Abstract
Myasthenia gravis (MG) is a chronic neuromuscular disorder that can lead to various degrees of neurologic dysfunction. Initial patient presentation may be a diagnostic dilemma to the family physician unfamiliar with testing methods for and the treatment and care of patients with MG. The author focuses on the clinical features, electrodiagnostic testing, and treatment of patients with MG.
Myasthenia gravis (MG) is an autoimmune disorder that affects the neuromuscular junction (NMJ) at the postsynaptic level. Although the cause of the disorder is unknown, the role of immune responses (circulating antibodies directed against the nicotinic acetylcholine receptor) in its pathogenesis is well established. The disorder is characterized by fluctuating, fatigable weakness of muscles under voluntary control. Some patients may have symptoms only late in the day or after physical exertion (eg, exercise). As this disorder is highly treatable, prompt recognition is crucial. During the past decade, significant progress has been made in our understanding of the disease, leading to new treatment modalities and a significant reduction in morbidity and mortality. With prompt intervention, the patient's overall quality of life is also improved.
Physiology of Neuromuscular Transmission
The NMJ is composed of the nerve terminal, the synaptic cleft, and the highly organized postjunctional folds on the muscle membrane. The nerve terminal is the site of synthesis and storage of the neurotransmitter acetylcholine, which is released in the discrete quanta. The quanta are located in three separate stores: primary (immediately available), secondary (mobilization store), and tertiary (reserve store). When a nerve action potential depolarizes the presynaptic terminal, voltage-dependent calcium channels are activated, allowing an influx of calcium that results in a release of acetylcholine from the presynaptic terminal. The acetylcholine diffuses across the synaptic cleft and binds to acetylcholine receptors (AchR) on the postsynaptic membrane, resulting in an end-plate potential (EPP).
Under normal circumstances, the EPP always rises above the threshold level, resulting in a muscle fiber–action potential. The amplitude of the EPP above the threshold value needed to generate a muscle fiber–action potential is called the safety factor. For patients who have a disorder of neuromuscular transmission, this safety factor is reduced.
During repetitive nerve stimulation (RNS), all measurements are made on the compound muscle fiber–action potential, the sum of the individual muscle fiber–action potentials generated in a muscle. For patients with NMJ disorders, RNS will cause a depletion of quanta and reduce the amplitude of the EPP. With a reduced safety factor, the EPP of some muscle fibers will fall below the threshold level and an action potential will not be generated. This reduction of action potentials accounts for the decremental response when performing RNS studies in the neurophysiology laboratory.
Etiology
The pathophysiology of MG is now well understood. The condition is caused by sensitized T-helper cells and an immunoglobulin antibody G (IgG)–directed attack on the nicotinic acetylcholine receptor of the NMJ.
1 A variety of experimental studies
1 support this hypothesis:
acetylcholine receptor antibodies are present in most patients with MG;
acetylcholine receptor antibodies can be transferred passively to animals producing experimental autoimmune MG;
removal of acetylcholine receptor antibodies leads to recovery;
animals immunized with an acetylcholine receptor begin producing acetylcholine receptor antibodies, which can provoke an autoimmune disease (ie, experimental autoimmune MG) closely resembling the naturally occurring disease.
Epidemiology
The prevalence of MG in the United States is roughly 14.2 cases per 1 million people.
2 Although MG may appear at any age, it has a bimodal peak of age at onset. In women, the onset usually occurs between 20 and 40 years of age; among men, the onset is usually at 40 to 60 years of age. Familial occurrence of MG is rare, though first-degree relatives do have a higher incidence of other autoimmune disease.
3
Clinical Features
Although the initial symptoms of MG typically involve the ocular muscles in approximately 60% of patients, virtually all patients will have ocular involvement within 2 years of disease onset.
4
Ptosis, which is very common and may occur while the patient is reading or during long periods of driving, may be unilateral or bilateral. Extraocular muscle weakness may also present asymmetrically.
Patients with mild diplopia may initially seek the help of an optometrist, requesting eyeglasses or a change in lens prescription to correct the problem. Diplopia usually manifests when the patient has visual convergence or upward gaze.
