Physical Examination

 Ptosis as myasthenia gravis often affects the extraocular and bulbar musculature.
 

Forward arm abduction time (5 min)

 

 

A. Characteristic signs and symptoms

One or more of the following:

  1.  

  2. Dramatic improvement in strength following administration of anticholinesterase drug (edrophonium (Tensilón®) and neostigmine);

and one or more of the following:

B. EMG and repetitive stimulation of a peripheral nerve: In myasthenia gravis repetitive stimulation at a rate of 2 per second shows characteristic decremental response which is reversed by edrophonium or neostigmine. Single fiber studies show increased jitter.

C. Antibodies to Acetylcholine Receptors

Exclusions:

  • Congenital myasthenic syndrome, progressive restricted myopathies, steroid and inflammatory myopathies, motor neuron disease

  • Multiple sclerosis, variants of Guillain-Barré syndrome (e.g., Miller-Fisher syndrome)

  • Organophosphate toxicity, botulism, black widow spider venom

  • Eaton-Lambert syndrome

  • Stroke

  • Medications: neuromuscular blocking agents, aminoglycosides, penicillamine, antimalarial drugs, colistin, streptomycin, polymyxin B, tetracycline

  • Hypokalemia; hypophosphatemia

Severity: (Osserman classification):

I: Ocular myasthenia
IIA: Mild generalized myasthenia with slow progression: no crises, responsive to drugs
IIB. : Moderately severe generalized myasthenia : severe skeletal and bulbar involvement but no crises; drug response less than satisfactory
III: Acute fulminating myasthenia, rapid progression of severe symptoms, with respiratory crises and poor drug response
IV: Late severe myasthenia, same as III but progression over 2 years from class I to II

 

Related Criteria

McDonald Diagnostic Criteria for Multiple Sclerosis (MS)

NIH Diagnostic Criteria for Neurofibromatosis

Diagnostic Criteria for Tuberous Sclerosis Complex (TSC)

Diagnostic Criteria for Neurocysticercosis

Diagnostic Criteria and Associated Features of Restless Legs Syndrome (RLS)

More...

 

References:

  1. Ossermann KE. Myasthenia gravis. New York: Grune and Stratton; 1958.

  2. Engel AG. Myasthenic syndromes. In: Engel AG, Franzini Armstrong C, editors. Myology. 2nd ed. New York: McGraw Hill; 1994. p. 1798-835.

 

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(muscle-specific tyrosine kinase.) antibodies

 

 Repetitive nerve stimulation: decrement of >15% 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

Abbreviations: AChR, acetylcholine receptor;

Antibodies to AChR, MuSK, or lpr4

Antibodies to ACh receptors are often present and can provide a measure of the degree of disease activity.

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. However, in an individual patient, a treatment-induced fall in the antibody level often correlates with clinical improvement, whereas a rise in the level may occur with exacerbations. Antibodies to MuSK have been found to be present in ~40% of AChR antibody–negative patients with generalized MG, and their presence is a useful diagnostic test in these patients. 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 neuromuscular junctions, as MuSK is known to do during early development. A small proportion of MG patients without antibodies to AChR or MuSK may have antibodies to lrp4, although a test for lrp4 antibodies is not yet commercially available. Finally, 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 thus may also interfere with clustering of AChRs at neuromuscular junctions. There may well be other—as yet undefined—antibodies that impair neuromuscular transmission.

Nerve Stimulation

Electromyography

Anti-AChE medication is stopped 6–24 h before testing. It is best to test weak muscles or proximal muscle groups. Electric shocks are 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 at these rates of stimulation. However, in myasthenic patients, there is a rapid reduction of >10–15% in the amplitude of the evoked responses.

The muscle action potential, which provides a measure of the number of muscle cells that are contracting, decreases in size with repetitive stimulation in myasthenia gravis.

Anticholinesterase Test

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 extraocular muscles, impairment of speech, or the length of time that the patient can maintain the arms in forward abduction. 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 and electrodiagnostic test results. False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic lateral sclerosis, and in placebo-reactors. False-negative or equivocal tests may also occur. In some cases, it is helpful to use a longer-acting drug such as neostigmine (15 mg PO), because this permits more time for detailed evaluation of strength.

