Keywords

acetylcholine, dysphagia, edrophonium chloride, myasthenia gravis, myasthenic crisis, neuromuscular junction, skeletal muscle fatigue

 

Authors

  1. Vacca, Vincent M. Jr. MSN, RN, CCRN, SCRN, ENLS

Abstract

Abstract: Myasthenia gravis (MG) is the most commonly encountered autoimmune disease of the postsynaptic neuromuscular junction of skeletal muscles, affecting an estimated 700,000 individuals worldwide.1-3 MG has a variable age of onset, pattern of muscle involvement, severity, and clinical course. Approximately 15% to 20% of patients with MG will experience a myasthenic crisis (MC), typically within 2 years of diagnosis, which can lead to respiratory muscle compromise.4-6 Nurses must be knowledgeable about this disease and prepared to assist with pharmacologic testing and/or MC to ensure maximum safety for patients with MG before, during, and after evaluation.

 

Article Content

Myasthenia gravis (MG) is the most commonly encountered autoimmune disease affecting the postsynaptic neuromuscular junction (NMJ) of skeletal muscles. The number of individuals affected by MG has increased over the past 2 decades because of a combination of longer lifespans and earlier diagnosis.1,2 Of the estimated 700,000 people worldwide with MG, women are affected twice as often as men.1-3 However, a bimodal age distribution is common, affecting more women than men during the second and third decades of life, and more men than women during the sixth and seventh decades.1

  
Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

Caused by autoantibodies blocking nicotinic acetylcholine receptors (nAChRs) located on the postsynaptic motor endplate in the NMJ, MG leads to localized or generalized painless skeletal muscle fatigue and weakness.4,5 (See Physiology of the NMJ.) The characteristic pattern of muscle fatigue and weakness typically involves ocular, facial, pharyngeal, and proximal limb muscles.5

 

Although variable with respect to age of onset, pattern of muscle involvement, severity, and clinical course, approximately 15% to 20% of patients with MG will experience a myasthenic crisis (MC), typically within 2 years of diagnosis.4,6 An MC results from worsening muscle fatigue and weakness leading to respiratory muscle compromise requiring endotracheal intubation and mechanical ventilation or noninvasive positive pressure ventilation to avoid intubation.5

 

Pathophysiology

In MG, autoantibodies impair neuromuscular transmission by several mechanisms including blocking nAChRs, damaging cell membranes, and accelerating degradation of receptor sites. This becomes clinically evident with signs and symptoms such as fluctuating fatigue and painless muscle weakness, which are reported in more than 75% of patients with MG.7,8 Fatigue and muscle weakness worsen with activity and time.2,9 Skeletal muscles in the ocular and facial distribution are most commonly involved, so MG typically presents with a combination of ptosis and diplopia.1

 

When facial and pharyngeal muscles are involved, speech and swallowing can be affected, leading to dysarthria, dysphagia, and risk for aspiration.1,6 Dysphagia, because of the involvement of the pharyngeal and striated esophageal muscles, affects 30% to 60% of individuals with MG. In some cases, dysphagia may be the sole presenting symptom. Because MG is treatable, it should be considered in individuals with dysphagia, especially older adults, even in the absence of typical ocular and facial signs and symptoms.1

 

Although there are two recognized forms of MG (generalized and ocular), MG can also be subdivided based on the profile of serum autoantibodies, the age of onset, the presence or absence of thymic pathology, and the distribution of clinical weakness.10 For example, three defined subtypes of MG include:

 

1. Early-onset MG (predominantly in women under age 50)

 

2. Late-onset MG (more frequently seen in men over age 50)

 

3. MG associated with thymoma.7

 

 

The relationship of MG to the thymus gland has been recognized for almost 100 years.8 (See the section on MG and the thymus.)

