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11/22/13

Myasthenia Gravis

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Myasthenia Gravis
Author: Aashit K Shah, MD, FAAN, FANA; Chief Editor: Nicholas Lorenzo, MD, CPE more... Updated: Oct 1, 2013

Practice Essentials
Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies form against acetylcholine nicotinic postsynaptic receptors at the neuromuscular junction of skeletal muscles.[1, 2] Myasthenia gravis is sometimes identified as having an ocular and generalized form, although one is not exclusive of the other and the ocular form is considered an initial, milder form of illness that progresses to the more severe generalized form in most but not all patients. Essential update: Features of myasthenia gravis in pediatric patients In a surveillance study of 57 cases of pediatric myasthenia, including 34 generalized and 18 ocular cases of juvenile myasthenia gravis (JMG) and 5 cases of congenital myasthenic syndrome, ptosis was the most common symptom, occurring in all patients with ocular JMG and 82% of those with generalized JMG. Tests for acetylcholine receptor antibodies were positive in 67% of the patients with generalized JMG and 44% of those with ocular.[3, 4] All 33 patients with JMG who were treated with pyridostigmine showed improvement, and the majority of patients treated with steroids or intravenous immunoglobulin also improved. Of the 17 patients with ocular JMG treated with pyridostigmine, 88% improved.[4]

Signs and symptoms


The presentation of MG has the following characteristics: The usual initial complaint is a specific muscle weakness rather than generalized weakness Extraocular muscle weakness or ptosis is present initially in 50% of patients and occurs during the course of illness in 90% The disease remains exclusively ocular in only 16% of patients Rarely, patients have generalized weakness without ocular muscle weakness Bulbar muscle weakness is also common, along with weakness of head extension and flexion Limb weakness may be more severe proximally than distally Isolated limb muscle weakness is the presenting symptom in fewer than 10% of patients Weakness is typically least severe in the morning and worsens as the day progresses Weakness is increased by exertion and alleviated by rest Weakness progresses from mild to more severe over weeks or months, with exacerbations and remissions Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb muscles About 87% of patients have generalized disease within 13 months after onset Less often, symptoms may remain limited to the extraocular and eyelid muscles for years The following factors may trigger or worsen exacerbations: Bright sunlight Surgery Immunization Emotional stress Menstruation
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Intercurrent illness (eg, viral infection) Medication (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, statins) The Myasthenia Gravis Foundation of America Clinical Classification divides MG into 5 main classes and several subclasses [5] : Class I: Any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is normal Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Class IIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both Class III: Moderate weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IIIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Class IIIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IVa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both; use of a feeding tube without intubation Class V: Defined by the need for intubation, with or without mechanical ventilation, except when used during routine postoperative management See Clinical Presentation for more detail.

Diagnosis
The antiacetylcholine receptor (AChR) antibody test for diagnosing MG has the following characteristics: High specificity (up to 100% [6] ) Positive in as many as 90% of patients who have generalized MG Positive in only 50-70% of patients who have purely ocular MG False-positive anti-AChR antibody test results have been reported in patients with the following: Thymoma without MG Lambert-Eaton myasthenic syndrome Small cell lung cancer Rheumatoid arthritis treated with penicillamine 1-3% of the population older than 70 years Assays for the following antibodies may also be useful: Antistriated muscle antibody (present in about 84% of patients with thymoma who are younger than 40 years) Anti-MuSK antibody (present in about half of patients with negative results for anti-AChR antibody) Antistriational antibody (present in almost all patients with thymoma and MG, as well as in half of MG patients with onset of MG at 50 years or older) Other studies are as follows: Plain chest radiographs may identify a thymoma as an anterior mediastinal mass Chest computed tomography is important to identify or rule out thymoma or thymic enlargement in all cases of MG In strictly ocular MG, magnetic resonance imaging of the brain and orbit is helpful to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG
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Electrodiagnostic studies (repetitive nerve stimulation and single-fiber electromyography) See Workup for more detail.