Myasthenic weakness may mimic third, fourth, and sixth cranial nerve palsies as well as an internuclear ophthalmoplegia. Unlike third nerve palsies, MG never affects pupillary function.
Difficulty chewing, speaking, or swallowing may also be the cause for initial presentation, but the occurrence of these symptoms is less frequent than the aforementioned ocular symptoms.
4 Some patients may have severe fatigability and weakness during mastication, being unable to keep the jaw closed after chewing. Myasthenic speech is often nasal (from weakness of the soft palate) and slurred (from weakness of the tongue, lips, and face), though there is no difficulty with language fluency.
Patients also may complain of fatigue and fluctuating weakness. The weakness worsens after exertion and typically improves with rest. The distinguishing clinical feature of MG is pathologic fatigability. In mild disease, neck flexor weakness may be the only finding. In general, upper extremity weakness is more common than lower extremity weakness. Patients may complain of difficulty when reaching with their arms, getting up from a chair, or going up and down stairs. A key point to remember is that if a patient has generalized limb weakness without ocular involvement, the diagnosis of MG should be questioned. As the disorder is limited to the NMJ, no abnormality of cognition, sensory function, or autonomic function is present. Further, it is not uncommon for a patient with MG to exhibit symptoms of depression.
5
Examination of a patient with MG therefore is directed at muscle strength and demonstrating pathologic fatigability. A few maneuvers that may be used are having the patient look up for several minutes (examining for ptosis or extraocular weakness), counting aloud to 100 (listening for nasal or slurred speech), or by repetitively testing the proximal muscles.
6 The results for the remainder of the neurologic examination are usually normal.
Differential Diagnosis
Before diagnosing MG, it is necessary to exclude other conditions that may appear with somewhat similar features. Thyroid disease is a common disorder to rule out. Also, patients with MG may have a coexistent autoimmune disorder. Other forms of NMJ disorders, acquired myopathies, and motor neuron disease should be excluded. In a patient with ocular MG, mitochondrial myopathy, thyroid ophthalmopathy, and other cranial neuropathies should be considered.
Table 1 summarizes the conditions that should be excluded prior to diagnosis of MG.
Table 1
Neurologic Conditions Mimicking Myasthenia Gravis
Condition
|
Signs and Symptoms
|
|---|
| Amyotrophic lateral sclerosis | Asymmetric muscle weakness and atrophy |
| Botulism | Generalized limb weakness |
| Guillain-Barré syndrome | Ascending limb weakness |
| Inflammatory muscle disorders | Proximal symmetric limb weakness |
| Lambert-Eaton syndrome | Proximal symmetric limb weakness |
| Multiple sclerosis | Bilateral internuclear ophthalmoplegia |
Periodic paralysis
| Intermittent generalized muscle weakness
|
Table 1
Neurologic Conditions Mimicking Myasthenia Gravis
Condition
|
Signs and Symptoms
|
|---|
| Amyotrophic lateral sclerosis | Asymmetric muscle weakness and atrophy |
| Botulism | Generalized limb weakness |
| Guillain-Barré syndrome | Ascending limb weakness |
| Inflammatory muscle disorders | Proximal symmetric limb weakness |
| Lambert-Eaton syndrome | Proximal symmetric limb weakness |
| Multiple sclerosis | Bilateral internuclear ophthalmoplegia |
Periodic paralysis
| Intermittent generalized muscle weakness
|
×
In some patients, MG may be induced by certain drugs, including some antiarrythmics, D-penicillamine, and antimalarials.
7 In addition, many classes of drugs can lead to worsening of the symptoms present in patients with MG (
Table 2).
