The term myasthenia gravis (MG) means “grave muscle weakness.”1,2 MG is a chronic autoimmune disease in which muscles gradually lose strength and function. It is the most common primary disorder of neuromuscular transmission.1 The disease was first mentioned in 1672 by English physician Thomas Willis, who described patients as having “fatigable weakness of the limbs and bulbar muscles.”3
In a normally functioning neuromuscular system, axons of motor neurons divide as they enter skeletal muscles and each of the axonal endings form a neuromuscular junction, which is separated by a synaptic cleft. Transmission of nerve impulses to the muscle occurs at the neuromuscular junctions. The neurotransmitter acetylcholine (ACh) is released from axonal ending, crosses the synaptic cleft, and attaches to ACh on muscle fibers that are then activated and generate a muscle contraction (see Neuromuscular junction). It is believed that the thymus gland produces the antibodies that block, alter, or destroy many of the receptor sites for ACh in the muscles, which prevents the muscle contraction from occurring. Normally the thymus gland, which is large in childhood and plays an important part in the development of the immune system, decreases in size and is replaced with fat as one ages. However, 70% of people with MG have thymus glands that continue to produce antibodies because of hyperplasia of the gland or tumors, called thymomas, which are usually benign.4
The exact mechanism for the thymus gland's antibody production is not clearly understood, but scientists believe that the thymus gland may give incorrect instructions to developing immune cells, which results in autoimmunity and the production of ACh receptor (AChR) antibodies.5 Researchers suspect that viruses or bacteria may trigger this autoimmune response.
Acquired MG occurs in two cases per 100,000 persons.3 The prevalence has increased in the last 20 years most likely because of increased longevity and earlier diagnosis. MG occurs in all ethnic groups and both sexes. It can occur at any age, but it most frequently affects women younger than 40 years and men older than 60 years.5 Onset at a young age is slightly more common in Asians than in other ethnic groups. Men with MG frequently have an atrophied thymus.6 A proportion of patients between 40 and 60 years present with a paraneoplastic disorder in association with thymoma.
MG is not hereditary, but there is a familial predisposition that accounts for 5% of all cases.7 Infection, surgery, and some leukocyte antigens are also implicated in the development of MG. Several medications, including aminoglycosides, fluoroquinolones, beta-blockers, calcium channel blockers, and class I antiarrhythmic agents, have exacerbated MG symptoms.7
In the past, if left untreated, MG had a significant mortality rate, as high as 30% to 40%.8 Today, individuals with MG have a near-normal life expectancy. Morbidity results from impairment of muscle strength that may cause aspiration, falls, or increased incidence of pneumonia while the mortality from myasthenic crisis is less than 5%.9
Signs and symptoms
MG may affect any voluntary muscle, and the onset of symptoms is usually insidious. Some incidences may have a fairly rapid development, possibly caused by infection, emotional upset, pregnancy, or anesthesia.
The first noticeable symptoms of MG may be weakness of eye muscles, difficulty in swallowing, or slurred speech. About 10% of patients have weakness only in the levator palpebrae superioris muscles that control eye movement or the extraocular muscles and is considered ocular MG.1 Two-thirds of patients who have MG present with these initial symptoms.
Within a year of onset, approximately two-thirds of symptoms follow a craniocaudal direction progressing from bulbar to the torso and limb muscles.10 This is characterized by chewing and swallowing difficulties and weakness in the trunk, arms, and legs.7 Unilateral or bilateral double vision (diplopia) and drooping of one or both eyelids (ptosis) occur initially, followed by weakness in facial, speech, and mastication muscles with periods of dysarthria and dysphagia (see Ptosis). Muscles of chewing can become tired, sometimes halfway through a meal especially if eating something difficult to chew. Choking and regurgitation of fluids through the nose occur and may lead to considerable weight loss as well as aspiration and the development of aspiration pneumonia. The voice becomes weak with a muffled, nasal quality, while smiles appear as snarls or grimaces.
The fine motor movement of the hands becomes impaired, resulting in difficulty with handwriting. Less often, the muscles of the shoulders and the flexors of the neck become involved. Fatigue in the muscle of the cervical neck results in the head jutting forward while fatigue in the erector spinae muscles results in difficulty maintaining a sitting or walking posture. In more advanced cases of MG, muscles that control respiratory and bladder function are also affected.
MG is usually classified according to the skeletal muscles affected and symptoms indicated by the MG Foundation of America classification scale.7 Muscle fatigue and weakness of the extraocular, pharyngeal, facial, cervical, proximal limb, and respiratory musculature may occur. Autoimmune MG is divided into several groups that are clinically and immunopathologically distinct. The most common form is AChR-MG, while another form is muscle-specific tyrosine kinase MG (MuSK-MG).