Management
Therapy for MG includes the following: Anticholinesterase (AchE) inhibitors Immunomodulating agents Intravenous immune globulin (IVIg) Plasmapheresis Thymectomy AchE inhibitors Initial treatment for mild MG Pyridostigmine is used for maintenance therapy [7, 8] Neostigmine is generally used only when pyridostigmine is unavailable Corticosteroid therapy provides a short-term benefit Azathioprine, usually after a dose of corticosteroids, is the mainstay of therapy for difficult cases Cyclosporine A and occasionally methotrexate and cyclophosphamide are used for severe cases IVIg Moderate or severe MG worsening into crisis (no value in mild disease)[9] Elderly patients Patients with complex comorbid diseases (eg, acute respiratory failure)[10] Patients with severe weakness poorly controlled with other agents Plasmapheresis Generally reserved for myasthenic crisis and refractory cases Also effective in preparation for surgery Improvement is noted in a couple of days, but does not last for more than 2 months Can be used long-term on a regular weekly or monthly basis can be used if other treatments cannot control the disease Thymectomy The standard of care for all patients with thymoma and for patients aged 10-55 years without thymoma but with generalized MG Proposed as a first-line therapy in most patients with generalized myasthenia In ocular MG, should be delayed at least 2 years to allow for spontaneous remission Not recommended in patients with antibodies to muscle-specific kinase (MuSK) Controversial in prepubescent patients and, to a lesser extent, patients older than 55 years See Treatment and Medication for more detail.

Image library

Increasing left ptosis developing upon sustained upw ard gaze in patient w ith myasthenia gravis (A through F). Note limited elevation of left eye, denoting superior rectus palsy (A). A initially, C after around 20 seconds, F after 1 minute.

Background
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Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies form against nicotinic acetylcholine (ACh) postsynaptic receptors at the neuromuscular junction (NMJ) of the skeletal muscles. The basic pathology is a reduction in the number of ACh receptors (AChRs) at the postsynaptic muscle membrane brought about by an acquired autoimmune reaction producing anti-AChR antibodies. The reduction in the number of AChRs results in a characteristic pattern of progressively reduced muscle strength with repeated use and recovery of muscle strength after a period of rest. The ocular and bulbar muscles are affected most commonly and most severely, but most patients also develop some degree of fluctuating generalized weakness.[11] The most important aspect of MG in emergency situations is acute worsening of weakness and diagnosis of myasthenic versus cholinergic crisis and its management. MG is a treatable and, at times, curable neurologic disorder. Pharmacologic therapy includes anticholinesterase medication and immunosuppressive agents, such as corticosteroids, azathioprine, cyclosporine, plasmapheresis, and intravenous immune globulin (IVIg). Plasmapheresis and thymectomy are also employed to treat MG. Thymectomy is an especially important option if a thymoma is present. Patients with MG require close follow-up care in cooperation with the primary care physician.

Anatomy
In MG, autoantibodies (immunoglobulin G [IgG]) develop against ACh nicotinic postsynaptic receptors at the NMJ of skeletal muscles .[1, 2] The reasons for this development are unknown, although it is clear that certain genotypes are more susceptible.[12] To understand MG, it is necessary to be familiar with the normal anatomy and functioning of the NMJ. The nerve terminal of the motor nerve enlarges at its end to form the so-called bouton terminale, or terminal bulb. This bulb lies within a groove or indentation along the muscle fiber. The presynaptic membrane (on the nerve), postsynaptic membrane (on the muscle membrane), and the synaptic cleft (the space between the 2 membranes) together constitute the NMJ (see the image below).

Normal neuromuscular junction show ing a presynaptic terminal w ith a motor nerve ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane w ith multiple folds and embedded w ith several acetylcholine receptors.

ACh molecules are hydrolyzed by the enzyme acetylcholinesterase (AChE), which is abundantly present at the NMJ. The surface area of the postsynaptic membrane is increased by infolding of the membrane adjacent to the nerve terminal. This increase in surface area enables the NMJ to utilize the ACh fully. AChRs are present in small quantities over most of the muscle membrane surface but are concentrated heavily at the tips of the NMJs. Adult AChR comprises 5 subunits (2 alpha, 1 beta, 1 gamma, and 1 delta), each of which is a membranespanning protein molecule. These subunits are homologous across different species, suggesting that the encoding genes evolved from a common ancestral gene. The subunits are arranged in a circle, forming a central opening that acts as an ion channel (see the image below). When an ACh molecule binds to an AChR, the AChR undergoes a 3-dimensional conformational change that opens the channel.

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Acetylcholine receptor. Note 5 subunits, each w ith 4 membrane-spanning domains forming a rosette w ith a central opening. The central opening acts as an ion channel.

The presynaptic terminal contains vesicles filled with ACh. When an action potential travels down a motor nerve and reaches the nerve terminal, the contents of these vesicles are released into the synaptic cleft in a calciumdependent manner. The released ACh molecules diffuse across the synapse and bind to the AChRs at the peaks of the folds on the postsynaptic membrane. This binding causes the ion channels in the AChR to open briefly, allowing sodium ions into the interior of the muscle cell and thereby bringing about partial depolarization of the postsynaptic membrane and generation of an excitatory postsynaptic potential (EPSP). If the number of open sodium channels reaches a threshold value, a self-propagating muscle action potential is generated in the postsynaptic membrane.

