eMedicine Specialties > Emergency Medicine > Neurology

Myasthenia Gravis

William D Goldenberg, MD, Clinical Assistant Instructor, Department of Emergency Medicine, Kings County Hospital Center and SUNY Downstate Medical Center
Richard H Sinert, DO, Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Updated: Jan 30, 2009

Introduction

Background

Myasthenia gravis (MG) is a relatively rare autoimmune disorder of peripheral nerves in which antibodies form against acetylcholine (ACh) nicotinic postsynaptic receptors at the myoneural junction. A reduction in the number of ACh receptors results in a characteristic pattern of progressively reduced muscle strength with repeated use of the muscle and recovery of muscle strength following a period of rest.

The bulbar muscles are affected most commonly and most severely, but most patients also develop some degree of fluctuating generalized weakness.¹ The most important aspect of myasthenia gravis for emergency physicians is the detection and management of the myasthenic crisis.

Pathophysiology

Autoantibodies (immunoglobulin G [IgG]) develop against ACh nicotinic postsynaptic receptors for unknown reasons, although certain genotypes are more susceptible.

Cholinergic nerve conduction to striated muscle is impaired by a mechanical blockage of the binding site by antibodies and, ultimately, by destruction of the postsynaptic receptor.

Patients become symptomatic once the number of ACh receptors is reduced to approximately 30% of normal. The cholinergic receptors of smooth and cardiac muscle have a different antigenicity than skeletal muscle and are not affected by the disease.

The role of the thymus in the pathogenesis of myasthenia gravis is not entirely clear, but 75% of patients with myasthenia gravis have some degree of thymus abnormality (eg, hyperplasia in 85% of cases, thymoma in 15% of cases). Given the immunologic function of the thymus and the improvement in the clinical condition of patients following thymectomy, the thymus is suspected to be the site of autoantibody formation. However, the stimulus that initiates the autoimmune process has not been identified

Frequency

United States

The prevalence of myasthenia gravis in the United States ranges from 0.5-14.2 cases per 100,000 people. The prevalence has increased over the past 2 decades, primarily because of the increased life span of patients with the disease but also because of earlier diagnosis.²

Mortality/Morbidity

• In the past (pre-1960), untreated myasthenia gravis carried a mortality rate of 30-70%. In the modern era, patients with myasthenia gravis have a near-normal life expectancy.
• Morbidity results from intermittent impairment of muscle strength, which may cause aspiration, increased incidence of pneumonia, falls, and even respiratory failure if not treated.³  In addition, the medications used to control the disease may produce adverse effects.
• With prompt diagnosis and treatment, the mortality rate of myasthenic crisis is less than 5%.

Race

Onset of myasthenia gravis at a young age is slightly more common in Asians than in other races.²

Sex

• The male-to-female ratio of myasthenia gravis in children and adults is 2:3.
• A female predominance exists in the young adult peak (ie, patients aged 20-30 y), and a slight male predominance exists in the older adult peak (ie, patients older than 50 y).^1,2
• The male-to-female ratio in children with myasthenia gravis and another autoimmune condition is 1:5.

Age

Onset of myasthenia gravis peaks in neonates because of transfer of maternal autoantibodies, in those aged 20-30 years, and in those older than 50 years.

Clinical

History

Most patients who present to the ED have an established diagnosis of myasthenia gravis (MG) and are already taking appropriate medications. The activity of the disease fluctuates, and adjustments in medication dosages must be made accordingly. Noncompliance with medications, infection, and other physiologic stressors may result in a fulminant exacerbation of the disease.