 

Diagnosis

Diagnosing MG begins with patient history and clinical presentation and is confirmed by a variety of nonpharmacologic, pharmacologic, serologic, and electrodiagnostic tests.1

 

When suspecting MG based on the presence of ptosis and diplopia, application of an ice pack for 2 minutes can be diagnostic. The physiologic theory behind the ice-pack test is that by cooling the skeletal muscle fibers, acetylcholinesterase activity is inhibited, resulting in more available ACh at the NMJ that leads to greater muscle depolarization, strength, and improvement in ptosis.11 One study showed that the positive predictive value of the ice-pack test was 88%, and the negative predictive value was 95%.12

 

Resolution of ptosis has been reported in over 90% of patients with ocular muscle weakness associated with MG after the ice-pack test. The ice pack should not be used for more than 2 minutes because it may be uncomfortable for the patient or damage tissues, and a reduction of muscle fiber temperature below 71.6[degrees] F (22[degrees] C) will reduce the contractile force of the muscle and create potential false-negatives.13 Although ptosis and diplopia are presenting symptoms in the majority of patients with MG, approximately half of these individuals will go on to develop generalized muscle weakness.14

 

Pharmacologic diagnosis

A diagnostic pharmacologic test for MG is I.V. administration of the acetylcholinesterase inhibitor edrophonium chloride.1 Edrophonium is a rapid-acting and quickly removed drug that prevents breakdown of ACh by competitively inhibiting acetylcholinesterase at the NMJ. This results in an increase in synaptic ACh, providing maximum saturation of the limited available and functional nAChRs, resulting in a temporary improvement in muscle strength. Nurses must be knowledgeable and prepared to assist with edrophonium pharmacologic testing for MG to ensure maximum safety for patients before, during, and after evaluation.15

 

Administered as an I.V. injection, edrophonium rapidly improves the signs and symptoms of ocular MG. Edrophonium onset of action begins within 30 to 60 seconds after injection, and the effects resolve within 5 to 10 minutes.15 Ptosis and ocular motility deficits should be assessed, documented, and (if permitted) photographed, before and after administration. Initially, a test dose is given, and if there is no idiosyncratic reaction, a larger dose is injected after 2 minutes. If eyelid position, ocular alignment, or eye motility do not improve within 1 minute, additional doses are injected, preferably in small increments, waiting 45 to 60 seconds between injections. However, large doses often do not produce a positive result if lower doses are ineffective.15

 

The test is positive if muscle strength improves within 1 minute of any dose increment and providers do not need to administer any further edrophonium. Paradoxical worsening of ocular motility has been reported in up to 25% of cases because of a depolarizing block caused by the excess of ACh. The edrophonium test is best evaluated by observing for increased strength of a single muscle, such as the levator, rather than changes in relative strength of multiple muscles, as with ocular alignment.13

 

Edrophonium can cause various adverse reactions from increased muscarinic activity resulting from an excess of ACh. These include lacrimation, salivation, hyperhidrosis, abdominal cramping, and diarrhea. More serious adverse reactions include bradycardia, hypotension, bronchospasm, and syncope. Appropriate personnel and clinical location are essential for safety when testing with edrophonium. Emergency equipment including a bag-valve-mask and anticholinergic medications such as atropine should be readily available during testing. The testing should be carried out with continuous BP, SpO2, and cardiac monitoring. The test is contraindicated in patients with bronchial asthma and cardiac diseases; sensitivity is 95% in generalized MG and approximately 86% for ocular MG.13

 

Serologic diagnosis

Autoantibodies to the nAChRs are present in approximately 85% of individuals with generalized muscle weakness and 50% of those with purely ocular involvement. The autoantibodies can be measured (normal level, <0.1 nmol/L).6,7 The vast majority of patients with generalized MG (~85%) and pure ocular MG (~50%) will have antibodies to the skeletal muscle nAChR.16

 