Inherited Myasthenic Syndromes

The congenital myasthenic syndromes (CMS) comprise a heterogeneous group of disorders of the neuromuscular junction that are not autoimmune but rather are due to genetic mutations in which virtually any component of the neuromuscular junction 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 skeletal muscles, in some cases involving extraocular muscles (EOMs), lids, and proximal muscles, similar to the distribution in autoimmune MG. CMS should be suspected when symptoms of myasthenia have begun in infancy or childhood and AChR antibody tests are consistently negative. By far the most common genetic defects occur in the AChR or other postsynaptic molecules (67% in the Mayo Clinic series of 350 CMS patients), with about equal frequencies of abnormalities in AChE (13%) and the various maintenance molecules (DOK7, GFPT, etc.; ~14%). In the forms that involve the AChR, a wide variety of mutations have been identified in each of the subunits, but the ε subunit is affected in ~75% of these cases. 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 four most common forms of CMS are summarized in Table 461-2. Although clinical features and electrodiagnostic and pharmacologic tests may suggest the correct diagnosis, molecular analysis is required for precise elucidation of the defect; this may lead to helpful treatment as well as genetic counseling.

BLE 461-2 The Congenital Myasthenic Syndromes

Type Clinical Features Electrophysiology Genetics End-Plate Effects Treatment
Slow channel Most common; weak forearm extensors; onset second to third decade; variable severity Repetitive muscle response on nerve stimulation; prolonged channel opening and MEPP duration Autosomal dominant; α, β, ε; AChR mutations Excitotoxic end-plate myopathy; decreased AChRs; postsynaptic damage Quinidine, fluoxetine: decrease end-plate damage; made worse by anti-AChE
Low-affinity fast channel Onset early; moderately severe; ptosis, EOM involvement; weakness and fatigue Brief and infrequent channel openings; opposite of slow channel syndrome Autosomal recessive; may be heteroallelic Normal end-plate structure 3,4-DAP; anti-AChE
Severe AChR deficiencies Early onset; variable severity; fatigue; typical MG features Decremental response to repetitive nerve stimulation; decreased MEPP amplitudes Autosomal recessive; ε mutations most common; many different mutations Increased length of end plates; variable synaptic folds Anti-AChE; 3,4-DAP
AChE deficiency Early onset; variable severity; scoliosis; may have normal EOM, absent pupillary responses Decremental response to repetitive nerve stimulation Mutant gene for AChE’s collagen anchor (COLQ) Small nerve terminals; degenerated junctional folds Worse with anti-AChE drugs; use albuterol, ephedrine, 3,4-DAP

Abbreviations: AChE, acetylcholinesterase; AChR, acetylcholine receptor; EOM, extraocular muscles; MEPP, miniature end-plate potentials; MG, myasthenia gravis; 3,4-DAP, 3,4-diaminopyridine.

Differential Diagnosis

Other conditions that cause weakness of the cranial and/or somatic musculature include the nonautoimmune CMS discussed above, 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) may result in true autoimmune MG, but the weakness is usually mild, and recovery occurs within weeks or months after discontinuing its use. Aminoglycoside antibiotics or procainamide can cause exacerbation of weakness in myasthenic patients; very large doses can cause neuromuscular weakness in normal individuals.

LEMS is a presynaptic disorder of the neuromuscular junction 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 response and, at low rates of repetitive stimulation (2–3 Hz), decremental responses like those of MG; however, at high rates (50 Hz), or following exercise, incremental responses occur. LEMS is caused by autoantibodies directed against P/Q-type calcium channels at the motor nerve terminals, which can be detected in ~85% of LEMS patients by radioimmunoassay. These autoantibodies result in impaired release of ACh from nerve terminals. Many patients with LEMS have an associated malignancy, most commonly small-cell carcinoma of the lung, which may express calcium channels that stimulate the autoimmune response. The diagnosis of LEMS may signal the presence of a tumor long before it would otherwise be detected, permitting early removal. Treatment of LEMS involves plasmapheresis and immunosuppression, as for MG. 3,4-Diaminopyridine (3,4-DAP) and pyridostigmine may also be symptomatically helpful. 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. 178) 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 findings of presynaptic neuromuscular blockade with reduced compound muscle action potentials (CMAPs) that increase in amplitude 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. 462e).

Search for Associated Conditions

(Table 461-3) Myasthenic patients have an increased incidence of several associated disorders. 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 computed tomography (CT) scanning of the anterior mediastinum. 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. Because of the association of MG with other autoimmune disorders, blood tests for rheumatoid factor and antinuclear antibodies should also be carried out. Chronic infection of any kind can exacerbate MG and should be sought carefully. Finally, measurements of ventilatory function are valuable because of the frequency and seriousness of respiratory impairment in myasthenic patients.


