Review Article

Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome Donald B. Sanders, MD, FAAN; Jeffrey T. Guptill, MD, MA, MHS ABSTRACT Purpose of Review: This article reviews the clinical presentations, diagnostic findings, and treatment options for autoimmune myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome. Recent Findings: Immunologic research is unraveling the immunopathology of MG and identifying targets for novel immune-based therapy of this condition. MG patients with antibodies to muscle-specific tyrosine kinase (MuSK) frequently present with symptoms and clinical findings that suggest nerve or muscle disease. Summary: Early diagnosis and treatment have a marked effect on outcome in these diseases. In most cases, the diagnosis of MG or Lambert-Eaton myasthenic syndrome can be made from the history, supplemented with directed questions, and a physical examination designed to demonstrate variable weakness in affected muscle groups. Appropriate confirmatory tests almost always establish the diagnosis. Although several novel treatment modalities for MG are under investigation, currently available therapies produce substantial improvement in function and quality of life in most patients with this condition. Knowledge about the dosing, adverse effects, and costs of immunomodulatory therapies is essential for the effective management of patients with MG and Lambert-Eaton myasthenic syndrome. Continuum (Minneap Minn) 2014;20(5):1413–1425.

INTRODUCTION Diseases that affect the neuromuscular junction are characterized by weakness that predominantly affects certain muscle groups and fluctuates over time, worsening with use and improving after rest. Autoimmune myasthenia gravis (MG), although rare, is the most common neuromuscular junction disorder, estimated to affect about 60,000 people in the United States. Lambert-Eaton myasthenic syndrome (LEMS) is even rarer. This article identifies clinical features that should lead the practicing neurologist to consider one of these conditions. The treatments currently available are reviewed and treatment approaches based on the experience of the authors of this article and published Continuum (Minneap Minn) 2014;20(5):1413–1425

Address correspondence to Dr Donald B. Sanders, Box 3403, Duke University Medical Center, Durham, NC 27710, [email protected] Relationship Disclosure: Dr Sanders has served as a speaker for Athena Diagnostics, Inc; as a consultant for Accordant Health Services, GlaxoSmithKline, Jacobus Pharmaceutical Company, Inc, and UCB, Inc; and has participated in review activities with Alexion and Cytokinetics, Inc. Dr Guptill serves as a consultant for Grifols and UCB, Inc, and receives research support from the Myasthenia Gravis Foundation of America. Dr Guptill’s institution receives grants from Grifols and UCB, Inc. Unlabeled Use of Products/Investigational Use Disclosure: Drs Sanders and Guptill discuss the unlabeled use of amifampridine and rituximab for the treatment of Lambert-Eaton myasthenic syndrome and the unlabeled use of azathioprine, cyclosporine A, mycophenolate mofetil, and rituximab for the treatment of myasthenia gravis. * 2014, American Academy of Neurology.

data are proposed, although few have been proven by clinical trials. Pathophysiology of Myasthenia Gravis Healthy neuromuscular transmission requires release of acetylcholine from the motor nerve followed by acetylcholine binding to the pentameric acetylcholine receptor (AChR). In addition to the AChR, the structure of the neuromuscular junction is maintained by several proteins that include agrin, low-density lipoprotein receptorYrelated protein 4 (LRP4), and muscle-specific tyrosine kinase (MuSK). Agrin released from the motor nerve interacts with postsynaptic LRP4, which, in turn, activates MuSK.

Supplemental digital content: Videos accompanying this article are cited in the text as Supplemental Digital Content. Videos may be accessed by clicking on links provided in the HTML, PDF, and iPad versions of this article; the URLs are provided in the print version. Video legends begin on page 1423.

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Myasthenia Gravis and LEMS

MuSK then plays an important role in clustering AChRs at the endplate.1 Autoimmune MG is caused by autoantibodies directed against neuromuscular junction proteins. Most commonly, MG is a T-cellYdependent disease with antibodies directed against postsynaptic AChR (85%). AChR antibodies are predominantly immunoglobulin (Ig)G1 and IgG3 that activate complement. These antibodies disrupt neuromuscular transmission via three mechanisms: (1) complement-mediated activation of membrane attack complex and destruction of the postsynaptic membrane; (2) cross-linking AChRs, which leads to AChR degradation through internalization by endocytosis; and (3) direct blockade of the acetylcholine binding site on the AChR.2 Antibodies against MuSK, LRP4, and agrin are less common.3Y5 MuSK antibodies are most important since they have been demonstrated to be pathogenic and their presence may affect patient management (see ‘‘Treatment of Myasthenia Gravis’’). MuSK antibodies are primarily IgG4, which do not activate complement but inhibit MuSK’s role in clustering AChRs at the endplate. The

