The diagnosis is suspected on the basis of weakness and fatigability in the typical distribution described above, without loss of reflexes or impairment of sensation or other neurologic function (Table 440-1). The suspected diagnosis should always be confirmed definitively before treatment is undertaken; this is essential because (1) other treatable conditions may closely resemble MG and (2) the treatment of MG may involve surgery and the prolonged use of drugs with potentially adverse side effects.
TABLE 440-1Diagnosis of Myasthenia Gravis (MG) |Favorite Table|Download (.pdf) TABLE 440-1 Diagnosis of Myasthenia Gravis (MG)
| Diplopia, ptosis, dysarthria, dysphagia, dyspnea |
| Weakness in characteristic distribution: proximal limbs, neck extensors, generalized |
| Fluctuation and fatigue: worse with repeated activity, improved by rest |
| Effects of previous treatments |
|Physical examination |
| Evaluation for ptosis at rest and following one minute of exercise, extraocular muscles and subjective diplopia, orbicularis oculi and oris strength, jaw opening and closure |
| Assessment of muscle strength in neck and extremities |
| Weakness following repeated shoulder abduction |
| Vital capacity measurement |
| Absence of other neurologic signs |
|Laboratory testing |
| Anti-AChR radioimmunoassay: ~85% positive in generalized MG; 50% in ocular MG; definite diagnosis if positive; negative result does not exclude MG; ~40% of AChR antibody–negative patients with generalized MG have anti-MuSK antibodies |
| Repetitive nerve stimulation: decrement of >10% at 3 Hz: highly probable |
| Single-fiber electromyography: blocking and jitter, with normal fiber density; confirmatory, but not specific |
| Edrophonium chloride (Enlon®) 2 mg + 8 mg IV; highly probable diagnosis if unequivocally positive |
| For ocular or cranial MG: exclude intracranial lesions by CT or MRI |
If a patient has ptosis, application of a pack of ice over a ptotic eye often results in improvement if the ptosis is due to an NMJ defect. This is hypothesized to be due to less depletion of quanta of AChR in the cold and reduced activity of AChE at the NMJ. It is a quick and easy test to do in the clinic or at the bedside of a hospitalized patient.
Autoantibodies Associated with MG
As previously mentioned, anti-AChR antibodies are detectable in the serum of ~85% of all myasthenic patients but in only about 50% of patients with weakness confined to the ocular muscles. The presence of anti-AChR antibodies is virtually diagnostic of MG, but a negative test does not exclude the disease. The measured level of anti-AChR antibody does not correspond well with the severity of MG in different patients. Antibodies to MuSK are present in ~40% of AChR antibody–negative patients with generalized MG. MuSK antibodies are rarely present in AChR antibody–positive patients or in patients with MG limited to ocular muscles. These antibodies may interfere with clustering of AChRs at NMJs. A small proportion of MG patients without antibodies to AChR or MuSK have antibodies to LRP4. Interestingly, antibodies against agrin have recently been found in some patients with MG. Agrin is a protein derived from motor nerves that normally binds to LRP4 and important for normal clustering of AChRs at NMJ. Additionally, anti-striated muscle antibodies directed against titin and other skeletal muscle components are found in ~30% of myasthenic without thymoma, 24% of thymoma patients without myasthenia, and 70–80% of patients with both myasthenia and thymoma. Furthermore, antibodies directed against Netrin-1 receptors and Caspr2 (contactin-associated protein-like 2) often coexist and are associated in patients with thymoma who have MG and neuromyotonia or Morvan syndrome.
Repetitive nerve stimulation may provide helpful diagnostic evidence of MG. Anti-AChE medication should be stopped 6–12 h before testing. It is best to test weak muscles or proximal muscle groups. Electrical stimulation is delivered at a rate of two or three per second to the appropriate nerves, and action potentials are recorded from the muscles. In normal individuals, the amplitude of the evoked muscle action potentials does not change by >10% at these rates of stimulation. However, in myasthenic patients, there is a rapid reduction of >10% in the amplitude of the evoked responses.
