Published: February 2014
Myasthenia gravis (MG) is the most commonly occurring disorder of neuromuscular junction transmission and is characterized by weakness and fatigue of skeletal muscles. It is a T-cell dependent antibody-mediated autoimmune disease.
The annual incidence of MG is approximately 10 to 20 new cases per million with a prevalence of about 150 to 200 per million.1 Its prevalence has been increasing over the past several decades secondary to better recognition and increased survival. The age of onset is characterized by a bimodal distribution with an early incidence peak in the 2nd to 3rd decades affecting young women and a late peak in the 6th to 8th decades that is primarily seen in men.2 MG is often associated with other autoimmune diseases including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, vitiligo and neuromyelitis optica.3 Several medications including penicillamine, pyrithioxine and hydroxychloroquine are capable of inducing autoimmune MG. Genetics also play a role as the pathogenesis and clinical manifestations of MG vary among different ethnic populations with distinct HLA associations.2
MG results from antibody mediated dysfunction of synaptic transmission. Two major components implicated in its pathogenesis are acetylcholine receptors (AChR) and muscle-specific tyrosine kinase receptors (MuSK), both located on the postsynaptic membrane. Autoimmune antibodies to AChR (AChR-Ab) are detected in 70% to 90% of MG patients while MuSK (MuSK-Ab) is seen in 5% to 8% of MG patients. Antibody binding to AChR leads to complement activation and AChR cross-linking, which results in increased AChR internalization and degradation on the postsynaptic membrane.4 The majority of MG patients with positive AChR-Ab have thymic abnormalities with hyperplasia seen in 60% to 70% and thymoma in 10% to 12% of patients. MuSK plays a pivotal role in the normal assembly and stabilization of AChR. MG animal models deficient in MuSK function demonstrate significant reduction of AChR clusters and destructional changes in the neuromuscular junction.5 Unlike those with MG-AChR, most MG-MuSK patients do not have thymic pathologies.6 Antibodies to lipoprotein-related protein 4 may also be seen in a minority of MG patients who are MuSK Ab positive or otherwise seronegative.7
Seronegative MG patients lack antibodies to both AChR and MuSK on standard assays, and accounts for approximately 5% to 25% of MG patients. Using a more sensitive cell-based immunofluorescence assay, low affinity antibody to clustered AChR can be detected in 50% to 60% of seronegative MG patients.8
The cardinal feature of MG is a fluctuating skeletal muscle weakness that worsens with repetitive movement. More than 90% of MG patients have ptosis or diplopia without pupillary involvement. On bedside examination, ptosis can be induced or exacerbated by a sustained upgaze for more than 30 seconds, and diplopia can be induced or exacerbated by a sustained horizontal gaze for more than 30 seconds. Bulbar symptoms include dysarthria, dysphagia, and chewing difficulty. Patients with facial muscle weakness experience difficulty in closing their eyes and mouth. Neck flexor weakness results in difficulty elevating the head up from a pillow while neck extensor weakness may present as "dropped head syndrome." Limb weakness in MG is predominantly proximal. Muscles in arms tend to be more affected than legs. Respiratory muscle weakness leads to respiratory insufficiency and in severe cases, respiratory failure necessitating intubation, a life-threatening situation termed "myasthenic crisis."
Ocular MG refers to isolated weakness of the levator palpebrae superioris, orbicularis oculi and/or extraocular muscles without clinically significant involvement of other muscles, and accounts for approximately 15% of MG patients. Of all MG patients initially presenting with weakness restricted to the ocular region, two-thirds will develop weakness of other muscles and one-third will remain as purely ocular.9
Unique clinical phenotypes of MG-MuSK have been described, including profound atrophy of tongue and facial muscles, and restricted weakness of cervical and respiratory weakness. MG-MuSK tends to occur in young female patients.10
Careful history taking and a thorough physical examination reveal fatigable weakness of specific muscle groups. Various bedside maneuvers, laboratory tests and electrodiagnostic tests are also helpful.
Two easily performed bedside maneuvers include the ice pack test, which is performed by placing a small ice bag over the ptotic eye for 2 to 5 minutes and then assessing the degree of ptosis for noticeable improvement.11 The other is the Tensilon (edrophonium) test, which may be used for patients with ptosis or ophthalmoparesis, but is not widely available. Edrophonium is a short-acting acetylcholinesterase inhibitor that may be administered intravenously after which the patient is observed immediately for objective improvement.