Approximately 40% to 70% of seronegative individuals have antibodies against muscle-specific receptor tyrosine kinase (MuSK).16 Studies have reported that up to 50% of AChR- and MuSK-double seronegative patients also have low-density lipoprotein receptor-related protein 4 (LRP4) antibodies. Triple-seronegative MG individuals (that is, patients who have no detectable AChR, MuSK, or LRP4 antibodies) have serum antibodies against agrin, and represent approximately 2% to 3% of all MG patients.17

 

Some of these seronegative individuals have low-affinity antibodies to nAChRs that cannot be detected in standard assays. Antibodies against MuSK are present in about 40% of seronegative generalized MG cases, and sometimes antibodies against LRP4 are detectable.16,17

 

Previous studies suggest a critical role of the agrin/LRP4/MuSK pathway in formation of the NMJ. The process requires neuronal agrin, which acts by binding to LRP4 to stimulate MuSK. This makes LRP4 essential for maintaining the structural and functional integrity of the NMJ. Loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms.18

 

Electrophysiologic diagnosis

Repetitive nerve stimulation (RNS) and single-fiber electromyography (SFEMG) are the two electrophysiologic tests used to diagnose MG. RNS is positive in 75% of generalized MG cases and 50% of ocular MG cases. SFEMG is the most sensitive test for diagnosis of seronegative MG (between 95% and 99% sensitive); however, this test is not widely available and is more technically demanding than RNS.19,20

 

Treatment

Because MG is a heterogeneous disease, no single treatment approach is best for all patients.19 Current treatment options include acetylcholinesterase inhibitors, which are effective in enhancing stimulation of functionally competent and available nAChRs. However, acetylcholinesterase inhibitors such as pyridostigmine bromide or neostigmine do not alter the underlying autoimmune process, and therefore do not prevent further destruction of functional nAChRs and progression of the disease. Immunomodulator medications such as steroids and monoclonal antibodies may improve the underlying autoimmune process and reduce or prevent progression of the disease.6

 

A major factor in improving the prognosis for patients with MG has been the increased use of immunomodulating therapies. Plasmapheresis, also known as plasma exchange (PLEX), and intravenous immune globulin (IVIG) are short-term effective treatments for life-threatening signs and symptoms such as respiratory insufficiency and significant bulbar dysfunction. PLEX and IVIG can also be considered when other treatments are ineffective, in preparation for surgery, and prior to beginning corticosteroid therapy if determined necessary to prevent or minimize exacerbations. Treatment with PLEX or IVIG is also dependent on availability. They are equally effective in treating severe generalized MG, but are most effective in patients who do not improve, are worsening, or have severe complications. Response to treatment generally occurs after 2 days. The proposed mechanism of action for both PLEX and IVIG is rapid depletion of pathogenic antibodies from plasma, which causes an osmotic equilibration between extra and intravascular spaces, leading to reduction of antibodies in the NMJ.15

 

A small percentage of individuals with generalized MG are categorized as refractory. These individuals experience relapse when immunotherapy is reduced or stopped, their symptoms do not respond to immunotherapy, or they suffer serious complications associated with immunotherapy.21 IVIG can be considered maintenance therapy for patients with refractory MG.19 Corticosteroids are used in conjunction with IVIG and PLEX. Because it takes 2 weeks to work, high-dose prednisone may be initiated concurrently with IVIG or PLEX; its timing coincides with the waning effects of PLEX and/or IVIG. Cyclosporine may be considered after initiation of IVIG or PLEX in patients who cannot tolerate or who are refractory to corticosteroids, but providers must consider that the onset of action of cyclosporine is 1 to 2 months.15

 

MG and the thymus

Thymomas or thymic tumors are present in 10% to 15% of patients with MG. Up to 70% of patients with MG have hyperplastic thymus gland changes. A thymoma is associated with a worse prognosis in MC (discussed in the next section).3,22,23 Providers should perform a chest computed tomography scan of patients with MG to exclude thymoma because it is more sensitive than chest X-rays in delineating anterior mediastinal masses. Magnetic resonance imaging does not improve diagnostic sensitivity, and iodinated contrast agents (ICA), perhaps due to osmolality of the ICA, may worsen myasthenic weakness.15,24

