/n 30 dquid Chapter Objectives After reading this chapter, you will be able to: List the anatomic alterations of the lungs associated with nimyasthenia gravis. • Describe the etiology and epidemiology of myasthenia gravis. • Discuss the screening for and diagnosis of myasthenia Myasthenia Gravis gravis. • List the cardiopulmonary clinical manifestations associated with myasthenia gravis. • Describe the general management of myasthenia gravis. • Describe the clinical strategies and rationales of the SOAPS presented in the case study. • Define key terms and complete self-assessment questions on the Evolve website. Key Terms Acetylcholine (ACh) Acetylcholinesterase Inhibitors Anticholinesterase Inhibitors Binding ACHR Antibodies Test Chronic Immunotherapies CMAP Amplitude Decremental Response Diplopia Anatomic Alterations of the Lungs Associated With Myasthenia Gravis Myasthenia gravis is the most common chronic disorder of the neuromuscular junction. The disorder interferes with the chemical transmission of acetylcholine (ACh) between the axonal terminal and the receptor sites of voluntary muscles (Fig. 30.1). The hallmark clinical feature of myasthenia gravis is fluctuating skeletal muscle weakness, often with true muscle fatigue. The fatigue and weakness usually improve after rest. There are two clinical types of myasthenia gravis: ocular and generalized. In ocular myasthenia gravis, the muscle weakness is limited to the eyelids and extraocular muscles. In generalized myasthenia gravis, the muscle weakness involves a variable combination of (1) muscles of the mouth and throat responsible for speech and swallowing Neck extensor and flexor muscles are commonly affected, (called bulbar muscles), (2) limbs, and (3) respiratory muscles. producing "dropped head syndrome." The facial muscles are often involved, causing the patient to appear expressionless. Generalized myasthenia gravis may or may not involve Edrophonium (Tensilon) Test Electromyography Generalized Myasthenia Gravis Ice Pack Test Immunoglobulin G (IgG) Antibodies Inadvertent Right Mainstem Bronchial Intubation Intravenous Immune Globulin (IVIG) Muscle-Specific Receptor Tyrosine Kinase (MUSK) Myasthenic Crisis Mycophenolate Mofetil Neuromuscular Junction Ocular Myasthenia Gravis Ophthalmoparesis Ophthalmoplegia Plasmapheresis Ptosis Pyridostigmine (Mestinon) Rapid Immunotherapies Repetitive Nerve Stimulation (RNS) Seronegative Myasthenia Gravis Seropositive Myasthenia Gravis Single-Fiber Electromyography (SFEMG) Symptomatic Treatment Thymectomy Thymoma the ocular muscles. Because the disorder affects only the myoneural (motor) junction, sensory function is not lost. The abnormal weakness may be confined to an isolated group of muscles (e.g., the drooping of one or both eyelids), or it may manifest as a generalized weakness that in severe cases includes the diaphragm. When the diaphragm is involved, ventilatory failure can develop, producing myasthenic crisis. In these cases, mechanical ventilation is required. If the patient is not properly managed (e.g., via the Airway Clearance Therapy Protocol, Protocol 10.2; Ventilator Initiation and Management Protocol, Protocol 11.1; and Ventilator Weaning Protocol, Protocol 11.2), mucus accumulation with airway obstruction, alveolar consolidation, and atelectasis may develop. The major pathologic or structural changes of the lungs associated with a poorly managed myasthenic crisis are as follows: . Mucus accumulation Airway obstruction Alveolar consolidation Atelectasis . ● 445 AT ACh MNF OR AB MRS ME FIGURE 30.1 Myasthenia gravis, a disorder of the neuromuscular junction that interferes with the chemical transmission of acetylcholine. AB, antibody; ACh, acetylcholine; AT, axonal terminal; D, dendrite; MF, muscle fiber; MNF, myelinated nerve fiber; MRS, muscle receptor site; V, vesicle. Note that the antibodies have a physical structure similar to that of ACh, which permits them to connect to (and block ACh from) the muscle receptor sites. Inset: atelectasis, a common secondary anatomic alteration of the lungs. Etiology and Epidemiology The cause of myasthenia gravis appears to be related to ACh receptor (AChR) antibodies (immunoglobulin G [IgG] antibodies) that block the nerve impulse transmissions at the neuromuscular junction. Patients who have detectable antibodies to the AChR, or to muscle-specific receptor