Myasthenia Gravis
Wilma J. Koopman
Joanne V. Hickey
Acquired myasthenia gravis (MG) is an uncommon chronic disease of the neuromuscular junction (NMJ) in which an autoimmune process in most cases attacks the acetylcholine (ACh) receptors at the postsynaptic muscle membrane. In other cases, nonACh components of the NMJ, such as muscle-specific receptor kinase (MuSK) may be the target of the attack. There are two clinical forms of the disease; ocular and generalized. In ocular MG, the weakness is restricted to the eyelids and extraocular muscles and about 50% will have detectable acetylcholine receptor (AChR) antibodies. In contrast, generalized MG affects to a variable degree the eyes, face, bulbar, limb, and respiratory muscles with 80% having detectable AChR antibodies.1 In 15% to 20% of AChR antibody negative MG, the anti-MuSK antibodies have been implicated and this form is often considered to have a distinct generalized form.2
The hallmark of MG is fluctuating muscle weakness that worsens with effort or exercise and improves with rest. MG used to have a fatal outcome for many people, but treatment now available is highly effective, although there is no cure. MG is classified as an autoimmune disease, and persons with MG may have other autoimmune conditions. The thymus gland in anti-AChR positive generalized MG cases will have abnormalities; thymic hyperplasia in greater than 50% or a thymoma in 10% to 15%. The prevalence of MG is about 20 per 1,00,000 in the US population.3 It affects people of all ages, and women are affected more frequently than men by a 3:2 ratio. The highest incidence noted is in women in their 20s and 30s and men after the age of 60. The estimated annual health plan paid costs for treating MG were $15,675. Home health services represent 23% of MG patient costs, largely driven by IVIg administration.4
NEUROMUSCULAR TRANSMISSION AND PATHOPHYSIOLOGY
Normal neuromuscular transmission is an important concept to understand from the diagnostic and treatment perspective. The region between the motor nerve terminal and the motor muscle endplate is named the NMJ. The motor nerve terminal is a specialized region forming a bulb containing synaptic vesicles. The neurotransmitter, ACh is synthesized and packaged in the nerve terminal. The synaptic cleft separates the motor nerve terminal from the muscle endplate. The muscle membrane at the endplate is characterized by junctional folds which increases the muscle surface. AChRs are located on the crests of the folds and the enzyme, acetylcholinesterase (AChE) is found deep in the clefts of the folds.
In normal neuromuscular transmission, an influx of calcium through voltage-gated calcium channels occurs due to the depolarization of the presynaptic nerve terminal. The neurotransmitter at peripheral NMJs, ACh, housed in vesicles, binds with the presynaptic nerve terminal membrane and is released into the synaptic cleft. ACh, then, interacts with the AChR on the postsynaptic muscle endplate (Figure 33-1). This coupling of the ACh molecules with the AChR produce increased permeability and an influx of sodium and potassium resulting in endplate depolarization producing an action potential and muscle contraction. There is a safety margin for neuromuscular transmission with excess release of Ach, and AChE hydrolyzes the excess ACh or it is diffused from the NMJ allowing a self-limited depolarization. In acquired MG, normal neuromuscular transmission is interrupted by autoantibodies attached to proteins at the NMJ. In 80% to 85% of the time, these antibodies are directed against the skeletal muscle nicotinic AChR and interfere with neuromuscular transmission. This interruption can occur through binding of the AChR antibody to the cholinergic binding site; crosslinking and internalization of the muscle surface AChRs thereby reducing the number of AChR binding sites, or by binding complement resulting in the destruction of the muscle motor endplate and the AChRs. The resynthesis of AChR allows some recovery. Antibodies to MuSK, another postsynaptic neuromuscular protein is found in 10% to 15% of anti-AChR antibody negative MG patients and present with a distinct generalized form of this disease. Current evidence suggests that anti-MuSK antibodies change the normal functioning integrity of the NMJ through the agrin/MuSK pathway. MG is an immune-mediated disease based on the evidence of an association of other autoimmune diseases found both in patients and family members, HLA typing with subgroups, and abnormalities of the thymus.
Signs and Symptoms
The onset of MG is usually gradual, although rapid onsets have been reported in association with respiratory infections or emotional upset. The course of the illness is extremely variable. In some patients, the disease is unchanged for months and may or may not progress whereas in others, there is rapid involvement of other muscle groups. The muscle groups affected have a characteristic pattern. Table 33-1 provides a widely adopted classification for the staging from the Myasthenia Gravis Foundation of America (MGFA).5 Early findings in most patients are ptosis and diplopia, which involve the levator palpebrae and extraocular muscles. Ptosis may be unilateral or bilateral and becomes intensified when the
patient attempts to look upward for a period of time. Pupillary response to light and accommodation remains normal.
patient attempts to look upward for a period of time. Pupillary response to light and accommodation remains normal.
