procainamide worsened muscle dysfunction in a rat model of human MG. These studies suggest that procainamide as well as other type Ia antiarrhythmic agents should be avoided or used with extreme caution in MG patients. [24]

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 patients undergoing surgery. [29] Succinylcholine is the only depolarizing neuromuscular blocker available in the U.S. market. [24] Succinylcholine's ability to induce or worsen MG is unclear. It has been suggested to cause life-threatening side effects such as rhabdomyolysis, myotonia, and hyperkalemia in patients with muscle disease although the role of succinylcholine in causing these side effects also remains unclear. [29] Until more evidence on these issues becomes available and since there are other neuromuscular blocking agents without these deleterious side effects, the use of succinylcholine in MG (and other neuromuscular disorders) should probably be avoided where feasible. [24] [29]

Inhalation anesthetics: Inhalation anesthetics are general anesthetics that are delivered by inhalation generally for patients undergoing surgery. MG patients 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 MG patients 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. [24] [30] These studies suggest that inhalation anesthetics are best avoided in MG patients but if used close post-operation monitoring should be conducted for MG patients being anesthetized with these agents [24] and sugammadex should be considered for routine use in MG patients anesthetized with these agents who undergo thymectomy [31] or other types of surgery. [24]

Glucocorticoids: Glucocorticoids are anti-inflammatory agents that in initial studies were used at high dosages and found to worsen MG in 25-75% of cases. [32] However, further studies found that glucocorticoids do have favorable effects on MG when taken long-term. Two glucocorticoids, oral prednisone and prednisolone, are now the first line immunosuppressive treatment for MG. To avoid exacerbation of MG, it is recommended that the corticosteroids should be started at a low dose and gradually increased to the dose achieving maximal responses. To achieve a faster therapeutic responses in cases with severe MG symptoms, it has been recommended to start with high doses of oral or intravenous glucocorticoids after first treating patients with plasmapheresis or intravenous immunoglobulin therapy, each of which reduces the chance of having a severe reaction to the corticosteroids. [24] [33] [34]

Calcium channel blockers: Calcium channel blockers (e.g., felodipine, nifedipine, and verapamil) are drugs that lower blood pressure in patients with hypertension. Felodipine and nifedipine are reported to worsen MG and nifedipine and verapamil are reported to cause respiratory failure in patients with severe generalized MG. MG patients, especially those who are in remission or have well-controlled disease, generally can be treated with these blockers using their lowest effective doses and close monitoring for the worsening of MG symptoms. [24]

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 MG and/or develop low concentrations of antibodies to AChR. [35] Their MG is often mild and predominantly ocular MG, 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. It is recommended that penicillamine be discontinued and thereafter avoided in patients who develop MG symptoms when treated with it. [24]

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 MG in individuals with subclinical MG, and exacerbations of previously controlled MG. 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 MG patients without side effects or with only short-lived dysphagia or diplopia. Botulinum toxin A treatment, it is suggested, is best avoided in MG patients but may be offered with caution to patients with mild or stable MG using gradual increases in its dosages and close monitoring. [24]

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. [24] 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 patients with underlying MG. [24] [36] It is suggested that magnesium when given intravenously or when given orally at high doses should be used with extreme caution in MG patients. [24]

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 MG patients 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 patients with MG. [37] [38]

Other Drugs: Rare cases of MG exacerbations have been reported in patients 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 MG), dabrafenib, and trametinib; 3) antipsychotic drugs, i.e., chlorpromazine, pimozide, thioridazine, clozapine, olanzapine, haloperidol, quetiapine, risperidone, and olanzapine; 4) IFN-α (may also cause MG); and 5) the chemical element, lithium. These agents can be used in MG patients because reports on their exacerbation (or induction) of MG are rare. [24]

Pathophysiology

MG 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. [39] [40] Other, less frequent antibodies are found against LRP4, agrin, and titin proteins. [8] [41]

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. [42] [43]

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. [44]

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. [45] Signs and symptoms in pregnant mothers tend to improve during the second and third trimesters. Complete remission can occur in some mothers. [46] Immunosuppressive therapy should be maintained throughout pregnancy, as this reduces the chance of neonatal muscle weakness, and controls the mother's myasthenia. [47]

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. [45] [47] 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. [45] 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. [47] [48]

Diagnosis

MG can be difficult to diagnose, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders. [20]

Three types of myasthenic symptoms in children can be distinguished: [49]

  1. Transient neonatal myasthenia gravis occurs in 10 to 15% of babies born to mothers afflicted with the disorder, and disappears after a few weeks.
  2. Congenital myasthenia, the rarest form, occurs when genes are present from both parents.
  3. Juvenile myasthenia gravis is most common in females.

