MG Brochures. Autoimmune MG and Diagnostic Tests. MG Crisis. MG Patient Registry. Clinical Overview of MG. Volunteer Today. MG Quick Facts. The most common form of MG is a chronic autoimmune neuromuscular disorder characterized by fluctuating weakness of the voluntary muscle groups.
In the U. However, as myasthenia gravis often remains underdiagnosed, the prevalance is most likely higher. MG can occur regardless of race, gender and age MG is not thought to be directly inherited nor contagious, but may occur in more than one member of the same family MG is not transmitted via intimate or any form of contact There is no known cure for MG, but there are many effective treatments that can make managing life with MG easier Myasthenia gravis, or MG, is not the only medical condition referred to as MG.
What happens in the body when someone has MG? A World Without MG. Long-term use of corticosteroids can increase the risk of diabetes, cataracts, osteoporosis, gastric ulcers, weight gain, and bruising. Immunosuppressive medications can carry a small risk of blood or skin cancers. Other therapies include plasmapheresis, in which the abnormal antibodies are filtered out of the blood, and high-dose intravenous immunoglobulin, in which the immune system is modified by the infusion of normal antibodies from donated blood.
However, benefits of these two treatments usually last only a few weeks. Surgical removal of the thymus gland, a procedure called a thymectomy, may improve symptoms for people who have a thymoma. A neurologist will determine the best treatment options for each patient. With the therapies available, many people with myasthenia gravis are able to lead normal or mostly normal lives.
Some cases of the disease may go into remission, either temporarily or permanently. Researchers at Barrow are looking at a synthetic protein that may have the potential to counteract the damage done in the muscles of patients with myasthenia gravis.
Ladha said. To give you the best possible experience, this site uses cookies. By continuing to use the site, you agree that we can save them on your device. Facebook 0 Tweet 0 LinkedIn 0. What is Myasthenia Gravis? Increased awareness of myasthenia gravis will lead to proper diagnosis, research to develop better treatments, and support for the challenges that patients and families are facing.
Edrophonium chloride is an acetylcholinesterase inhibitor with rapid onset approximately 30 seconds and short duration approximately 5 minutes of pharmacologic action. Edrophonium chloride temporarily improves the safety factor of neuromuscular transmission and may elicit improved strength in patients with abnormal neuromuscular transmission. Edrophonium testing is considered positive when unequivocal improvement in strength follows intravenous administration of edrophonium.
Development of increased weakness may also suggest abnormal neuromuscular transmission. The primary limitation of edrophonium testing relates to selection of an objective muscle strength parameter for assessment. Therefore, edrophonium testing is most useful in patients who have significant ptosis or restricted extraocular movements that can be graded objectively. In other muscles, volition and the muscarinic effects of edrophonium may complicate strength measurement and render the test uninterpretable.
False positive edrophonium testing may occur in other neurological conditions including lower motor neuron disorders and brainstem tumors [ 16 — 19 ].
During testing, up to 10 mg of intravenous edrophonium chloride may be administered. Because of the potential for serious muscarinic side effects including bronchospasm and bradycardia, atropine should be readily available. Typical muscarinic side effects include increased sweating, lacrimation, salivation, nausea, and diarrhea.
An incremental dosing schedule should be utilized with one minute observation periods following each dose of edrophonium. If muscle strength improves clearly within one minute following any dose increment, the test is considered to be positive and the procedure is concluded. This strategy reduces the risk of giving excessive edrophonium and producing untoward muscarinic side effects.
An initial 2 mg dose and subsequent doses of 2 mg, 3 mg, and 3 mg are given if needed. With low rates of motor nerve stimulation 2—5 Hz , RNS depletes the immediate stores of acetylcholine at the neuromuscular junction. This reduces the safety factor and probability of successful neuromuscular transmission. In neuromuscular junction disorders, the safety factor is reduced, and further reduction by RNS causes some endplate potentials to fail to reach depolarization threshold.
This results in a failure to elicit muscle fiber action potentials. With a reduced number of individual muscle fiber action potentials, the compound muscle action potential CMAP becomes reduced in both amplitude and area with a resulting decremental response. This may not be present in stimulus trains recorded following rest, but it may only develop in trains collected subsequent to an exercise period as a consequence of postactivation exhaustion. The sensitivity of RNS is increased when recordings are made from clinically weak muscles.
Careful attention to proper technique is important to avoid erroneous results. In general, proximal muscles including facial muscles, trapezius, deltoid, and biceps brachii are more likely to exhibit abnormal findings.