• Many other factors influence cholinergic transmission, including drugs, temperature, and emotional state. 
• The adverse effects of many medications may provoke exacerbations; therefore, carefully obtaining a medication history is important. Some of the medications reported to cause exacerbations of myasthenia gravis include the following:
  • Antibiotics - Macrolides, fluoroquinolones, aminoglycosides, tetracycline, and chloroquine
  • Antidysrhythmic agents - Beta-blockers, calcium channel blockers, quinidine, lidocaine, procainamide, and trimethaphan
  • Miscellaneous - Diphenylhydantoin, lithium, chlorpromazine, muscle relaxants, levothyroxine, adrenocorticotropic hormone (ACTH), and, paradoxically, corticosteroids²
• Thyroid disorders may be seen in as many as 10% of patients with myasthenia gravis, and symptoms of hyperthyroidism or hypothyroidism may be present.  
• Rarely does a patient present with undiagnosed myasthenia gravis. However, if this situation does occur, typical complaints are of generalized weakness and reduced exercise tolerance that improves with rest. Patients with myasthenia gravis do not present with primary complaints of sleepiness or muscle pain. The patient may also complain of a specific weakness of certain muscle groups (eg, those used when climbing stairs).  
• The distribution of muscle weakness follows a characteristic pattern; initially 85% of patients have involvement of the eyelids and extraocular muscles resulting in ptosis and/or diplopia.¹ The involvement of the facial muscles results in changes in expression and speech, whereas involvement of the pharyngeal muscles results in progressive difficulty with mastication and deglutition.  
• In 15-20% of patients, myasthenia gravis affects the bulbar muscles alone. The other patients progress to generalized myasthenia gravis.¹  
• Neck and proximal limb weakness may occur.  
• Respiratory weakness may be present. Respiratory failure occurs in 1% of patients.  
• Eighty-five percent of patients with bulbar weakness go on to develop generalized weakness involving the limbs.

Physical

Patients with myasthenia gravis can present with a wide range of signs and symptoms, depending on the severity of the disease.

• Mild presentations of myasthenia gravis may be associated with only subtle findings, such as ptosis, that are limited to bulbar muscles. Findings may not be apparent unless muscle weakness is provoked by repetitive or sustained use of the muscles involved.  
• Recovery of strength is seen after a period of rest or with application of ice to the affected muscle. Conversely, increased ambient or core temperature may worsen muscle weakness.  
• Severe exacerbations of myasthenia gravis may present dramatically. 
  •  Facial muscles may be slack, and the face may be expressionless.
  • The patient may be unable to support his or her head, which will fall onto the chest while the patient is seated.
  • Jaw is slack.
  • Voice has a nasal quality.
  • Body is limp.
  • Gag reflex is often absent, and such patients are at risk for aspiration of oral secretions.⁴
• Respiratory distress
  • The patient's ability to generate adequate ventilation and to clear bronchial secretions are of utmost concern with severe exacerbations of myasthenia gravis.
  • Inability to cough leads to an accumulation of secretions; therefore, rales, rhonchi, and wheezes may be auscultated locally or diffusely. The patient may have evidence of pneumonia (ie, fever, cough, dyspnea, consolidation).
• Cholinergic crisis
  • One of the confusing factors in treating patients with myasthenia gravis is that insufficient medication (ie, myasthenic crisis) and excessive medication (ie, cholinergic crisis) can present in similar ways.
  • Cholinergic crisis results from an excess of cholinesterase inhibitors (ie, neostigmine, pyridostigmine, physostigmine) and resembles organophosphate poisoning. In this case, excessive ACh stimulation of striated muscle at nicotinic junctions produces flaccid muscle paralysis that is clinically indistinguishable from weakness due to MG.
  • Myasthenic crisis or cholinergic crisis may cause bronchospasm with wheezing, bronchorrhea, respiratory failure, diaphoresis, and cyanosis.⁴
  • Miosis and the SLUDGE syndrome (ie, salivation, lacrimation, urinary incontinence, diarrhea, GI upset and hypermotility, emesis) also may mark cholinergic crisis. However, these findings are not inevitably present.
  • Despite muscle weakness, deep tendon reflexes are preserved.

Causes

• The cause of myasthenia gravis is unknown, but it is clearly an autoimmune disease in which the specific antibody completely has been characterized. In up to 90% of generalized cases, IgG to the nicotinic Ach receptor is present.³
• Females and people with certain human leukocyte antigen (HLA) types have a genetic predisposition to autoimmune diseases. 
• As with other autoimmune diseases, a derangement of immune regulation occurs.
• Sensitization to a foreign antigen that has cross-reactivity with the nicotinic ACh receptor has been proposed as a cause of myasthenia gravis, but the triggering antigen has not yet been identified.

Differential Diagnoses

Myocardial Infarction
Pulmonary Embolism

Workup

Laboratory Studies

• No laboratory tests are available in a time frame that is useful to confirm the emergency diagnosis of myasthenia gravis (MG).
• An arterial blood gas determination can help guide respiratory management and should be obtained early. An elevated pCO₂ suggests progressive respiratory failure and may indicate the need for emergency airway management.

Imaging Studies

• Chest radiography is indicated to determine the presence of aspiration or other pneumonias, which commonly occur in patients with myasthenia gravis.
• CT scan or MRI of the chest is highly accurate in detecting thymoma. Every patient with myasthenia gravis should be screened for thymoma. Chest radiography is relatively insensitive in screening for thymoma, as it does not detect up to 30% of cases.