Pathophysiology
With every nerve impulse, the amount of ACh released by the presynaptic motor neuron normally decreases because of a temporary depletion of the presynaptic ACh stores (a phenomenon referred to as presynaptic rundown). In MG, there is a reduction in the number of AChRs available at the muscle endplate and flattening of the postsynaptic folds. Consequently, even if a normal amount of ACh is released, fewer endplate potentials will be produced, and they may fall below the threshold value for generation of an action potential. The end result of this process is inefficient neuromuscular transmission. Inefficient neuromuscular transmission together with the normally present presynaptic rundown phenomenon results in a progressive decrease in the amount of muscle fibers being activated by successive nerve fiber impulses. This explains the fatigability seen in MG patients. Patients become symptomatic once the number of AChRs is reduced to approximately 30% of normal. The cholinergic receptors of smooth and cardiac muscle have a different antigenicity than skeletal muscle and usually are not affected by the disease. The decrease in the number of postsynaptic AChRs is believed to be due to an autoimmune process whereby antiAChR antibodies are produced and block the target receptors, cause an increase the turnover of the receptors, and damage the postsynaptic membrane in a complement-mediated manner. Clinical observations support the idea that immunogenic mechanisms play important roles in the pathophysiology of MG. Such observations include the presence of associated autoimmune disorders (eg, autoimmune thyroiditis, systemic lupus erythematosus [SLE], and rheumatoid arthritis [RA]) in patients with MG. Moreover, infants born to myasthenic mothers can develop a transient myasthenialike syndrome. Patients with MG will have a therapeutic response to various immunomodulating therapies, including plasmapheresis, corticosteroids, intravenous immunoglobulin (IVIg), other immunosuppressants, and thymectomy. Anti-AChR antibody is found in approximately 80-90% of patients with MG. Experimental observations supporting an autoimmune etiology of MG include the following: Induction of a myasthenialike syndrome in mice by injecting a large quantity of immunoglobulin G (IgG) from MG patients (ie, passive transfer experiments) Demonstration of IgG and complement at the postsynaptic membrane in patients with MG Induction of a myasthenialike syndrome in rabbits immunized against AChR by injecting them with AChR
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isolated from Torpedo californica (the Pacific electric ray) The exact mechanism of loss of immunologic tolerance to AChR, a self-antigen, is not understood. MG can be considered a B cellmediated disease, in that it derives from antibodies (a B cell product) against AChR. However, the importance of T cells in the pathogenesis of MG is becoming increasingly apparent. The thymus is the central organ in T cellmediated immunity, and thymic abnormalities such as thymic hyperplasia or thymoma are well recognized in myasthenic patients. Antibody response in MG is polyclonal. In an individual patient, antibodies are composed of different subclasses of IgG. In most instances, 1 antibody is directed against the main immunogenic region (MIR) on the alpha subunit. The alpha subunit is also the site of ACh binding, though the binding site for ACh is not the same as the MIR. Binding of AChR antibodies to AChR results in impairment of neuromuscular transmission in several ways, including the following: Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and degradation of AChR molecules Causing complement-mediated destruction of junctional folds of the postsynaptic membrane Blocking the binding of ACh to AChR Decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs Patients without anti-AChR antibodies are recognized as having seronegative MG (SNMG). Many patients with SNMG have antibodies against muscle-specific kinase (MuSK). MuSK plays a critical role in postsynaptic differentiation and clustering of AChRs. Patients with anti-MuSK antibodies are predominantly female, and respiratory and bulbar muscles are frequently involved. Another group has reported patients who exhibit prominent neck, shoulder, and respiratory weakness.[13, 14] The role of the thymus in the pathogenesis of MG is not entirely clear, but 75% of patients with MG have some degree of thymus abnormality (eg, hyperplasia or thymoma). Histopathologic studies have shown prominent germinal centers. Epithelial myoid cells normally present in the thymus do resemble skeletal muscle cells and possess AChRs on their surface membrane. These cells may become antigenic and unleash an autoimmune attack on the muscular endplate AChRs by molecular mimicry. The question of why MG afflicts the extraocular muscles first and predominantly remains unanswered. The answer probably has to do with the physiology and antigenicity of the muscles in question.