Table 2
Medications That Induce or Exacerbate Myasthenia Gravis *
Anti-infective Agents
|
Cardiovascular Agents
|
Other Agents
|
|---|
| Aminoglycosides | Acebutolol hydrochloride | Chloroquine |
| Ampicillin sodium | Oxyprenolol hydrochloride | Corticosteroids |
| Ciprofloxacin hydrochloride | Practolol | d-penicillamine |
| Erythromycin | Procainamide hydrochloride | Interferon α (INF-α) |
| Imipenem | Propafenone hydrochloride | Mydriatics |
| Kanamycin sulfate | Propranolol hydrochloride | Phenytoin sodium |
| Pyrantel | Quinidine | Trihexyphenidyl hydrochloride |
| Timolol maleate | Trimethadione |
|
| Verapamil hydrochloride
|
Table 2
Medications That Induce or Exacerbate Myasthenia Gravis *
Anti-infective Agents
|
Cardiovascular Agents
|
Other Agents
|
|---|
| Aminoglycosides | Acebutolol hydrochloride | Chloroquine |
| Ampicillin sodium | Oxyprenolol hydrochloride | Corticosteroids |
| Ciprofloxacin hydrochloride | Practolol | d-penicillamine |
| Erythromycin | Procainamide hydrochloride | Interferon α (INF-α) |
| Imipenem | Propafenone hydrochloride | Mydriatics |
| Kanamycin sulfate | Propranolol hydrochloride | Phenytoin sodium |
| Pyrantel | Quinidine | Trihexyphenidyl hydrochloride |
| Timolol maleate | Trimethadione |
|
| Verapamil hydrochloride
|
×
Diagnostic Testing
A quick bedside technique for diagnosing MG is the ice test.
8,9 For a patient with ptosis, a small cube of ice is placed over the eyelid for about 2 minutes. Improvement of the ptosis after this procedure suggests a disorder of neuromuscular transmission.
Laboratory Studies
Certain studies should be performed to exclude other disorders that are in the differential diagnosis. Physicians who suspect their patients have MG should order the laboratory studies listed in
Figure 1.
The most sensitive and specific test for MG is the presence of acetylcholine receptor antibodies (AchR-Ab). Not all patients who have MG have positive AchR-Ab titers, however. False-positive results do occur but are rare.
10 Whereas 45% to 65% of patients with ocular MG have positive antibodies, approximately 90% of patients with generalized MG have positive antibodies.
11,12 An important point when reviewing results with patients is to note that the degree of “positivity” for the test results does not correlate with the severity of disease.
13,14
Three laboratory studies are commercially available and may be used when testing for the presence of AchR-Ab (ie, binding, modulating, and blocking). The binding antibody is the most common initial screening study. Patients with very mild disease, or those in the early stages, may be seronegative. Acetylcholine receptor–modulating antibodies are detected using cultured human cells. This laboratory study should be done for patients who test negative for the binding antibodies.
The assay for the blocking antibody, which uses bungarotoxin, is rarely administered. Tests for striational muscle antibodies may be useful in late-onset MG to exclude the possibility of a thymoma.
3
A more recently available commercial test is the muscle-specific receptor tyrosine kinase (MuSK).
15 This assay is most useful when testing patients who have MG but are AchR-Ab negative.
Radiographic Studies
Approximately 20% of patients with MG have a thymoma present, whereas about 70% have thymic hyperplasia.
16 To exclude this abnormality, all patients with MG should have a computed tomography (CT) scan of the chest done with contrast. Routine chest radiography may be done but should not be done in place of the CT scan of the chest.
Pharmacologic Studies
Edrophonium chloride (Tensilon) is a short-acting acetylcholine esterase inhibitor. During this test, the patient should be hooked up to a cardiac monitor. Also, atropine must be available at the bedside in the event of bradycardia. A total of 10 mg of edrophonium may be used. A small test dose (2 mg) is injected intravenously and if, after 1 minute, there is no improvement in strength, the remainder of the dose should be given slowly. The effects of the edrophonium usually last fewer than 10 minutes.
For the test results to be considered positive, there must be an unequivocal improvement of strength (eg, ptosis that improves). The patient may have cholinergic side effects such as increased salivation, eye tearing, muscle fasciculations, or abdominal cramps. If patients report a subjective improvement of overall strength or a reduction in fatigue, the test results should not be considered positive. Such premature diagnoses frequently lead to unnecessary neuromuscular consultations.
