Adverse effects of ChE inhibitors may result from ACh accumulation at muscarinic receptors on smooth muscle and autonomic glands and at nicotinic receptors of skeletal muscle.
Central nervous system side effects are rarely seen with the doses used to treat myasthenia gravis. Gastrointestinal complaints are common; queasiness, loose stools, nausea, vomiting, abdominal cramps, and diarrhea.
Increased bronchial and oral secretions are a serious problem in patients with swallowing or respiratory insufficiency. Symptoms of muscarinic overdosage may indicate that nicotinic overdosage weakness is also occurring. Excessive nicotinic receptor overdosage results in Myasthenic Crisis characterized by severe generalized weakness and respiratory failure. Thymectomy is recommended by many physicians for most patients with myasthenia gravis.
Most reports do not correlate the severity of weakness before surgery and the timing or degree of improvement after thymectomy. The maximal favorable response generally occurs 2 to 5 years after surgery. However, the response is relatively unpredictable and significant impairment may continue for months or years after surgery.
Sometimes, improvement is only appreciated in retrospect. The best responses to thymectomy are in young people early in the course of their disease, but improvement can occur even after 30 years of symptoms.
Patients with disease onset after the age of 60 rarely show substantial improvement from thymectomy. Patients with thymomas do not respond as well to thymectomy as do patients without thymoma.
A large, international multi-center clinical trial began in to determine the role of thymectomy in steroid-treated patients. Much of the improvement occurs in the first 6 to 8 weeks, but strength may increase to total remission in the months that follow.
The best responses occur in patients with recent onset of symptoms, but patients with chronic disease may also respond. The severity of disease does not predict the ultimate improvement. Patients with thymoma have an excellent response to prednisone before or after removal of the tumor. The most predictable response to prednisone occurs when treatment begins with a daily dose of 1.
About one-third of patients become weaker temporarily after starting prednisone, usually within the first 7 to 10 days, and lasting for up to 6 days. Treatment can be started at low dose to minimize exacerbations; the dose is then slowly increased until improvement occurs.
Exacerbations may also occur with this approach and the response is less predictable. The major disadvantages of chronic corticosteroid therapy are the side effects. Azathioprine reverses symptoms in most patients but the effect is delayed by 4 to 8 months. Once improvement begins, it is maintained for as long as the drug is given, but symptoms recur 2 to 3 months after the drug is discontinued or the dose is reduced below therapeutic levels. Patients who fail corticosteroids may respond to azathioprine and the reverse is also true.
Some respond better to treatment with both drugs than to either alone. Because the response to azathioprine is delayed, both drugs may be started simultaneously with the intent of rapidly tapering prednisone when azathioprine becomes effective.
Approximately one-third of patients have mild dose-dependent side effects that may require dose reductions but do not require stopping treatment. Cyclosporine inhibits predominantly T-lymphocyte-dependent immune responses and is sometimes beneficial in treating myasthenia gravis. Most patients with myasthenia gravis improve 1 to 2 months after starting cyclosporine and improvement is maintained as long as therapeutic doses are given. Maximum improvement is achieved 6 months or longer after starting treatment.
After achieving the maximal response, the dose is gradually reduced to the minimum that maintains improvement. Renal toxicity and hypertension, the important adverse reactions of cyclosporine. Many drugs interfere with cyclosporine metabolism and should be avoided or used with caution. Cyclophosphamide has been used intravenously and orally for the treatment of myasthenia gravis. More than half of patients become asymptomatic after one year.
Side effects are common. Life-threatening infections are an important risk in immunosuppressed patients, but in our experience, this risk is limited to patients with invasive thymoma. The long-term risk of malignancy is not established, but there are no reports of an increased incidence of malignancy in patients with myasthenia gravis receiving immunosuppression.
It also suppresses the formation of antibodies active in complement-dependent lysis and antibody-dependent, cell-mediated cytotoxicity, a necessary feature to promote many autoimmune diseases. While case reports, pilot studies and retrospective series have demonstrated a potential role for MMF as a corticosteroid-sparing agent and as adjunctive or primary therapy in refractory MG, a large clinical trial did not show superiority of MMF as a corticosteroid-sparing agent.
Similar findings were found for methotrexate MTX. Others are using both as a preferred treatment because of their faster onset of action when compared to azathioprine. Both the MMF and MTX trials have been criticized for study design failings and the fact that prednisone was a much better drug than anyone thought it was. Despite these failings the majority of experts continue to use MMF as a primary and secondary treatment for MG.