Etiology
MG is idiopathic in most patients. Although the main cause behind its development remains speculative, the end result is a derangement of immune system regulation. MG is clearly an autoimmune disease in which the specific antibody has been characterized completely. In as many as 90% of generalized cases, IgG to AChR is present. [15] Even in patients who do not develop clinical myasthenia, anti-AChR antibodies can sometimes be demonstrated. Patients who are negative for anti-AChR antibodies may be seropositive for antibodies against MuSK. Muscle biopsies in these patients show myopathic signs with prominent mitochondrial abnormalities, as opposed to the neurogenic features and atrophy frequently found in MG patients positive for anti-AChR. The mitochondrial impairment could explain the oculobulbar involvement in anti-MuSKpositive MG.[16] Numerous findings have been associated with MG. For example, females and people with certain human leukocyte antigen (HLA) types have a genetic predisposition to autoimmune diseases. The histocompatibility complex profile includes HLA-B8, HLA-DRw3, and HLA-DQw2 (though these have not been shown to be associated with the strictly ocular form of MG). Both SLE and RA may be associated with MG. Sensitization to a foreign antigen that has cross-reactivity with the nicotinic ACh receptor has been proposed as a cause of myasthenia gravis, but the triggering antigen has not yet been identified. Various drugs may induce or exacerbate symptoms of MG, including the following: Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin, and ampicillin) Penicillamine - This can induce true myasthenia, with elevated anti-AChR antibody titers seen in 90% of cases; however, the weakness is mild, and full recovery is achieved weeks to months after discontinuance of the drug
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Beta-adrenergic receptor blocking agents (eg, propranolol and oxprenolol) Lithium Magnesium Procainamide Verapamil Quinidine Chloroquine Prednisone Timolol (ie, a topical beta-blocking agent used for glaucoma) Anticholinergics (eg, trihexyphenidyl) Neuromuscular blocking agents (eg, vecuronium and curare) - These should be used cautiously in myasthenic patients to avoid prolonged neuromuscular blockade Nitrofurantoin has also been linked to the development of ocular MG in 1 case report; discontinuance of the drug resulted in complete recovery. Thymic abnormalities are common: Of patients with MG, 75% have thymic disease, 85% have thymic hyperplasia, and 10-15% have thymoma. Extrathymic tumors may include small cell lung cancer and Hodgkin disease.[17, 18] Hyperthyroidism is present in 3-8% of patients with MG and has a particular association with ocular MG.

Epidemiology
United States statistics
MG is uncommon. The estimated annual US incidence is 2 per 1,000,000. The prevalence of MG in the United States ranges from 0.5 to 14.2 cases per 100,000 people. This figure has risen over the past 2 decades, primarily because of the increased lifespan of patients with MG but also because of earlier diagnosis.[7] About 15-20% of patients will experience a myasthenic crisis. Three fourths of these patients experience their first crisis within 2 years of diagnosis.[12]

International statistics
In the United Kingdom, the prevalence of MG is 15 cases per 100,000 population. In Croatia, it is 10 cases per 100,000. In Sardinia, Italy, the prevalence increased from 0.75 per 100,000 in 1958 to 4.5 cases per 100,000 in 1986.

Age-related demographics
MG can occur at any age. Female incidence peaks in the third decade of life, whereas male incidence peaks in the sixth or seventh decade. The mean age of onset is 28 years in females and 42 years in males. Transient neonatal MG occurs in infants of myasthenic mothers who acquire anti-AChR antibodies via placental transfer of IgG. Some of these infants may suffer from transient neonatal myasthenia due to effects of these antibodies. Most infants born to myasthenic mothers possess anti-AChR antibodies at birth, yet only 10-20% develop neonatal MG. This may be due to protective effects of alpha-fetoprotein, which inhibits binding of anti-AChR antibody to AChR. High maternal serum levels of AChR antibody may increase the chance of neonatal MG; thus, lowering the maternal serum titer during the antenatal period by means of plasmapheresis may be useful.

Sex-related demographics
Classically, the overall female-to-male ratio has been considered to be 3:2, with a female predominance in younger adults (ie, patients aged 20-30 years) and a slight male predominance in older adults (ie, patients older than 50 years).[11, 7] Studies show, however, that with increased life expectancy, males are coming to be affected at the same rate as females. Ocular MG shows a male preponderance. The male-to-female ratio in children with MG and another autoimmune condition is 1:5.