Other Tests

• Tensilon (edrophonium) challenge test is useful in diagnosing myasthenia gravis and in distinguishing myasthenic crisis from cholinergic crisis due to its rapid onset and short duration of action.^5,6 A positive response is not completely specific for myasthenia gravis because several other conditions (eg, amyotrophic lateral sclerosis) may also respond to edrophonium with increased strength. Once the patient's airway and ventilation are secured, an initial test dose of edrophonium is given. Some patients may respond noticeably to a small dose (1 mg). If no adverse reaction occurs following the test dose, another dose (3 mg) of edrophonium should produce noticeable improvement in muscle strength within 1 minute.⁶ If no improvement occurs, an additional dose of 5 mg can be administered to total no more than 10 mg.⁵
  • Patients who respond generally show dramatic improvement in muscle strength, regaining facial expression, posture, and respiratory function within 1 minute.
  • During this procedure, the patient must be monitored carefully because edrophonium can cause significant bradycardia, heart block, and asystole. The risk of serious bradyarrhythmias and syncope was only 0.16%, but atropine still should be available at the bedside.⁵ The return of muscle weakness after edrophonium wears off combined with residual increased oral secretions can exacerbate respiratory distress and the risk of aspiration.
  • Patients with a cholinergic crisis may respond to edrophonium challenge by increasing salivation and bronchopulmonary secretions, diaphoresis, and gastric motility (ie, SLUDGE syndrome).^6,7 These changes should be managed expectantly, as the half-life of edrophonium is short (ie, approximately 10 min).
  • If muscle strength fails to improve following the maximum dose of edrophonium, the patient is having a cholinergic crisis or has another cause of weakness that is unrelated to myasthenia gravis.
  • The effects of edrophonium are brief, and repeated doses may be required before oral anticholinesterase medication can take effect.⁶
  • In patients with less severe exacerbations, the degree of improvement with edrophonium may be subtle. Many authors recommend having several blinded observers assess the patient's response in these cases. Some authors also suggest that a clear endpoint, such as improvement in eyelid ptosis or extraocular movements, since these muscles are independent of voluntary effort.⁵
• Ice pack test
  • Cooling may improve neuromuscular transmission. In a patient with myasthenia gravis who has ptosis, placing ice over an eyelid will lead to cooling of the lid, which leads to improvement of the ptosis.
  • Lightly placing ice that is in a surgical glove or that is wrapped in a towel over the eyelid will cool it within 2 minutes.
  • A positive test is clear resolution of the ptosis.⁵
  • This test has a pooled sensitivity and specificity of 82% and 96%, respectively. However, the literature generally overestimates the usefulness since most of the studies were case-control designs.⁸
• Additional tests (eg, standard electromyography, single-fiber electromyography, repetitive nerve stimulation, assays for acetylcholine receptor antibody [ARA]) are used to confirm the diagnosis of myasthenia gravis, but these tests usually are not available on an emergent basis.⁵ The ARA test offered the highest specificity of these additional tests since these other tests only reveal a disorder of neuromuscular conduction.⁸
• Patients with respiratory distress should have an evaluation of pulmonary function, providing that the patient is not in obvious respiratory failure. 
  • This evaluation includes pulse oximetry, a measure of pulmonary function (ie, peak expiratory flow, forced expiratory volume in 1 second [FEV1]), and ABG sampling to determine PCO₂ level.⁴
  • Evidence of hypoxemia, poor respiratory effort, or CO₂ retention is an indication for intubation and mechanical ventilation.⁴

Treatment

Prehospital Care

• Field personnel should recognize generalized muscle weakness of any etiology as a potential cause of respiratory failure.
• Patients with generalized weakness require transport to the hospital, and provisions for active airway intervention should be made en route.
• Patients in frank respiratory arrest should be intubated and ventilated prior to transport, if possible.
• Suctioning of pulmonary secretions may be required to adequately ventilate the patient.
• Supplemental oxygen is indicated in all cases, and intravenous access is desirable prior to initiating transport.

Emergency Department Care

Patients with myasthenia gravis (MG) who are in respiratory distress may be experiencing a myasthenic crisis or a cholinergic crisis. Before these possibilities can be differentiated, ensuring adequate ventilation and oxygenation is important. Patients with myasthenic crisis can develop apnea very suddenly, and they must be observed closely. Evidence of respiratory failure may be noted on ABG determination, pulmonary function tests, or pulse oximetry.