Congenital myasthenias cause muscle weakness and fatigability similar to those of MG. [50] The signs of congenital myasthenia usually are present in the first years of childhood, although they may not be recognized until adulthood. [51]

Subgroup classification

Myasthenia Gravis Foundation of America Clinical Classification [52]
ClassDescription
IAny eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
IIEye muscle weakness of any severity, mild weakness of other muscles
IIaPredominantly limb or axial muscles
IIbPredominantly bulbar and/or respiratory muscles
IIIEye muscle weakness of any severity, moderate weakness of other muscles
IIIaPredominantly limb or axial muscles
IIIbPredominantly bulbar and/or respiratory muscles
IVEye muscle weakness of any severity, severe weakness of other muscles
IVaPredominantly limb or axial muscles
IVbPredominantly bulbar and/or respiratory muscles
VIntubation needed to maintain airway

When diagnosed with MG, patient 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. [53]

Based on the affected muscle group, patients can be sub-grouped into ocular MG or generalized MG. Ocular MG is characterized by exclusively ocular symptoms, droopy eyelids, or double vision. Generalized MG has muscle weakness with a variable combination of the bulbar, axial, or limb and respiratory muscles. [54]

Patients can also be sub-grouped by the age of onset: juvenile-onset MG (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). [55]

The subgroup of the autoantibody profile includes AChR seropositive, MuSK seropositive, LRP4 seropositive, and agrin seropositive. [56]

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. [20] 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. [20]

Blood tests

If the diagnosis is suspected, serology can be performed:

Electrodiagnostics

A chest CT-scan showing a thymoma (red circle) Tumor Thymoma1.JPG
A chest CT-scan showing a thymoma (red circle)
Photograph of a person showing right partial ptosis (left picture), the left lid shows compensatory pseudo lid retraction because of equal innervation of the m. levator palpabrae superioris (Hering's law of equal innervation): Right picture: after an edrophonium test, note the improvement in ptosis. Myasthenia gravis ptosis reversal.jpg
Photograph of a person showing right partial ptosis (left picture), the left lid shows compensatory pseudo lid retraction because of equal innervation of the m. levator palpabrae superioris (Hering's law of equal innervation): Right picture: after an edrophonium test, note the improvement in ptosis.

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, [20] 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. [59]

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. [60]

Edrophonium test

This test requires the intravenous administration of edrophonium chloride or neostigmine, drugs that block the breakdown of acetylcholine by cholinesterase (acetylcholinesterase inhibitors). [61] This test is no longer typically performed, as its use can lead to life-threatening bradycardia (slow heart rate) which requires immediate emergency attention. [62] Production of edrophonium was discontinued in 2008. [23]

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. [63] MRI of the cranium and orbits may also be performed to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles. [64]

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. [65] [66]

Differential diagnoses

The muscle weakness that worsens with activity (abnormal muscle fatigue) in myasthenia gravis [67] 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. [68] [69] Also, like myasthenia gravis, [67] 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"). [70] [71] A small minority of patients with McArdle disease also have the comorbidity of ptosis (drooping upper eyelid). [72] 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. [73]

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; [74] as do some limb-girdle muscular dystrophy-dystroglycanopathies such as MDDGC3 (a.k.a. LGMDR15 and LGMD2O). [73] [75] Myofibrillar myopathy 10, [76] dimethylglycine dehydrogenase deficiency, [77] erythrocyte lactate transporter defect, [78] and myopathy with myalgia, increased serum creatine kinase, with or without episodic rhabdomyolysis (MMCKR) [79] 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. [80]

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. [81]

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. [82]

Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune condition that attacks the neuromuscular junction, either as a paraneoplastic syndrome (typically older patients) or associated with a non-cancerous primary autoimmune condition (typically younger patients). 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. [83]

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. [5] [84] Thymectomy is a surgical method to treat MG. [85] [86]

Medication

Neostigmine, chemical structure Neostigmine.svg
Neostigmine, chemical structure
Azathioprine, chemical structure Azathioprine.svg
Azathioprine, chemical structure

About 10% of people with generalized MG are considered treatment-refractory. [87] 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. [88]

Efgartigimod alfa (Vyvgart) was approved for medical use in the United States in December 2021. [89] [90] [91]

Efgartigimod alfa/hyaluronidase (Vyvgart Hytrulo) was approved for medical use in the United States in June 2023. [92] [93]

Rozanolixizumab (Rystiggo) was approved for medical use in the United States in June 2023. [94] [95]

Acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors can provide symptomatic benefit and may not fully remove a person's weakness from MG. [96] While they might not fully remove all symptoms of MG, they still may allow a person the ability to perform normal daily activities. [96] 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. [97] 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. [98] Generally, it is discontinued in those who are being mechanically ventilated, as it is known to increase the amount of salivary secretions. [98] 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. [84]

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. [98] Research suggests that up to 15% of patients do not positively respond to immune suppressants. [99] [100] [5] Due to the myriad symptoms that steroid treatments can cause, it is not the preferred method of treatment. [98] Other immune suppressing medications may also be used including rituximab [101] or azathioprine. [1]

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. [98] [102]

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. [23] [62] Even if surgery is performed to remove a thymoma, it generally does not lead to the remission of MG. [98] 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. [103] A 2016 randomized, controlled trial, however, found some benefits. [104]

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. [18] 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. [105]

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. [106]

Prognosis

The prognosis of people with MG is generally good, as is quality of life, when given very good treatment. [107] 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. [98] Generally, the most disabling period of MG might be years after the initial diagnosis. [96] Assistive devices may be needed to assist with mobility. [1] 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. [98]

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. [23] [108] In the United Kingdom, an estimated 15 cases of MG occur per 100,000 people. [62] The mortality rate of MG is around 5-9%. [109]

History

The first to write about MG were Thomas Willis, Samuel Wilks, Erb, and Goldflam. [19] The term "myasthenia gravis pseudo-paralytica" was proposed in 1895 by Jolly, a German physician. [19] Mary Walker treated a person with MG with physostigmine in 1934. [19] Simpson and Nastuck detailed the autoimmune nature of the condition. [19] In 1973, Patrick and Lindstrom used rabbits to show that immunization with purified muscle-like acetylcholine receptors caused the development of MG-like symptoms. [19]

Research

Immunomodulating substances, such as drugs that prevent acetylcholine receptor modulation by the immune system, are currently being researched. [110] Some research recently has been on anti-c5 inhibitors for treatment research as they are safe and used in the treatment of other diseases. [14] Ephedrine seems to benefit some people more than other medications, but it has not been properly studied as of 2014. [10] [111] 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. [112] Recent years, scientists have been working on finding the reliable biomarkers for MG to monitor the disease development and assess the severity.

Related Research Articles

Angela Vincent is a British neuroscientist who is emeritus professor at the University of Oxford and a Fellow of Somerville College, Oxford.

<span class="mw-page-title-main">Lambert–Eaton myasthenic syndrome</span> Autoimmune disorder causing muscular weakness

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs. It is also known as myasthenic syndrome, Eaton–Lambert syndrome, and when related to cancer, carcinomatous myopathy.

Neuromyotonia (NMT) is a form of peripheral nerve hyperexcitability that causes spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. NMT along with Morvan's syndrome are the most severe types in the Peripheral Nerve Hyperexciteability spectrum. Example of two more common and less severe syndromes in the spectrum are cramp fasciculation syndrome and benign fasciculation syndrome. NMT can have both hereditary and acquired (non-inherited) forms. The prevalence of NMT is unknown.

<span class="mw-page-title-main">Edrophonium</span> Type of acetylcholinesterase inhibitor

Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction. It is sold under the trade names Tensilon and Enlon.