SFEMG is the most sensitive diagnostic test for detecting abnormal neuromuscular transmission. In most normal muscles, this arrangement facilitates recordings from two individual muscle fiber action potentials. The variability in time interval between the firing of one muscle fiber potential with relation to the other is termed the neuromuscular jitter [ 21 ]. SFEMG should be performed in a clinically weak muscle whenever possible.
In many laboratories, the extensor digitorum communis EDC is studied initially. If the findings are normal in the EDC, a facial muscle should be studied [ 22 ]. A finding of normal jitter in a clinically weak muscle virtually excludes MG as a cause of weakness in that muscle. However, SFEMG also demonstrates abnormal neuromuscular transmission related to other motor unit disorders including motor neuropathic and myopathic disorders.
Normal SFEMG fiber density measurements can aid in distinguishing primary disorders of neuromuscular transmission from other motor unit disorders such as motor neuropathic or myopathic processes. In light of its reduced specificity, SFEMG must be performed and interpreted in the appropriate clinical context to avoid false positive results due to diseases other than those primarily affecting the neuromuscular junction.
It is a time-consuming test that requires special expertise and equipment that are not available in all centers. The assay is very specific, and positive antibody studies confirm MG in a patient with appropriate symptoms and clinical findings. About one-half of prepubertal children with MG are SN [ 26 ]. Rarely, false positive results in AChR binding antibody assays have been observed in patients with other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory neuropathy.
False positive results have also been reported in motor neuron disease, patients with thymoma without MG, and relatives of patients with MG [ 27 ]. Some initially SN patients may seroconvert within the first several months of disease.
Seroconversion may be identified in these patients by repeating the AChR binding antibody studies after six months of symptoms [ 28 ]. The AChR modulating and blocking antibody assays are probably useful only when the AChR binding antibody assay is negative, since they increase diagnostic sensitivity only slightly.
Anti-striated muscle or anti-striational antibodies react with contractile elements of skeletal muscle. These antibodies may be useful as a serological marker for thymoma in younger patients.
Following thymoma resection, a rise in anti-striated muscle antibody titer may suggest recurrent tumor [ 30 ]. Patients with MuSK MG are predominantly female and may exhibit prominent bulbar, neck, shoulder girdle, and respiratory weakness [ 1 , 2 , 4 ]. MuSK appears to facilitate clustering of AChR at the end plate region in the developing neuromuscular junction, though the role of MuSK antibodies in producing disease at mature neuromuscular junctions has not yet been defined.
Antibodies against the intracellular skeletal muscle protein titin may be present in patients with thymoma, but they are also present in about half of patients with late-onset MG without thymoma [ 32 , 33 ].
Ryanodine antibodies are also associated with late-onset MG. Patients with ryanodine antibodies may exhibit severe, treatment-resistant MG associated with malignant thymomas [ 34 ].
Although the role for these antibodies in the diagnosis of MG has yet to be determined, they may have prognostic value and expedite chest imaging studies for detection of thymoma. Chest computerized tomography CT should be performed in patients with MG to exclude the presence of thymoma.
Chest CT is more sensitive than plain chest radiographs for delineating anterior mediastinal masses, and chest MRI does not improve diagnostic sensitivity. Iodinated contrast agents have rarely precipitated significant worsening of myasthenic weakness [ 35 , 36 ].
Though this is an uncommon phenomenon [ 37 ], we do not routinely use iodinated contrast agents during chest CT studies performed to assess for thymoma. Since MG often co-exists with other autoimmune disorders, particularly autoimmune thyroid disease, patients should undergo thyroid function testing along with testing for other autoimmune disorders when clinically appropriate.
Pharmacologic testing with intravenous edrophonium is sensitive when performed in patients with significant ptosis or external ophthalmoparesis. RNS studies may demonstrate impaired neuromuscular transmission, especially when performed recording from clinically weak muscles, though they are relatively insensitive in ocular and in mild generalized MG.
Differential diagnosis includes other disorders of the neuromuscular junction including Lambert Eaton syndrome, botulism, congenital myasthenic syndromes, and tick paralysis. In addition, acute inflammatory demyelinating polyradiculoneuropathy AIDP and variants of AIDP affecting cranial muscles such as the Miller-Fisher and cervical-brachial-pharyngeal variants may simulate MG, though the weakness does not have the same variability.
Mitochondrial neuromuscular disorders, particularly those featuring external ophthalmoplegia and ptosis, may simulate MG. However, the onset of symptoms is gradual, and the weakness does not fluctuate greatly. Motor neuron disease involving oropharyngeal weakness may appear similar to MG, though the presence of corticobulbar features and increased fiber density measurements on SFEMG can assist in distinguishing these entities.