TABLE 461-3 Disorders Associated with Myasthenia Gravis and Recommended Laboratory Tests

Associated disorders
Disorders of the thymus: thymoma, hyperplasia
Other autoimmune disorders: Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, 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 461-4)
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 lupus erythematosus, antinuclear antibody, rheumatoid factor, antithyroid antibodies
 Thyroid function tests
 PPD skin test
 Fasting blood glucose, hemoglobin A1c
 Pulmonary function tests
 Bone densitometry

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PPD, purified protein derivative.

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TABLE 461-4 Drugs with Interactions in Myasthenia Gravis (MG)
Drugs That May Exacerbate MG
Antibiotics
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)
Magnesium
Decreases acetylcholine release
Penicillamine
May cause MG
Drugs with Important Interactions in MG
Cyclosporine
Broad range of drug interactions, which may raise or lower cyclosporine levels.
Azathioprine
Avoid allopurinol—combination may result in myelosuppression.

Because of the side effects of glucocorticoids and other immunosuppressive agents 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.

 

 

 

The distribution of muscle weakness often has a characteristic pattern. The cranial muscles, particularly the lids and extraocular muscles, are typically involved early in the course of MG; diplopia and ptosis are common initial complaints. Facial weakness produces a “snarling” expression when the patient attempts to smile. Weakness in chewing is most noticeable after prolonged effort, as in chewing meat. Speech may have a nasal timbre caused by weakness of the palate or a dysarthric “mushy” quality due to tongue weakness. Difficulty in swallowing may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to nasal regurgitation or aspiration of liquids or food. Bulbar weakness is especially prominent in MuSK antibody–positive MG. In ~85% of patients, the weakness becomes generalized, affecting the limb muscles as well. If weakness remains restricted to the extraocular muscles for 3 years, it is likely that it will not become generalized, and these patients are said to have ocular MG. The limb weakness in MG is often proximal and may be asymmetric. Despite the muscle weakness, deep tendon reflexes are preserved. If weakness of respiration becomes so severe as to require respiratory assistance, the patient is said to be in crisis.

(Table 461-1) 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. 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.


Injection of anticholinesterase drugs, such as neostigmine or edrophonium chloride, may reverse the fatigue and help to confirm the diagnosis.

 

Myasthenia gravis should not be confused with the myasthenic syndrome (Lambert–Eaton syndrome), an autoimmune disease seen in the context of systemic neoplasms (especially those affecting the lung and breast). In the myasthenic syndrome, abnormal antibodies directed against presynaptic Ca2+ channels interfere with the release of ACh from the presynaptic ending at the neuromuscular junction.

 

See: Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles.

Abnormal, gradual tiring of the muscles for eye movement and chewing is suggestive of fatigue at the neuromuscular junction. The healthy neuromuscular junction can transmit at high frequencies so that this type of fatigue does not normally occur. The prominence of muscular fatigue suggested a diagnosis of myasthenia gravis in this patient. The absence of sensory deficits tends to confirm the diagnosis. Electromyography is a useful procedure for confirmation of the diagnosis; the muscle action potential, which provides a measure of the number of muscle cells that are contracting, decreases in size with repetitive stimulation in myasthenia gravis. In addition, antibodies to ACh receptors are often present and can provide a measure of the degree of disease activity. Injection of anticholinesterase drugs, such as neostigmine or edrophonium chloride, may reverse the fatigue and help to confirm the diagnosis. Treatment centers on the use of anticholinesterase drugs and immunosuppressants, including corticosteroids, which decrease the rate of anti-ACh receptor antibody production. In some patients, thymectomy is effective.

Comment: Myasthenia gravis often affects the extraocular and bulbar musculature. Myasthenia gravis should not be confused with the myasthenic syndrome (Lambert–Eaton syndrome), an autoimmune disease seen in the context of systemic neoplasms (especially those affecting the lung and breast). In the myasthenic syndrome, abnormal antibodies directed against presynaptic Ca2+ channels interfere with the release of ACh from the presynaptic ending at the neuromuscular junction.

 

Treatment centers on the use of anticholinesterase drugs and immunosuppressants, including corticosteroids, which decrease the rate of anti-ACh receptor antibody production. In some patients, thymectomy is effective.

