Receptor antibodies. Antibody status is useful in diagnosing MG, not only because MuSK-positive patients are more likely to have facial, respiratory, and proximal muscle weakness,3 but also because it can impact treatment plans. Serum assay for elevated levels of AChR antibodies has a sensitivity of 80% to 90% for the diagnosis of MG.3 Approximately 40% of those without acetylcholine antibodies have MuSK antibodies.1
Only 6% to 12% of patients with MG are truly seronegative (i.e., have negative standard assays for AChR antibodies and MuSK antibodies).8 These individuals may also be referred to as double negative, as the term seronegative was previously used only for those who were AChR-antibody-negative prior to the discovery of the MuSK antibody. Essentially all patients (98% to 100%) with MG and thymoma are seropositive for acetylcholine antibodies.8
In individuals with purely ocular MG, the sensitivity of AChR-antibody testing is considerably lower; specifically, AChR antibodies are seen in 80% of those with generalized MG and in only 55% of those with ocular MG.2,8 Titin and ryanodine receptor antibodies may additionally be helpful for classification.5
Negative antibody titers do not necessarily exclude the disease. Seronegative MG is clinically indistinguishable from seropositive disease.2 There is also evidence that those without either antibody may have low-affinity antibodies or other as yet undefined antibodies that impair neuromuscular transmission.1 Ideally, serologic testing for AChR antibodies should be performed prior to initiating immunomodulating therapy for MG, as such therapy can sometimes lead to apparent seronegativity.8 While there are three AChR-antibody assays (i.e., binding, blocking, and modulating), the term AChR antibody is used synonymously with the binding antibodies, and these are what are referred to in most studies.8 Table 3 provides more information about the acetylcholine antibody subtypes and MuSK antibodies.
Table 3. Antibody status1,5,8
|Muscle-specific kinase (MuSK)|
Characteristics of MuSK-positive patients:
AchR-antibody level does not correspond with severity of disease; however, in an individual patient, a treatment-induced drop in antibody level often correlates with clinical improvement, while a rise in level may occur with exacerbation.1 Longitudinal measurement of AChR antibodies can be helpful in evaluating treatment effect and in differentiating between MG and non-MG symptoms experienced by the patient.5
Tensilon and ice-pack tests. These well-known tests are relied on less and less to diagnose MG. The ice-pack test can be used in individuals with ptosis, particularly when the Tensilon test is considered too risky.
Fill a bag or surgical glove with ice, and place it on the patient’s closed eyelid for two minutes. Once the ice pack is removed, ptosis is immediately assessed based on the principle that neuromuscular transmission improves at lower temperatures. If the ptosis resolves, the test is positive. The sensitivity of the test is about 80% in patients with prominent ptosis.8
The Tensilon test is used to confirm a diagnosis of MG by observing patient response to a short-acting acetylcholinesterase inhibitor. In an individual with MG, intravenous edrophonium (Tensilon) should show five minutes of obvious improvement in muscle strength. IV neostigmine (Prostigmin) can also be administered, and the response should last approximately two hours.3 The patient should be fatigued prior to receiving the medication.
While performing the test, have atropine ophthalmic (Atropine-Care, Atropisol, Atrosulf-1, Isopto Atropine, Ocu-tropine) available to reverse muscarinic side effects (e.g., diarrhea, nausea, and increased salivation).3,6 Because of the risk of bradycardia and hypotension, the Tensilon test should always be administered with cardiac monitoring.4 In the emergency department (ED), where antibody testing may not be available, the Tensilon test can help confirm diagnosis and delineate cholinergic crisis from myasthenic crisis, as those in cholinergic crisis will have no improvement from the test.4
The Tensilon test should be used only in individuals with obvious ptosis or ophthalmoparesis in whom improvement after infusion of the drug can easily be observed.8 The sensitivity of the Tensilon test is in the range of 80% to 90%, but it is associated with many false-negative and false-positive results.8 Some patients with clearly established MG may have equivocal or no response to the edrophonium. The Tensilon test can actually have an adverse effect on patients with MuSK-positive myasthenia.
A positive test is not specific for MG, as it can also occur in conditions that can present in a similar fashion, such as motor neuron disease, brainstem tumors, and compressive cranial neuropathies.8 The longer-acting neostigmine reduces the incidence of false-negative evaluations.6 Antibody testing or electrodiagnostic testing is a more reliable indicator of MG.