• Airway maneuvers
  • Open the airway by suctioning secretions after positioning the jaw and tongue.
  • Administer high-flow oxygen, and measure oxygen saturation by pulse oximetry.
  • If respirations remain inadequate, ventilate by bag-valve mask while preparing to intubate.
  • In the patient without an intact gag reflex, an oral airway may be placed.
  • Endotracheal intubation⁴
    • Rapid sequence intubation should be modified because depolarizing paralytic agents (eg, succinylcholine) have less predictable results in patients with myasthenia gravis. The relative lack of ACh receptors makes these patients relatively resistant to succinylcholine; therefore, higher doses must be used to induce paralysis. Once paralysis is achieved, it may be prolonged.
    • A rapid-onset nondepolarizing agent (ie, rocuronium, vecuronium) is the preferred paralytic agent for these patients. Although nondepolarizing agents delay the onset of paralysis, compared with succinylcholine, these medications do not result in unwanted prolonged paralysis.
    • Following paralysis, intubation is accomplished as usual. ABG sampling guides ventilator settings.
• Preliminary studies suggest that bilevel positive airway pressure (BiPAP) can prevent intubation in patients with myasthenic crisis without overt hypercapnia and should be considered in the patient who can be closely monitored.^4,9 Hypercapnia present at the time of BiPAP initiation predicted failure and the need to proceed to endotracheal intubation.¹⁰
• Once the airway is secured, investigation into the cause of the exacerbation of myasthenia gravis may proceed, with the most common reason for an exacerbation being inadequate treatment with cholinesterase inhibitors. Differentiation from cholinergic crisis can proceed as described above.
  • In less severely ill patients, oral pyridostigmine can be administered until clinical improvement is seen. The patient should be closely observed and monitored during this trial. Other reasons for the exacerbation can then be investigated. Infection: Although patients with myasthenia gravis can develop any common infection that can result in decompensation, the most likely source of infection is pulmonary. Cultures of blood, sputum, and urine may be indicated on an individual basis. Chest radiography is important in detecting pneumonia. Appropriate broad-spectrum antibiotics are indicated for sepsis and pneumonia. It is important to consider that fluoroquinolones and antibiotics may adversely affect cholinergic transmission in patients with myasthenia gravis, and these antibiotics should be avoided if possible.
  • Fever: Patients with myasthenia gravis are sensitive to high temperatures (core or ambient), and their muscle strength can improve when temperature is lowered with cooling measures or antipyretics.
• Reports indicate that thymectomy results in complete remission of the disease in up to 35% of patients.

Consultations

• Emergent consultation with a neurologist is indicated.
• Patients with severe exacerbations requiring intubation and mechanical ventilation are managed in an intensive care setting with appropriate consultation.

Medication

Myasthenia gravis (MG) is controllable with cholinesterase-inhibiting medications. Edrophonium primarily is used as a diagnostic tool because its half-life is so brief. Pyridostigmine is used for long-term maintenance. High doses of corticosteroids commonly are used to suppress autoimmunity. Patients with myasthenia gravis also may be taking other immunosuppressive drugs (eg, azathioprine, cyclosporine). Adverse effects of these medications must be considered in assessing the clinical picture. Bronchodilators may be useful in overcoming the bronchospasm associated with a cholinergic crisis.

Cholinesterase inhibitors

These agents increase the amount of available ACh at the myoneural junction by inhibiting the degradation of ACh. A wide variability exists in the effective dose, depending on the severity and current activity of the disease and the presence of other factors that influence cholinergic transmission (eg, certain antibiotics, antidysrhythmic medications, impaired renal function).^7,11

Most patients are able to titrate the dosage of their medication to control the symptoms of the disease, but severe exacerbations can occur in patients with previously well-controlled disease.¹¹

Edrophonium (Tensilon, Enlon, Reversol)

Primarily used as diagnostic tool to predict the response to longer-acting cholinesterase inhibitors. As with other cholinesterase inhibitors, it decreases metabolism of ACh, increasing the cholinergic effect at the myoneural junction (Pacuzzi, 2001).