tyrosine kinase (MuSK), are said to have seropositive myasthenia gravis, whereas those lacking both ACHR and MuSK antibodies on standard assays are said to have seronegative myasthenia gravis. About 50% of patients with only ocular myasthenia gravis are seropositive. About 90% of cases of generalized myasthenia gravis are seropositive. It is believed that the IgG antibodies disrupt the chemical transmission of ACh at the neuromuscular junction by (1) blocking the ACh from the receptor sites of the muscular cell, (2) accelerating the breakdown of ACh, and (3) destroying the receptor sites (see Fig. 30.1). Receptor-binding antibodies are present in 85% to 90% of persons with myasthenia gravis. Although the specific events that activate the formation of the antibodies remain unclear, the thymus gland is often abnormal; it is generally presumed that the antibodies arise within the thymus or in related tissue. According to the Myasthenia Gravis Foundation of America, there are between 36,000 to 60,000 cases of myasthenia gravis in the United States (20 per 100,000 population). The disease usually has a peak age of onset in females of 15 to 35 years, compared with 40 to 70 years in males. The clinical manifestations associated with myasthenia gravis are often provoked by emotional upset, physical stress, exposure to extreme temperature changes, febrile illness, and pregnancy. Death caused by myasthenia gravis is possible, especially during the first few years after onset. Screening and Diagnosis Screening methods and tests used to diagnose myasthenia gravis include (1) clinical presentation and history, (2) bedside tests, (3) immunologic studies, (4) electrodiagnostic studies, and (5) evaluation of conditions associated with myasthenia gravis. inical Presentation and History The hallmark of myasthenia gravis is chronic muscle fatigue. The muscles become progressively weaker during periods of activity and improve after periods of rest. Signs and symptoms include facial muscle weakness; ptosis (drooping of one or both eyelids); diplopia (double vision); ophthalmoplegia (paralysis or weakness of one or more of the muscles the control eye movement); difficulty in breathing, speaking chewing, and swallowing; unstable gait; and weakness in arms, hands, fingers, legs, and neck brought on by repetitive motions. The muscles that control the eyes, eyelids, face, and throat are especially susceptible and are usually affected first The respiratory muscles of the diaphragm and chest wall can become weak and impair the patient's ventilation. Impairment in deep breathing and coughing predisposes the patient to retain bronchial secretions, atelectasis, and pneumonia. The signs and symptoms of myasthenia gravis during the early stages are often elusive. The onset can be subtle, intermittent or sudden and rapid. The patient may (1) demonstrate normal health for weeks or months at a time, (2) show signs of weakness only late in the day or evening, or (3) develop a sudden and transient generalized weakness that includes the diaphragm Because of this last characteristic, ventilatory failure is always a sinister possibility. In most cases, the first noticeable symptom is weakness of the eye muscles (droopy eyelids) and a change in the patient's facial expressions. As the disorder becomes more generalized, weakness develops in the arms and legs. The muscle weakness is usually more pronounced in the proximal parts of the extremities. The patient has difficulty in climbing stairs, lifting objects, maintaining balance, and walking. In severe cases, the weakness of the upper limbs may be such that the hand cannot be lifted to the mouth. Muscle atrophy or pain is rare Tendon reflexes almost always remain intact. Bedside Diagnostic Tests Ice Pack Test The ice pack test is a very simple, safe, and reliable procedure for diagnosing myasthenia gravis in patients who have ptosis (droopy eye). In addition, the ice pack test does not require special medications or expensive equipment and is free of adverse effects. The test consists of the application of an ice pack to the patient's symptomatic eye for 3 to 5 minutes (Fig 30.2). The test is considered positive for myasthenia gravis when there is improvement of the ptosis (an increase of at least 2 mm in the palpebral fissure from before the test to after). only when ptosis is present. Even though the