Eculizumab, a humanized monoclonal antibody to the fifth component of complement C5 , was shown to be successful in improving strength in patients with refractory failing at least 2 immunotherapies for at least 1 year generalized myasthenia gravis. This first-in-kind therapy is currently in Phase 3 trials. Plasma exchange is used as a short-term intervention for patients with sudden worsening of myasthenic symptoms for any reason, to rapidly improve strength before surgery, and as a chronic intermittent treatment for patients who are refractory to all other treatments.
The need for plasma exchange, and its frequency of use is determined by the clinical response in the individual patient. Almost all patients with acquired myasthenia gravis improve temporarily following plasma exchange. Maximum improvement may be reached as early as after the first exchange or as late as the fourteenth. Improvement lasts for weeks or months and then the effect is lost unless the exchange is followed by thymectomy or immunosuppressive therapy.
Most patients who respond to the first plasma exchange will respond again to subsequent courses. Repeated exchanges do not have a cumulative benefit.
Possible mechanisms of action include down-regulation of antibodies directed against AChR and the introduction of anti-idiotypic antibodies. The common adverse effects of IVIG are related to the rate of infusion. The mechanism of action is not known but is probably non-specific down regulation of antibody production. Most recently a subcutaneous form of the preparation is available and may be used as an alternative treatment option, especially in patients with limited intravenous access.
In about two-thirds of the patients, the involvement of extrinsic ocular muscles EOMs presents as the initial symptom, usually progressing to involve other bulbar muscles and limb musculature, resulting in generalized myasthenia gravis gMG. Sex and age appear to influence the occurrence of myasthenia gravis. Over 50 years, it occurs more commonly in males [ 3 ]. In , Wilhelm Erb Heidelberg, Germany described three cases of myasthenia gravis in the first paper dealing entirely with this disease, whilst bringing attention to features of bilateral ptosis, diplopia, dysphagia, facial paresis, and weakness of neck muscles [ 8 ].
In , Samuel Goldflam Warsaw, Poland described three cases with complete description of myasthenia and also analyzed the varying presentations, severity, and prognosis of his cases. The first two words of this syndrome gradually got accepted as the formal name of this disorder. In , Mary Walker realized that MG symptoms were similar to those of curare poisoning, which was treated with physostigmine, a cholinesterase inhibitor. She demonstrated that physostigmine promptly improved myasthenic symptoms.
In , Blalock reported improvement in myasthenic patients after thymectomy. Following these discoveries, cholinesterase inhibitor therapy and thymectomy became standard and accepted forms of treatment for MG [ 12 ]. In , Nastuk et al. In the s prednisone and azathioprine were introduced as treatment modalities for MG followed by plasma exchange that was introduced for acute treatment of severe MG, all supporting the autoimmune etiology [ 16 ].
Thymoma-associated MG may also have additional paraneoplasia-associated antibodies e. They have atypical clinical features like selective facial, bulbar, neck, or respiratory muscle weakness with occasional marked muscle atrophy and with relative sparing of the ocular muscles.
Respiratory crises are more common with involvement of muscle groups like paraspinal and upper esophageal muscles. Enhanced sensitivity, nonresponsiveness, or even clinical worsening to anticholinesterase medications has also been reported. Disease onset is earlier with female predominance and thymus histology is usually normal [ 20 ]. Seronegative MG lacks both anti-AChR and anti-MuSK antibodies and forms a clinically heterogenous group with purely ocular, mild generalized, or severe generalized disease.
Some patients may have low-affinity anti-AChR antibodies, nondetectable by current assays. They are essentially indistinguishable from patients with anti-AChR antibodies in terms of clinical features, pharmacological treatment response, and possibly even thymic abnormalities [ 21 , 22 ]. Thymomas are frequently associated with autoimmunity. Neoplastic epithelial cells in thymomas express numerous self-like antigens including AChR-like, titin-like, and ryanodine-receptor-like epitopes [ 19 , 23 ].
These antibodies react with epitopes on the muscle proteins titin and ryanodine receptor, are found mainly in association with thymoma and late-onset myasthenia gravis, and may correlate with myasthenia gravis severity. These striational antibodies are principally detected only in the sera of patients with MG and rarely found in AChR antibody-negative MG.
The frequencies of striational antibodies in thymoma-associated MG patients are high. Since the presence of striational autoantibodies is associated with a more severe disease in all MG subgroups, these antibodies can therefore be used as prognostic determinants in MG patients [ 25 ]. Neurophysiological examination with repetitive nerve stimulation and jitter measurements are important in establishing the initial diagnosis, especially in patients without detectable antibodies [ 16 ].
It is designed to identify subgroups of patients with MG who share distinct clinical features or severity of disease that may indicate different prognoses or responses to therapy. It should not be used to measure outcome and is as follows.