pathogenicity of LRP4 and agrin autoantibodies is under investigation. Symptoms of Myasthenia Gravis Patients with MG present with symptoms of specific muscle dysfunction. As demonstrated by Case 14-1, ptosis or diplopia is the initial symptom of MG in two-thirds of patients; almost all have both of these symptoms within 2 years of onset.6,7 Bulbar dysfunction (difficulty chewing, swallowing, or talking) produces the presenting symptoms in one-sixth of patients with MG. In about 10%, the initial symptoms are due to weakness of individual muscle groups (neck or finger extensors, hip flexors, or ankle dorsiflexors). These symptoms typically fluctuate during the day, being less severe in the morning and worse as the day progresses and after prolonged use of involved muscles. Ocular symptoms are frequently worse in bright light. Chewing typically becomes worse during a meal, particularly of hard-to-chew foods. The voice may become nasal, slurred, or hoarse, especially after prolonged talking. Patients with perioral muscle weakness may drool, and liquids may escape through the nose if the palate is weak. Coughing or frequent throat

Case 14-1 A 20-year-old woman was referred for evaluation of intermittent slurred speech during the previous 2 weeks. She had no previous neurologic diagnoses, but 6 months earlier, while dressing in the evening, had thought her right eyelid was lower than the left. This persisted for about a week, then cleared. On examination at 10:30 AM, she was a healthy-appearing young woman weighing 110 pounds, with normal vital signs. She appeared to be slightly depressed and anxious, but her speech was initially normal. There was no lid ptosis, but her right eyebrow was elevated and the right frontalis was furrowed. After talking for about 5 minutes, her speech became slurred in a lingual pattern. She volunteered that this was what usually happened when she talked ‘‘a lot.’’ On formal examination, she developed moderate right eyelid ptosis and divergent gaze after looking up for 30 seconds. Gaze was initially normal to both sides, but horizontal diplopia developed after she looked to either side for 30 seconds. The remainder of the examination was normal. Comment. This is a classic case of myasthenia gravis in a young woman, initially affecting the ocular and oropharyngeal muscles.

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clearing during or after a meal indicates impaired swallowing. Careful questioning often reveals evidence of earlier, unrecognized weakness due to MG. Patients may frequently change eyeglasses to correct blurry vision, avoid foods that are difficult to chew or swallow, or give up activities that require prolonged use of specific muscles, such as singing.

Antibodies to MuSK are found in 8% to 10% of MG patients (MuSK MG). Females are predominantly affected by MuSK MG, which may begin as early as childhood. Patients with MuSK MG frequently have findings atypical for MG (Case 14-2). In the experience of the authors, about 50% of patients with MuSK MG present with typical MG

Case 14-2 A 45-year-old woman developed fatigable lingual and nasal dysarthria. One year later, she had a single episode of transient unilateral eyelid ptosis and dysphagia. At age 53, when she presented to the authors’ clinic, she had severe lingual dysarthria, marked atrophy of the tongue and facial muscles, and minimal lid ptosis (Figure 14-16). EMG of the tongue demonstrated motor unit potentials that varied markedly from discharge to discharge, indicating abnormal neuromuscular transmission. Single-fiber EMG demonstrated increased jitter and frequent blocking in facial and limb muscles.

FIGURE 14-1

Muscle-specific tyrosine kinase myasthenia gravis with marked upper facial muscle weakness and atrophy. At rest (A) slight bilateral lid ptosis is present. No visible (or palpable) contraction of the frontalis muscle is seen on attempted elevation of the eyebrows (B), and she does not bury the eyelashes during forced eyelid closure (C). Tongue is markedly wasted (D). Reprinted with permission from Sanders DB, Massey JM, Elsevier.6 B 2008 Elsevier, Inc.