 

Thymectomy and Prednisone

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, and plasmapheresis or intravenous immunoglobulin (IVIg) (Fig. 461-2).

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. Pyridostigmine is the most widely used anticholinesterase drug. The beneficial action of oral pyridostigmine begins within 15–30 min and lasts for 3–4 h, but individual responses vary. Treatment is begun with a moderate dose, e.g., 30–60 mg three to four times daily. 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 ofpyridostigmine rarely exceeds 120 mg every 4–6 h during daytime. 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. In the absence of a tumor, the available evidence suggests that up to 85% of patients experience improvement after thymectomy; of these, ~35% achieve drug-free remission. However, the improvement is typically delayed for months to years. The advantage of thymectomy is that it offers the possibility of long-term benefit, in some cases diminishing or eliminating the need for continuing medical treatment. Review of the published studies showed that following thymectomy, MG patients were 1.7 times as likely to improve and twice as likely to attain remission as those who did not have surgical thymectomy. In view of these potential benefits and of the negligible risk in skilled hands, thymectomy has gained widespread acceptance in the treatment of MG. It is the consensus that thymectomy should be carried out in all patients with generalized MG who are between the ages of puberty and at least 55 years. Whether thymectomy should be recommended in children, in adults >55 years of age, and in patients with weakness limited to the ocular muscles is still a matter of debate. There is also evidence that patients with MuSK antibody–positive MG respond less well to thymectomy than those with AChR antibody. Thymectomy must be carried out in a hospital where it is performed regularly and where the staff is experienced in the pre- and postoperative management, anesthesia, and surgical techniques of total 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, but it is helpful to try to avoid immunosuppressive agents because of the risk of infection.

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 tacrolimusgenerally 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. The initial dose should be relatively low (15–25 mg/d) to avoid the early weakening that occurs in up to one-third 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- to 3-day intervals), until there is marked clinical improvement or a dose of 50–60 mg/d is reached. This dose is maintained for 1–3 months and then is gradually modified to an alternate-day regimen over the course of an additional 1–3 months; the goal is to reduce the dose on the “off day” to zero or to a minimal level. Generally, patients begin to improve within a few weeks after reaching the maximum dose, and improvement continues to progress for months or years. The prednisone dosage may gradually be reduced, but usually months or years may be needed to determine the minimum effective dose, and close monitoring is required. Few patients are able to do without immunosuppressive agents entirely. 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. 406.

Other Immunosuppressive Drugs

Mycophenolate mofetil, azathioprine, cyclosporinetacrolimus, rituximab, and occasionally cyclophosphamide are effective in many patients, either alone or in various combinations.

Mycophenolate mofetil has become one of the most widely used drugs in the treatment of MG because of its 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.

Until recently, azathioprine has been the most commonly used immunosuppressive agent for MG because of its relative safety in most patients and long track record. Its therapeutic effect may add to that of glucocorticoids and/or allow the glucocorticoid dose to be reduced. However, up to 10% of patients are unable to tolerate azathioprine because of idiosyncratic reactions consisting of flu-like symptoms of fever and malaise, bone marrow suppression, or abnormalities of liver function. An initial dose of 50 mg/d should be used for several days 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. The beneficial effect of azathioprine takes 3–6 months to begin and even longer to peak. In patients taking azathioprine, allopurinol should never be used to treat hyperuricemia. 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 (FK506) are approximately as effective as azathioprine and are being used increasingly in the management of MG. Their beneficial effect appears more rapidly than that of azathioprine. Either drug may be used alone, but they are usually used as an adjunct to glucocorticoids to permit reduction of the glucocorticoid dose. The usual dose of cyclosporine is 4–5 mg/kg per day, and the average dose of tacrolimus is 0.07–0.1 mg/kg per day, given in two equally divided doses (to minimize side effects). Side effects of these drugs include hypertension and nephrotoxicity, which must be closely monitored. “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 now an extensive literature on the benefit of rituximab in MG. It is particularly effective in MuSK antibody–positive MG, although some patients with AChR antibody MG respond to it as well. The usual dose is 375 mg/m2, given IV in 4 weekly infusions, or 1 g, given IV on two occasions 2 weeks apart.