Electrodiagnostic testing. Several types of electrodiagnostic testing can be used to detect MG. A decrementing muscle response (<15%) to repetitive stimulation of motor nerves indicates a disturbance of neuromuscular transmission.1,3 With needle electromyography, affected muscles show a marked variation in configuration and size of individual motor unit potentials, and single-fiber electromyography reveals an increased jitter in the time interval between two muscle fiber action potentials from the same motor unit.3 Single-fiber electromyography is the most sensitive clinical test of neuromuscular transmission.2
Imaging. To rule out coexisting thymoma, obtain lateral and anteroposterior x-rays of the chest, as well as CT scans with and without contrast.3 In patients who are not stable, iodinated contrast can worsen myasthenic weakness. For individuals with ocular or cranial MG, use CT or MRI to exclude intracranial lesions.1
The four basic therapies used in the treatment of MG are symptomatic treatment (i.e., anticholinesterase agents), chronic immunomodulating therapy (i.e., glucocorticoids and other immunosuppressive drugs), rapid immunomodulating therapy (i.e., plasmapheresis [PLEX] and IV immune globulin [IvIg]), and surgery (i.e., thymectomy).
Symptomatic treatment. Anticholinesterase drugs provide symptomatic benefit without influencing the underlying course of the disease. Inhibition of acetylcholinesterase reduces the hydrolysis of acetylcholine, thereby increasing the amount of acetylcholine at the postsynaptic membrane. Anticholinesterase agents include neostigmine and pyridostigmine (Mestinon). Pyridostigmine is most commonly used at a dose of 30 mg to 180 mg (average 60 mg) four times daily.3
Be wary of overmedication, which can temporarily increase weakness that is, unlike myasthenic weakness, unaffected or worsened by IV edrophonium.3,6 Such cholinergic crises may be accompanied by pallor, sweating, nausea, vomiting, salivation, colicky abdominal pain, and miosis.3,6
Anticholinesterase medications are typically ineffective for patients in myasthenic crisis and are often discontinued to obviate the need to distinguish myasthenic crisis from cholinergic crisis.2 Because this group of medications does not affect underlying immunopathology, immunomodulating therapy serves as the mainstay for most patients with MG.
Chronic immunomodulating therapy. Immunotherapeutic drugs commonly used to treat MG include prednisone, azathioprine (Azasan, Imuran), cyclosporine (Gengraf, Neoral, Sandimmune, Sangcya), and mycophenolate mofetil (CellCept). In some individuals, particularly those with refractory MG, such agents as rituximab (Rituxan), monthly pulse cyclophosphamide (Cytoxan), and tacrolimus (Hecoria, Prograf) may be considered.9
Prednisone is often used in individuals who have responded poorly to anticholinesterase drugs. Some providers choose to introduce steroids in the hospital setting since these agents can initially aggravate weakness;3 however, many neurologists feel comfortable administering prednisone on an outpatient basis. Alternate-day therapy may be better tolerated from a side-effect standpoint, but if weakness worsens on nontreatment days, daily dosage may be needed.3
An initially high dose of 60 mg to 100 mg daily can gradually be tapered to a relatively low maintenance dose (5 mg to 15 mg daily) as improvement occurs.3,6 While total withdrawal may never be possible,3 the goal is to treat at the lowest required dose. Counsel patients on the long-term side effects of steroids (e.g., osteoporosis, cataracts, myopathy, effects on BP and blood glucose, and increased risk of gastric ulcers).
Steroid-sparing immundomodulators are needed when patients are unable to successfully taper to a low maintenance dose of prednisone. These agents include azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, and occasionally cyclophosphamide.1 Glucocorticoids, cyclosprorine, or tacrolimus generally produce improvement in one to three months, while the benefits of azathioprine and mycophenolate mofetil typically begin after many months.1
Azathioprine is one of the more common immunosuppressants used in the treatment of MG. The usual dose is 2mg/kg to 3mg/kg orally daily after a lower initial dose.3 Scientific evidence for its effect in individuals with MG is lacking, but a controlled trial showing the superiority of the combination prednisolone-azathioprine over prednisolone alone is much cited.5 Azathioprine is listed among drugs that should not be used in pregnancy, but formal evidence of teratogenic effects in MG patients is lacking.5
Because of risk of leukopenia, the numbers of leucocytes and leucocyte subgroups must be counted weekly during the first few months of treatment.5 The clinical effect of azathioprine is slow to appear. Improvement should not be expected until after three to six months, and full effect of the drug first occurs after one to two years.5 For this reason, azathioprine is usually combined with such other immunoactive treatments as prednisone, particularly in the initial phase.