Serological testing to detect circulating AChR-Ab and/or MuSK-Ab is a key step in the laboratory confirmation of MG. There are three subtypes of AChR-Ab: binding, blocking, and modulating antibodies. Binding antibodies are the most sensitive and also highly specific for MG. Assays for blocking and modulating antibodies increase the sensitivity by less than 5% when added to binding antibodies, and may increase the false-positive rate slightly. AChR antibody titers correlate poorly with disease severity. Patients with low antibody titers may have more severe symptoms. MuSK-antibody testing should be considered for patients who exhibit specific phenotypes as discussed above, or who are negative for AChR antibodies.
Electrophysiological tests usually allow a confirmation of MG diagnosis in seronegative patients, seropositive patients with unusual clinical features or seriously ill patients who require immediate treatment decisions. Two types of electrophysiological tests available are repetitive nerve stimulation study (RNS) and single fiber electromyography (SFEMG). RNS is performed with a slow rate of repetitive electrical stimulation and is positive with the presence of a decremental motor response (>10%). However, a decremental response on RNS is not specific for MG as this may be seen in other neuromuscular disorders, such as motor neuron disease or myopathy. SFEMG is more technically demanding than RNS and less widely available.
Chest CT or MRI with contrast should be performed in all MG patients to exclude the presence of a thymoma.
The differential diagnosis for MG varies according to the clinical presentation. For example, differential diagnoses for patients with ocular weakness may include thyroid ophthalmopathy, oculopharyngeal muscular dystrophy and mitochondrial myopathy. In general, a lack of fluctuation in the ocular symptoms distinguishes these disorders from MG. The differential diagnosis for MG patients with limb weakness is broader and may include motor neuron disease, Guillain-Barré syndrome, myopathy and chronic inflammatory demyelinating polyneuropathy. These disorders can usually be distinguished based on the clinical presentation, laboratory testing, (e.g., creatinine kinase) and electrophysiological studies.
Lambert-Eaton myasthenic syndrome (LEMS) is another autoimmune disorder of neuromuscular junction with several distinct clinical features. Its earliest presentation is usually difficulty in rising from a chair due to proximal leg weakness. Symptoms in LEMS tend to improve with exercise. Autonomic symptoms such as erectile dysfunction or dry mouth are frequently observed. Brief exercise and RNS at high stimulation rate (20-50 Hz) produce a marked increase in motor nerve amplitudes otherwise known as an incremental response in LEMS patients in contrast with MG patients who demonstrate a decremental response. Antibodies to P/Q type calcium channel are detected in more than 90% of cases, and approximately half of patients have small cell lung cancer.12
Therapeutic strategies for MG are fairly effective and lead to sustained remission in most patients. Treatment goals in MG include symptomatic improvement, relapse reduction, and avoidance of medication side effects.
The initial step in most patients with mild or moderate symptoms is the usage of Ach inhibitors. Ach inhibitors slow down the degradation of acetylcholine, prolong its effect at neuromuscular junction and improve MG symptoms. Ptosis, dysphagia and dysarthria generally respond well to Ach inhibitors. Pyridostigmine (mestinon) is the usual choice of Ach inhibitors. It has a rapid onset (15-30 minutes) of action lasting for 3 to 4 hours. Its starting dosage is usually 60 mg three to four times daily. The dosage of pyridostigmine is limited by its muscarinic side effects, which include nausea, diarrhea, abdominal cramping, sweating, and bradycardia.
Patients with severe or rapidly worsening symptoms should be treated with rapid induction therapies such as intravenous immunoglobulin (IVIg) or plasmapheresis. The efficacy of both plasmapheresis and IVIg starts quickly within days and lasts for 3 to 6 weeks. These therapeutic modalities are used in a variety of settings, including myasthenic crisis, preoperative prophylaxis, bridge therapy when initiating slower acting immunotherapies, or maintenance treatment in refractory MG patients who failed chronic immunosuppressive agents.
Plasmapheresis directly removes AChR and MuSK antibodies, cytokines and immune complexes from the circulation. Several retrospective studies revealed improvement in more than 80% of MG patients following plasmapheresis.13,14 Typically four to six pheresis sessions are performed. The most adverse events associated with plasmapheresis include line infection, thrombosis, air embolism, hypotension, cardiac arrhythmia, coagulopathy, and hypocalcaemia.
IVIg may accelerate the catabolism of antibody, suppress antibody production, neutralize autoantibodies, and inhibit complement activation. IVIg has been shown to improve muscle strength in patients with severe symptoms.15 The dosage of IVIg varies, but is usually 400 mg/kg/day for 5 days in the setting of crisis. Side effects of IVIg included nephrotoxicity, anaphylaxis, and thromboembolic events.
Trials comparing the efficacy of IVIg and plasmapheresis in acute and severe MG did not reveal differences in efficacy.16,17 The choice between plasmapheresis and IVIg is often based on the patient's ability to tolerate each treatment. Since IVIg is easier to administer and associated with fewer adverse events than plasmapheresis, it is usually the preferred treatment.