Finally, brainstem ischemia may simulate the fluctuating character of MG, though unlike MG, consciousness, balance and coordination, and sensation are often impaired. Treatment must be individualized to each patient with MG. The overall goal is to reestablish or to approximate normal clinical neuromuscular function while minimizing adverse effects. Few treatments have been subjected to rigorous, prospective, placebo-controlled study in MG.
Factors to be considered in selecting treatment include the distribution, duration, and severity of myasthenic weakness and functional impairment, the risk for treatment complications related to medical comorbidities, age, and gender, and the ability of the patient to obtain medication and comply with drug dosing schedules and toxicity monitoring. In general, the increased risks related to long-term immune modulation become more acceptable in more severe MG to offset increased morbidity and mortality related to uncontrolled disease.
A detailed review of treatment issues in autoimmune MG may be found elsewhere [ 38 ]. Acetylcholinesterase inhibitors slow the hydrolysis of acetylcholine at the neuromuscular junction and provide temporary improvement in strength in many patients with MG.
Although acetylcholinesterase inhibitors were among the earliest and remain one of the most widely prescribed treatments for MG, there are no controlled clinical trials of these agents in MG.
Acetylcholinesterase inhibitors are a symptomatic therapy for MG and do not retard the underlying autoimmune attack on the neuromuscular junction. The roles for acetylcholinesterase inhibitors in MG include treatment of ocular and mild generalized disease, treatment in patients who cannot receive immune suppression, and adjunctive treatment for patients receiving immunotherapy with residual or refractory myasthenic weakness.
Effective dosing of acetylcholinesterase inhibitors reduces myasthenic weakness, minimizes muscarinic medication side effects, and must be individualized to each patient's distribution of weakness and diurnal symptom fluctuation.
For example, patients with prominent dysphagia may benefit by taking pyridostigmine 30 minutes before meals and those with more symptoms in the afternoon and evening may shift their dosing to later in the day to better target symptoms.
Pyridostigmine bromide is generally better tolerated than neostigmine bromide due to fewer gastrointestinal side effects. A long-acting form of pyridostigmine bromide is available, though it is absorbed irregularly and tends to be overdosed. Initial dosing of pyridostigmine bromide is usually 30 mg three times a day and may be advanced to 90 mg three to four times a day.
Improvement in strength begins about 20 to 30 minutes after ingestion. Peak improvement is usually observed at about 45 minutes after ingestion, and benefits may last four hours or more. The most salient side effects of acetylcholinesterase inhibitors relate to increased muscarinic activity and include nausea, vomiting, abdominal cramping, diarrhea, diaphoresis, and increased lacrimation, salivation, and bronchial secretions.
These dose dependent and self-limited side effects may be treated with glycopyrrolate, and the gastrointestinal side effects may be treated with diphenoxylate hydrochloride with atropine or loperamide hydrochloride. Cholinergic crisis may develop with excessive dosing of acetylcholinesterase inhibitors in patients with more severe MG.
In cholinergic crises, depolarization blockade at diseased neuromuscular junctions results in increased weakness, and increased muscarinic activity generates copious oropharyngeal and bronchial secretions that may obstruct the airway or be aspirated.
Signs of cholinergic crisis include weakness indistinguishable from myasthenic weakness, muscle fasciculations, and symptoms of increased muscarinic activity including bradycardia.
Corticosteroids are the most widely used immune modulating agents for MG. Although the mechanism of action in MG is unknown, corticosteroids have numerous effects on the immune system including reduction of cytokine production [ 39 ]. Corticosteroids are often used as the initial immunotherapy in patients with ocular and generalized MG, particularly in patients with unsatisfactory responses to acetylcholinesterase inhibitors. These agents may produce rapid improvement in MG, though they are often associated with the liability of significant dose-dependent side effects and occasionally elicit transient and potentially serious myasthenic exacerbations within the first two weeks of treatment.
Prednisone treatment produced significant improvement in strength within two to three weeks in retrospective studies of MG [ 40 , 41 ], and a Cochrane review cites significant short term benefit in MG with corticosteroids [ 42 ].
The most reliable clinical responses to corticosteroids occur with a high-dose daily regimen that is gradually tapered based on clinical improvement in strength. This initial dose is maintained for two to four weeks, and strength is reassessed. Occasional patients are unable to tolerate an alternating-day regimen due to mood instability, variation in MG, or difficult glycemic control in occasional diabetic patients.