As many as to 10% of patients are unable to tolerate azathioprine secondary to an idiosyncratic reaction consisting of flulike symptoms (i.e., fever and malaise), bone-marrow suppression, or abnormalities in liver function tests.1 In individuals taking azathioprine, allopurinol (Lopurin, Zyloprim) should never be used to treat hyperuricemia, as both drugs share a common degradation pathway that can result in bone-marrow suppression attributable to the effects of azathioprine.1
Mycophenolate mofetil is another immunosuppressant that may provide benefit and allow the corticosteroid dose to be reduced.3 This agent selectively inhibits proliferation of T and B lymphocytes and has been used as an immunosuppressant with only modest side effects (i.e., diarrhea, nausea, abdominal pain, fever, leukopenia, and edema).6 The standard dose is 1 g orally b.i.d. Several studies indicate patients taking mycophenolate mofetil improve or are able to lower their steroid dose, but usually after a delay of several months.6
Calcineurin inhibitors, including cyclosporine and tacrolimus, tend to work more rapidly than azathioprine.1 Significant side effects include hypertension and nephrotoxicity.1 Cyclosporine has a broad range of drug interactions, so many other drugs may raise or lower cyclosporine level.1 Cyclophosphamide should be reserved for those refractory to other drugs.1 Methotrexate (Rheumatrex, Trexall) is also sometimes used.
Rituximab should be reserved for patients with severe MG in whom treatment with prednisolone and at least two other standard immunosuppressive drugs has failed.5 Rituximab is a monoclonal antibody that depletes CD20 B cells and at times has been dramatically successful, particularly against MuSK-positive MG.1
For milder MG, the risk of progressive multifocal leukoencephalopathy and other potential long-term side effects likely outweigh the therapeutic potential of rituximab.5 However, studies show benefit for both AChR and MuSK antibody patients with refractory, generalized MG when treated with rituximab.10 These results include sustained clinical improvement as well as a reduced need for conventional immunotherapies and AChR antibody titers. More studies need to be done in this area, as an ideal dose schedule has not yet been established.10
Rapid immunomodulating therapy. The rapid therapies used in the treatment of MG are also immunomodulating but are distinct because of their quick onset, transient benefit, and use in select situations.9 PLEX and IvIg start to work quickly (over days), but the benefits are only short-term (weeks to months). These therapeutic modalities are used most often in myasthenic crisis, preoperatively before thymectomy or other surgery, or as a bridge to slower immunotherapies.9
Rapid immunomodulating therapy can also be used periodically to maintain remission in patients with MG that is not well-controlled despite the use of chronic immunomodulating drugs.9
PLEX removes AChR antibodies and is indicated in patients who require rapid improvement; high-dose IvIg is also associated with rapid improvement.4 While easier to administer than PLEX, IvIg is more expensive. PLEX is not a useful long-term treatment, since the need for repeated exchanges often leads to problems with venous access.
Treatment typically consists of five exchanges (3 to 5 L of plasma each) over seven to 14 days.9 Significant chronic catheter complications can result, including infection and thrombosis.9 PLEX can also produce such other adverse effects as bleeding, hypotension, cardiac arrhythmias, muscle cramps, and a toxic reaction to the citrate used in the procedure.9 ACE inhibitors must be withheld 24 to 72 hours before treatment and until treatment is complete.
The effect of IvIg also is typically seen in less than a week, and the benefit can last for three to six weeks.9 The mechanism of action is not fully understood. The total dose of IvIg is 2 g/kg, usually over two to five days; spreading the dose over more days is preferable in patients who have renal disease, congestive heart failure, or are elderly.9
Side effects of IvIg (i.e., headache, chills, dizziness, and fluid retention) are typically mild and usually related to the infusion rate. Uncommon complications include aseptic meningitis, acute renal failure, thrombotic events, and anaphylaxis.9 Anaphylaxis has been associated with immunoglobulin A deficiency but is rarely seen in patients treated for autoimmune neuromuscular diseases.9 IvIg should not be used as a long-term management strategy.
Plasma exchange and IvIg have a similar clinical effect, but the clinical impression may be a somewhat faster and more extensive effect with plasma exchange.5 Patients responding to plasma exchange and IvIg are not necessarily the same, so if one treatment fails, the other may be worth trying.5
Surgery. Thymectomy usually leads to symptomatic benefit or remission of MG. All of the 10% to 15% of patients with thymoma should undergo thymectomy to remove a potentially infiltrating tumor. Thymectomy should always be considered as a therapeutic measure in early-onset generalized MG, particularly when a patient has a hyperplastic thymus. Postoperative improvement usually occurs gradually over the course of two to 24 months. Thymectomy can also be considered in individuals without any detectable antibodies who have generalized symptoms of MG.5
The major benefit of surgery, particularly for children facing many years of treatment, is that thymectomy often facilitates immunosuppression. In the absence of a tumor, the evidence suggests that up to 85% patients experience improvement after thymectomy; of these, 35% experience drug-free remission.1
In general, thymectomy leads to drug-free remission in one third of patients and reduced treatment needs in a second third of patients, and has no benefit in the final of patients.