A long-term immunosuppressive agent is usually required for patients who remain symptomatic on pyridostigmine, and virtually all patients with generalized MG. The long-acting immunosuppressive agents for MG include corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, and others. The choice of agents depends on comorbidities including diabetes (relative contraindication to corticosteroids), liver disease (precludes azathioprine usage), renal dysfunction (precludes cyclosporine usage), or leukopenia (restrictive for azathioprine and mycophenolate mofetil). The desired time of response onset and cost are also important considerations.
The most commonly used immunosuppressive agent for the treatment of MG is prednisone. Observational studies, clinical experience, and limited controlled trials suggest that prednisone usage leads to remission or marked improvement in 70% to 80% of patients with ocular or generalized MG.18 Prednisone may also halter the progression of ocular MG to the generalized form.19
Caution should be used when high-dose prednisone is given to patients as up to 50% of patients may develop a transient deterioration with possible precipitation of MG crisis. The transient worsening usually occurs 5 to 10 days after dose initiation and lasts for about a week. For this reason, high-dose prednisone should be started in hospitalized patients receiving concurrent rapid induction immunotherapy. Alternatively, a slow dose escalation regimen should be used to reach a target dose of 1mg/kg (usually 50-80 mg/day) over 3 to 4 weeks. In patients with mild to moderate MG symptoms, a lower dose of 20 to 40 mg per day is sufficient.
There is no set approach for tapering prednisone in MG patients. In general, 2 to 3 months after patients have achieved maximal control of symptoms, a steroid taper should be considered due to the side effect profile of chronic steroid use. It is important to taper prednisone slowly to avoid MG relapse (~5-10 mg/month). Patients should be maintained on the lowest possible dose of prednisone if the drug cannot be discontinued. In those cases, other immunotherapeutic agents may be considered either in lieu of or in addition to corticosteroids as a "corticosteroid-sparing" agent.
The side effects of prednisone commonly include weight gain, cushingoid features, easy bruising, cataract, glaucoma, hypertension, diabetes, dyslipidemia, osteoporosis and rarely avascular necrosis of femoral or humeral head. Patients are advised to take calcium (1,500 mg/day) and vitamin D (400 to 800 IU/day) supplements. For those most at risk for osteoporosis, treatment with bisphosphonate should be considered.
Azathioprine interferes with DNA synthesis and interrupts the proliferation of B- and T lymphocytes. The onset of beneficial effects from azathioprine is delayed at 6 to 12 months, with the maximal efficacy often appearing after 1 to 2 years of treatment.20 The starting dosage of azathioprine is usually a daily dose of 50 mg, followed by an increase every 2 weeks up to a typical maintenance dose of 2 to 3 mg/kg/day. Common side effects include fever, nausea, vomiting, and malaise, and less frequently hematological abnormalities, abnormal liver function, or pancreatitis. Blood cell counts and liver function tests should be monitored every week for the first 2 months then every month for at least the first year. Some individuals are homozygous for a mutant allele in the thiopurine methyltransferase gene, and such patients should not receive azathioprine because of their inability to metabolize the medication leading to potential life-threatening bone marrow suppression.21
Mycophenolate mofetil inhibits purine synthesis and decreases the proliferation of B- and T- lymphocytes. The starting dose is 500 mg twice daily and the usual maintenance dose is 1,000 to 1,500 mg twice daily. It is a well-tolerated medication with fewer side effects and it has been increasingly used in MG management. A slow development of clinical benefit is observed after months of mycophenolate therapy, similarly to azathioprine.22 Common side effects of mycophenolate include nausea, diarrhea, and infections such as urinary tract infection. Leukopenia can occur but rarely to the degree that leads to a discontinuation of mycophenolate. Similarly to azathioprine, a monthly complete blood count during the first 6 months of therapy is needed, and less frequently afterwards. As mycophenolate exposure in pregnancy results in a high incidence of major fetal malformation, its usage in pregnant patients is discouraged.23
Cyclosporine inhibits the function of calcineurin and blocks synthesis of interleukin-2 and interferon by helper T-cells. Its onset of action appears faster and clinical benefit can often be appreciated as early as 1 to 2 months.24 A maintenance dose of 5 mg/kg/day and a serum level of 100 to 150 ng/mL are generally recommended. However, the renal toxicity and interactions with other medications make cyclosporine a less favorable choice than other agents. Tacrolimus has a similar action to cyclosporine but has the advantage of being less nephrotoxic. The reported dosage varies from 0.05 to 0.1 mg/kg/day with targeted plasma levels of 2 to 9 ng/mL. Side effects included hypomagnesemia, tremor, and paresthesia.24
Rituximab is a monoclonal antibody that acts against the B cell membrane marker CD20 and leads to B lymphocyte depletion. A growing number of case series supports its usage in patients with severe generalized MG refractory to multiple immunosuppressive agents. Rituximab is particularly effective for MG-MuSK, often resulting in a significant reduction of MuSK antibody titers and a long lasting treatment effect.25,26 The standard dosage is 375 mg/m2 per week for 4 consecutive weeks. Minimal infusion reactions, which include flushing, pruritis, chills, and rigors, are seen mostly with the initial infusion. Patients may be more susceptible to certain infections such as reactivation of herpes zoster but overall rituximab is well tolerated.