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

<span class="mw-page-title-main">Physostigmine</span> Chemical compound

Physostigmine is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and the fruit of the Manchineel tree.

<span class="mw-page-title-main">Pyridostigmine</span> Medication used to treat myasthenia gravis

Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is also used off-label to treat some forms of Postural orthostatic tachycardia syndrome. It is typically given by mouth but can also be used by injection. The effects generally begin within 45 minutes and last up to 4 hours.

<span class="mw-page-title-main">End-plate potential</span> Voltages associated with muscle fibre

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. Myopathy means muscle disease. This meaning implies that the primary defect is within the muscle, as opposed to the nerves or elsewhere.

Ocular myasthenia gravis (MG) is a disease of the neuromuscular junction resulting in hallmark variability in muscle weakness and fatigability. MG is an autoimmune disease where anomalous antibodies are produced against the naturally occurring acetylcholine receptors in voluntary muscles. MG may be limited to the muscles of the eye, leading to abrupt onset of weakness/fatigability of the eyelids or eye movement. MG may also involve other muscle groups.

<span class="mw-page-title-main">Neuromuscular disease</span> Medical condition

A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junctions, or skeletal muscles, all of which are components of the motor unit. Damage to any of these structures can cause muscle atrophy and weakness. Issues with sensation can also occur.

A tensilon test, also called an edrophonium test, is a pharmacological test used for the diagnosis of certain neural diseases, especially myasthenia gravis. It is also used to distinguish a myasthenic crisis from a cholinergic crisis in individuals undergoing treatment for myasthenia gravis. The test has fallen out of use due to suboptimal sensitivity and specificity as well as associated adverse risks. Edrophonium is no longer available in the United States and many other countries as of 2018.

<span class="mw-page-title-main">Triethylcholine</span> Chemical compound

Triethylcholine is a drug which mimics choline, and causes failure of cholinergic transmission by interfering with synthesis of acetylcholine in nerve endings.

Ambenonium is a cholinesterase inhibitor used in the management of myasthenia gravis.

Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference being that CMS is not an autoimmune disorder. There are only 600 known family cases of this disorder and it is estimated that its overall frequency in the human population is 1 in 200,000.

Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.

<span class="mw-page-title-main">Inflammatory myopathy</span> Muscular inflammatory disease of unknown origin

Inflammatory myopathy, also known as idiopathic inflammatory myopathy (IIM), is disease featuring muscle weakness, inflammation of muscles (myositis), and in some types, muscle pain (myalgia). The cause of much inflammatory myopathy is unknown (idiopathic), and such cases are classified according to their symptoms and signs, electromyography, MRI, and laboratory findings. It can also be associated with underlying cancer. The main classes of idiopathic inflammatory myopathy are polymyositis (PM), dermatomyositis (DM), inclusion-body myositis (IBM), immune-mediated necrotising myopathy (IMNM), and focal autoimmune myositis.

<span class="mw-page-title-main">Epigenetics of neurodegenerative diseases</span> Field of study

Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.

<span class="mw-page-title-main">Neuromuscular drug</span>

Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.

Transient neonatal myasthenia gravis, i.e., TNMG, and its more severe form, fetal acetylcholine receptor inactivation syndrome, is one of the various types of myasthenia gravis. MG is an autoimmune disease in which individuals form antibodies that circulate in their blood, enter tissues, bind to certain proteins in the neuromuscular junctions of skeletal muscles, and thereby reduce the number or ability of these skeletal muscles to contract when appropriately stimulated by acetylcholine. The affected skeletal muscles are easily fatigable, i.e., weakened after relatively little use. There are at least 3 types of antibodies that are known to cause the non-FARIS form of TNMG: antibodies binding to the adult form of the nicotinic acetylcholine receptor, i.e., adult nAChR, are responsible for most cases of non-FARIS MG while antibodies binding to two proteins near these nAChRs, i.e., the MuSK protein and low-density lipoprotein receptor-related protein 4 are responsible for many of the remaining non-FARIS TNMG cases. Studies suggest that antibodies directed against another protein near the nAChRs receptor, i.e., agrin, may be responsible for rare cases of non-FARIS MG. Antibodies directed at the fetal form of nAChRs are responsible for all cases of the FARIS form of TNMT.

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