For the occasional patient with MG that is genuinely refractory to optimal treatment with conventional immunosuppressive agents, 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. At present, 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 over 5 days (400 mg/kg per day). If tolerated, the total dose of IVIg can be given over a 3- to 4-day period. 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 should rarely be used as a long-term treatment in place of rationally managed immunosuppressive therapy. Unfortunately, there is a tendency for physicians unfamiliar with immunosuppressive treatments to rely on repeated IVIg infusions, which usually produce only intermittent benefit, do not reduce the underlying autoimmune response, and are very costly. The intermediate and long-term treatment of myasthenic patients requires other methods of therapy outlined earlier in this chapter.

MANAGEMENT OF MYASTHENIC CRISIS

Myasthenic crisis is defined as an exacerbation of weakness sufficient to endanger life; it usually consists of respiratory failure caused by diaphragmatic and intercostal muscle weakness. Crisis rarely occurs in properly managed patients. Treatment should be carried out in intensive care units staffed with teams experienced in the management of MG, respiratory insufficiency, infectious disease, and fluid and electrolyte therapy. 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, respiratory assistance (preferably noninvasive, using bilevel positive airway pressure), 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 have been reported to exacerbate weakness in patients with MG (Table 461-4), but not all patients react adversely to all of these. Conversely, not all “safe” drugs can be used with impunity in patients with MG. As a rule, the listed drugs should be avoided whenever possible, and myasthenic patients should be followed closely whenany new drug is introduced.


Algorithm for the management of myasthenia gravis.
 FVC, forced vital capacity; MRI, magnetic resonance imaging.

To evaluate the effectiveness of treatment as well as drug-induced side effects, it is important to assess the patient’s clinical status systematically at baseline and on repeated interval examinations. Because of the variability of symptoms of MG, the interval history and physical findings on examination must be taken into account. The most useful clinical tests include forward arm abduction time (up to a full 5 min), spirometry with determination of forced vital capacity, range of eye movements, and time to development of ptosis on upward gaze. Manual muscle testing or, preferably, quantitative dynamometry of limb muscles, especially proximal muscles, is also important. An interval form can provide a succinct summary of the patient’s status and a guide to treatment results; an abbreviated form is shown in Fig. 461-3. A progressive reduction in the patient’s AChR antibody level also provides clinically valuable confirmation of the effectiveness of treatment; conversely, a rise in AChR antibody levels during tapering of immunosuppressive medication may predict clinical exacerbation. For reliable quantitative measurement of AChR antibody levels, it is best to compare antibody levels from prior frozen serum aliquots with current serum samples in simultaneously run assays.


Abbreviated interval assessment form
 for use in evaluating treatment for myasthenia gravis.

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The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack.

 

Neuromuscular transmission disorder characterized by fluctuating weakness and fatigability of bulbar and other voluntary muscles without loss of reflexes or impairment of sensation or other neurologic function.

 

How the autoimmune response is initiated and maintained in MG is not completely understood, but the thymus appears to play a role in this process.

The thymus is abnormal in ~75% of patients with AChR antibody–positive MG; in ~65% the thymus is “hyperplastic,” with the presence of active germinal centers detected histologically, although the hyperplastic thymus is not necessarily enlarged. An additional 10% of patients have thymic tumors (thymomas).

Muscle-like cells within the thymus (myoid cells), which express AChRs on their surface, may serve as a source of autoantigen and trigger the autoimmune reaction within the thymus gland.

At the neuromuscular junction (Fig. 461-1Video 461-1), acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in vesicles (quanta).

Image not available.

Diagrams of (A) normal and (B) myasthenic neuromuscular junctions. AChE, acetylcholinesterase. See text for description of normal neuromuscular transmission. The myasthenia gravis (MG) junction demonstrates a normal nerve terminal; a reduced number of acetylcholine receptors (AChRs) (stippling); flattened, simplified postsynaptic folds; and a widened synaptic space. See Video 461-1 also. (Modified from DB Drachman: N Engl J Med 330:1797, 1994; with permission.)

In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or “simplified.” These changes result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction.

The amount of ACh released per impulse normally declines on repeated activity (termedpresynaptic rundown). In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electrodiagnostic testing.