Drugs that inhibit the enzyme AChE allow ACh to interact repeatedly with the limited number of AChRs in MG, producing improvement in muscle strength. Edrophonium is used most commonly for diagnostic testing because of the rapid onset (30 s) and short duration (~5 min) of its effect. An objective end point must be selected to evaluate the effect of edrophonium, such as weakness of EOMs, impairment of speech, or the length of time that the patient can maintain the arms in forward. An initial IV dose of 2 mg of edrophonium is given. If definite improvement occurs, the test is considered positive and is terminated. If there is no change, the patient is given an additional 8 mg IV. The dose is administered in two parts because some patients react to edrophonium with side effects such as nausea, diarrhea, salivation, fasciculations, and rarely with severe symptoms of syncope or bradycardia. Atropine (0.6 mg) should be drawn up in a syringe and ready for IV administration if these symptoms become troublesome. The edrophonium test is now reserved for patients with clinical findings that are suggestive of MG but who have negative antibody, electrodiagnostic testing, or ice-pack test. False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic lateral sclerosis (Chap. 429), and in placebo-reactors. False-negative or equivocal tests may also occur.
Measurements of ventilatory function are valuable because of the frequency and seriousness of respiratory impairment in myasthenic patients (Chap. 278).
Other conditions that cause weakness of the cranial and/or somatic musculature include the nonautoimmune congenital myasthenia, drug-induced myasthenia, Lambert-Eaton myasthenic syndrome (LEMS), neurasthenia, hyperthyroidism (Graves’ disease), botulism, intracranial mass lesions, oculopharyngeal dystrophy, and mitochondrial myopathy (Kearns-Sayre syndrome, progressive external ophthalmoplegia). Treatment with penicillamine (used for scleroderma or rheumatoid arthritis) and check point inhibitors for cancer may also result in autoimmune MG. Aminoglycoside antibiotics or procainamide can cause exacerbation of weakness in myasthenic patients; very large doses can cause neuromuscular weakness in normal individuals.
The congenital myasthenic syndromes (CMS) comprise a rare heterogeneous group of disorders of the NMJ that are not autoimmune but rather are due to genetic mutations in which virtually any component of the NMJ may be affected. Alterations in function of the presynaptic nerve terminal, in the various subunits of the AChR, AChE, or the other molecules involved in end-plate development or maintenance, have been identified in the different forms of CMS. These disorders share many of the clinical features of autoimmune MG, including weakness and fatigability of proximal or distal extremity muscles, and often involving EOMs and the eyelids similar to the distribution in autoimmune MG. CMS should be suspected when symptoms of myasthenia have begun in infancy or childhood, but they can present in early adulthood. As in acquired autoimmune MG, repetitive nerve stimulation is associated with a decremental response. Some forms (e.g., AChE deficiency, prolonged open channel syndrome) have a feature of after-discharges which are not seen in MG. An additional clue is the absence of AChR and MuSK antibodies though these are absent in ~10% of generalized MG patients (so-called double seronegative MG) antibodies.
The prevalence of CMS is estimated at ~3.8 per 100,000. The most common genetic defects occur in the ε subunit of the AChR, accounting for ~50% of CMS cases, with mutations in the genes encoding for rapsin, COLQ, DOK7, agrin, and GFPT together accounting for ~40%. In most of the recessively inherited forms of CMS, the mutations are heteroallelic; that is, different mutations affecting each of the two alleles are present. Features of the most common forms of CMS are summarized in Table 440-2. Molecular analysis is required for precise elucidation of the defect; this may lead to helpful treatment as well as genetic counseling. Some forms of CMS improve with AChE inhibitors, while others (e.g., slow channel syndrome, AChE deficiency, DOK-7 related CMS) actually worsen. Fluoxetine and quinidine can be useful for slow channel syndrome, and albuterol for mutations affecting AChE, DOK-7, rapsyn, and agrin. Additionally, ephedrine and 3,4 diaminopyridine (3,4 DAP) may be of benefit in some forms of CMS.