While thymectomy in patients older than age 55 years is still debated, age should not be a strict contraindication for the procedure. Some individuals who experience their first symptoms of MG after age 50 years have hyperplastic thymus and other features in common with the early-onset MG group and are expected to respond to thymetcomy.
Symptoms for a longer period of time, atrophic thymus, and presence of non-AChR antibodies against titin and/or ryanodine receptor all count against thymectomy. Thymectomy is not usually recommended in persons with purely ocular MG or anti-MuSK antibodies.5
The surgeon and the anesthesiologist involved in the procedure must be aware that the patient has MG, as this can affect the type of anesthesia used. The patient should be stable at the time of surgery, and the threshold for preoperative treatment with PLEX or IvIg should be low.5
Treating acute presentations. Individuals who present in severe crisis require a chest radiograph to evaluate for aspiration pneumonia.4 Forced vital capacity (FVC) should be measured as well, since respiratory-muscle weakness may be present in those who do not appear short of breath.2 Normal FVC values should range from 60 mL/kg to 70 mL/kg; as the FVC approaches 15 mL/kg, intubation is often necessary.4
Negative inspiratory force can also be used to measure respiratory strength. In the clinic setting or at bedside, have the patient count from one to 25 with one breath. With sequential performance of this exercise, a decline in respiratory function will be detected as the patient fails to count as high as on the prior attempt.4 Management of acute MG in the ED should focus on treating the airway and respiratory compromise. Patients may require suctioning of secretions and supplemental oxygen.
In the ED, it is also important to distinguish myasthenic crisis from cholinergic crisis. Cholinergic crisis is a state of increased cholinergic drive caused by overmedication with cholinesterase inhibitors.2 Cholinergic crisis can cause respiratory-muscle weakness, pinpoint pupils, increased bronchial secretions, salivation, diarrhea, nausea, vomiting, and diaphoresis.2,4
Be aware of all patient medications. A number of drugs can unmask or exacerbate existing MG (Table 4). While these drugs should be avoided in individuals with MG, the disease is not an absolute contraindication for their use.
Table 4. Medications that can complicate myasthenia gravis 1,3,4,6
|Adrenocorticotropic hormone||Neuromuscular blocking agents (i.e., succinylcholine [Anectine], tubocurarine, vecuronium [Norcuron])|
|Botulinum toxin||Penicillamine (Cuprimine, Depen)|
|Certain antibiotics (i.e., aminoglycosides, erythromycin, tetracycline, and fluoroquinolones)||Phenothiazines|
|Certain hypertension medications (i.e., beta-blockers and calcium channel blockers)||Phenytoin (Di-Phen, Dilantin, Phenytek)|
|Corticosteroids||Polymyxin E (colistin)|
|Iodinated contrast agents||Procainamide (Procanbid)|
|Lithium (Eskalith, Lithobid)||Quinine (Qualaquin), quinidine|
|Magnesium (including milk of magnesia, magnesium hydroxide [Maalox], and Epsom salt)|| *Additional medications have been reported to worsen weakness
related to myasthenia gravis
Alternative therapies should be pursued if possible, particularly when a patient is in exacerbation. All MG patients should be closely followed whenever a new drug is added, as many drugs can impair neuromuscular transmission.
Associated conditions. Thymic abnormalities occur in 75% of individuals diagnosed with MG. Enlargement of the thymus in patients older than age 40 years is highly suspicious for thymoma.1 Hyperthyroidism is seen in 3% to 8% of patients with MG, so obtain thyroid-function tests in all patients with suspected MG.1 Because of the association MG has with other autoimmune diseases (e.g., lupus), perform a blood test for rheumatoid factor and antinuclear antibody.1
Vaccines. The role and safety of vaccines in patients with MG is not clear. Certainly, individuals with generalized MG who develop respiratory infections are at increased risk of exacerbations and respiratory compromise, which would support standard vaccination protocol.9
This would also apply to patients with ocular MG of more recent onset (within the past three years), as they are still at risk to progress. Current guidelines recommend annual seasonal influenza vaccination for all individuals receiving immunosuppressive therapy and for those with neurologic conditions — including such neuromuscular disorders as generalized MG or ocular MG within three years of onset — that could compromise the handling of respiratory secretions.9
There is a concern vaccines could activate the immune system and cause an MG flare. A population-based study suggests that the inactivated (intramuscular) influenza vaccine is safe in adults with MG, but live vaccines should be avoided.9
More study is warranted in this area, but many neurologists feel it is safe to administer vaccines when patients are stable. Avoid vaccinations in those experiencing an exacerbation.