 

Thymectomy is a recommended treatment for MG based on evidence that supports a central role of the thymus gland in the pathogenesis of the disease.3 It is recommended that nearly all patients with MG should undergo tumor removal, including all thymus tissue, even though it may not result in MG improvement. If the thymoma is incompletely resected, an interdisciplinary treatment approach is warranted, including radiotherapy and chemotherapy.22 Thymectomy for MG is an elective procedure because of the long delay in effect onset. Patients should be stable and able to cope with factors such as postoperative pain that can compromise respiratory function.3

 

Patients with nonthymomatous MG can consider thymectomy as an option for potential improvement or disease remission.3,23,25 In August 2016, the results of the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) prospective multicenter randomized trial comparing extended transsternal thymectomy and prednisone versus prednisone without surgery as primary treatment for MG were published.22 MGTX clearly showed that patients can expect a reasonable probability that doses of prednisone will be reduced by one-third, and symptoms on average will be less severe. They can expect fewer hospitalizations for exacerbations of their disease. Most important, patients have a 67% chance of achieving minimal symptom manifestation status and avoiding an MC within a year after thymectomy, as compared with a 37% chance after a year or a 47% chance after 3 years of medical therapy alone.22,23

 

Myasthenic crisis

Rapid worsening of MG can lead to a serious and life-threatening situation: an MC.3 An MC is a true neurologic emergency.2,9,15,25 It is characterized by severe weakness of the bulbar (innervated by cranial nerves) and/or respiratory muscles, enough to cause respiratory failure that requires artificial airway or ventilatory support. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours are in MC.15

 

Although data are limited, the proportion of patients with MG who experience at least one MC may be as high as 20%.26 In many patients who present with MC, it is the first manifestation of MG. Most MCs occur in the first few years after MG diagnosis, when the disease is in its most active phase.26

 

Overall, women are twice as likely as men to experience an MC. However, women under age 55 are affected four times as often as men, and after age 55, an MC affects women and men equally.25

 

Postoperative patients are also frequently affected by an MC, where exacerbation of muscle weakness causes unexpected prolonged intubation and mechanical ventilation. Some of these individuals may not have been diagnosed with MG prior to surgery, and it should be considered if providers cannot wean and extubate patients following surgery. Tracheostomy ranges from 14% to 40% in cases associated with an MC. Of those patients admitted with an MC, 18% will require discharge to a rehabilitation center.25

 

Signs and symptoms of MC include dysphagia, nasal regurgitation, nasal or staccato speech, jaw or tongue weakness, and bifacial paresis. Bulbar muscle weakness can lead to alterations in speech and failure of airway protection reflexes, which can result in pulmonary aspiration. It is difficult to handle secretions that accumulate in the oropharynx. In an MC, both inspiratory and expiratory respiratory muscles can be affected, manifesting as dyspnea severe enough to compromise both upper airway patency and breathing.2,9,15,25

 

Although up to half of patients may have no precipitating cause for their MC, the most common precipitating factors include:1,5,15,25

 

* respiratory infection

 

* aspiration

 

* changes in immunosuppressant dosing

 

* corticosteroid initiation

 

* administration of medications that are known to increase weakness such as beta-blockers, calcium channel blockers, magnesium, aminoglycoside, and fluoroquinolone antibiotics

 

* pregnancy

 

* presence of thymoma

 

* emotional stress

 

* surgery or trauma.