Comment. The clinical presentation in this patient did not suggest myasthenia gravis; there was marked atrophy of the tongue, and ocular muscle function was normal. These findings had led to an initial diagnosis of motor neuron disease in this patient who was ultimately diagnosed with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). In the authors’ clinic, about one-third of patients with MuSK MG have a clinical pattern similar to this patient. This case demonstrates the value of assessing motor unit variability during EMG. Continuum (Minneap Minn) 2014;20(5):1413–1425

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Myasthenia Gravis and LEMS KEY POINTS

h Myasthenia gravis with acetylcholine receptor antibodies is the most common neuromuscular junction disorder. It typically presents with fluctuating, fatigable ocular symptoms, and signs that are frequently ascribed to CNS disease.

h Muscle-specific tyrosine kinase (MuSK) myasthenia gravis usually affects young females and may have clinical findings suggestive of nerve or muscle disease. Suspect MuSK myasthenia gravis if there is isolated head drop, facial muscle or tongue weakness and atrophy, or weakness that predominates in neck or shoulder muscles.

h Patients and clinicians should be aware of and avoid medications known to exacerbate myasthenia gravis and Lambert-Eaton myasthenic syndrome weakness.

h Examination of patients with suspected myasthenia gravis should focus on demonstrating fatigable weakness in affected muscle groups with particular attention to ocular muscles. Eyelid ptosis that shifts from one eye to the other is virtually diagnostic of myasthenia gravis.

h The weakness in myasthenia gravis typically comes and goes and may not be present during the examination.

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findings: fluctuating ocular, bulbar, and limb weakness. The others have predominant weakness and atrophy of cranial and bulbar muscles, suggesting nerve disease, or prominent neck, shoulder, and respiratory weakness, suggesting muscle disease. These patients frequently have little or no involvement of ocular muscles, which makes the clinical diagnosis challenging. MuSK MG should be considered if there is facial or tongue weakness with atrophy, or weakness that predominates in neck or shoulder muscles. MG follows a variable course, but usually progresses. Weakness remains limited to the ocular muscles in about 10% of patients.6 The other 90% have oropharyngeal and limb muscle weakness within 2 years of onset. Maximum weakness occurs during the first year in two-thirds of patients. Spontaneous improvement is common early in the disease, even for long periods, but these ‘‘remissions’’ are rarely permanent. Factors that may worsen myasthenic symptoms include systemic illness (especially viral respiratory infections), hypothyroidism or hyperthyroidism, pregnancy, the menstrual cycle, iodinated contrast agents, drugs that affect neuromuscular transmission, increased body temperature, and emotional upset. Curariform neuromuscular blocking agents have exaggerated and prolonged effects in MG. Many other medications are known to exacerbate the weakness in patients with MG or LEMS, sometimes with fatal outcome. Aminoglycoside, fluoroquinolone, or macrolide antibiotics are the drugs most frequently involved, as are magnesium salts, especially IV magnesium replacement. Telithromycin should never be used in myasthenic patients. Some antiarrhythmics (quinine, quinidine, and procainamide) compromise neuromuscular transmission and increase weakness in many patients with MG. Many other drugs may exacerbate

the weakness in some patients with MG and LEMS (see www.myasthenia.org).8 All MG and LEMS patients should be observed for increased weakness whenever any new medication is started. The unusual distribution and varying severity of weakness of MG may be misdiagnosed as psychiatric illness.6 Ptosis and diplopia may suggest increased intracranial pressure and lead to unnecessary cranial imaging studies. Physical Examination The examination of patients with suspected MG should assess weakness in specific muscle groups repetitively during maximum effort and after brief periods of rest to determine fatigability. Performance on these tests may fluctuate in other conditions as well, or if testing causes pain. Ocular and oropharyngeal muscle function is less likely to be affected by inconsistent effort. Except for those with MuSK antibodies, virtually all MG patients have weakness of ocular muscles, although close examination may be necessary to demonstrate this. Asymmetrical ptosis that varies during sustained activity or shifts from side to side is virtually diagnostic of MG. Frontalis muscle contraction, producing a worried or surprised appearance, results from lid weakness. The medial rectus muscles are usually affected, producing incomplete or variable medial deviation of the adducting eye on lateral gaze to the opposite side, which is worse when the adducted eye is covered (Supplemental Digital Content 14-1, links.lww.com/CONT/A129). Mild weakness of the medial rectus can also be demonstrated by divergent gaze on sustained upgaze (Supplemental Digital Content 14-2, links.lww.com/CONT/ A130). Eye closure is weak in almost all MG patients, even in those in otherwise complete remission (Supplemental Digital Content 14-3, links.lww.com/ CONT/A131).