Dosing

Adult

Test dose: 0.1-0.2 mg IV; 1-2 mg IV if no response; 5-9 mg slow IV if still no response (Pacuzzi, 2001)

Pediatric

0.2 mg/kg slow IV; not to exceed 10 mg

Interactions

Atropine, nondepolarizing muscle relaxants, procainamide, and quinidine may decrease effects of edrophonium; succinylcholine, digoxin, IV acetazolamide, neostigmine, and physostigmine may increase effects

Contraindications

Documented hypersensitivity; GI or GU obstruction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Bronchial asthma and those receiving a cardiac glycoside; overdose may cause cholinergic crisis, which may be fatal; IV atropine should be readily available for treatment of cholinergic reactions; patients with cholinergic crisis respond to edrophonium by increasing salivation and bronchopulmonary secretions, diaphoresis, and gastric motility (ie, SLUDGE syndrome)

Pyridostigmine (Mestinon, Regonol) (Keesey, 2004; Saperstein, 2004)

Acts in smooth muscle, CNS, and secretory glands where it blocks the action of ACh at parasympathetic sites. Longer-acting cholinesterase inhibitor used for maintenance therapy.

Dosing

Adult

60 mg PO tid initially followed by a maintenance dose of 60-1500 mg/d
2 mg IV/IM q2-3h; or 1/30 of PO dose

Pediatric

7 mg/kg/d PO in 5-6 divided doses
0.05-0.15 mg/kg/dose IV/IM; dose must be individualized

Interactions

Pyridostigmine increases effects of depolarizing neuromuscular blockers; increases toxicity of edrophonium

Contraindications

Documented hypersensitivity; GI or GU obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Bronchial asthma; those receiving a cardiac glycoside; overdose may cause cholinergic crisis, which may be fatal; IV atropine should be readily available for treatment of cholinergic reactions

Neostigmine (Prostigmin)

Longer-acting cholinesterase inhibitor that can be used when edrophonium is effective. Inhibits destruction of ACh by acetylcholinesterase, which facilitates the transmission of impulses across the myoneural junction.

Dosing

Adult

15 mg/dose PO q3-4h; not to exceed 375 mg/d
0.5-2.5 mg IV/IM/SC q1-3h; not to exceed 10 mg/d

Pediatric

2 mg/kg/d PO divided q3-4h
0.01-0.04 mg/kg IV/IM/SC q2-4h

Interactions

Atropine antagonizes muscarinic effects of neostigmine; conversely, the effects of neuromuscular agents are increased

Contraindications

Documented hypersensitivity; GI or GU obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Epilepsy, asthma, bradycardia, hyperthyroidism, cardiac arrhythmias, or peptic ulcer; anticholinesterase insensitivity can develop for brief or prolonged periods

Corticosteroids

These agents are used to treat idiopathic and acquired autoimmune disorders. They have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

There is no significant evidence from RCTs to show the effectiveness of steroids whatever the severity of the disease, the dosage, or the route of administration in the use for MG.¹²  “However, numerous observational studies strongly support the efficacy of corticosteroid and therefore many experts conclude that corticosteroids are the mainstay of the treatment for MG.”¹²

Prednisone (Deltasone, Orasone, Sterapred)

Effective in decreasing the severity of exacerbations of MG by suppressing the formation of autoantibodies. However, clinical effects often are not seen for several weeks. Some experts believe that the long-term administration of prednisone is beneficial, but others use the drug only during acute exacerbations to limit the adverse effects of chronic steroid use. Lowest effective dose should be used on a long-term basis. Because of the delayed onset of effects, steroids are not recommended for routine use in the ED. Patients who are taking long-term moderate or high doses of steroids may have suppressed adrenal function and may require stress doses (hydrocortisone 100 mg IV in an adult) during acute exacerbations (Saperstein, 2004).

Dosing

Adult

50-100 mg PO qd (Schneider-Gold, 2005)

Pediatric

1-2 mg/kg PO qd

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use (Richman, 2003)

Methylprednisolone (Solu-Medrol)

May be used in place of prednisone in patients who are intubated and in those unable to tolerate oral intake. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dosing

Adult

60 mg IV q6-8h

Pediatric

1-2 mg/kg IV q6-8h

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin lesions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use (Richman, 2003)

Beta-agonist bronchodilators

These agents are used to alleviate the respiratory distress and bronchospasm resulting from cholinergic medications used to treat myasthenia gravis.

Albuterol, salbutamol (Proventil, Ventolin)

Standard unit doses of beta-agonist nebulizer treatment may improve respirations in a cholinergic crisis. Continuous beta-agonist nebulizer treatment may be indicated in severe cases. Otherwise, the standard dosing regimen of 2 puffs from a metered dose inhaler or 2.5-5 mg nebulized q4-6h often will suffice in achieving bronchodilation.

