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Diagnosis and Treatment of Myasthenia Gravis
By Richard Finkelman, M.D., Division of Neurology/Neuromuscular Disorders
Myasthenia Gravis (MG) is a chronic autoimmune disease of the neuromuscular junction (NMJ), the site where nerve cells connect with the muscles they control. It is characterized by A newsletter for physicians and health care professionals Winter 2007 fluctuating and variable muscle weakness of the body’s voluntary muscles, with rapid fatigue and loss of strength upon exertion, and improvement upon rest. The estimated prevalence of MG in the United States is 14 cases/100,000, or about 42,000 cases. Among women, MG is most common between the ages of 18-25, while in men this disorder generally develops between the ages of 60-80.
Pathophysiology
The symptoms of Myasthenia Gravis are the result of abnormalities in the transmission of nerve impulses to muscles. Under normal conditions, impulses travel down the nerve and cause nerve endings to release the neurotransmitter acetylcholine (ACh). ACh moves across the neuromuscular junction and binds to ACh receptors. These receptors are activated and cause a muscle contraction.
In a patient with MG, antibodies block or alter receptors for ACh at the neuromuscular junction and disrupt the normal communication between nerve and muscle, resulting in muscle weakness.
(CT image of thymoma)
It is thought that the antibodies disrupting the ACh receptors are produced as the result of an immune response likely originating in the thymus gland, although exact details are uncertain. Some ten percent of MG patients have a typically benign thymic tumor, or thymoma, and 70% have benign hyperplasia, indicating an active immunologic response.
Clinical Features
MG typically presents in an insidious fashion, with patients complaining of a specific muscle weakness rather than generalized fatigue. About 2/3 patients present initially with oculomotor complaints, frequently ptosis or diplopia. About 1/6 of patients present with oropharyngeal symptoms, including dysphagia or dysarthria. About 10% of patients present with limb weakness. This weakness is often variable, worsening following exertion or as the day progresses. Symptoms may also be triggered by fever, systemic illness, emotional stress, menses, or pregnancy. Various medications may worsen MG, including antibiotics, beta-blockers, anti-arrhythmics, and penicillamine.
Only about 10-15% of MG patients have weakness restricted to ocular muscles. Within two years of onset, about 85-90% of patients develop generalized myasthenia gravis, characterized by involvement of other muscle groups, including trunk or limb muscles.
Physical findings may vary depending on location and time of day. There may be observable ptosis or oculomotor palsies. Ptosis may be increased by sustained upgaze or repeated blinking. In unilateral ptosis, the controlateral lid may become ptotic by lifting the affected lid (Herring phenomenon or curtain sign). With rapid shift from downgaze to primary position, both lids may briefly overshoot (Cogan’s lid twitch sign). Placing an ice pack over an affected lid for 2 minutes may transiently reduce ptosis. Pupils are classically unaffected.
Testing for Myasthenia Gravis
Since weakness is a common symptom for many disorders, delays in the diagnosis of MG are not unusual, particularly if the patient presents initially with a mild weakness or has weakness in only a few muscles. If MG is suspected, there are a number of tests available to confirm a diagnosis.
Blood test for antibodies
Testing for acetylcholine receptor antibodies (anti-AcHR) is positive in 85-90% adults with generalized MG but only in 50-70% of patients with ocular MG. Rare false positives are seen in thymoma without MG, immune liver disorders, primary lung cancers, and some healthy older patients. The antibody titer does not correlate well with clinical severity, although a 50% or greater reduction generally is seen with clinical improvement.
Tensilon test
A bedside test for MG consists of administration of edrophonium (Tensilon), a short-acting inhibitor of acetylcholinesterase. This increases the amount of ACh in the synaptic cleft, resulting in increased neuromuscular transmission. The test is positive if there is significant improvement in an identifiable endpoint, such as ptosis or numbers counted on one breath. False positives may be seen with other neuromuscular disorders such as ALS or processes affecting oculomotor nerves such as cavernous sinus tumors.
Electrophysiologic Studies
A variety of electrophysiologic studies are helpful in confirming a diagnosis of MG. Repetitive nerve stimulation (RNS) involves recording of action potentials following a train of stimuli. In affected patients, there is a 10% or greater decrement in the amplitude of the 4th potential. This may be enhanced following brief isometric exercise. There is reduced yield in purely ocular MG. Single-fiber electromyography (SFEMG) involves measurement of jitter, a variation in firing between adjacent muscle fibers from the same motor unit. This is characteristically increased in MG patients. One may also see blocking, a failure in transmission resulting in loss of action potentials. The test has up to 95% sensitivity in MG, although false positives may be seen with other neuromuscular disorders.
Imaging
Imaging of the brain and orbits may be performed to rule out compressive mass lesions that may affect cranial nerves. CT of the chest should be performed to exclude an abnormal thymus gland or thymoma.
Treatment
Symptomatic treatment involves medications that improve neuromuscular transmission. Most frequently employed are acetylcholinesterase inhibitors. They act in a similar manner to Tensilon, blocking enzymatic breakdown of ACh in the synaptic cleft. The most widely used medication is pyridostigmine bromide (Mestinon). Adverse effects reflect cholinergic excess, including salivation, cramping, and diarrhea. These may respond to anticholinergics such as loperamide or glycopyrrolate. In extreme cases of cholinergic excess, there may be increased muscle weakness, analogous to myasthenia, referred to as a cholinergic crisis. In emergencies, a short-acting parenteral drug, Neostigmine, may be employed.
Treatment of the underlying immune process results in clinical improvement. Traditionally, corticosteroids have been the first drugs employed. Higher doses may paradoxically increase weakness. Prednisone is usually begun at 10-20 mg/day and increased every few days. Larger doses may be started on alternate days with lower likelihood of side effects, but may delay the onset of therapeutic benefit. Maximum dosage is usually 1mg/kg/day. Slow tapering after 2-3 months is advised if clinical benefit is achieved. If there is delayed or inadequate response, a second-line drug, such as azathioprine (Imuran) is begun. Newer medications under study include mycophenolate, cyclosporine, and tacrolimus. These are less proven and generally more toxic, but may prove useful in resistant cases.
Thymectomy is generally reserved for patients with known thymoma or younger, medically stable patients who are tolerating medications poorly. Clinical improvement may be delayed for 6-12 months.
Myasthenic Crisis
Myasthenic crisis is defined as a sudden worsening of respiratory function and/or profound muscle weakness in MG patients. Such a medical emergency may require use of a respirator for improved ventilation. Crises occur most often in the first two years after diagnosis, and may be triggered by infections or other systemic processes. These must be differentiated from cholinergic crisis, as treatments differ. Treatment involves respiratory support, treatment of infections or metabolic disturbances, and adjustment of medication dosages. Specific treatments involve removal or neutralization of circulating autoantibodies and immune complexes. Methods include plasma exchange (PXE) and intravenous immunoglobulins (IVIG). The former involves removal of a volume of blood, filtering of antibodies, and reintroduction of blood cells with albumin. Patients typically receive 5-6 exchanges every 2-3 days. Risks include problems with venous access, fluid imbalance, and hypercoaguability. IVIG may be preferable to PXE in elderlyor hemodynamically unstable patients, or in those with limited venous access. Its exact mechanism of action is unclear. Side effects include flu-like symptoms, aseptic meningitis, and rarely renal failure.
Prognosis
While there is no known cure for Myasthenia Gravis, recent years have witnessed advances in timely diagnosis and treatment options that have improved management of this disorder. With appropriate treatment, MG patients may experience significant improvement in their muscle weakness, fewer restrictions on activity, and improved quality of life.
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