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Patients with facial muscle weakness may appear depressed due to drooping of the corners of the mouth. Attempts to smile give the appearance of a sneer due to contraction of the medial portion of the upper lip and horizontal contraction of the corners of the mouth (Figure 14-2). Several speech abnormalities may be heard: a nasal quality when the palate is weak, hoarseness and difficulty making high-pitched sounds with laryngeal weakness, or slurring when the tongue is weak. These speech abnormalities typically progress and become more prominent during sustained conversation. If jaw muscles are weak, the patient may have to hold the jaw closed manually. The patient may hold the jaw closed with the thumb under the chin, the middle finger curled under the nose or lower lip, and the index finger extended up the cheek, producing a studious or attentive appearance (Figure 14-3). In non-MuSK MG, neck flexors are usually weaker than neck extensors, but the opposite pattern is frequently seen in patients with MuSK antibodies. Weakness is frequently greater in the deltoids, triceps, and extensors of the wrist and fingers and dorsiflexors of the ankles than in other limb muscles. Differential Diagnosis In patients with typical MG, the diagnosis is usually clear, particularly if lid ptosis clearly fluctuates or alternates from side to side. In patients with lesstypical manifestations, the differential includes motor neuron disease, primary muscle diseases, CNS lesions affecting the brainstem nuclei, cavernous sinus thrombosis, various toxins, botulism, diphtheritic neuropathies, and other rare conditions. Appropriate application of the following diagnostic procedures will greatly narrow the differential and usually lead to the correct diagnosis. Continuum (Minneap Minn) 2014;20(5):1413–1425

Patient with myasthenia gravis, who, during attempted smile, shows contraction of the medial portion of the upper lip and horizontal contraction of the corners of the mouth without the natural upward curling, producing a ‘‘sneer.’’

FIGURE 14-2

Reprinted with permission from Sanders DB, Massey JM. Elsevier.6 B 2008 Elsevier, Inc.

The edrophonium chloride (Tensilon) test. This classic test for MG is used infrequently now, but can be especially valuable when antibody or EMG testing is unrevealing or not immediately available. Weakness from abnormal neuromuscular transmission characteristically improves after IV administration of edrophonium chloride. The test is most reliable when the patient has ptosis or diplopia, and is positive in more than 90% of patients with MG.9 The optimum dose cannot be predetermined, and an incremental dosing schedule is recommended, beginning with 2 mg injected intravenously. The response is monitored for 60 seconds. Subsequent injections of 3 mg and 5 mg may then be given, although 2 mg to 3 mg is usually adequate to produce a response (Supplemental Digital Content 14-4, links.lww.com/CONT/A132). If unequivocal improvement is seen within 60 seconds after any dose, the www.ContinuumJournal.com

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Myasthenia Gravis and LEMS

FIGURE 14-3

KEY POINTS

h The edrophonium test is positive in 90% of myasthenia gravis patients. Improvement in lid ptosis, oculomotor weakness, or both are usually produced with 2 mg to 3 mg. Patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis may become worse or develop profuse fasciculations after edrophonium.

h Acetylcholine receptor antibodies are present in most myasthenia gravis patients, but in only about 50% of those with weakness limited to ocular muscles. Consider testing for muscle-specific tyrosine kinase (MuSK) antibodies if acetylcholine receptor antibodies are not found and in patients with prominent bulbar, proximal extremity, or respiratory weakness.

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Typical facial appearance in myasthenia gravis. The patient holds the ptotic left lid open with his index finger and closes the jaw with his thumb.

test is positive and no further injections are necessary. Normal muscle is not weakened by 10 mg of edrophonium, thus, weakness that becomes worse after the injection also indicates a neuromuscular transmission defect. A survey of physicians using edrophonium testing revealed that 37 of 23,000 tests (0.16%) were associated with a serious complication, most often bradyarrhythmias and syncope.10 Since some people are sensitive to even small doses of edrophonium, atropine sulfate should be immediately available for IM injection, if needed. Patients with MuSK MG frequently develop profuse fasciculations and may actually have worse weakness after edrophonium.11 IM neostigmine, which has a longer duration of action, is particularly useful in diagnosis of infants and children. The IM dose in children under 12 years of age is 0.2 mg to 0.5 mg. Acetylcholine receptor and musclespecific tyrosine kinase antibodies. Three different assay techniques are used to measure AChR antibodies: binding to