Electrodiagnostic Studies
The electrophysiologic evaluation of MG involves routine nerve-conduction testing, repetitive nerve stimulation, exercise testing, and, in certain instances, single-fiber electromyelogram (EMG). As a general rule, test results are normal for patients with MG when routine nerve-conduction studies are done. If the results of the nerve-conduction studies are abnormal, physicians should question the diagnosis of MG. Then, RNS is done; the results should demonstrate a greater than 10% decrement to be considered positive (
Figure 2). The yield of the test increases if proximal nerves are stimulated (eg, spinal accessory, facial), limb temperature is increased,
17 or the test is conducted following exercise of the appropriate muscle(s). Exercise testing should be done with all RNS studies because the decrement is often enhanced following exercise (
Figure 2).
Single-fiber EMG is used to measure the relative firing of adjacent muscle fibers from the same motor unit. The variation in firing between these fibers is called
jitter. For patients with MG, increased jitter is seen. Although single-fiber EMG is the most sensitive test for demonstrating neuromuscular transmission (>95%), it is not specific; the results may be abnormal in a variety of neuropathic or myopathic disorders.
4,18,19 An important point is that the electrophysiologic studies should always be interpreted in the context of the clinical setting.
4
Treatment
There is no distinct protocol for the treatment of patients who have MG. Physicians need to decide when aggressive management must be undertaken. In general, the rate of disease progression and distribution of weakness as well as severity are the most important considerations when developing a treatment plan. Other factors that may influence long-term treatment would be age, sex, and the presence (or absence) of other systemic illness.
The goal of therapy is to achieve remission, which is to have the patient symptom-free and not taking maintenance medication. In general, most patients do become symptom-free, but they need to stay on a low-dose immunosuppressive medication.
Table 3 summarizes the oral preparations used in treating patients with MG.
Table 3
Medications Commonly Used to Treat Myasthenia Gravis
Medication
|
Starting Dosage
|
|---|
| Azathioprine | 50 mg test dose; increase up to 3 times daily |
| Cyclophosphamide | 25 mg daily; increase as needed |
| Cyclosporine | 25 mg twice daily; increase as needed |
| Mycophenolate mofetil | 250 mg twice daily; increase as needed |
| Prednisone | 5 mg daily; increase dose by 5 mg every 5 days until a dose of 40 mg to 60 mg daily is reached |
Pyridostigmine bromide
| 30 mg to 60 mg every 4 hours during waking hours or 180 mg at bedtime
|
Table 3
Medications Commonly Used to Treat Myasthenia Gravis
Medication
|
Starting Dosage
|
|---|
| Azathioprine | 50 mg test dose; increase up to 3 times daily |
| Cyclophosphamide | 25 mg daily; increase as needed |
| Cyclosporine | 25 mg twice daily; increase as needed |
| Mycophenolate mofetil | 250 mg twice daily; increase as needed |
| Prednisone | 5 mg daily; increase dose by 5 mg every 5 days until a dose of 40 mg to 60 mg daily is reached |
Pyridostigmine bromide
| 30 mg to 60 mg every 4 hours during waking hours or 180 mg at bedtime
|
×
Acetylcholinesterase Inhibitors
This class of medication remains the first line of therapy in symptomatic patients. The most common agent used is pyridostigmine bromide. Acetylcholinesterase inhibitors effectively increase the amount of neurotransmitter (ie, acetylcholine) available at the NMJ. The optimal dose of pyridostigmine varies from patient to patient. In general, a patient is started on 30 mg (half tablet) every 4 to 6 hours while awake and the dosage is titrated depending on clinical symptoms and patient tolerability.
Pyridostigmine has a short half-life of approximately 3 to 6 hours. The possible adverse effects are those of cholinergic excess: abdominal cramping, increased salivation, and diarrhea. If patients receive too much of this medication, increased weakness may develop (ie, cholinergic crisis).
When the patient has problems during sleep or awakens with weakness or ptosis, a long-acting form of pyridostigmine bromide (Mestinon Timespan tablets) is usually prescribed at 180 mg daily. This long-acting form is not recommended for use throughout the day, however. Neostigmine has a shorter but more pronounced effect. It can be administered orally, parenterally, or even intranasally.