TABLE 440-2Congenital Myasthenic Syndromes |Favorite Table|Download (.pdf) TABLE 440-2 Congenital Myasthenic Syndromes
|CMS Subtype ||Gene ||Clinical Features ||Electrophysiological Features ||Response to AChE Inhibitors ||Treatment |
|Presynaptic Disorders |
|CMS with paucity of ACh release || |
|AR; early onset, respiratory failure at birth, episodic apnea, improvement with age ||Decremental response to RNS ||Improve ||AChE inhibitors; 3,4 DAP |
|Synaptic Disorders |
|AChE deficiency ||COLQ ||AR; early onset; variable severity; axial weakness with scoliosis; apnea; +/- EOM involvement, slow or absent pupillary responses ||After discharges on nerve stimulation and decrement on RNS ||Worsen ||Albuterol; ephedrine; 3,4 DAP; avoid AChE inhibitors |
|Postsynaptic Disorders Involving AChR Deficiency or Kinetics |
|Primary AChR deficiency ||AChR subunit genes ||AR; early onset; variable severity; fatigue; typical MG features ||Decremental response to RNS ||Improve ||AChE inhibitors; 3,4 DAP |
|AChR kinetic disorder: slow channel syndrome ||AChR subunit genes ||AD; onset childhood to early adult; weak forearm extensors and neck; respiratory weakness; variable severity ||After discharges on nerve stimulation and decrement on RNS ||Worsen ||Fluoxetine and quinidine; avoid AChE inhibitors |
|AChR kinetic disorder: fast channel syndrome ||AChR subunit genes ||AR; early onset; mild to severe; ptosis, EOM involvement; weakness and fatigue ||Decremental response to RNS ||Improve ||AChE inhibitors; caution with 3,4 DAP |
|Postsynaptic Disorders Involving Abnormal Clustering/Function of AChR |
| ||DOK 7 ||AR; limb girdle weakness with ptosis but no EOM involvement ||Decremental response to RNS ||Variable ||Albuterol; ephedrine; may worsen with AChE inhibitors |
|Rapsyn ||AR; early onset with hypotonia, respiratory failure, and arthrogryposis at birth to early adult onset resembling MG ||Decremental response to RNS ||Variable ||Albuterol |
|Agrin ||AR; limb girdle or distal weakness, apnea ||Decremental response to RNS ||Variable ||Albuterol; may worsen with AChE inhibitors |
|MuSK ||AR; congenital or childhood onset of ptosis, EOM and progressive limb girdle weakness ||Decremental response to RNS ||Variable || |
Variable response to AChE inhibitors and 3,4, DAP
Positive response to albuterol
|LPR4 ||AR; congenital onset with hypotonia; ventilatory failure, mild ptosis, and EOM weakness ||Decremental response to RNS ||Worsen ||Worsen with AChE inhibitors |
|Other Postsynaptic Disorders |
|Limb-girdle CMS with tubular aggregates || |
GFPT1; DPAGT1; ALG2;
|AR; limb girdle weakness usually without ptosis or EOM weakness; onset in infancy or early adult ||Decremental response to RNS ||Variable || |
Albuterol; ephedrine; variable response to AChE inhibitors and 3,4, DAP;
|Congenital muscular dystrophy with myasthenia ||Plectin ||AR; infantile or childhood onset of generalized weakness including ptosis and EOM; epidermolysis bullosa simplex; elevated CK ||Decremental response to RNS ||Variable ||No response to AChE and 3,4 DAP |
LEMS is a presynaptic disorder of the NMJ that can cause weakness similar to that of MG. The proximal muscles of the lower limbs are most commonly affected, but other muscles may be involved as well. Cranial nerve findings, including ptosis of the eyelids and diplopia, occur in up to 70% of patients and resemble features of MG. However, the two conditions are usually readily distinguished because patients with LEMS have depressed or absent reflexes and experience autonomic changes such as dry mouth and impotence. Nerve stimulation produces an initial low-amplitude compound muscle action potential and, at low rates of repetitive stimulation (2–3 Hz), a decremental responses as seen in MG; however, at high rates (20–50 Hz), or following brief exercise, incremental responses occur. LEMS is caused by autoantibodies directed against P/Q-type calcium channels at the motor nerve terminals detected in ~85% of LEMS patients. These autoantibodies impair the release of ACh from nerve terminals. In young adults, particularly women, LEMS is not associated with an underlying cancer. However, in older adults, most LEMS is associated with malignancy, most commonly small-cell lung cancer (SCLC) The tumor cells may express calcium channels that stimulate the autoimmune response. Treatment of LEMS involves plasmapheresis and immunotherapy, as for MG. 3,4-Diaminopyridine (3,4-DAP) and pyridostigmine can also help with symptoms. 3,4-DAP acts by blocking potassium channels, which results in prolonged depolarization of the motor nerve terminals and thus enhances ACh release. Pyridostigmine prolongs the action of ACh, allowing repeated interactions with AChRs.