purified human AChRs labeled with radioiodinated !-bungarotoxin, inhibition (blocking) of binding of radiolabeled !-bungarotoxin to AChRs, and rate of loss of labeled AChRs from cultured human myotubes (modulation). In the authors’ experience, AChR-binding antibodies are found in 80% of patients with acquired generalized MG and 55% with ocular myasthenia. The binding AChR antibody level varies widely and does not predict the severity of disease in individual patients. AChR antibodies may not be detectible at symptom onset but become elevated later. Thus, it is appropriate to repeat the test after several months if initial values are normal. Low levels of AChR-binding antibodies are rarely found in other diseases (eg, systemic lupus erythematosus, inflammatory neuropathy, ALS, rheumatoid arthritis taking D-penicillamine), non-MG thymoma, and asymptomatic relatives of patients with MG. Modulating AChR antibodies are increased in about 10% of MG patients in the absence of the binding antibodies and are present in high levels in many MG patients with thymoma.12 Blocking AChR antibodies are only very rarely found in the absence of the binding antibodies, and have no clinical utility. In general, finding elevated AChR binding or modulating antibodies in a patient with compatible clinical features confirms the diagnosis of MG, but normal antibody levels do not exclude the diagnosis. The marked variability among patients makes it impossible to use AChR antibody measurements to assess disease severity. AChR antibody levels fall after immunosuppression in most patients but do not usually become normal, even if the patient achieves clinical remission. Antibody levels also fall after immunosuppression in patients who do not improve, so the fall in AChR antibody levels cannot be used to infer clinical improvement.13 Failure for the antibody

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level to fall implies ineffective or inadequate immunosuppression. Patients without AChR-binding antibody are not likely to have a thymoma. The presence of both striated muscle antibodies and AChR-binding antibodies is not diagnostic for thymoma, but in early-onset MG should raise the clinical suspicion for thymoma,14 and we measure both antibodies in all MG patients. Antibodies to MuSK are found in 40% to 50% of MG patients who do not have AChR antibodies and should be measured if AChR antibodies are not elevated. EMG. Abnormal neuromuscular transmission can be demonstrated by repetitive nerve stimulation or jitter testing. Jitter is classically measured with single-fiber EMG, but few EMG laboratories use this technique, instead measuring jitter with conventional concentric electrodes.15 These tests are particularly valuable when the clinical findings, antibody testing, and response to acetylcholinesterase (AChE) inhibitors do not give conclusive diagnostic information. Repetitive nerve stimulation is abnormal in a hand or shoulder muscle in 60% of patients with MG.6 Testing facial muscles increases the diagnostic sensitivity somewhat, but repetitive nerve stimulation is normal in all tested muscles in many patients with MG. Measurement of jitter is the most sensitive clinical test of neuromuscular transmission and is abnormal in almost all patients with MG if clinically involved muscles are tested.16 Neuromuscular transmission is also abnormal in motor neuron disease, peripheral neuropathies, and some muscle diseases, thus appropriate nerve conduction tests and EMG must be performed to exclude these conditions whenever repetitive nerve stimulation testing or jitter measurements are abnormal. In MuSK MG, electrodiagnostic abnormalities may not be as widespread Continuum (Minneap Minn) 2014;20(5):1413–1425

as in non-MuSK MG, and it may be necessary to examine clinically weak muscles to demonstrate abnormal neuromuscular transmission.17 Chest imaging. Chest CT or MRI is performed to exclude thymoma after the diagnosis of MG has been confirmed; chest imaging is not a diagnostic test for MG. Thymoma is unlikely unless AChR antibodies are elevated.14 Treatment of Myasthenia Gravis The best treatment approach for each MG patient is determined by many factors, including the severity, distribution, and rate of progression of weakness, age, comorbidity, and degree of functional impairment. Patients and other health care providers should be educated about factors that may worsen myasthenic weakness. The use of contraindicated drugs, such as quinolone antibiotics, too frequently leads to exacerbations of weakness or crisis that could have been avoided. AChE inhibitors should be used as initial therapy in all MG patients. Pyridostigmine is usually the first agent used. The response to slow release formulations of pyridostigmine is more variable, probably due to erratic absorption, and the authors of this article prefer the regular release tablets. Because AChE inhibition provides only symptomatic improvement, patients should be evaluated soon after starting these medications to assess their response and the possible need for steroids or other immunosuppressive or immunomodulatory therapy. Patients with MuSK MG may become worse or develop profuse fasciculations even with low doses of pyridostigmine, in which case it should be discontinued. In patients with purely ocular weakness, pyridostigmine is used until or unless the disease spreads to oropharyngeal or limb muscles. If this spread is going to occur, it will almost always do

KEY POINTS

h EMG studies of neuromuscular transmission are most likely to be abnormal in clinically involved muscles in myasthenia gravis.

h Chest imaging should be performed in patients with myasthenia gravis to exclude thymoma, which is unlikely unless acetylcholine receptor antibodies are elevated.