20
Immunosuppressive Therapy
As MG is an autoimmune condition, the mainstay of treatment involves attacking the immune system. The more common immunosuppressive agents are listed in
Table 3. When using any of these agents, careful monitoring of the complete blood cell count (CBC), electrolyte panel, and the liver and renal profiles is essential. The doses may need to be adjusted according to the patient's white blood cell count.
▪
Steroid Therapy—As a general rule, most patients with MG require steroid therapy at some point during treatment. Steroids may potentially reduce the AchR-Ab titer in patients with MG.
21
The typical dosage of prednisone is 1 mg per kilogram of body weight daily, administered as a single oral dose. It is important to start patients on a low dose of prednisone and gradually titrate the dose up. Patients may have transient worsening of MG symptoms during the first 2 to 3 weeks of prednisone therapy. Patients should be warned of these potential adverse effects at the initial stages of therapy and reassured that they will have benefits in 6 to 8 weeks after therapy is initiated.
The drug is usually started at 5 mg daily and may be increased by 5 mg every 4 to 7 days until a clinical benefit is achieved or 1 mg per kilogram of body weight is reached. Once a therapeutic dose is achieved, the patient should remain on this dose for about 2 months. Then a regimen to switch to alternate-day therapy should be instituted. Once the patient's condition is stabilized, the dosage may be slowly tapered downward. In general, the dose should be tapered downward by 5 mg every month. It is not uncommon for patients to relapse after the steroids have been tapered off—another hazard they should be alerted to in advance of a change in dosage. Most patients who have MG generally require long-term low-dose prednisone therapy to maintain remission of symptoms.
Patients should also be informed in advance of other adverse effects not relating to their current symptoms of MG: acne, bruising (occur easily and difficulty in healing), cataracts, imbalances on electrolyte panel test results, hirsutism, hyperglycemia, hypertension, necrosis of the femoral head, obesity, osteoporosis, and steroid-induced myopathy. Patients with type 2 diabetes mellitus who are taking oral agents to control symptoms of MG may require insulin therapy to treat diabetes symptoms during this period. Appropriate precautionary measures should be followed to avoid any of the aforementioned adverse effects.
▪
Azathioprine—The most commonly used drug to treat patients with MG is now azathioprine.
3 It allows tapering of steroid dosage and reduces some of the adverse effects of steroid therapy. Commonly, the patient will not have clinical benefit from azathioprine for about 4 to 6 months and sometimes longer.
The typical starting dose of azathioprine is 50 mg daily for the first week (test dose), and then the dose is titrated up to a maximum of 2 mg to 3 mg per kilogram of body weight daily in two or three divided doses.
The most common adverse effects are neutropenia and liver function abnormalities. Thus, results from regular CBC counts and liver profile tests should be routinely followed for patients receiving azathioprine therapy.
Rarely, an acute hypersensitive reaction develops when initiating this treatment modality. Therefore, a test dose is commonly used during the first week of treatment. Although the long-term effects of azathioprine are not well known, some concern has been raised about an increased risk of malignancy.
22
▪ Cyclosporine—A powerful immunosuppressant that inhibits T-cell activation is cyclosporine. This agent is usually prescribed for patients who have failed to respond to combination therapy with prednisone and azathioprine and those who cannot tolerate azathioprine.
The standard starting dose for cyclosporine is 25 mg twice daily and titrated up to a maximum of approximately 3 mg to 6 mg per kilogram of body weight. However, immunosuppressive therapy should always be tailored to the individual patient; combination therapy is often more efficacious (ie, allowing for reduced dosage and fewer adverse effects) than monotherapy.
23
While patients' are receiving this treatment, their blood levels (troughs) of cyclosporine should be checked periodically. The most important adverse effects are nephrotoxicity and hypertension.
▪ Cyclophosphamide—In general, cyclophosphamide is used only when other agents have failed or are not well tolerated by the patient. Cyclophosphamide therapy may be started at 25 mg daily and gradually increased up to a maximum of approximately 2 mg to 5 mg per kilogram of body weight daily.
An increased incidence of hemorrhagic cystitis accompanies the use of this medication in some patients.