Botulism (Chap. 148) is due to potent bacterial toxins produced by any of eight different strains of Clostridium botulinum. The toxins enzymatically cleave specific proteins essential for the release of ACh from the motor nerve terminal, thereby interfering with neuromuscular transmission. Most commonly, botulism is caused by ingestion of improperly prepared food containing toxin. Rarely, the nearly ubiquitous spores of C. botulinum may germinate in wounds. In infants, the spores may germinate in the gastrointestinal (GI) tract and release toxin, causing muscle weakness. Patients present with myasthenia-like bulbar weakness (e.g., diplopia, dysarthria, dysphagia) and lack sensory symptoms and signs. Weakness may generalize to the limbs and may result in respiratory failure. Reflexes are present early, but they may be diminished as the disease progresses. Mentation is normal. Autonomic findings include paralytic ileus, constipation, urinary retention, dilated or poorly reactive pupils, and dry mouth. The demonstration of toxin in serum by bioassay is definitive, but the results usually take a relatively long time to be completed and may be negative. Nerve stimulation studies reveal reduced compound muscle action potential (CMAP) amplitudes that increase following high-frequency repetitive stimulation. Treatment includes ventilatory support and aggressive inpatient supportive care (e.g., nutrition, deep vein thrombosis prophylaxis) as needed. Antitoxin should be given as early as possible to be effective and can be obtained through the Centers for Disease Control and Prevention. A preventive vaccine is available for laboratory workers or other highly exposed individuals.
Neurasthenia is the historic term for a myasthenia-like fatigue syndrome without an organic basis. These patients may present with subjective symptoms of weakness and fatigue, but muscle testing usually reveals the “give-away weakness” characteristic of nonorganic disorders; the complaint of fatigue in these patients means tiredness or apathy rather than decreasing muscle power on repeated effort. Hyperthyroidism is readily diagnosed or excluded by tests of thyroid function, which should be carried out routinely in patients with suspected MG. Abnormalities of thyroid function (hyper- or hypothyroidism) may increase myasthenic weakness. Diplopia resembling that in MG may occasionally be due to an intracranial mass lesion that compresses nerves to the EOMs (e.g., sphenoid ridge meningioma), but magnetic resonance imaging (MRI) of the head and orbits usually reveals the lesion.
Progressive external ophthalmoplegia is a rare condition resulting in weakness of the EOMs, which may be accompanied by weakness of the proximal muscles of the limbs and other systemic features. Most patients with this condition have mitochondrial disorders that can be detected on muscle biopsy (Chap. 441).
Search for Associated Conditions
Myasthenic patients have an increased incidence of several associated disorders (Table 440-3). Thymic abnormalities occur in ~75% of AChR antibody–positive patients, as noted above. Neoplastic change (thymoma) may produce enlargement of the thymus, which is detected by chest computed tomography (CT). A thymic shadow on CT scan may normally be present through young adulthood, but enlargement of the thymus in a patient age >40 years is highly suspicious of thymoma. Hyperthyroidism occurs in 3–8% of patients and may aggravate the myasthenic weakness. Thyroid function tests should be obtained in all patients with suspected MG. Other autoimmune disorders, most commonly systemic lupus erythematosus and rheumatoid arthritis, can coexist with MG; associations also occur with neuromyelitis optica, neuromyotonia, Morvan’s syndrome (encephalitis, insomnia, confusion, hallucinations, autonomic dysfunction, and neuromyotonia), rippling muscle disease, granulomatous myositis/myocarditis, and chronic inflammatory demyelinating polyneuropathy.
TABLE 440-3Disorders Associated with Myasthenia Gravis and Recommended Laboratory Tests |Favorite Table|Download (.pdf) TABLE 440-3 Disorders Associated with Myasthenia Gravis and Recommended Laboratory Tests
|Associated disorders |
| Disorders of the thymus: thymoma, hyperplasia |
| Other autoimmune neurological disorders: chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica |
| Other autoimmune disorders: Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus, skin disorders, family history of autoimmune disorder |
| Disorders or circumstances that may exacerbate myasthenia gravis: hyperthyroidism or hypothyroidism, occult infection, medical treatment for other conditions (see Table 440-4) |
| Disorders that may interfere with therapy: tuberculosis, diabetes, peptic ulcer, gastrointestinal bleeding, renal disease, hypertension, asthma, osteoporosis, obesity |
|Recommended laboratory tests or procedures |
| CT or MRI of chest |
| Tests for antinuclear antibodies, rheumatoid factor |
| Thyroid function tests |
| Testing for tuberculosis |
| Fasting blood glucose, hemoglobin A1c |
| Pulmonary function tests |
| Bone densitometry |
An infection of any kind can exacerbate typical MG, and should be sought carefully in patients with relapses. Because of the side effects of glucocorticoids and other immunotherapies used in the treatment of MG, a thorough medical investigation should be undertaken, searching specifically for evidence of chronic or latent infection (such as tuberculosis or hepatitis), hypertension, diabetes, renal disease, and glaucoma.