 

 

The combination of bulbar and respiratory muscle weakness can lead to acute respiratory failure requiring mechanical ventilatory support. A majority (up to 90%) of patients with an MC require intubation and mechanical ventilation. The majority of individuals with respiratory failure associated with an MC initially develop hypercarbia with hypoxemia a late finding. However, both hypercarbia and hypoxemia associated with aspiration can occur early in an MC.9

 

Early recognition and targeted interventions are important to prevent and treat an MC.25 Providers should identify and correct factors that could affect muscle strength. For example, by decreasing oxygen-carrying capacity, a hematocrit less than 30% might adversely affect muscle weakness. After patients demonstrate definitive improvement in muscle strength, usually several days after the initiation of IVIG or PLEX, acetylcholinesterase inhibitors, typically oral pyridostigmine, may be started or reinitiated prior to or following extubation. Oral pyridostigmine is preferred, but it may be given I.V. Providers should start patients on a low dose of the medication and then titrate to symptomatic relief and clinical status.25

 

Either PLEX or IVIG are indicated to manage an MC. The choice between PLEX and IVIG depends on individual patient factors, and providers must consider the various treatment options in the context of individual patient factors.3 For example, PLEX is contraindicated in patients with sepsis and may carry a greater risk of hemodynamic and venous access complications. IVIG is contraindicated in patients in hypercoagulable states, renal failure, or with a hypersensitivity to immunoglobulin. Other immunomodulating agents such as azathioprine or mycophenolate are not useful for an MC because of their long latency of action.3,25

 

Advances in mechanical ventilation, MC treatments, and critical care management have reduced mortality, which declined from 42% in the early 1960s to less than 5% in 2016.4,21,25

 

Respiratory assessment and management in MC

An MC affects both inspiratory and expiratory respiratory muscles.25 During an MC, respiratory muscles cannot maintain adequate tidal volume, decreasing functional residual capacity, and resulting in atelectasis. Breathing is more difficult and exacerbated by muscle weakness, which alters the ventilation-perfusion relationship and causes hypoxemia and hypercapnia. Anxiety accompanied by tachycardia and tachypnea may be the first sign of air hunger leading to an MC.15

 

Inspiratory muscle function can be measured in vital capacity (VC) and negative inspiratory force (NIF); expiratory function, by positive expiratory force (PEF). A VC under 20 to 25 mL/kg, an NIF under 20 cm H2O, and/or a PEF under 40 cm H2O are indicators of significant respiratory weakness and can indicate an MC.15 Other indicators of significant inspiratory muscle weakness include recruitment of accessory muscles; a weak cough or difficulty counting to 20 in a single breath can indicate expiratory muscle weakness.25

 

When measuring VC, NIF, and PEF, providers must take facial muscle weakness into account or risk inaccurate measurements of pulmonary indices. It is important to note that the need for mechanical ventilation regardless of pulmonary mechanics is sufficient to diagnose an MC.25

 

Over 20% of patients experiencing an MC require intubation during evaluation in the ED, and about 60% are intubated following admission to the ICU. Elective intubation is recommended over emergent intubation.25 Once intubated, patients are placed on assist control modes of volume controlled mechanical ventilation. The mechanical support required is patient-specific, but typically settings with tidal volumes of 8 to 10 mL/kg ideal body weight and pressure support of 8 to 15 cm H2O help prevent atelectasis and minimize the work of breathing.25

 

Use paralytics and neuromuscular blocking agents with caution when intubating these patients. Depolarizing agents such as succinylcholine are less potent because fewer functional postsynaptic nAChRs are available. Nondepolarizing agents such as vecuronium have increased potency in MG and effects last longer so reduced doses are required for paralysis.25

 

Wean patients from the ventilator after they demonstrate clinical improvement, which is typically when VC is greater than 15 mL/kg, although increased neck flexors and other adjunct muscle strength can also be useful assessments for tracking clinical improvement. Transition patients to a spontaneous mode of ventilation such as pressure support ventilation (all breaths are initiated by patient effort). With continued improvement of respiratory muscle strength, gradually decrease the level of pressure support to minimal settings. If the patient does not tolerate weaning, consider a return to an assist control mode of volume-controlled ventilation.25

 

In one series of patients, three independent risk factors for prolonged intubation (over 14 days) were present in 88% of patients:

 

* age over 50

 

* peak VC less than 25 mL/kg on postintubation days 1 to 6

 

* serum bicarbonate of 30 mEq/L or more.