Cyclophosphamide is an alkylating agent which interferes with DNA replication and in turn decreases the production of lymphocytes, monocytes and macrophages. Due to serious potential side effects, which include myelosuppression, hemorrhagic cystitis, skin, bladder and blood malignancies, cyclophosphamide is used sparingly and is usually reserved for severe cases that are refractory to other immunosuppressive agents.27
Patients with a thymoma should be considered for surgical removal of the thymus. If it is not possible, chemoradiotherapy can be considered for both the relief of myasthenic symptoms and the prevention of local invasion. However, the need for thymectomy is less certain in MG patients without thymoma.28 Many experts believe thymectomy is beneficial in patients with generalized MG without thymoma who are younger than 60 years of age and whose symptoms are poorly controlled on low doses of immunosuppression.29 Thymectomy should be performed as soon as the patient's degree of weakness is sufficiently controlled to permit surgery. A relatively low dose of corticosteroids is preferred to avoid postoperative problems with wound healing. IVIg or plasmapheresis treatment could be considered to optimize the patient 1 to 2 weeks prior to thymectomy. There is no consensus as to whether a sternum-splitting approach is better than less invasive technique such as videoscopic thymectomy. The available evidence does not support a role for thymectomy in MuSK antibody-associated MG. The role of thymectomy in ocular MG is controversial.
Myasthenic crisis is defined as respiratory muscle weakness that is severe enough to necessitate intubation or delay extubation. Prognosis in myasthenic crisis has dramatically improved over the last 4 decades from a mortality rate of 75% to the current 4.5%. It is prudent to closely observe MG patients with respiratory difficulty in a supervised setting. The forced vital capacity (FVC) and the negative inspiratory force (NIF) are the main respiratory parameters for monitoring, and both should be measured frequently during the hospital admission. Abnormalities of arterial blood gases are insensitive measures of respiratory muscle weakness as they often are late-occurring abnormalities only after the onset of life-threatening respiratory failure. Elective intubation should be considered if serial FVC measurements show values less than 20 mL/kg or if the NIF is less than 30 cm H2O.30 Rapid induction therapies such as plasmapheresis or IVIg should be considered. In most cases, initiation or maintenance of high-dose corticosteroids is also necessary.
No special preventative strategies exist for MG as its cause is unknown. However, care must be taken in all MG patients to avoid an exacerbation or MG crisis. Many conditions (temperature extremes – especially heat, pain, stress and overexertion) may temporarily exacerbate MG symptoms and should be kept to a minimum. Many medications may increase weakness in MG and should be avoided or used with great caution. The list is long but ones deserving particular attention include penicillamine, procainamide, quinidine, and aminoglycosides.2 Screening for MG is not feasible secondary to the low incidence.
The course of MG in pregnancy is unpredictable. Approximately a third each of women with MG will experience remission, exacerbation or no change during pregnancy. The highest risk of exacerbation occurs in the first trimester and acute postpartum period. Ach inhibitors are usually safe during pregnancy, but a dosage adjustment may be needed due to increased renal clearance. Steroid and azathioprine are relatively safe, but the latter may rarely cause spontaneous abortion, preterm labor or low birth weight. A vaginal delivery is still the preferred choice as the uterus is not affected as it does not consist of striated muscle. Magnesium sulfate is contraindicated in pregnant patients with MG. Transient MG occurs in 10% to 20% neonates from MG mothers. Their symptoms usually appear within 48 hours of birth but may persist up to 3 months. All infants of MG mothers need to be observed in a special care nursery for the first 48 to 72 hours of life.31
The hallmark of MG is a fluctuating muscle weakness that affects ocular, bulbar, cervical, proximal limb, and respiratory muscles. Antibody testing and electrodiagnostic studies are the mainstays of diagnostic approaches. Successful usage of immunomodulating therapy is the key in achieving a remission and needs to be individualized in most MG patients.
Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011; 76:294–300.
Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2012; 78:1009–1015.
Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010; 17:893–902.