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Myasthenia Gravis and LEMS

so within 2 years after symptom onset. If the ocular weakness is disabling despite optimum pyridostigmine treatment, treat with prednisone, consider immunosuppressives, and, in some patients, consider thymectomy. Thymectomy Abnormalities of the thymus are common in MG: tissue removed at thymectomy shows lymphoid follicular hyperplasia in 70% of patients, and 10% to 15% of MG patients have a thymoma. Empiric evidence that removal of the thymus improves MG comes from more than 70 years of clinical observations. Evidence for the role of the thymus in MG comes from observations that hyperplastic thymus contains all the components required for an immune response to AChR, and possibly also MuSK; these include T cells, B cells, and plasma cells, and AChR-expressing myeloid cells, which also express MuSK.18 However, the relationship between thymic histology and response to thymectomy is not clear, and thymic histology alone should not be used to decide for or against thymectomy. An evidence-based review of published reports concluded that ‘‘For patients with nonthymomatous autoimmune MG, thymectomy is recommended as an option to increase the probability of remission or improvement.’’19 The first prospective trial of thymectomy in MG is currently in progress and is scheduled to be completed in late 2015.20 Based on current knowledge, thymectomy is the only treatment for MG that carries a realistic probability of drug-free remission. Thymectomy is performed to potentially avoid chronic immunosuppressive therapy or if immunotherapy has failed or patients have had intolerable side effects from immunotherapy. Thymectomy should be considered early, ie, within 1 to 2 years

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after onset, in patients between 15 and 50 years old and in peripubertal children with moderate to severe AChR antibody positive MG. In children 5 to 10 years old, thymectomy should only be considered after failure of drug therapy (eg, AChE inhibitors, steroids). Thymectomy is always elective, and the perioperative mortality is very low if performed when the patient is stable. If weakness is generalized, particularly if oropharyngeal or respiratory muscles are impaired, treat with plasma exchange or IV immunoglobulin (IVIg) before surgery. If weakness is still severe, treat with prednisone before thymectomy. If thymectomy is performed without immunosuppression and significant weakness persists 12 months after surgery, prednisone or other immunosuppression should then be considered. With few exceptions, surgery is indicated in all patients with thymoma, and all thymic tissue should be removed along with the tumor. Imaging may not demonstrate small thymomas, which must be sought assiduously during all thymectomy procedures. Palliative radiation therapy for thymoma can be considered in the elderly and in patients with significant comorbidities. Incompletely resected thymomas should be treated after surgery with an interdisciplinary treatment approach (eg, radiotherapy, chemotherapy).21 Endoscopic thymectomy is used increasingly in patients without thymoma and, in experienced centers, has a good track record for safety. The transsternal and minimally invasive surgical techniques are felt to lead to clinically comparable results, although data from randomized, controlled studies are not available. Open surgery is still preferred for removal of thymomas. A task force of the Myasthenia Gravis Foundation of America is currently developing MG treatment guidelines based on consensus of experts, which

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should be available by late 2014. These guidelines will discuss, among other issues, the role of thymectomy in ocular and late-onset myasthenia and in patients without AChR antibodies. The authors’ recommendations for thymectomy may be modified after these guidelines and the results of the ongoing thymectomy trial are published. Immunosuppression. If prednisone fails to produce improvement, consider plasma exchange or IVIg and the addition of azathioprine. Azathioprine may also be given as the initial immunosuppressant for relatively mild disease or if steroids are contraindicated. Azathioprine may also be used as a steroid-sparing agent in patients who have improved on prednisone. Although two clinical trials failed to demonstrate superiority of mycophenolate mofetil to prednisone in MG,22,23 extensive clinical experience and observational studies provide substantial evidence of efficacy as monotherapy or as a steroid-sparing agent.24 The authors use mycophenolate mofetil instead of azathioprine if the latter is ineffective or produces unacceptable side effects.25 Some patients also opt for mycophenolate mofetil over azathioprine based on some evidence for a more rapid onset of clinical effect. Rituximab may be considered as a treatment option in patients who develop unacceptable side effects or have not responded to adequate use of other immunotherapies. In patients over 50, concurrent illness is a major factor in determining the best therapeutic approach. If there is no evidence of thymoma and pyridostigmine does not produce a satisfactory response, treat with azathioprine, mycophenolate, prednisone, plasma exchange, IVIg, or a combination of these. Consider thymectomy in these patients if this approach does not produce a satisfactory response. When patients have achieved their optimal response to medical therapy, Continuum (Minneap Minn) 2014;20(5):1413–1425