▪
Mycophenolate Mofetil—A novel immunosuppressive agent for treatment of MG that has already been shown to be of benefit in transplantation medicine is mycophenolate mofetil. Recent openlabel trials in patients with MG have shown this medication to provide significant benefit.
24-27
The standard daily dosage for this medication is 1 g to 2 g. Patients may be started at 250 mg of mycophenolate mofetil twice daily, and the dosage can be titrated upward as needed. When starting this agent, the patient's CBC count should be checked every week for the first month of treatment, every 2 weeks for the next 6 to 8 weeks, and monthly thereafter.
Currently, this agent is considered a useful alternative treatment modality for patients who have severe MG. This medication should also be considered for use in treatment when standard immunosuppressive agents fail.
Plasmapheresis
Plasma exchange, or plasmapheresis, is an effective means of therapy but is transient in its response. This technique is particularly useful when treating patients in myasthenic crises or those in preparation for surgery.
The goal of this therapeutic intervention is to remove the circulating immune complexes and AchR-Ab. Patients usually undergo a 2-week course of 5 to 6 exchanges.
Risks involved in this treatment include fluid imbalance and hypercoagulation. However, a more common problem for patients is the difficulties that may arise as a result of physicians using vascular access procedures to do this therapeutic procedure.
28
Intravenous Immunoglobulin Therapy
The administration of intravenous immunoglobulin (IVIG) serves as an alternate mode of therapy to plasmapheresis. This procedure is especially helpful when vascular access is a problem.
The exact mechanism of action of IVIG therapy on MG is not well understood, though several options have been suggested.
29 Intravenous immunoglobulin is given as a dose of 2 g per kilogram of body weight over 2 to 5 days.
Intravenous immunoglobulin therapy is a relatively safe treatment method and has few adverse effects, though headache, chills, and fever have been reported in some patients.
4 Usually, premedication with acetaminophen and diphenhydramine alleviates these symptoms. Other rare adverse events include aseptic meningitis and renal failure.
4
Surgical Intervention
There is general agreement that a thymectomy should be done in patients with MG only if those patients are medically stable and aged 60 years or younger. If a patient has a thymoma, it should clearly be removed.
4
There has been some controversy recently as to which surgical approach is better. In general, a median sternotomy is preferred and allows for maximal exposure to ensure that all thymic tissue is removed at the time of surgery.
30
Clinical improvement is typically delayed by 6 months to 1 year after surgery.
Myasthenic Crisis
Rarely, the initial presentation of a patient with MG may occur when that patient is in myasthenic crisis. Alternatively, a patient with known MG may reach a crisis.
A myasthenic crisis is defined as the sudden worsening of respiratory function and/or profound muscle weakness. Recognition and treatment of myasthenic crisis is a neurologic emergency. With early recognition, effective therapy, and modern intensive care units, mortality from such crises is now a rare occurrence.
Crisis can occur as a result of a variety of causes, including concurrent infection or the addition of new medications that are known to exacerbate MG or worsen its symptoms (see
Table 2).
Frequently, in response to worsening weakness, patients decide to take progressively more acetylcholinesterase inhibitors without consulting their physicians, not realizing that excessive acetylcholinesterase treatment can by itself lead to increased muscle weakness (ie, cholinergic crisis). If this condition is not recognized early, the patient usually has respiratory collapse or aspirates from increasing bulbar weakness.
Patients with myasthenic or cholinergic crisis must be treated aggressively. However, it is frequently difficult to distinguish cholinergic crisis from myasthenic crisis.
Some have suggested administering the edrophonium test to distinguish between the two types of crisis. In other words, if there is a worsening of symptoms after the edrophonium test is done, the diagnosis should be cholinergic crisis; if there is improvement, myasthenic crisis. However, it is difficult to administer this test to patients in acute distress. As a general rule, immediately treat the patient for the more severe of the two conditions, myasthenic crisis.
Comment
The purpose of this article was to provide a better understanding of MG for family physicians. This understanding should lead to better physician interactions with the consulting neurologist. Family physicians should play an active role in the diagnosis and management of patients with MG.
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