Dosing

Adult

2.5-5 mg nebulized in isotonic sodium chloride solution q4-6h; titrate to desired effect

Pediatric

<1 year: Not established
>1 year: 0.05-0.15 mg/kg nebulized q4-6h

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, tricyclic antidepressants, and sympathomimetic agents

Contraindications

Documented hypersensitivity; severe tachycardia

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Anticholinergic bronchodilators

These agents cause the reversal of cholinergic medication effects that induce bronchospasm. These drugs can act synergistically or independently with beta-agonists to produce bronchodilation. They are quaternary amines, and they are poorly absorbed across the pulmonary epithelium. As a result, they have minimal systemic side effects.

Ipratropium (Atrovent)

Chemically related to atropine. Has antisecretory properties, and when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa.

Dosing

Adult

20-40 mcg through inhalation

Pediatric

Administer as in adults

Interactions

Drugs with anticholinergic properties, such as dronabinol, may increase toxicity; albuterol increases effects of ipratropium

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Not indicated for acute episodes of bronchospasm; caution in narrow-angle glaucoma, prostatic hypertrophy, and bladder neck obstruction

Glycopyrrolate (Robinul)

Acts in smooth muscle, CNS, and secretory glands where it blocks the action of acetylcholine at parasympathetic sites.

Dosing

Adult

4.4 mcg/kg IM

Pediatric

<12 years: Not recommended
>12 years: Administer as in adults

Interactions

Levodopa decreases glycopyrrolate effects; conversely, amantadine and cyclopropane increase glycopyrrolate toxicity

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; tachycardia; ulcerative colitis; paralytic ileus; acute hemorrhage; Down syndrome

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Glycopyrrolate may increase chances of developing megacolon, hyperthyroidism, CHF, CAD, hiatal hernia, and BPH

Immunomodulators

Most of the studies reviewed had few participants and found it difficult to assess the efficacy of the addition of immunosuppressive therapy to the previous regimens of corticosteroids and cholinesterase inhibitors. As a result “good RCT data on the use of immunosuppressive agents as monotherapy or dual therapy with steroids are absent.”¹³ However, limited evidence indicates that ciclosporin and cyclophosphamide improve symptoms in MG and decrease the amount of corticosteroid usage. “The more common drugs used in MG- azathioprine, MMG, and tacrolimus, show no clear benefit in use.”¹³

Azathioprine (Imuran)

Imidazolyl derivative of 6-mercaptopurine. Many of the biological effects are similar to those of parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 h after taken.
Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. Mechanism whereby azathioprine affects autoimmune diseases unknown. Works primarily on T cells. Suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. Works very slowly; may require 6-12 mo of trial prior to effect. Up to 10% of patients may have idiosyncratic reaction disallowing use. Do not allow WBC count to drop below 3000/mL or lymphocyte count to drop below 1000/mL.
Available in tablet form for oral administration or in 100-mg vials for IV injection.

Dosing

Adult

1 mg/kg/d PO initial dose; increase gradually to desired effect, usually 2-3 mg/kg/d qd; may be divided ac if adverse GI effects are bothersome
Some experts advocate dose increases until RBC MCV >100 fL; do not increase dose if patient develops leukopenia

Pediatric

Maintenance: 1-2 mg/kg/d PO

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated

Cyclosporine (Neoral, Sandimmune)

An 11-amino acid cyclic peptide and natural product of fungi. Acts on T-cell replication and activity.
Specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of cell cycle suggested.
Binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin 2 and the subsequent recruitment of activated T cells.
Has about 30% bioavailability, but there is marked interindividual variability. Specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.
Suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.

Dosing

Adult

Clinical and immunological effects correlate with serum concentration, and dose usually adjusted to achieve trough serum level of 100-200 ng/mL (as determined by HPLC)
4-10 mg/kg/d PO in 2-3 divided doses has been used

Pediatric

Administer as in adults

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; methylprednisolone and cyclosporine mutually inhibit one another resulting in increased plasma levels of each drug

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Immune Globulins

Usually used on admitted patients and rarely started in the ED. IVIG is recommended for MG crisis, in patients with severe weakness poorly controlled with other agents, or in lieu of plasma exchange at a dose of 1 g/kg.^14,3 RCT demonstrated the efficacy of IVIG versus placebo in moderate or severe MG worsening into crisis, but does not exhibit value in mild disease.¹⁵  Data do not support or refute a role for IVIG in chronic MG.³ To be included in the studies with IVIG, patients were required to be auto-antibody positive. Therefore, the use of IVIG in a seronegative patient is not supported by the literature.³

Immune globulin intravenous (Carimune, Gammagard S/D, Gammar-P, Gamunex, Polygam S/D)

High-dose IVIg successfully treats MG. Like plasma exchange, has rapid onset of action, but effects last only short time. Best used in crisis management (eg, myasthenic crisis and perioperative period).