medications should be reduced gradually and sequentially to the fewest medications and the minimal effective dose of each. As a general rule, medications with the shortest duration of action are reduced first. Being able to discontinue AChE inhibitors in immunosuppressed patients is evidence of adequate immunosuppression. MuSK MG usually responds well to plasma exchange and corticosteroids, and may improve with other immunomodulatory therapies.17,26 Many anecdotal reports suggest marked and prolonged benefit from rituximab.27Y29

KEY POINT

h Muscle-specific tyrosine kinase (MuSK) myasthenia gravis patients often require more aggressive immunosuppression, particularly early in the course of the disease. Consider rituximab in these patients.

Lambert-Eaton Myasthenic Syndrome LEMS is a rare condition in which weakness results from a presynaptic abnormality of acetylcholine release at the neuromuscular junction. LEMS results from an autoimmune attack against the voltage-gated calcium channels on the presynaptic motor nerve terminal. Although LEMS has been reported rarely in children, it usually begins in later life. Approximately half of LEMS patients have an underlying malignancy, usually a small cell lung cancer, and the differential diagnosis usually includes cachexia, polymyositis, or other paraneoplastic neuromuscular disease. The clinical presentations of MG and LEMS are quite distinct. Difficulty walking is the initial symptom in most LEMS patients; bulbar and ocular muscles are usually spared or only mildly affected. (Case 14-3). The weakness itself is rarely life threatening in LEMS. Unlike MG, in LEMS, the symptoms are typically out of proportion to the degree of weakness found on examination. Strength improves immediately after exercise in many patients, and this is marked in about half. Tendon reflexes are absent or reduced and can frequently be increased by brief activation of the appropriate muscles or by tapping the tendon www.ContinuumJournal.com

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Myasthenia Gravis and LEMS KEY POINTS

h Lambert-Eaton myasthenic syndrome is characterized by the triad of weakness, dry mouth, and reduced or absent tendon reflexes. Weakness on examination is frequently less than the symptoms would suggest.

h Lambert-Eaton myasthenic syndrome patients should have an initial malignancy workup. If negative, this should be repeated periodically depending on the patient’s risk of cancer.

Case 14-3 A 63-year-old woman developed difficulty going up and down stairs and generalized fatigue during a 3-month period. On questioning, she admitted having dry mouth and dry eyes. Examination revealed mild bilateral ptosis, a prominent waddling gait, proximal weakness that was worse in the legs, and barely elicitable reflexes. With exercise, the biceps, triceps, and knee reflexes were enhanced. Electrodiagnostic studies demonstrated low-amplitude muscle responses and marked facilitation after muscle activation, typical of Lambert-Eaton myasthenic syndrome. She had never smoked, and extensive evaluation for malignancy was unrevealing. P/Q-type voltage-gated calcium channel antibodies were elevated. Amifampridine (3,4-diaminopyridine) (15 mg 3 times a day) produced significant improvement in walking and endurance. Comment. The symptoms in Lambert-Eaton myasthenic syndrome are often more prominent than the physical findings. Patients may not report dry mouth or dry eyes unless specifically questioned. Weakness is usually most marked in the proximal muscles, especially in the legs; ocular and oropharyngeal muscles are usually spared or only slightly involved. Amifampridine improves function and quality of life in most patients.

repeatedly. Dry mouth is a major and frequent symptom but may be volunteered only on specific questioning. Other manifestations of autonomic dysfunction are common, including postural hypotension, and erectile dysfunction in males. Edrophonium testing or pyridostigmine improves strength in some patients but this is rarely as dramatic as in MG. LEMS may be discovered when prolonged paralysis follows the use of neuromuscular blocking agents during surgery. Weakness may be exacerbated by agents that also worsen MG. The diagnosis of LEMS is confirmed by the typical electrodiagnostic findings: low-amplitude compound muscle action potentials that facilitate after brief maximum muscle contraction or during high-frequency nerve stimulation. P/Q-type voltage-gated calcium channel antibodies are elevated in most patients with LEMS. Treatment of Lambert-Eaton Myasthenic Syndrome When the diagnosis of LEMS has been confirmed, an extensive search for malignancy should be carried out