 

 

Patients without these risk factors were intubated for less than 2 weeks. Patients with a prolonged intubation were hospitalized three times longer and were less likely to be functionally independent upon discharge.25 (See Predictors of reintubation.)

 

One retrospective study found that 20% of patients in an MC could be successfully supported with noninvasive ventilation, and it may prevent initial endotracheal intubation or reintubation of these patients.25 Noninvasive bilevel positive airway pressure (BiPAP), for example, applies positive pressure during both phases of respiration. BiPAP enhances airflow, alleviates the work of breathing during inspiration, and prevents airway collapse and atelectasis.25

 

Nursing care

Because of ineffective cough in patients with MC, it is essential that nurses apply or assist with appropriate pulmonary interventions. In severe cases, this might include aggressive chest physiotherapy, therapeutic fiberoptic bronchoscopy, percussion, vibration, postural drainage, and airway clearance interventions such as regular suctioning.

 

Adequate nutritional support (25 to 35 calories/kg, via enteral route if possible) can avoid negative energy balance and declining muscle strength.15,27 Patients with hypercarbia and difficulty weaning from mechanical ventilation should receive low-carbohydrate feedings. Replace potassium, magnesium, and phosphate because they can exacerbate an MC. Because anemia can increase weakness, experts recommend transfusions when hematocrit values are under 30%. Glycemic control, venous thromboembolism (VTE) prophylaxis, and hemodynamic stability are essential and strongly recommended as part of overall care.15,27

 

Assess neck flexors and accessory muscles to track improvement in bulbar and respiratory muscle strength. This benchmark can be a useful tool for assessing clinical improvement and readiness to wean from mechanical ventilation.

 

The most common complication associated with an MC is fever.15 Infectious complications include pneumonia, bronchitis, urinary tract infections, Clostridium difficile colitis, and bacteremia. This patient population is also more likely to experience sepsis, VTE, and cardiac complications.15

 

Anticholinesterase therapy should be temporarily withdrawn after establishing mechanical ventilatory support because it is unnecessary in this situation and can complicate pulmonary management and promote cholinergic crisis, cardiac dysrhythmias, and myocardial infarction.15 Although the recommended timing is not well established, oral or enteral feeding tube administration of cholinergic agents, such as pyridostigmine, should be restarted when the patient shows clinical improvement before weaning mechanical ventilation.15

 

Immunomodulatory treatment including PLEX and IVIG is the standard of care for patients with an MC. IVIG is an IgG-purified blood derivate that exerts maximum therapeutic effects in about 5 days. Nurses are essential in preventing, recognizing, and managing potential adverse reactions of immunomodulatory therapy, including fever, fluid overload, nausea, and headache.

 

The importance of patient education about this life-threatening condition cannot be underestimated. Nurses should provide support and information to patients and families confronted with MG and during an MC. Refer to the Myasthenia Foundation of America for the latest evidence (http://www.myasthenia.org).

 

Physiology of the NMJ

Following stimulation, motor nerve terminals within the NMJ release acetylcholine (ACh) across the synapse and activate nAChRs on striated skeletal muscle cells in the postsynaptic NMJ membrane. ACh causes depolarization, resulting in corresponding muscle contraction.7

  
Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

Source: Porth CM. Essentials of Pathophysiology. 3rd ed. Philadelphia, PA: Wolters Kluwer Health; 2010.

 

Predictors of reintubation15,25

Reintubation is a significant event because patients requiring reintubation have significantly longer ICU and hospital stays. Extubation failure, prolonged intubation, and a higher incidence of reintubation are associated with:

 

* Weak cough

 

* Inability to maintain a clear and patent airway

 

* Acidosis

 

* Decreased VC

 

* Atelectasis

 

* Need for noninvasive ventilatory support

 

 

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