Class I MG is characterized by the following: i any ocular muscle weakness. Class II MG is characterized by the following: i mild weakness affecting muscles other than ocular muscles, ii may also have ocular muscle weakness of any severity. Class IIa MG is characterized by the following: i predominantly affecting limb, axial muscles, or both ii may also have lesser involvement of oropharyngeal muscles.
Class IIb MG is characterized by the following: i predominantly affecting oropharyngeal, respiratory muscles, or both, ii may also have lesser or equal involvement of limb, axial muscles, or both. Class III MG is characterized by the following: i moderate weakness affecting muscles other than ocular muscles, ii may also have ocular muscle weakness of any severity.
Class IIIa MG is characterized by the following: i predominantly affecting limb, axial muscles, or both, ii may also have lesser involvement of oropharyngeal muscles. Class IIIb MG is characterized by the following: i predominantly affecting oropharyngeal, respiratory muscles, or both, ii may also have lesser or equal involvement of limb, axial muscles, or both.
Class IV MG is characterized by the following: i severe weakness affecting muscles other than ocular muscles, ii may also have ocular muscle weakness of any severity. Class IVa MG is characterized by the following: i predominantly affecting limb, axial muscles, or both, ii may also have lesser involvement of oropharyngeal muscles. Class IVb MG is characterized by the following: i predominantly affecting oropharyngeal, respiratory muscles or both, ii may also have lesser or equal involvement of limb, axial muscles, or both.
Class V MG is characterized by the following: i intubation with or without mechanical ventilation, except when employed during routine postoperative management, ii the use of feeding tube without intubation places the patient in class IVb. The NMJ postsynaptic membrane has deep folds with acetylcholine receptors AChR tightly packed on the top of these folds. When the nerve action potential reaches the synaptic bouton, depolarization opens voltage gated Calcium channels on the presynaptic membrane, triggering release of ACh into the synaptic cleft.
The ACh diffuses into the synaptic cleft to reach postsynaptic membrane receptors where it triggers off the end-plate potential EPP and gets hydrolyzed by AChE within the synaptic cleft.
MuSK muscle specific tyrosine kinase , a postsynaptic transmembrane protein, forms part of the receptor for agrin, a protein present on synaptic basal lamina. Rapsyn, a peripheral membrane protein on the postsynaptic membrane, is necessary for the clustering of AChR. NMJ findings that influence susceptibility to muscle weakness and MG: EPP generated in normal NMJ is larger than the threshold needed to generate the postsynaptic action potential by a measure of multiple folds.
Reduction in number or activity of the AChR molecules at the NMJ decreases the EPP, which may be adequate at rest; but when the quantal release of ACh is reduced after repetitive activity, the EPP may fall below the threshold needed to trigger the action potential [ 29 ]. This translates as clinical muscle weakness, and when EPP, at rest is consistently below the action potential threshold, it leads to persistent weakness.
Th2 cells secrete anti-inflammatory cytokines, like IL-4, IL-6, and IL, which are important inducers of humoral immune responses. Th1 cells are indispensible in the development of EAMG as proven in animal models. Tregs in MG patients may be functionally impaired and are shown to increase after thymectomy with correlated symptom improvement. MG patients have been shown to have increased serum level of IL, which tends to decrease with clinical improvement [ 35 ]. Other ethnic groups or locations e.
Some human muscle cell culture studies have shown cell cycle arrest, downregulation of AChR subunit with rapsyn, and other muscle protein expression, on exposure to sera from anti-MuSK-positive MG patients [ 2 ]. Other antimuscle cell protein antibodies e. The cardinal feature of MG is fluctuating weakness that is fatigable, worsening with repetitive activities and improving with rest.
Weakness is worsened by exposure to heat, infection, and stress [ 3 ]. The fluctuating feature distinguishes MG from other disorders that present with a similar weakness. Typically the weakness involves specific skeletal muscle groups.
The distribution of the weakness is generally ocular, bulbar, proximal extremities and neck, and in a few patients, it involves the respiratory muscles. It presents with fluctuating ptosis and diplopia or sometimes blurry vision. Diplopia can be elicited by having the patient look laterally for 20—30 seconds resulting in eye muscle fatigue uncovering myasthenic weakness.
The ptosis can be unilateral or bilateral, fatigues with upgaze, and sustained upgaze for 30 or more seconds will usually induce it. The ptosis can be severe enough to totally occlude vision if it is bilateral. The most commonly involved extraocular muscle is the medial rectus. On clinical examination, usually more than one extraocular muscle is weak with pupillary sparing.
The weakness does not follow any pattern of specific nerve or muscle involvement, distinguishing it from other disorders such as vertical gaze paresis, oculomotor palsy, or internuclear ophthalmoplegia INO. The lack of ocular involvement in these patients may be misdiagnosed as motor neuron disease. Weakness involving respiratory muscles is rarely the presenting feature in the first 2 years of onset [ 35 ].