symptoms A major disadvantage of the ice pack test is that it is u associated with diplopia (double vision) also may improve with the ice pack test, the reliability of the ice pack to patients with diplopia without ptosis is usually questionable because the patient's personal impression of the diplopia is s useful ang insiden baxis in fatigue. riods of mptoms one or oplegia es that de studies, asthenia eaking, Less in etitive e, and d first. ll can ment ent to early ttent, -rmal ness and agm. ys a tom e in ore scle arts irs, ses, nd re. re is -e of e S t A FIGURE 30.2 Ice pack test. (A) Myasthenia gravis in a patient who has ptosis (droopy left eye). (B) Same patient after 5-minute application of an ice pack. Note that the patient's left eye lid is no longer droopy. subjective. Therefore, caution should be exercised in patients with isolated diplopia without visible ptosis. The ice pack test may be especially useful in patients in whom the edrophonium that is contraindicated by either cardiac status or age. Edrophonium (Tensilon) Test The Immunologic Studies Serologic tests to detect the presence of circulating acetylcholine receptor antibodies (AChR-Abs) is the first step in the laboratory confirmation of myasthenia. There are three AChR-Ab assays: binding, blocking, and modulating. The binding ACHR antibodies test is highly specific for myasthenia gravis (80% to 90%). Most experts use the term AChR-Abs as synonymous with the binding antibodies. In some patients, assays for blocking and modulating antibodies also may be helpful. Blocking AChR-Abs are found in about 50% of patients with generalized myasthenia gravis. Assays for modulating AChR-Abs increase the diagnostic sensitivity by about 5% when combined with the binding studies. When AChR-Abs are negative, an assay for the antibodies to MuSK proteins should be performed. Electrodiagnostic Studies repetitive nerve stimulation (RNS) and single-fiber electromyography (SFEMG) tests are important diagnostic supplements to the immunologic studies. The RNS study is the most frequently used electrodiagnostic test for myasthenia gravis. The RNS study is performed by electrically stimulating the motor nerve of selected muscles 6 to 10 times at low rates (2 or 3 Hz). In the normal muscle, there is no change in the compound muscle action potential (CMAP) amplitude. In patients with myasthenia gravis, there may be a progressive decline in the CMAP amplitude within the first four to five stimuli-called a decremental response. The RNS is considered positive when the decrement is greater than 10%. The edrophonium (Tensilon) test is used in patients with unneedle electrode allows simultaneous recording of the action The SFEMG is the most sensitive diagnostic test for myasthenia gravis, although it is technically more difficult. A specialized ophthalmoparesis. Edrophonium, a short- or obvious ptosis acting drug, blocks cholinesterase from breaking down ACh after it has been released from the terminal axon. This action increases the myoneural concentration of ACh, which in turn offsets the influx of antibodies at the neuromuscular When muscular weakness is caused by myasthenia junction. gravis, a dramatic transitory improvement in muscle function (lasting about 10 minutes) is seen after the administration of edrophonium. A disadvantage of the edrophonium test is that it can be complicated by cholinergic side effects that include cardiac arrhythmias and cardiopulmonary arrest. Cardiac monitoring, or avoiding this test altogether, is suggested in the elderly or those with a history of arrhythmia or heart disease. Although the sensitivity of the Tensilon test for the diagnosis of myasthenia gravis is in the 80% to 90% range, it is associated with many false-negative and false-positive results. potential of two muscle fibers innervated by the same motor axon. The variability in time between the two action potentials is called jitter. In patients with myasthenia gravis, the jitter is increased. The SFEMG is positive in more than 95% of patients with generalized myasthenia gravis. The sensitivity of the SFEMG ranges between 85% and 95% in ocular myasthenia gravis. Evaluation of Conditions Associated With Myasthenia Gravis Thymic Tumors and Other Malignancies Thymic abnormalities are often seen in patients with myasthenia gravis. Computed tomography (CT) or magnetic resonance