Myasthenic relapses may be delayed for three weeks after reductions in corticosteroid dosing, and rapid tapering may precipitate myasthenic exacerbations or crises. Therefore, corticosteroid tapering must be slow, judicious, and preceded by clinical reassessment of strength.
Subsequent tapering by 2. The adverse effects of corticosteroids are numerous, well known, and largely dose-dependent. Individuals at particular risk for side effects include those who are diabetic or glucose intolerant, obese, hypertensive, osteoporotic or post-menopausal, and those with affective or thought disorders. An alternative immune modulator may be considered in such patients.
A high protein, low fat, low carbohydrate, low sodium diet is recommended to prevent untoward weight gain, hyperlipidemia, and fluid retention. Serum electrolytes, glucose, blood pressure, and weight are monitored periodically during treatment. In post-menopausal women, a baseline bone density evaluation is performed and repeated every six months during treatment. Before initiating treatment with corticosteroids or any long-term immunotherapy, PPD testing should be considered as a screen for tuberculosis.
The increased weakness develops within 7—10 days after treatment begins and may last for up to one week before strength improves [ 40 , 43 ]. When beginning corticosteroid treatment in such patients, strength and respiratory function should be closely monitored. Plasma exchange PEX may be performed prior to starting corticosteroids to circumvent or minimize corticosteroid-related MG exacerbations.
In such cases, corticosteroids are initiated after a clear improvement in strength attributable to PEX is documented. An alternative dosing strategy of starting corticosteroids at a low initial dose with gradual dose increases has been advocated to reduce the risk for corticosteroid-related MG exacerbations [ 44 ]. However, this strategy does not eliminate the risk for exacerbation [ 45 ], and onset of strength improvement is less predictable and may be significantly delayed.
Azathioprine is hepatically converted to 6-mercaptopurine, an active anti-metabolite that blocks nucleotide synthesis and T-lymphocyte proliferation. Azathioprine is an effective agent for long-term immune modulation in MG as a steroid sparing drug or as initial immunotherapy.
Compared to corticosteroids, azathioprine has a favorable side effect profile for long-term use. However, the typically long delay of four to eight months from beginning treatment with azathioprine to improved strength in MG is a significant liability to its usefulness, particularly in MG patients with progressive disease or functionally limiting symptoms.
In a prospective, randomized, double-blind study comparing prednisolone with prednisolone plus azathioprine, the prednisolone plus azathioprine treatment group exhibited longer remissions, fewer treatment failures, fewer side effects, and reduced maintenance doses of prednisolone [ 46 ].
Side effects include dose dependent myelosuppression with macrocytic anemia, leukopenia, and thrombocytopenia, toxic hepatitis, and alopecia. Hypersensitivity pancreatitis represents a rare, but serious idiosyncratic reaction, and patients with sustained abdominal pain taking azathioprine should be screened with serum amylase and lipase assays. With long-term use, there is a small increased risk for lymphoma [ 47 ].
Azathioprine is potentially teratogenic, and women of child bearing potential using azathioprine should practice effective contraception.
The reaction resolves within one day of stopping azathioprine, and will recur if the patient is rechallenged with the drug. Monitoring for myelosuppression is recommended with weekly blood count and liver transaminase measurements weekly for the first month of treatment, then monthly for the first year, then every three months thereafter unless the dosage is increased.
Erythrocyte macrocytosis is expected and acceptable within the therapeutic dosage range. Cyclosporine exerts an immunomodulatory effect by blocking interleukin-2 production and T lymphocyte proliferation. Although effective, the use of cyclosporine in MG has been limited by its nephrotoxicity and numerous drug interactions. In light of this, cyclosporine is used in MG as a steroid-sparing agent or for refractory generalized disease. After therapeutic levels of cyclosporine are achieved and maintained, improvement in strength is usually observed within two months.
In a population of steroid-dependent patients with MG, a randomized, double blind, placebo-controlled study of cyclosporine demonstrated significantly improved strength in the cyclosporine treatment group [ 50 ]. The typical cyclosporine dose is 2. Side effects of cyclosporine include hypertension, nephropathy, tremor, hirsutism, gingival hypertrophy, headaches, and nausea.
Accordingly, relative contraindications to cyclosporine include poorly controlled hypertension, renal insufficiency or failure, malignancy, and inability to comply with blood monitoring or medication precautions. Periodic monitoring is necessary to achieve therapeutic trough cyclosporine levels and to prevent nephrotoxicity.
Assessments of blood pressure, serum creatinine and the trough serum cyclosporine level should be performed frequently until a stable, therapeutic dose of cyclosporine is achieved and after new medications are begun that have the potential to interact with cyclosporine.
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