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during the initial evaluation, especially in smokers and when symptoms have been present for less than 2 years. This should include CT or MRI scan of the chest, and bronchoscopy if imaging studies are normal. The initial treatment should be aimed at any tumor present, since the weakness may improve with effective cancer therapy,30 and some patients may require no further treatment for LEMS. The search for malignancy should be repeated periodically based on the patient’s risk of cancer. Patients younger than 50 without a history of chronic smoking have a low risk of cancer, especially if there is evidence for a coexisting autoimmune disease. Patients over 50 with a history of chronic smoking almost certainly have an underlying lung cancer, which must be assiduously sought. AChE inhibitors do not usually produce significant improvement in LEMS, although they may improve dry mouth. In the authors’ experience, more than 85% of LEMS patients have significant clinical benefit from amifampridine, which increases the release of ACh from the autonomic

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and motor nerve terminal.31Y34 The effect of amifampridine begins within about 20 minutes and lasts about 4 hours, although the maximum response to a given dosage may not be seen for 2 to 3 days. In most patients, pyridostigmine enhances and prolongs the duration of action of amifampridine and permits use of lower doses. The optimal dose must be determined individually for each patient, and is between 15 mg/d and 80 mg/d in most patients, taken with pyridostigmine. Doses greater than 100 mg/d may cause seizures, thus amifampridine should not be used in patients with known seizures. Otherwise, side effects are minimal and usually limited to perioral and digital paresthesia at doses of 10 mg or more. The phosphate salt of amifampridine is approved for clinical use in LEMS in Europe, and clinical trials of amifampridine in LEMS are currently in progress. Pending the results of these trials, amifampridine is available to physicians for their LEMS patients on a ‘‘compassionate use’’ basis (see www.clinicaltrials.gov for the latest information on these trials). As in MG, plasma exchange or IVIg produces relatively rapid, albeit temporary, improvement in most LEMS patients. Immunosuppression with prednisone or azathioprine may provide modest benefit,35 and there are isolated reports of medium-term benefit from rituximab.36 The treating physician must determine if aggressive immunotherapy is justified when weakness is relatively mild or controlled by amifampridine. Also, there is a theoretical concern that immunosuppression may reduce the immunologic suppression of tumor growth. Aggressive immunotherapy is more readily justified in patients without cancer. Continuum (Minneap Minn) 2014;20(5):1413–1425

KEY POINT

VIDEO LEGENDS

h Amifampridine is a

Supplemental Digital Content 14-1

Mild diplopia in myasthenia gravis. Video shows an 84-year-old man who has had myasthenia gravis for 3 years. The disease began with neck weakness, followed by asymmetric, bilateral lid ptosis. Examination demonstrates mild, fatigable diplopia on lateral gaze to either side, unmasked by cover/uncover maneuver. links.lww.com/CONT/A129 B 2014 American Academy of Neurology

mainstay of treatment for patients with Lambert-Eaton myasthenic syndrome; acetylcholinesterase inhibitors and immunosuppression are usually much less effective.

Supplemental Digital Content 14-2

Diplopia on upgaze in myasthenia gravis. Video shows the same patient as in Supplemental Digital Content 14-1. Examination demonstrates horizontal diplopia that develops on upgaze. links.lww.com/CONT/A130 B 2014 American Academy of Neurology Supplemental Digital Content 14-3

Weak eyelid closure in myasthenia gravis. Video shows the same patient as in Supplemental Digital Content 14-1 and Supplemental Digital Content 14-2. Examination demonstrates mild weakness of forced eyelid closure. links.lww.com/CONT/A131 B 2014 American Academy of Neurology Supplemental Digital Content 14-4

Edrophonium chloride (Tensilon) test in myasthenia gravis. Video shows a 64-year-old man with acetylcholine receptor antibodyYpositive myasthenia gravis. After withholding pyridostigmine for several days, the patient has moderate right lid ptosis and horizontal diplopia at rest. These resolved within 30 seconds after injection of 2 mg edrophonium chloride (Tensilon) and recurred 60 seconds later. links.lww.com/CONT/A132 B 2014 American Academy of Neurology

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Myasthenia gravis and Lambert-Eaton myasthenic syndrome.

This article reviews the clinical presentations, diagnostic findings, and treatment options for autoimmune myasthenia gravis (MG) and Lambert-Eaton my...
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