imaging (MRI) scans may be used to identify an abnormal thymus gland or the presence of a thymoma (a usually benign tumor of the thymus gland that may be associated with myasthenia gravis). A thymectomy has been shown to reduce symptoms of myasthenia gravis. In fact, a thymectomy may be recommended even when there is no tumor. The removal of the thymus seems to improve the condition in many patients. Differential Diagnosis Studies to rule out other disease in the differential diagnosis of myasthenia gravis are indicated in some patients. For example, in cases with ocular or bulbar symptoms, an MRI of the brain is indicated. CT scanning or ultrasound of the orbits is helpful in the differential diagnosis of ocular myasthenia and thyroid ophthalmopathy. A lumbar puncture may be helpful in ruling out lymphomatous or carcinomatous meningitis in some cases. Blood tests should include thyroid function tests. In patients who have symptoms associated with a rheumatologic disorder, assays for antinuclear antibodies and rheumatoid factor should be performed. Pulmonary Function Testing Pulmonary function testing may be performed to help evaluate the patient's ventilatory status and the possibility of ventilatory failure-that is, a myasthenic crisis. Serial testing is advised. Table 30.1 provides a widely accepted clinical classification system of myasthenia gravis, which was developed by the Myasthenia Gravis Foundation of America. CHAPTER 30 Myasthenia Gravis 447 TABLE 30.1 Clinical Classifications of Myasthenia Gravis Class I Class II Class lla Class llb Class III Class Illa Class Illb Class IV Class IVa 017 Class IVb ● Class V Any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is normal Mild weakness affecting other ocular muscles; may also have ocular muscle weakness of any severity Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both Moderate weakness affecting other ocular muscles; may also have ocular muscle weakness of any severity Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both Severe weakness affecting other ocular muscles; may also have ocular muscle weakness of any severity Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles ITO AN Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both; use of a feeding tube without intubation Defined by the need for intubation, with or without mechanical ventilation, except when used during routine postoperative management From Jaretzki A, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000;55(1):16-23. H OVERVIEW of the Cardiopulmonary Clinical Manifestations Associated With Myasthenia Gravis The following clinical manifestations result from the pathologic mechanisms caused (or activated) by atelectasis (see Fig. 10.7), alveolar consolidation (see Fig. 10.8), and excessive bronchial secretions (see Fig. 10.11)-the major anatomic alterations of the lungs associated with myasthenia gravis, which may occur when the patient is not properly managed via the Airway Clearance Therapy Protocol, Protocol 10.2; Ventilator Initiation and Management Protocol, Protocol 11.1; and Ventilator Weaning Protocol, Protocol 11.2 (see Fig. 30.1).1 CLINICAL DATA OBTAINED AT THE PATIENT'S BEDSIDE The Physical Examination Respiratory Rate Varies with the degree of respiratory muscle paralysis Apnea (in severe cases) Cyanosis (in severe cases) Chest Assessment Findings • Diminished breath sounds • Crackles 'It should be noted that the clinical manifestations associated with myasthenia gravis may occur over hours or days, depending on how quickly the paralysis progresses. CLINICAL DATA OBTAINED FROM LABORATORY TESTS AND SPECIAL PROCEDURES Pulmonary Function Test Findings2 (Restrictive Lung Pathology) FORCED EXPIRATORY VOLUME AND FLOW RATE FINDINGS FEF25%-75% FVC FEVT FEV₁/FVC ratio ↓ Nor T Nor FEF 50% Nor↓ VT 5→ → Nor VC FEF 20 200-1200 LUNG VOLUME AND CAPACITY FINDINGS IRV ↓ Nort ERV ↓ PEFR Nort FRC ↓ RV 1 IC TLC ↓ 1 MAXIMUM INSPIRATORY PRESSURE (MIP) MVV Nord RV/TLC ratio N 2Progressive worsening of these values is key to anticipating the onset of ventilatory failure. Arterial Blood Gases MODERATE TO SEVERE MYASTHENIA GRAVIS Acute Ventilatory Failure With Hypoxemia3 (Acute Respiratory Acidosis) PaCO₂ HCO34 pH4 ↓ ↑ ↑ (but normal) S Qs/QT ↑ . PaO2 SaO₂ or SpO2 ↓ ↓ Oxygenation Indices5 DO₂6 VO₂ C(a-V)O2 O₂ER N N ↓ General Management of Myasthenia Gravis In the past, many patients