Dosing

Adult

1 g/kg slow IV infusion over 2-5 d

Pediatric

Administer as in adults

Interactions

Globulin preparation may interfere with immune response to live-virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG (use an IgA-depleted product if deficient, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Follow-up

Further Inpatient Care

• Patients who present to the ED with myasthenic or cholinergic crisis or with increasing muscle weakness of a less severe degree require admission to a monitored setting because their course is unpredictable.¹⁶   
• Patients with complications of the disease or treatment are admitted to a level of care corresponding to the nature and severity of the complication.  
• Patients with pneumonia should be admitted because they often are taking immunosuppressing medications and are at a high risk for aspiration pneumonia.  
  • Plasmapheresis has been found to be an effective short-term treatment of acute exacerbations of myasthenia gravis.¹⁷ Plasmapheresis removes circulating antibodies including the autoimmune antibodies responsible for the disease.
  • Clinical improvement takes several days to occur and lasts up to 3 weeks.¹¹ Because of the delayed onset of beneficial effects, plasmapheresis has limited utility in the ED setting.
• Immunotherapy with intravenous gamma globulin appears to diminish the activity of the disease for unknown reasons. The benefit begins within 2 weeks and may last for several months. Approximately 65% of patients with myasthenia gravis respond to intravenous gamma globulin.³
• Thymectomy is associated with clinical improvement in 85% of cases, and 35% of patients appear to have complete remission.¹   
  • Patients past the age of puberty and younger than 50 years should have elective thymectomy as part of their treatment.¹⁸
  • The need for anticholinesterase medication fluctuates significantly in the postoperative period but overall is less than it was prior to thymectomy.²

Further Outpatient Care

• All patients with myasthenia gravis should be referred to a neurologist for ongoing care.

Inpatient & Outpatient Medications

• Pyridostigmine
• Prednisone
• Azathioprine
• Cyclosporine

Transfer

• Patients with severe exacerbations of myasthenia gravis or cholinergic crisis should be transferred only after they have been stabilized and the airway has been secured.
• Persistent hypoxemia, hypercarbia, dysrhythmias, or unstable vital signs make transfer unwise, unless appropriate care cannot be delivered at the original facility.

Complications

• The most common severe complication of myasthenia gravis is respiratory failure, which often presents with the rapid deterioration of respiratory effort that ultimately results in apnea.
• Hypoxemia and respiratory acidosis often render the patient somnolent or unresponsive, in which case a clear history may be difficult to obtain.
• Pneumonia is a common complication in patients with myasthenia gravis and often is the cause of death in fatal cases.
• Community-acquired pneumonia often is more severe in patients with myasthenia gravis because of their marginal respiratory function, inability to cough effectively, and inability to maintain tachypnea for long periods. Other types of pneumonia are more common in patients with myasthenia gravis because these patients have a higher risk of aspiration. They also have relative immunocompromise because of immunosuppressive medications. Consequently, these patients are at risk for aspiration pneumonia with mixed aerobic and anaerobic organisms, as well as unusual organisms associated with immunocompromise (eg, Pseudomonas, other gram-negative organisms, fungi).
• Chronic respiratory insufficiency
• Medication effects  
  • Excessive use of cholinesterase inhibitors can result in a cholinergic crisis.
  • Chronic use of corticosteroids can result in a large number of serious complications, including opportunistic infection, GI bleeding, hyperglycemia, osteoporosis, aseptic necrosis, and cataract formation.
  • Other immunosuppressive medications increase the incidence of opportunistic infections, renal insufficiency, and hypertension.

Prognosis

• Given the current treatment that combines cholinesterase inhibitors, immunosuppressive drugs, plasmapheresis, immunotherapy, and supportive care in an ICU setting (when appropriate), most patients with myasthenia gravis have a near-normal life span.
• Thymectomy results in complete remission of the disease in a number of patients. However, the prognosis is highly variable, ranging from remission to death.
• The mortality rate is probably less than 4%.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize impending respiratory failure
• Failure to institute appropriate monitoring and treatment, resulting in precipitous decompensation and death
• Myasthenia gravis (MG) can mimic other diagnoses in elderly persons and vice versa. Examples of such pathology include diagnoses such as congestive heart failure, pulmonary embolism, and acute myocardial infarction.

