AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 intermittent generalized weakness. The most important aspect of MG for emergency physicians is the detection and management of the myasthenic crisis, which is described below.

Pathophysiology

Autoantibodies 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 MG is not entirely clear, but 75% of patients with MG 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 MG 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.

Mortality/Morbidity

• In the past, untreated MG carried a mortality rate of 30-70%. In the modern era, patients with MG have a near-normal life expectancy.
• Morbidity results from intermittent impairment of muscle strength, which may cause aspiration, increased incidence of pneumonia, and falls. 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 MG at a young age is slightly more common in Asians than in other races.

Sex

• The male-to-female ratio 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).
• The male-to-female ratio in children with MG and another autoimmune condition is 1:5.

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 MG 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, corticosteroids

• Thyroid disorders may be seen in as many as 10% of patients with MG, and symptoms of hyperthyroidism or hypothyroidism may be present.
• Rarely does a patient present with undiagnosed MG. However, if this situation does occur, typical complaints are of generalized weakness and reduced exercise tolerance that improves with rest. Patients with MG 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 involving the eyelids and extraocular muscles resulting in ptosis diplopia. The involvement of the facial muscles results in changes in expression and speech, while involvement of the pharyngeal muscles results in progressive difficulty with mastication and deglutition.
• In 20% of patients, MG affects the bulbar muscles alone.
• 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 MG can present with a wide range of signs and symptoms, depending on the severity of the disease.

• Mild presentations of MG 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 MG 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.

• Respiratory distress
• • The patient's ability to generate adequate ventilation and to clear bronchial secretions are of utmost concern with severe exacerbations of MG.

  • 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 MG 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.

  • 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 MG is unknown, but it is clearly an autoimmune disease in which the specific antibody completely has been characterized.
• 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 case of MG, but the triggering antigen has not yet been identified.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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 MG.
• CT scan or MRI of the chest is highly accurate in detecting thymoma. Every patient with MG 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 MG and in distinguishing myasthenic crisis from cholinergic crisis. A positive response is not completely specific for MG 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. If no improvement occurs, an additional dose of 5 mg can be administered to total no more than 10 mg.

  • 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 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). 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 MG.

  • The effects of edrophonium are brief, and repeated doses may be required before oral anticholinesterase medication can take effect.

  • 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.

• Ice pack test
• • Cooling may improve neuromuscular transmission. In a patient with MG 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.

  • The test is thought to be positive in about 80% of patients with ocular myasthenia.

• Additional tests (eg, standard electromyography, single-fiber electromyography, assays for acetylcholine receptor antibody [ARA]) are used to confirm the diagnosis of MG, but these tests usually are not available on an emergent basis.
• 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.

  • Evidence of hypoxemia, poor respiratory effort, or CO₂ retention is an indication for intubation and mechanical ventilation.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 in 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 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 intubation
• • Rapid sequence intubation should be modified because depolarizing paralytic agents (eg, succinylcholine) have less predictable results in patients with myasthenia. 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.



• Once the airway is secured, investigation into the cause of the exacerbation of MG 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 MG 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 MG, and these antibiotics should be avoided if possible.
  
  
  
  • Fever: Patients with MG 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 MG 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.

Drug Category: 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.

Drug Category: Beta-agonist bronchodilators

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

Drug Category: 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.

Drug Category: Cholinesterase inhibitors

These agents increase the amount of available ACh at the myoneural junction by inhibiting the degradation of ACh. There is a wide variability 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).

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients who present to the ED with myasthenic or cholinergic crisis or increasing muscle weakness of a less severe degree require admission to a monitored setting because their course is unpredictable.
• 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 for acute exacerbations of MG.
• • 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. 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 MG respond to intravenous gamma globulin.
• Thymectomy is associated with clinical improvement in 85% of cases, and 35% of patients appear to have complete remission.
• • Patients past the age of puberty and younger than 50 years should have elective thymectomy as part of their treatment.

  • The need for anticholinesterase medication fluctuates significantly in the postoperative period but overall is less than it was prior to thymectomy.

Further Outpatient Care

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

In/Out Patient Meds

• Pyridostigmine
• Prednisone
• Azathioprine
• Cyclosporine

Transfer

• Patients with severe exacerbations of MG 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 MG 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 MG 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 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 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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

• MG 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 MG develop clinical signs of neonatal MG.
• 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. May 19 2004;291(19):2367-75. [Medline].
• 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].
• Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Semin Neurol. Mar 2004;24(1):75-81. [Medline].
• Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. Apr 2004;29(4):484-505. [Medline].
• Lacomis D. Myasthenic crisis. Neurocrit Care. 2005;3(3):189-94. [Medline].
• Latov N, Chaudhry V, Koski CL, et al. Use of intravenous gamma globulins in neuroimmunologic diseases. J Allergy Clin Immunol. Oct 2001;108(4 Suppl):S126-32. [Medline].
• 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].
• Mehta S. Neuromuscular disease causing acute respiratory failure. Respir Care. Sep 2006;51(9):1016-21; discussion 1021-3. [Medline].
• Palace J, Vincent A, Beeson D. Myasthenia gravis: diagnostic and management dilemmas. Curr Opin Neurol. Oct 2001;14(5):583-9. [Medline].
• Pascuzzi RM. The edrophonium test. Semin Neurol. Mar 2003;23(1):83-8. [Medline].
• Pascuzzi RM. Pearls and pitfalls in the diagnosis and management of neuromuscular junction disorders. Semin Neurol. Dec 2001;21(4):425-40. [Medline].
• Rabinstein AA, Wijdicks EF. Warning signs of imminent respiratory failure in neurological patients. Semin Neurol. Mar 2003;23(1):97-104. [Medline].
• Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology. Dec 23 2003;61(12):1652-61. [Medline].
• Rivner MH. Steroid treatment for myasthenia gravis: steroids are overutilized. Muscle Nerve. Jan 2002;25(1):115-7. [Medline].
• Saperstein DS, Barohn RJ. Management of myasthenia gravis. Semin Neurol. Mar 2004;24(1):41-8. [Medline].
• Scherer K, Bedlack RS, Simel DL. Does this patient have myasthenia gravis?. JAMA. Apr 20 2005;293(15):1906-14. [Medline].
• Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. Jun 30 2001;357(9274):2122-8. [Medline].

Article Last Updated: Mar 14, 2007