with myasthenia gravis died within the first few years of diagnosis of the disease. Today, several therapeutic measures provide most patients with marked relief of symptoms and allow them to live a normal life. Close respiratory monitoring with frequent measurements of the patient's forced vital capacity (FVC), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), blood pressure, oxygen saturation, and, when indicated, arterial blood gases (ABGs) should be performed. Mechanical ventilation should be initiated when the clinical data demonstrate impending or acute ventilatory failure. Good clinical indicators of impending acute ventilatory SVO₂ Pon 25 of 92 ↑ see Fig. 5.3 and Table 5.5 and related discussion for the acute pH, PaCO2, and HCO changes associated with acute ventilatory failure. When tissue hypoxia is severe enough to produce lactic acid, the pH and HCO3 values will be lower than expected for a particular PaCO₂ level. Ola-v)0₂, Arterial-venous oxygen difference; DO2, total oxygen delivery; O₂ER, oxygen extraction ratio; Qs/QT, pulmonary shunt fraction; SVO₂, mixed venous oxygen saturation: VO₂, oxygen consumption. The DO₂ may be normal in patients who have compensated to the decreased oxygenation status with (1) an increased cardiac output, (2) an increased hemoglobin level, or (3) a combination of both. When the DO₂ is normal, the OER is usually normal. cm failure include the following: FVC less than 20 mL/kg of . MIP below -30 cm H₂O-In other words, the patient is unable to generate a maximum inspiratory pressure 30 H₂O would confirm severe muscle weakness and, importantly, that acute ventilatory failure is likely. MEP less than 40 cm H₂O PaCO₂ greater than 45 mm Hg pH less than 7.35. gravis are inhibitors.. The four basic therapy modalities used to treat myasthenia e (1) symptomatic treatment (acetylcholinesterase (2) immunotherapies (e.g., chronic glucocorticoids and other immunosuppressive drugs), (3) rapid immunotherapies (plasma exchange and intravenous immune globulins [IVIG]), and (4) thymectomy. cal Manifestations Associated RADIOLOGIC FINDINGS Chest Radiograph • Normal, or • Increased opacity (when atelectasis or consolidation are present) If the ventilatory failure associated with myasthenia gravis is properly managed (e.g., via the Airway Clearance Therapy Protocol, Protocol 10.2; Ventilator Initiation and Management Protocol, Protocol 11.1; and Ventilator Weaning Protocol, Protocol 11.2), the chest radiograph should appear normal. However, if the patient is not properly managed, mucus accumulation, alveolar consolidation, and atelectasis may develop-as part of the myasthenic crisis. In these cases, the chest radiograph may show an increased density of the lung segments affected. Other Gastric aspiration pneumonia is also a complication of patients with myasthenia gravis while being mechanically ventilated. Symptomatic Treatment: Acetylcholinesterase Inhibitors Acetylcholinesterase inhibitors are recommended as the first line of treatment for symptomatic myasthenia gravis. Pyridostigmine (Mestinon) is usually the first choice. Pyridostigmine inhibits the function of acetylcholinesterase. This action increases the concentration of ACh to compete with the circulating anti- ACh antibodies, which interfere with the ability of ACh to stimulate the muscle receptors. Although the anticholinesterase inhibitors are effective in mild cases of myasthenia gravis, they are not completely effective in severe cases. Chronic Immunotherapies Most patients with myasthenia gravis need some form of immunotherapy in addition to an acetylcholinesterase inhibitor (see previous section). It is recommended that immunotherapy be administered to patients who remain acetylcholinesterase significantly symptomatic while on an inhibitor or who become symptomatic after a temporary response to an acetylcholinesterase inhibitor. Common immunotherapy agents include glucocorticoids, azathioprine, mycophenolate mofetil, and cyclosporine. Immunotherapy agents are usually used for more severe cases. The patient's strength often improves strikingly with steroids. Patients receiving long-term steroid therapy, however, may develop serious complications such as diabetes, cataracts, steroid myopathy, gastrointestinal bleeding, infections, aseptic necrosis of the bone, osteoporosis, and psychoses. CHAPTER 30 Myasthenia Gravis 449