The neuromuscular abnormalities in MG are caused by an autoimmune response mediated by specific anti-AChR antibodies. The anti-AChR antibodies reduce the number of available AChRs at neuromuscular junctions by three distinct mechanisms: (1) accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors; (2) damage to the postsynaptic muscle membrane by the antibody in collaboration with complement; and (3) blockade of the active site of the AChR, i.e., the site that normally binds ACh. An immune response to muscle-specific kinase (MuSK), a protein involved in AChR clustering at neuromuscular junctions, can also result in MG, with reduction of AChRs demonstrated experimentally. Anti-MuSK antibody occurs in about 40% of patients without AChR antibody. A small proportion of patients whose sera are negative for both AChR and MuSK antibodies have antibodies to another protein at the neuromuscular junction—low-density lipoprotein receptor-related protein 4 (lrp4)—that is important for clustering of AChRs. The pathogenic antibodies are IgG and are T cell dependent. Thus, immunotherapeutic strategies directed against either the antibody-producing B cells or helper T cells are effective in this antibody-mediated disease.

 

When an action potential travels down a motor nerve and reaches the nerve terminal, ACh from 150 to 200 vesicles is released and combines with AChRs that are densely packed at the peaks of postsynaptic folds. The AChR consists of five subunits (2α, 1β, 1δ, and 1γ or ε) arranged around a central pore. When ACh combines with the binding sites on the α subunits of the AChR, the channel in the AChR opens, permitting the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the muscle fiber. If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber, triggering muscle contraction. This process is rapidly terminated by hydrolysis of ACh by acetylcholinesterase (AChE), which is present within the synaptic folds, and by diffusion of ACh away from the receptor.

MG is not rare, having a prevalence as high as 2–7 in 10,000. It affects individuals in all age groups, but peaks of incidence occur in women in their twenties and thirties and in men in their fifties and sixties. Overall, women are affected more frequently than men, in a ratio of ~3:2.

 

 

History

 
 
 
 

 

Physical Exam

 

Laboratory Tests

X-ray

 

Essentail Criteria to Establish Diagnosis

 

 

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The course of MG is often variable. Exacerbations and remissions may occur, particularly during the first few years after the onset of the disease. Remissions are rarely complete or permanent. Unrelated infections or systemic disorders can lead to increased myasthenic weakness and may precipitate “crisis” (see below).

 

A 26-year-old woman is diagnosed with myasthenia gravis in the setting of complaints of diplopia, dysphagia, and weakness with fatigability. Acetylcholine receptor antibodies are positive. She is initially treated with pyridostigmine 60 mg three times daily with improvement. She is further evaluated for concomitant conditions. A CT scan of the neck reveals a “thymic shadow” but no evidence of thymoma. She is not found to have hyperthyroidism or any other autoimmune disorder. Her forced vital capacity after treatment with pyridostigmine is 2.9 L (73% predicted). What is the next best approach for treatment of this patient?

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The correct answer is E. You answered A.

The answer is E.  The treatment of MG may include a variety of modalities including anticholinesterase medications, immunosuppression, IVIg or plasmapheresis, or surgical intervention. Initial treatment of symptoms with anticholinesterase medications such as pyridostigmine yields partial improvement in most patients. However, few patients achieve complete relief with this class of medications alone. In addition, dose-limiting side effects such as diarrhea, abdominal cramping, and excessive salivation are frequent. Thymectomy should be considered in all patients with MG. When considering thymectomy, there are two separate issues to be considered. If the patient has evidence of thymoma, thymectomy is necessary because local spread may occur. However, presence of a thymic shadow on CT scan is not indicative of thymoma and is common in young adulthood. In individuals without evidence of thymoma, thymectomy should still be considered an important therapeutic option. Even in the absence of tumor, up to 85% of individuals will experience improvement in disease after thymectomy, with ~35% achieving drug-free remission. Current literature suggests that individuals who undergo thymectomy are 1.7 times more likely to improve and 2 times more likely to achieve remission than those who do not undergo thymectomy. It is now consensus that individuals between the ages of puberty and 55 with generalized MG should be referred for thymectomy if surgically appropriate candidates. In the absence of thymectomy, addition of immunosuppressants in the form of glucocorticoids or other steroid-sparing agents will yield further benefits and often control the disease. Prednisone at a dose of 15–25 mg daily is the initial choice in most patients and should be increased for residual symptoms. Other immunomodulatory agents with proven effectiveness in MG include mycophenolate mofetil, azathioprine, cyclosporine, and tacrolimus. In addition, rituximab may be considered in refractory cases. In acute presentations with myasthenic crisis, IVIg or plasmapheresis is used concomitantly with immunosuppressants. Anticholinesterase drugs are typically withheld during a myasthenic crisis because overdosage of these drugs can worsen weakness.

 

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