 Figure 33-1 ▪ Neuromuscular junction. (A) Acetylcholine (ACh) released from the motoneurons in the myoneural junction crosses the synaptic space to reach receptors that concentrated in the folds of the endplate of the muscle fiber. Once released, ACh is rapidly broken down by the enzyme acetylcholinesterase (AChesterase). (B) Decrease in ACh receptors in myasthenia gravis. Used with permission from Carol Mattson Porth. (2005). Pathophysiology concepts of altered health states (7th ed.). Philadelphia: Lippincott Williams & Wilkins. |
TABLE 33-1 MYASTHENIA GRAVIS FOUNDATION OF AMERICA CLASSIFICATION5 | ||||||||||||||||||||||||||
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Additional muscles that may be affected are the facial, masticator, speech, and neck muscles. While chewing food, the patient’s jaw becomes tired requiring a rest. After a few moments of rest, chewing can be resumed, but again muscles fatigue quickly. Because the facial muscle is affected, the mobility and expression of the face are altered. Any attempt to smile looks like a snarl, and there is flattening of the nasolabial fold. The voice is often nasal and weak and fades after talking. There may be problems in managing saliva because of difficulty with swallowing. Food must be eaten very slowly and consistencies may need to be altered to prevent aspiration.
Clinical Pearl: The hallmark of MG is fluctuating muscle weakness that worsens with effort or exercise and improves with rest.
Generalized weakness develops in a large percentage of patients. The limb muscles and often, primarily the proximal muscles, as well as the diaphragm and the neck extensor muscles, are affected. Weakness of the neck extensors causes the head to fall forward (head drop). If the shoulder girdle is involved, patients have difficulty keeping their arms above the head when reaching for an object, and with hair grooming. When the intercostal muscles or the diaphragm are involved and breathlessness and dyspnea are present, patients may also describe difficulty sleeping when lying flat; a condition called myasthenia crisis exists. Noninvasive ventilation (NIV) such as bilevel positive airway pressure (BiPAP) or intubation and mechanical ventilation may be necessary. In summary, the muscle groups affected tend to be weaker after use or toward the end of the day when the patient is fatigued. As the disease progresses, muscle fatigue is noted with less exertion and earlier in the day.
Diagnosis
The diagnosis of MG is based on history, physical examination, and confirmatory laboratory testing. The patient usually reports that certain muscles become weak with activity and that a period of rest may improve their motor function temporarily. On physical examination, there is fatigable muscle weakness. MG does not affect cognition,
deep tendon reflexes, coordination, or sensory perception. Confirmation of MG is based on results of the following tests: anticholinesterase test; ice-test; antibody titer for AChR, and MuSK; repetitive nerve stimulation; and single-fiber electromyography (EMG).6
deep tendon reflexes, coordination, or sensory perception. Confirmation of MG is based on results of the following tests: anticholinesterase test; ice-test; antibody titer for AChR, and MuSK; repetitive nerve stimulation; and single-fiber electromyography (EMG).6
Anticholinesterase testing: the drug commonly used is edrophonium chloride (Tensilon) because it has a rapid onset of 30 seconds and a short duration of about 5 to 10 minutes. The test is performed by drawing 10 mg of Tensilon into a syringe and administering 2 mg intravenously as a test dose. If no adverse symptoms appear, a subsequent dose of 3 to 8 mg is injected. If there is improvement in the muscle strength of a previously weak muscle that lasts 5 to 10 minutes, the test result is considered positive.
Ice-test: an ice-test is a bedside test with high sensitivity that is useful to differentiate MG from other similarly presenting conditions. The test is conducted by holding ice packs over the patient closed eyes for one minute and observing for resolution of ptosis. After application of the ice packs, the ptosis is markedly improved with a sustained effect of several minutes.7 An added advantage of this simple test is that treatment can be promptly initiated in response to a positive test.
Antibody titer for AChR: this is conducted by assay of blood. In 80% to 90% of patients with generalized myasthenia, the level of AChR antibody titer is elevated and in only in 55% of purely ocular myasthenia.8
Antibody titer for MuSK: this is conducted by assay of blood. In 40% of patients with AChR antibody negative generalized MG, this test is positive.9
Repetitive nerve stimulation: while electrical shocks are delivered to a nerve at the rate of 3 per second, surface electrodes over the muscle record electrical potentials. A rapid reduction of the amplitude of the muscle potential is considered positive.
