Myasthenia gravis (MG) is an autoimmune disorder characterized by changing muscle weakness and fatigability on exertion. There are two major types of antibodies routinely detected in MG. One antibody is against the acetylcholine receptor (AChR) and the other is to a muscle specific kinase (MuSK). Anti-AChR and anti-MuSK antibodies significantly interfere with neuromuscular transmission and the goal of treatment is the removal or blockage of these antibodies. MG patients without antibodies to either AChR or MuSK are defined as affected with “seronegative” MG.
Diagnosis
Weakness, one of the common symptoms of MG, can make early diagnosis difficult. Diagnosis can be delayed up to two year due to this nonspecific complaint. Clinical symptoms of MG, primarily impairment of eye movements, ptosis, and diplopia are frequent and assist in evaluation and diagnosis. Most of the diagnostic tests are based on the improvement of muscle weakness without changes in the sensory input.
Serum assays for anti–AChR or anti–MuSK antibodies and electrophysiologic testing is the gold standard in diagnosis. Binding antibodies are usually requested, because they are detected in approximately 90% of patients with generalized MG and 50% of patients with ocular MG.
The Tensilon or edrophonium test uses intravenous administration of edrophonium chloride to rapidly, though only briefly, relieve weakness in people with MG. The drug blocks the breakdown of acetylcholine and temporarily increases the levels of acetylcholine at the neuromuscular junction. Usually, 2 mg (0.2 cc) of edrophonium is injected intravenously. The patient is observed for 60 seconds. If the symptoms disappear or decrease, the test is considered positive and can be discontinued. The most noticeable improvement is in the decrease of ptosis and improvement of eye movements. This may be dramatic.
If there is a lack of response, a second dose of 4 mg edrophonium is given. The patient is again observed for changes in muscle strength. If there is still no improvement, a final dose of 4 mg is given. In patients with mild ocular symptoms, Maddox rod tests with prisms or diplopia fields may be performed before and after edrophonium. False-positive responses are rare.
Adverse effects may include fasciculation, warmth, diaphoresis, and nausea, but are usually mild. Major side effects from edrophonium are bradycardia, respiratory arrest, bronchospasm, syncopal episodes, or cholinergic crisis. The patient’s pulse and blood pressure should be monitored throughout the procedure, which should be performed with the patient seated in a chair that can be reclined and with resuscitation equipment on hand. These severe complications are treated by injecting an atropine sulfate (an anticholinergic) IV and maintaining vital signs. Patients with a history of cardiac or pulmonary disease may not be candidates for this procedure.
An alternative to the Tensilon test is the neostigmine methyl sulfate (Prostigmin) test. Neostigmine also inhibits the breakdown of acetacholine. This test is useful in patients without ptosis who may require a longer observation period for accurate measurements. A dosage of .022mg/kg IM is given with Atropine 0.011mg/kg IM given 30 minutes prior to injection. The most frequent side effects are salivation, fasciculation, and gastrointestinal discomfort. Patients should be monitored throughout the testing period for anaphylactic and cardiovascular complications. A positive test produces decreased symptoms within 30–45 minutes. If testing is inconclusive, it may be repeated the following day.
Electromyography (EMG) can also detect impaired nerve-to-muscle transmission. EMG measures the electrical potential of muscle cells when single muscle fibers are stimulated by electrical impulses. Repetitive stimulation of a nerve during a nerve conduction study may demonstrate gradual decreases of the muscle action (muscle fatigue) due to impaired nerve-to-muscle transmission. Muscle fibers in MG show a weakening in response to repeated electrical stimulation.
During the procedure a very thin needle electrode is inserted through the skin of the patient to the muscle. An electrode on the needle picks up the electrical activity given off by the muscles. Once the electrodes are placed, the patient is asked to contract the muscle by flexing the extremity. The patient should be informed to avoid lotions and creams prior to the procedure. Some patients may have soreness of the muscles following the procedure.
The sleep or rest test is a safe, simple test that eliminates the need for Tensilon testing in many patients who are not candidates due to severe pulmonary or cardiac disease. The patient is assessed for a baseline deficit and measures are documented. These include amount of ptosis, mobility, and strength measurements. The patient then rests quietly with eyes closed for 30 minutes. The measurements are repeated immediately after the patient “arises.” Improvement after rest is highly suggestive of MG.
The ice-pack test is often helpful for diagnosing patients with ptosis. An ice pack is placed over closed eyes for 2 minutes. Improvement of ptosis occurs in most patients with MG. The exception is the patient with complete ptosis whereby the cooling effect may be insufficient to overcome the severe weakness in these patients.
All MG patients must be investigated for tumors of the thymus. Diagnostic imaging of the chest, using computed tomography (CT) or magnetic resonance imaging (MRI), may be used to identify the presence of a thymoma. Ten percent of patients will have visible thymomas on CT scan though malignancy is rare.
Medications
The prevalence of MG in the United States is estimated at approximately 36,000 to 60,000 cases in the United States. Due to the relatively small group, treatment options have not changed drastically for several decades and research trails are small. The ultimate goal is to achieve complete stable remission, defined as no MG symptoms without treatment for at least one year.