TREATMENT Myasthenia Gravis
The prognosis has improved strikingly as a result of advances in treatment. Nearly all myasthenic patients can be returned to full productive lives with proper therapy. The most useful treatments for MG include anticholinesterase medications, immunosuppressive agents, thymectomy, plasmapheresis, and intravenous immunoglobulin (IVIg) (Fig. 440-2). ANTICHOLINESTERASE MEDICATIONS
Anticholinesterase medication produces at least partial improvement in most myasthenic patients, although improvement is complete in only a few. Patients with anti-MuSK MG generally obtain less benefit from anticholinesterase agents than those with AChR antibodies and may actually worsen. Pyridostigmine is the most widely used anticholinesterase drug and is initiated at a dosage of 30–60 mg three to four times daily. The beneficial action of oral pyridostigmine begins within 15–30 min and lasts for 3–4 h, but individual responses vary. The frequency and amount of the dose should be tailored to the patient’s individual requirements throughout the day. For example, patients with weakness in chewing and swallowing may benefit by taking the medication before meals so that peak strength coincides with mealtimes. Long-acting pyridostigmine may occasionally be useful to get the patient through the night but should not be used for daytime medication because of variable absorption. The maximum useful dose of pyridostigmine rarely exceeds 300 mg daily. Overdosage with anticholinesterase medication may cause increased weakness and other side effects. In some patients, muscarinic side effects of the anticholinesterase medication (diarrhea, abdominal cramps, salivation, nausea) may limit the dose tolerated. Atropine/diphenoxylate or loperamide is useful for the treatment of GI symptoms. THYMECTOMY
Two separate issues should be distinguished: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for MG. Surgical removal of a thymoma is necessary because of the possibility of local tumor spread, although most thymomas are histologically benign. Until recently there was a debate regarding the role of thymectomy in non-thymotous MG, but a recent large international trial of extended transternal thymectomy in non-thymomatous AChR antibody positive, generalized MG demonstrated that participants who underwent thymectomy had improved strength and function, required less prednisone and additions of second line agents (e.g., azathioprine), and fewer hospitalizations for exacerbations. Whether or not less invasive thymectomy may be beneficial is unknown. Also, patients with ocular myasthenia, MuSK-positive, and seronegative MG were excluded from the study; retrospective and anecdotal evidence suggest that these patients may not benefit from thymectomy. Thymectomy should never be carried out as an emergency procedure, but only when the patient is adequately prepared. If necessary, treatment with IVIg or plasmapheresis may be used before surgery to maximize strength in weak patients. IMMUNOSUPPRESSION
Immunosuppression using one or more of the available agents is effective in nearly all patients with MG. The choice of drugs or other immunomodulatory treatments should be guided by the relative benefits and risks for the individual patient and the urgency of treatment. It is helpful to develop a treatment plan based on short-term, intermediate-term, and long-term objectives. For example, if immediate improvement is essential either because of the severity of weakness or because of the patient’s need to return to activity as soon as possible, IVIg should be administered or plasmapheresis should be undertaken. For the intermediate term, glucocorticoids and cyclosporine or tacrolimus generally produce clinical improvement within a period of 1–3 months. The beneficial effects of azathioprine and mycophenolate mofetil usually begin after many months (as long as a year), but these drugs have advantages for the long-term treatment of patients with MG. There is a growing body of evidence that rituximab is effective in many MG patients, especially those with MuSK antibody. Glucocorticoid Therapy
Glucocorticoids, when used properly, produce improvement in myasthenic weakness in the great majority of patients. To minimize adverse side effects, prednisone should be given in a single dose rather than in divided doses throughout the day. In patients with only mild or moderate weakness, the initial dose should be relatively low (15–25 mg/d) to avoid the early weakening that occurs in perhaps 10–15% of patients treated initially with a high-dose regimen. The dose is increased stepwise, as tolerated by the patient (usually by 5 mg/d at 2–3 day intervals), until there is marked clinical improvement or a dose of 50–60 mg/d is reached. In patients with more severe weakness and those already in the hospital, starting at a high dose is reasonable. Patients are maintained on the dose that seems to control their symptoms for about a month, and then the dosage is slowly tapered (no faster than 10 mg a month until on 20 mg daily and then by 2.5–5 mg a month) to determine the minimum effective dose, and close monitoring is required. Some patients are able to be managed without the addition of other immunotherapies. Patients on long-term glucocorticoid therapy must be followed carefully to prevent or treat adverse side effects. The most common errors in glucocorticoid treatment of myasthenic patients include (1) insufficient persistence—improvement may be delayed and gradual; (2) tapering the dosage too early, too rapidly, or excessively; and (3) lack of attention to prevention and treatment of side effects.