Single-fiber EMG: this test can detect delay or failure of neuromuscular transmission in pairs of muscle fibers supplied by branches of a single nerve fiber. It is about 99% sensitive in confirming MG.
TABLE 33-2 IMMUNOSUPPRESSION IN MYASTHENIA GRAVIS
DRUG
DESCRIPTION
SIDE EFFECTS
Immediate Response
Intravenous immunoglobulin (IVIg)
2 g/kg administered over 5 days
Headache
Fluid overload
Rarely, renal failure
Intermediate: 1-3 Mos
Glucocorticoids (prednisone)
Begin low (15-25 mg/day) and increase stepwise up to maximum improvement or 50 mg/day
Optimal dose is maintained for 1-3 mos
Next, an alternate-day schedule is begun
Most patients need some form of chronic therapy
Peptic ulcer
Hyperglycemia
Fluid retention
Cyclophosphamide (Cytoxan) may be used with glucocorticoids
Rarely used except if unresponsive to other drugs
4-5 mg/kg/day in two divided doses
Hypertension
Nephrotoxicity
Response: Long-Term (Months to 1 Yr)
Azathioprine (Imuran) may be used with glucocorticoids
Used frequently after prednisone
Range: 2-3 mg/kg total body weight
Monitor white and red blood count
Works in 3-6 mos
Flu-like symptoms (fever, malaise)
Bone marrow depression
Hepatotoxicity
Anorexia, nausea, vomiting
Mycophenolate mofetil
1 g b.i.d.
Inhibits purine synthesis
Side effects rare
Diarrhea and leucopenia
Mediastinal CT or MRI: a CT or MRI of the mediastinal cavity may be ordered to determine whether the thymus gland is enlarged because many people with MG have a thymoma.
In addition to laboratory testing, making a diagnosis of MG requires an ability to rule out many possibilities on the differential diagnostic list. A clinical picture of fluctuating muscle weakness or other neurological, upper gastrointestinal, respiratory, or ophthalmic complaints point to a diagnosis of MG. The key diagnostic findings in MG are a specific muscle weakness that can be reproduced and exacerbated with sustained muscle use.10
Treatment
The four main options useful for the treatment of MG are anticholinesterase drugs, immunosuppressive therapy, therapeutic plasma exchange or intravenous (IV) immunoglobulin (Ig), and thymectomy.11 See Table 33-2 for a comparison of drugs including management of side effects and special issues. See also Table 12-10 for a brief overview of drugs used in MG. Note that various sources have slight variations in dosages of drugs. Rituximab has also been used in severe refractory cases of MG. After the diagnosis of MG has been established, an individualized management plan is developed because no single treatment plan is effective for all patients. The goal of treatment is to achieve a quality of life, that is, as symptom free as possible.
Anticholinesterase Drugs
Anticholinesterase drugs are the first-line approach for the management of symptoms of MG, although they do not treat the underlying disease. The use of anticholinesterase drugs is supported by a recent Cochrane review.12 Anticholinesterase drugs enhance the
neuromuscular transmission of an impulse by preventing the degradation of ACh by the enzyme cholinesterase (ChE).
neuromuscular transmission of an impulse by preventing the degradation of ACh by the enzyme cholinesterase (ChE).
Pyridostigmine (Mestinon). The ACh inhibitor drug that is the mainstay in managing symptoms of MG is pyridostigmine (Mestinon). Neostigmine (prostigmine), formerly prescribed, is used much less frequently, and most experts do not include it in their discussions of management. Muscarinic- and nicotinic-type side effects (discussed later) occur with both drugs. Mestinon is available in tablet, syrup, time-release, and IV forms. Its effects begin within 30 to 45 minutes, peak in about 2 hours, and last 3 to 6 hours. The daily dosage and time interval are carefully adjusted, using an affected muscle group to gauge effect. The goal of treatment is to produce maximal muscle strength with minimal side effects. For example, if the oropharyngeal muscles are weak, then dosage should be timed to enhance muscle strength optimally at mealtime.
There is no standard dosage of Mestinon because there are great variations among patients and in the same patient from time to time. However, it is commonly prescribed beginning at 30 mg ×4 per day (on an every 4- to 5-hour schedule, during the day while awake) with dose increases to 60 mg, 90 mg, up to 120 mg 4 to 5 times per day, depending on tolerance and maximal efficacy. Pyridostigmine (Mestinon SR) in 180-mg time-release tablets is sometimes advisable at bedtime for patients who have nocturnal or early morning MG symptoms especially dysphagia. If ChE inhibitors become ineffective in managing the symptoms or the MG is moderately severe, then other forms of therapy may be indicated and added to the treatment regimen.
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