Special Concerns

• Myasthenia gravis can be transmitted vertically from an affected mother to her fetus.
• Transplacental transfer of maternal autoantibodies against the ACh receptor results in the syndrome of neonatal myasthenia.
• Infants affected by this condition are floppy at birth, and they display poor sucking, muscle tone, and respiratory effort. They often require respiratory support and intravenous feeding as well as monitoring in a neonatal ICU.
• As the transferred maternal antibodies are metabolized over several weeks, symptoms abate and the infants develop normally.
• Treatment with cholinesterase inhibitors is effective in this age group as well. However, the dosage must be carefully titrated to clinical effect.
• Approximately 10% of infants of mothers with myasthenia gravis develop clinical signs of neonatal myasthenia gravis.
• Although most of these cases are apparent within 48 hours, the presentation may be delayed as long as 10 days after delivery. This delayed presentation should be kept in mind when evaluating newborn infants in the ED for weakness or poor feeding.

References

1. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. Feb 2008;37(2):141-9. [Medline].

2. Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. Apr 2004;29(4):484-505. [Medline].

3. [Best Evidence] Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. Jan 23 2008;CD002277. [Medline].

4. Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Semin Neurol. Mar 2004;24(1):75-81. [Medline].

5. Meriggioli MN, Sanders DB. Advances in the diagnosis of neuromuscular junction disorders. Am J Phys Med Rehabil. Aug 2005;84(8):627-38. [Medline].

6. Pascuzzi RM. Pearls and pitfalls in the diagnosis and management of neuromuscular junction disorders. Semin Neurol. Dec 2001;21(4):425-40. [Medline].

7. Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology. Dec 23 2003;61(12):1652-61. [Medline].

8. Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscul Disord. Jul 2006;16(7):459-67. [Medline].

9. Mazia CG, De Vito EL, Varela M. BiPAP in acute respiratory failure due to myasthenic crisis may prevent intubation. Neurology. Jul 8 2003;61(1):144; author reply 144. [Medline].

10. Seneviratne J, Mandrekar J, Wijdicks EF, Rabinstein AA. Noninvasive ventilation in myasthenic crisis. Arch Neurol. Jan 2008;65(1):54-8. [Medline].

11. Saperstein DS, Barohn RJ. Management of myasthenia gravis. Semin Neurol. Mar 2004;24(1):41-8. [Medline].

12. [Best Evidence] Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev. Apr 18 2005;CD002828. [Medline].

13. [Best Evidence] Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev. Oct 17 2007;CD005224. [Medline].

14. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. May 19 2004;291(19):2367-75. [Medline].

15. [Best Evidence] Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. Mar 13 2007;68(11):837-41. [Medline].

16. Rabinstein AA, Wijdicks EF. Warning signs of imminent respiratory failure in neurological patients. Semin Neurol. Mar 2003;23(1):97-104. [Medline].

17. Pascuzzi RM. The edrophonium test. Semin Neurol. Mar 2003;23(1):83-8. [Medline].

18. Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. Jun 30 2001;357(9274):2122-8. [Medline].

19. Evoli A, Batocchi AP, Tonali P. A practical guide to the recognition and management of myasthenia gravis. Drugs. Nov 1996;52(5):662-70. [Medline].

20. Lacomis D. Myasthenic crisis. Neurocrit Care. 2005;3(3):189-94. [Medline].

Keywords

myasthenia gravis, myasthenic crisis, muscle weakness, autoimmune disorder of peripheral nerves, MG, acetylcholine nicotinic postsynaptic receptors, ACh, cholinergic nerve conduction, reduced muscle strength, autoantibodies, cholinergic crisis

Contributor Information and Disclosures

Author

William D Goldenberg, MD, Clinical Assistant Instructor, Department of Emergency Medicine, Kings County Hospital Center and SUNY Downstate Medical Center
William D Goldenberg, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Richard H Sinert, DO, Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center
Richard H Sinert, DO is a member of the following medical societies: American College of Physicians and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Eric M Kardon, MD, FACEP, Attending Emergency Physician, Georgia Emergency Medicine Specialists; Physician, Division of Emergency Medicine, Athens Regional Medical Center
Eric M Kardon, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: WebMD Salary Employment

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Edward Newton, MD, and Nick Testa, MD, to the development and writing of this article.

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