Respiratory muscles become paralyzed in myasthenic crisis. Respiratory muscle weakness in AChR-MG often follows a specific pattern where the intercostals and accessory muscles for respiration weaken first, followed by the diaphragm. In MuSK-MG, bulbar weakness always precedes respiratory failure.7 This crisis may be triggered by infection, fever, an adverse reaction to medication, or emotional stress.
MG is often difficult to diagnose as the symptoms can be subtle and similar to other neurologic disorders.11 Because MG is relatively rare, diagnosis may be delayed or missed. Diagnosis begins with a thorough patient and family history, physical exam, and diagnostic testing. The first steps for diagnosing MG are to review the patient's medical history and perform a thorough physical and neurologic exam. Identifying fatigable weakness is an important characteristic in the diagnosis of this disease. Assessing the patient for impairment of eye movements or muscle weakness is imperative.
Lab studies should be conducted if MG is suspected. Thyroid function is evaluated because a small number of patients with MG have excessive levels of thyroid hormones. Serum thyroid function testing, including Thyroid stimulating hormone (TSH), Triiodothyronine (T3), Thyroxine (T4) and Thyroid antibodies (TA) are done to detect problems with the thyroid gland. Serum testing detects for the presence of AChR antibodies or MuSK antibodies, a surface membrane component essential in the development of the neuromuscular junction. It has been found that 80% of patients who have MG have serum antibodies that bind human AChRs and half of seronegative MG patients have antibodies to MuSK.12 A positive antibody test confirms the diagnosis of MG; however, a negative finding does not rule out the disease as patients with the ocular form of the disease may not have elevated serum antibodies.
A chest X-ray or computerized tomography may identify abnormal thymus gland or the presence of a thymoma (see Thymoma on chest X-ray). Spirometry or pulmonary function testing can assess respiratory function, reveal abnormalities in the respiratory system, and help predict whether respirations may fail and lead to myasthenic crisis. Forced vital capacity is monitored at intervals to monitor the gradual worsening of muscular weakness. Severe MG may cause respiratory failure because of the exhaustion of the respiratory muscles.13
The diagnosis for MG may be immediately confirmed by a patient's response to cholinergic drugs. This test requires I.V. administration of a cholinesterase inhibitor, edrophonium chloride or neostigmine bromide. These drugs slow the breakdown of ACh at the postsynaptic membrane and temporarily increase the levels of ACh at the neuromuscular junction. Edrophonium chloride is used more often because of its rapid onset of action and brief duration of action. Initially, 2 mg of edrophonium chloride is injected, over 30 seconds and, if tolerated, followed by an additional 8 mg injected over 30 seconds. Within 30 to 60 minutes of the first dose, most patients who have MG have a marked improvement in muscle tone that lasts 4 to 5 minutes. False-positive findings may be a result of increased muscle effort by the patient; false negative findings may be seen if the muscles are extremely weak or refractory to the drug. During testing, the patient should be placed on a cardiac monitor and resuscitation equipment should be readily accessible as edrophonium chloride testing may cause cardiac dysrhythmias. Atropine sulfate, the antidote for edrophonium chloride, must be readily available to treat muscarinic symptoms including bradycardia.
Electromyography (EMG) is another common diagnostic test performed to detect impaired nerve to muscle transmission. A repetitive nerve stimulation test is performed whereby single muscle fibers are stimulated repeatedly by electrical impulses. EMG measures the electrical potential of muscle cells as the muscle fibers of patients with MG respond well to repeated electrical stimulation. A decrease in amplitude of more than 10% between the first and fifth responses generally indicates a defective neuromuscular transmission characteristic. Single-fiber EMG is the most sensitive clinical test of neuromuscular transmission and reveals deficits of neuromuscular transmission in 86% of patients with MG.14
If a patient presents with ptosis, an ice-pack test is sometimes used in diagnostic testing. After placing an ice pack over the eyelid, improvement in ptosis indicates a positive test result; 80% of patients with ocular myasthenia have a positive result.15
There is no cure for MG; however, treatment may result in prolonged periods of remission. Methods of treatment include medication, surgery, plasmapheresis, and I.V. immunoglobulin (IVIg). Treatment usually depends on the degree of illness, and the sooner treatments are initiated the better the outcome is for the patient.
Symptom improvement can be seen in most patients with medications that increase the amount of ACh at the neuromuscular junction by allowing ACh to concentrate at the receptor site, promoting muscle contraction. Cholinesterase inhibitors, such as pyridostigmine and neostigmine, enhance communication between nerves and muscles, resulting in improved muscle contraction and strength. Pyridostigmine, a longer-acting cholinesterase inhibitor, blocks the action of ACh at parasympathetic sites, while neostigmine inhibits the destruction of ACh by acetyl cholinesterase, which facilitates the transmission of impulses across the myoneural junction. These medications are taken 30 minutes prior to meals to enhance swallowing and chewing.16
Acute exacerbations can occur because of overtreatment or undertreatment with cholinesterase inhibitors. Myasthenic crisis is a result of undermedication, while cholinergic crisis results from overmedication and often occurs within 60 minutes after the last dose. Beta-agonist bronchodilators are given to alleviate bronchospasm that may result from cholinergic medications. Caution is advised when other cholinesterase inhibitors are prescribed for the patient as increased toxicity may occur.