The management of patients treated with glucocorticoids is discussed in Chap. 379. Other Immunotherapies
Mycophenolate mofetil, azathioprine, cyclosporine, tacrolimus, rituximab, and occasionally cyclophosphamide are effective in many patients, either alone or in various combinations.
Mycophenolate mofetil is widely used because of its presumed effectiveness and relative lack of side effects. A dose of 1–1.5 g bid is recommended. Its mechanism of action involves inhibition of purine synthesis by the de novo pathway. Since lymphocytes have only the de novo pathway, but lack the alternative salvage pathway that is present in all other cells, mycophenolate inhibits proliferation of lymphocytes but not proliferation of other cells. It does not kill or eliminate preexisting autoreactive lymphocytes, and therefore clinical improvement may be delayed for many months to a year, until the preexisting autoreactive lymphocytes die spontaneously. The advantage of mycophenolate lies in its relative lack of adverse side effects, with only occasional production of GI symptoms, rare development of leukopenia, and very small risks of malignancy or progressive multifocal leukoencephalopathy inherent in nearly all immunosuppressive treatments. Although two published studies did not show positive outcomes, most experts attribute the negative results to flaws in the trial designs, and mycophenolate is widely used for long-term treatment of myasthenic patients.
Azathioprine has long been used for MG and a randomized, clinical trial demonstrated that it was effective in reducing the dosage of prednisone necessary to control symptoms. However, the beneficial effect of azathioprine can take a year or more to become evident. Approximately 10–15% of patients are unable to tolerate azathioprine because of idiosyncratic reactions consisting of flulike symptoms of fever and malaise, bone marrow suppression, or abnormalities of liver function. An initial dose of 50 mg/d is given for about a week to test for these side effects. If this dose is tolerated, it is increased gradually to about 2–3 mg/kg of total body weight, or until the white blood count falls to 3000–4000/μL. Allopurinol should never be used in combination with azathioprine because the two drugs share a common degradation pathway; the result may be severe bone marrow suppression due to increased effects of the azathioprine.
The calcineurin inhibitors cyclosporine and tacrolimus seem to be effective in MG and appear to work more rapidly than azathioprine and mycophenolate. However, they are associated with more frequent severe side effects including hypertension and nephrotoxicity. The usual dose of cyclosporine is 4–5 mg/kg per d, and the average dose of tacrolimus is 0.07–0.1 mg/kg per d, given in two equally divided doses. “Trough” blood levels are measured 12 h after the evening dose. The therapeutic range for the trough level of cyclosporine is 150–200 ng/L, and for tacrolimus, it is 5–15 ng/L.
Rituximab (Rituxan) is a monoclonal antibody that binds to the CD20 molecule on B lymphocytes. It has been widely used for the treatment of B cell lymphomas and has also proven successful in the treatment of several autoimmune diseases including rheumatoid arthritis, pemphigus, and some IgM-related neuropathies. There is an increasing literature on the benefit of rituximab in MG. It appears particularly effective in MuSK antibody–positive MG, although some patients with AChR antibody MG also respond. A large NIH sponsored trial is underway in AChR-positive MG. The usual dose is 1 g IV on two occasions 2 weeks apart. Periodically, a repeat course needs to be administered; some MuSK patients go 2–3 years between infusions.
Eculizumab is a monoclonal antibody that binds membrane attack complex and was beneficial in a small pilot study of MG patients. The results of a large phase 3 clinical trial were recently published and largely positive leading to recent FDA approval. The drug is administered intravenously every 2 weeks.