Pregnancy. Pregnancy has a variable effect on the course of MG. While it does not worsen the long-term outcome, symptoms may worsen during the course of pregnancy. The first trimester and the first month postpartum are the periods of highest risk of exacerbation.11
Pregnancy and birth for women with MG is usually uncomplicated, but operative intervention related to prolonged labor (e.g., Cesarean section, forceps use) occurs more frequently than in controls.5 The second stage of labor may be affected in patients with MG.11
Anticholinesterase drugs and prednisolone are considered to be safe during pregnancy. Azathioprine and other immunosuppressive drugs should be withdrawn before a planned pregnancy and avoided in the fetal-organ development period.5 PLEX and high-dose IvIg are reserved for cases in which conventional therapy of MG has failed and developing respiratory failure or profound dysphagia and weakness threatens the mother and the fetus.11 All infants of myasthenic mothers should be observed in a special-care nursery for the first 48 to 72 hours of life, as transient neonatal MG develops in 10% to 20% of infants born to myasthenic mothers.11
MG in children. Special consideration must to given to the pediatric population with regard to MG. Among girls, thyrotoxicosis can be found in almost 10% of patients. While the age of onset is older than age 10 years in 75% of patients, children can present earlier than this. The three main types of MG among the pediatric population are neonatal (transient), congenital (persistent), and juvenile (Table 5). Early video-assisted thoracoscopic thymectomy is beneficial in many patients whose disease is not confined to ocular symptoms, but the effect may not be immediate.12
Table 5. Types of childhood myasthenia gravis1,12
Despite being a commonly tested and frequently mentioned disease in the classroom, MG is not well-understood in practice. While specialist care is essential, all medical professionals should understand the basics of the disease.
Individuals diagnosed with MG must attend follow-up visits as outlined by their neurologist, and lab work is often required to ensure the safety of the immunosuppressants frequently used in the treatment of the disease. Because compliance is so vital to good disease control, support from all providers as a medical team is the best way to ensure good outcomes for patients with MG.
Carrie Smith, PA-C, is a physician assistant in the Neurosciences Department at The Medical University of South Carolina in Charleston, S.C., where David Stickler, MD, is associate professor and Director of Neuromuscular Services and the EMG Laboratory.
- Drachman DB. Myasthenia gravis and other diseases of the neuromuscular junction. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, N.Y.: McGraw-Hill; 2012:3480-3486.
- Drislane FW, Benatar M, Change B, et al, eds. Neurology Blueprints. 3rd ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:169-171.
- Aminoff MJ, Kerchner GA. Disorders of neuromuscular transmission. In: Papadakis MA, McPhee SJ. Current Medical Diagnosis & Treatment. 13th ed. New York, N.Y.: McGraw-Hill Medical; 2012:1032-1034.
- Roppolo LP, Davis D, Kelly SP, Rosen P, eds. Emergency Medicine Handbook: Critical Concepts for Clinical Practice. Philadelphia, Pa.: Mosby Elsevier; 2007:729-731.
- Gilhus NE, Owe JF, Hoff JM, et al. Myasthenia gravis: a review of available treatment approaches. Autoimmune Dis. 2011;2011:847393. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3189457/.
- Simon RP, Greenberg DA, Aminoff MJ. Clinical Neurology. 7th ed. New York, N.Y.; McGraw-Hill Professional; 2009:185-188.
- UpToDate. Bird SJ. Clinical manifestations of myasthenia gravis.
- UpToDate. Bird SJ. Diagnosis of myasthenia gravis.
- UpToDate. Bird SJ. Treatment of myasthenia gravis.
- Nowak RJ, Dicapua DB, Zebardast N, Goldstein JM. Response of patients with refractory myasthenia gravis to rituximab: a retrospective study. Ther Adv Neurol Disord. 2011;4:259-266.
- UpToDate. Bird SJ, Stafford IP, Dildy GA. Management of myasthenia gravis in pregnancy.
- Bernard TJ, Knupp K, Yang, ML, et al. Myasthenic syndromes. In: Hay Jr WW, Levin MJ, Deterding RR, et al, eds. Current Diagnosis and Treatment Pediatrics. 21st ed. New York, N.Y.: McGraw-Hill; 2012:821-822.
- Martin TJ. Neuro-ophthalmology. In: Palay DA, Krachmer JH, eds. Primary Care Ophthalmology. 2nd ed. Philadelphia, Pa.: Elsevier Mosby; 2005:225-226.
All electronic documents accessed November 15, 2012.