Cholinesterase inhibitors such as pyridostigmine enhance transmission between nerves and muscles. These inhibitors result in a decreased breakdown of acetylcholine. Neostigmine increases acetylcholine in the nerve synapse and reverses the neuromuscular blockade. These medications don’t cure the underlying condition, but they may improve muscle contraction and strength. These drugs are known to increase oral secretions and should be discontinued in patients with myasthenic crisis.
Long term corticosteroids are frequently used to inhibit the immune system and decrease antibody production. Prednisolone is usually started at a low dose on an alternate-day regimen, and gradually increased; it is the recommended first-choice for a short-term immunosuppressant. Azathioprine (Imuran) is often the first-choice drug for long-term immunosuppression, and it is usually started together with steroids to allow tapering of steroids to the lowest dose possible. Methotrexate, or tacrolimus, may be considered in patients who are intolerant of or unresponsive to azathioprine. Prolonged use of these drugs can lead to serious side effects, such as bone thinning, weight gain, diabetes and increased risk of infections. Patients should be well informed of potential side effects and when to call their health care provider.
Rituximab is a monoclonal antibody that is used in some cases of MG. This drug depletes certain white blood cells, altering the immune system and improving MG symptoms. Rituximab has grown as a potentially effective therapeutic option for treatment of MG when other immunotherapy fails. Patients with anti-MuSK antibodies associated MG respond well to rituximab. Rituximab is usually given in IV infusions. Repeat infusions are often done over a few weeks or months.
The thymus contains all the necessary elements for the pathogenesis of MG. It contains myoid cells that express the AChR antigen, and immunocompetent T-cells. Therefore thymectomy, the surgical removal of the thymus gland, reduces symptoms in some individuals, even those without thymoma, and may cure some people. This is thought to be caused by changing the immune response and re-balancing the immune system. The response to thymectomy may take years to fully evaluate and see benefits. Thymectomy is recommended for all individuals with thymoma and improvement in procedures make endoscopy to remove the thymus common. Depending on the surgical procedure the patients will usually have a chest tube and be hospitalized for several days.
Myasthenic crises and emergency care
A myasthenic crisis occurs when the respiratory muscles weaken to the point that ventilation is inadequate and intubation is required. Crisis may be triggered by infection, fever, or an adverse reaction to medication. Protocols have been established for the respiratory evaluation of patients in crisis since the weakness of accessory muscles may mask the distress of the patient. Continued overuse of respiratory muscles only adds to their weakness. Pulse oximetry and arterial blood gas measurements are NOT good indicators of respiratory strength in MG patients as abnormalities often develop only after life-threatening respiratory failure has already occurred. Single breath count test is more telling of muscle failure in these patients. Ask the patient to count out loud after maximal inspiration. The ability to reach 50 indicates a normal respiratory function. Single breath count of less than 15 indicates a dangerous low forced vital capacity. A patient with broken or halting speech in order to breathe is at risk. The potential for aspiration and hypoxia is great in these patients. A secure airway with supplemental oxygen should be instituted immediately.
Plasma exchange (plasmapheresis) in conjunction with corticosteroids is an option for patients in crisis. It is a method by which whole blood is removed from the body via central line and processed so that the red and white blood cells are separated from the plasma. The blood cells and platelets are then returned to the patient without the plasma, which the body quickly replaces. Researchers still are unsure exactly why plasma exchange works, but the technique seems to reduce the severity myasthenia. One hypothesis is that plasmapheresis can remove antibodies and other immune cell-derived factors that could contribute to increase of symptoms. This treatment is usually only given in patients who are having severe weakness, in crisis, or are refractory to drug therapy.
Intravenous immunoglobulin (IVIg) has a lower risk of side effects than does plasmapheresis and immune-suppressing therapy but improvement is usually brief. Patients with mild disease have shown little improvement with IVIg but patients in crisis benefit. It may take about a week to start working, and the benefits usually last no more than three to six weeks. This is usually enough time to identify the underlying cause of crisis and treat it effectively. Side effects, which usually are mild, may include chills, dizziness, headaches and fluid retention.
Current guidelines are based largely on clinical experience and retrospective analysis. At present adequate MG treatment usually permits a substantially full and productive life. Patients with MG should be taught to identify changes in breathing and swallowing. Nutritional techniques to reduce residue in the throat and avoid aspiration include moistening foods with creamy substances such as broth, sauces and yogurt, avoiding tough meats, and chewing food well. Items such as nuts, rice, popcorn or crackers should be avoided.
Physical therapy and breathing exercises are important to maintain strength without fatiguing muscles. Exercises should be modified depending on day to day functioning. Patients with MG should have consults with respiratory and physical therapists and nutritionists to ensure their optimal health.
References:
Mantegazza, Renato et. al. (2011). Current and emerging therapies for the treatment of myasthenia gravis. Neuropsychiatric Disease and Treatment, 7, 151-160. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083988/.
Myasthenia Gravis Fact Sheet. Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-She…
Myasthenia Gravis Foundation of America. Retrieved from http://myasthenia.org/
Sathasivam, S. (2008). Steroids and immunosuppressant drugs in myasthenia gravis. Nature Clinical Practice Neurology, 4 (6), 317-27. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18493241.
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