Race-related demographics
The onset of MG at a young age is slightly more common in Asians than in other races.[7]
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Prognosis
Given current treatment, which combines cholinesterase inhibitors, immunosuppressive drugs, plasmapheresis, immunotherapy, and supportive care in an intensive care unit (ICU) setting (when appropriate), most patients with MG have a near-normal life span. Mortality is now 3-4%, with principal risk factors being age older than 40 years, short history of progressive disease, and thymoma; previously, it was as high as 30-40%. In most cases, the term gravis is now a misnomer. Morbidity results from intermittent impairment of muscle strength, which may cause aspiration, increased incidence of pneumonia, falls, and even respiratory failure if not treated.[15] In addition, the medications used to control the disease may produce adverse effects. Today, the only feared condition arises when the weakness involves the respiratory muscles. Weakness might become so severe as to require ventilatory assistance. Those patients are said to be in myasthenic crisis. The disease frequently presents (40%) with only ocular symptoms. However, the extraocular almost always are involved within the first year. Of patients who show only ocular involvement at the onset of MG, only 16% still have exclusively ocular disease at the end of 2 years. In patients with generalized weakness, the nadir of maximal weakness usually is reached within the first 3 years of the disease. As a result, half of the disease-related mortality also occurs during this period. Those who survive the first 3 years of disease usually achieve a steady state or improve. Worsening of disease is uncommon after 3 years. Thymectomy results in complete remission of the disease in a number of patients. However, the prognosis is highly variable, ranging from remission to death. A retrospective study of 38 patients with MG indicates that the disease, particularly late-onset MG, is associated with a high risk for cancers outside of the thymus, whether or not the patient also has, as is common in MG, a thymoma.[17] Extrathymic neoplasms occurred in 12 of the study patients; all of these tumors were solid and heterogeneous to their organ of origin. Some of the tumors were diagnosed before and some after the patients were diagnosed with MG. Altogether the tumors represented 9 different types of neoplasm, as follows: 2 each of squamous cell carcinoma of the mouth, invasive bladder cancer, and prostate adenocarcinoma 1 each of basal cell skin cancer; lung, gastric, breast, and colon adenocarcinoma; and renal cell cancer The only statistically significant variable among the patients was age, with the extrathymic tumors being found only in patients over 50 years. None of the patients with these neoplasms had thyroid disease or an autoimmune disease other than MG.

Patient Education
Educate patients to recognize and immediately report impending respiratory crisis. Intercurrent infection may worsen symptoms of MG temporarily. Mild exacerbation of weakness is possible in hot weather. The risk of congenital deformity (arthrogryposis multiplex) is increased in offspring of women with severe MG. Neonates born to women with MG must be monitored for respiratory failure for 1-2 weeks after birth. Certain immunosuppressant drugs have teratogenic potential. Discuss these aspects with women in reproductive years before beginning therapy with these drugs. Certain medications (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, beta-blockers, procainamide, and quinidine) may exacerbate symptoms of MG; many others have been associated only rarely with exacerbation of MG. Patients should always consult a neurologist before starting any of these medications. Medications that induce the hepatic microsomal cytochrome P-450 system (eg, corticosteroids) may render oral contraceptives less effective. Statins may cause worsening of myasthenia without regard to type of MG or brand of statin. Worsening of weakness can occur independent of myalgic syndrome and usually involves oculobulbar symptoms within 1-16 weeks of the initiation of statin treatment.[19]
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Contributor Information and Disclosures


Author Aashit K Shah, MD, FAAN, FANA Professor of Neurology, Director, Comprehensive Epilepsy Program, Program Director, Clinical Neurophysiology Fellowship, Detroit Medical Center, Wayne State University School of Medicine Aashit K Shah, MD, FAAN, FANA is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Association Disclosure: UCB pharma Consulting fee Speaking and teaching; Cyberonics Consulting fee Consulting; UCB Pharma Grant/research funds Other Coauthor(s) William D Goldenberg, MD Assistant Professor, Department of Emergency Medicine, Uniformed Services University of Health Sciences; Staff Emergency Physician, Naval Hospital San Diego William D Goldenberg, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Chief Editor Nicholas Lorenzo, MD, CPE Chairman and CEO, Neurology Specialists and Consultants; Former Senior Vice President, Founding Executive Director, Continuing Medical Education, Gannett Education (Division Gannett Healthcare Group) Nicholas Lorenzo, MD, CPE is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and American College of Physician Executives Disclosure: Nothing to disclose. Additional Contributors Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa Disclosure: Baxter Grant/research funds Other; Amgen Grant/research funds None Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment

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