As MG is an autoimmune disease, drugs that inhibit immune system function, such as corticosteroids and immunosuppressants, are often used. Although immunosuppressive treatment effectiveness has been established through observational studies, most drugs have never been tested in a double-blind, prospective randomized trial and are considered off-label use.17 Corticosteroids, such as prednisone, and immunosuppressing agents, such as azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, and tacrolimus, help to improve muscle strength by suppressing abnormal antibody production.17 Immunomodulating treatments have significant adverse reactions, such as anemia, leukopenia, thrombocytopenia, nausea, vomiting and edema, and some patients are not able to tolerate them. Some patients also do not respond adequately to this treatment. Monitoring anti-AChR or MuSK antibodies is helpful in monitoring treatment success.
Thymectomy, removal of the thymus gland, is often recommended for patients who have thymomas or dysplasia of the thymus gland. It reduces symptoms in approximately 70% of these patients, but may take several years to obtain remission in 20% to 40% of patients.17 A transcervical approach is preferred as it is less invasive, and it is most effective if performed early in the disease process. Respiratory distress and wound complications appear to be the most common postoperative complication of a thymectomy.
This procedure is used in conjunction with other therapies and reserved for patients who are refractory to conventional therapy. It involves removal of anti-ACh antibodies from serum, thus improving symptoms that are life-threatening.4 It is an effective short-term treatment for acute exacerbation of MG. Clinical improvement may take several days to occur and improvement lasts up to 3 weeks.
Administration of IVIg improves symptoms in approximately 50% of patients. It has fewer adverse reactions than plasmapheresis, and improvement is usually seen within a week and may last several weeks or months. Significant improvement and fewer fatal episodes have been reported when IVIg have been included for patients with myasanthic crisis.20
Depression and myasthenic crisis
Patients with MG often develop depression when first diagnosed. Patients should be counseled on coping methods regarding the physical and psychological stressors of this disease, and set realistic goals to improve the patients' prognosis. Recognizing the early signs of depression is important. Seeking the help of a mental health professional is often required. Informing the therapist of the patient's history of MG is imperative as many antidepressant medications can worsen MG symptoms or may not be effective.
If the patient does not take medications as prescribed, infections, fever, tapering of immunosuppressive medications or emotional stress can easily lead to crisis. Myasthenic crisis is caused by severe weakness of the respiratory muscles, upper airway muscles or both.7 Teaching patients and their families methods to prevent, as well as recognize, the symptoms of crisis are essential. Hypertension, tachycardia, tachypnea, bowel and bladder incontinence and occasionally respiratory failure due to severe weakness of respiratory muscles may occur. Maintaining respiratory function is the priority and may require intensive care and the use of mechanical ventilation to assist breathing.
Patients are also at increased risk for developing community-acquired pneumonia because of the compromised respiratory system. Stressing the importance of annual flu shots, as well as the pneumococcal vaccine, is imperative. Patients with bulbar involvement (oropharyngeal muscle weakness) often have dysphagia and are at risk for aspiration. It is important to instruct the patients on methods to avoid this, such as eating an hour after taking a cholinesterase inhibitor. Assessment of gag reflex and ability to chew and swallow should be done for all patients with bulbar symptoms. Often swallowing evaluation is done to identify those at risk for aspiration. Small frequent feedings with food cut into small bites or a soft diet and high calorie snacks should be provided. Liquids that can cause chocking should be avoided and the use of thickened liquids encouraged. Fatigue and extreme heat or cold should be avoided as these can exacerbate symptoms. Taking medications as prescribed should also be emphasized. Other teaching points for a patient with MG include lowering emotional stress, getting adequate rest, avoiding medications, such as, d-penicillamine, propranolol, aminoglycoside and ciprofloxacin, that may increase muscle weakness and identifying signs of crisis. The patient is also taught to report to the health care provider any increase in symptoms as quickly as possible.
A lifelong commitment
MG is a chronic disease characterized by remissions and exacerbations; rapid acute exacerbations result in a 5% mortality from respiratory failure due to myasthenic or cholinergic crisis. The highest levels of weakness and mortality occur during the first 2 years of the disease.21 The earlier treatments are initiated, the better the outcome, and with treatment, patients with MG can expect to live nearly normal lives.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
chronic autoimmune disease; management of myasthenia gravis; myasthenic crisis