For the rare refractory MG patient, a course of high-dose cyclophosphamide may induce long-lasting benefit by “rebooting” the immune system. At high doses, cyclophosphamide eliminates mature lymphocytes but spares hematopoietic precursors (stem cells), because they express the enzyme aldehyde dehydrogenase, which hydrolyzes cyclophosphamide. This procedure is reserved for refractory patients and should be administered only in a facility fully familiar with this approach. Maintenance immunotherapy after rebooting is usually required to sustain the beneficial effect. PLASMAPHERESIS AND INTRAVENOUS IMMUNOGLOBULIN
Plasmapheresis has been used therapeutically in MG. Plasma, which contains the pathogenic antibodies, is mechanically separated from the blood cells, which are returned to the patient. A course of five exchanges (3–4 L per exchange) is generally administered over a 10- to 14-day period. Plasmapheresis produces a short-term reduction in anti-AChR antibodies, with clinical improvement in many patients. It is useful as a temporary expedient in seriously affected patients or to improve the patient’s condition prior to surgery (e.g., thymectomy).
The indications for the use of IVIg are the same as those for plasma exchange: to produce rapid improvement to help the patient through a difficult period of myasthenic weakness or prior to surgery. This treatment has the advantages of not requiring special equipment or large-bore venous access. The usual dose is 2 g/kg, which is typically administered >2–5 days. Improvement occurs in ~70% of patients, beginning during treatment or within a week, and continuing for weeks to months. The mechanism of action of IVIg is not known; the treatment has no consistent effect on the measurable amount of circulating AChR antibody. Adverse reactions are generally not serious but may include headache, fluid overload, and rarely aseptic meningitis or renal failure. IVIg or plasma exchange is occasionally used in combination with other immunosuppressive therapy for maintenance treatment of difficult MG. MANAGEMENT OF MYASTHENIC CRISIS
Myasthenic crisis is defined as an exacerbation of weakness sufficient to endanger life; it usually includes ventilatory failure caused by diaphragmatic and intercostal muscle weakness. Treatment should be carried out in intensive care units staffed with teams experienced in the management of MG. The possibility that deterioration could be due to excessive anticholinesterase medication (“cholinergic crisis”) is best excluded by temporarily stopping anticholinesterase drugs. The most common cause of crisis is intercurrent infection. This should be treated immediately because the mechanical and immunologic defenses of the patient can be assumed to be compromised. The myasthenic patient with fever and early infection should be treated like other immunocompromised patients. Early and effective antibiotic therapy, ventilatory assistance, and pulmonary physiotherapy are essentials of the treatment program. As discussed above, plasmapheresis or IVIg is frequently helpful in hastening recovery. DRUGS TO AVOID IN MYASTHENIC PATIENTS
Many drugs can potentially exacerbate weakness in patients with MG (Table 440-4). As a rule, the listed drugs should be avoided whenever possible.
Algorithm for the management of myasthenia gravis. FVC, forced vital capacity; MRI, magnetic resonance imaging.
TABLE 440-4Drugs with Interactions in Myasthenia Gravis (MG) |Favorite Table|Download (.pdf) TABLE 440-4 Drugs with Interactions in Myasthenia Gravis (MG)
|Drugs That May Exacerbate MG |
|Aminoglycosides: e.g., streptomycin, tobramycin, kanamycin |
|Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin |
|Macrolides: e.g., erythromycin, azithromycin |
|Nondepolarizing muscle relaxants for surgery |
|D-Tubocurarine (curare), pancuronium, vecuronium, atracurium |
|Beta-blocking agents |
|Propranolol, atenolol, metoprolol |
|Local anesthetics and related agents |
|Procaine, Xylocaine in large amounts |
|Procainamide (for arrhythmias) |
|Botulinum toxin |
|Botox exacerbates weakness |
|Quinine derivatives |
|Quinine, quinidine, chloroquine, mefloquine (Lariam) |
|Decreases acetylcholine release |
|May cause MG |
|Check point inhibitors |
|May cause MG and other autoimmune neuromuscular disorders (e.g., myositis, inflammatory neuropathy) |
|Drugs with Important Interactions in MG |
|Cyclosporine and Tacrolimus |
|Broad range of drug interactions, which may raise or lower levels. |
|Avoid allopurinol—combination may result in myelosuppression. |