Respiratory muscle weakness can lead to myasthenic crisis which can be life threatening, requiring mechanical ventilation and naso-gastric NG tube feeding. It can be precipitated by infections and certain medications such as aminoglycosides, telithromycin, neuromuscular blocking agents, magnesium sulfate, beta blockers, and fluoroquinolone antibiotics. Involvement of the limbs in MG produces predominantly proximal muscle weakness similar to other myopathic disorders.
However, the arms tend to be more often affected than the legs. Occasionally distal muscle weakness can occur in MG [ 40 ]. Facial muscles are frequently involved and make the patient appear expressionless.
Neck extensor and flexor muscles are commonly affected. Of those who will develop generalized myasthenia, virtually, all do so by two to three years [ 3 ]. Edrophonium chloride is a short-acting acetylcholinesterase inhibitor that prolongs the duration of action of acetylcholine at the NMJ.
Only unequivocal improvement in strength of a sentinel muscle should be accepted as a positive result. Patients must be connected to cardiac and blood pressure monitors prior to injection because of possible risk of arrhythmia and hypotension. Atropine should be available at bed side for use if an adverse event like severe bradycardia heart rate below 37 develops.
Side effects from Edrophonium include increased salivation and sweating, nausea, stomach cramping, and muscle fasciculation. Hypotension and bradycardia are infrequent and generally resolve with rest in the supine position. Tensilon test has a sensitivity of The ice pack test is a non pharmacological test which could be considered in patients with ptosis when the Edrophonium test is contraindicated.
It is performed by placing an ice pack over the eye for 2—5 minutes and assessing for improvement in ptosis [ 43 ]. The two principal electrophysiologic tests for the diagnosis of MG are repetitive nerve stimulation study and single fiber electromyography.
Repetitive nerve stimulation tests neuromuscular transmission. In the absence of the decrement, exercise can be used to induce exhaustion of muscles and document decrement. It is done by using a special needle electrode that allows identification of action potentials from individual muscle fibers.
It allows simultaneous recording of the action potentials of two muscle fibers innervated by the same motor axon.
Although highly sensitive, increased jitter is not specific for primary NMJ disease. It may be abnormal in motor neuron disease, polymyositis, peripheral neuropathy, Lambert-Eaton myasthenic syndrome LEMS , and other neuromuscular disorders. However, it is specific for a disorder of neuromuscular transmission when no other abnormalities are seen on standard needle EMG examination [ 42 ].
The most commonly used immunological test for the diagnosis of MG measures the serum concentrations of Anti-AChR antibodies and is highly specific for myasthenia gravis [ 46 ]. Anti-AChR antibody concentrations cannot be used to predict the severity of disease in individual patients since the concentration of the antibodies does not correlate with the clinical picture. Seronegativity may occur with immunosuppression or if the test is done too early in the disease [ 49 , 50 ].
As indicated above, striated muscle antibodies against muscle cytoplasmic proteins titin, myosin, actin, and ryanodine receptors are detected mainly in patients with thymomatous MG and also in some thymoma patients without MG [ 24 , 51 ]. The presence of these antibodies in early-onset MG raises the suspicion of a thymoma.
Whether low-affinity antibodies are present in oMG remains to be determined, but this cell-based assay might eventually provide a more sensitive diagnostic test in this subgroup.
Iodinated contrast agents should be used with caution because they might exacerbate myasthenic weakness [ 54 , 55 ]. MG often coexists with thyroid disease, so baseline testing of thyroid function should be obtained at the time of diagnosis.
Management of Myasthenia Gravis Management of MG should be individualized according to patient characteristics and the severity of the disease. There are two approaches for management of MG based on the pathophysiology of the disease.
The first is by increasing the amount of Acetylcholine that is available to bind with the postsynaptic receptor using an acetylcholinesterase inhibitor agent, and the second is by using immunosuppressive medications that decrease the binding of acetylcholine receptors by antibodies.
There are four basic therapies used to treat MG: i symptomatic treatment with acetylcholinesterase inhibitors, ii rapid short-term immunomodulating treatment with plasmapheresis and intravenous immunoglobulin, iii chronic long-term immunomodulating treatment with glucocorticoids and other immunosuppressive drugs, iv surgical treatment. Acetylcholinesterase inhibitors are the first-line treatment in patients with MG. Response to treatment varies from marked improvement in some patients to little or no improvement in others.
Acetylcholinesterase inhibitors are used as a symptomatic therapy and act by increasing the amount of available acetylcholine at the NMJ [ 56 ]. They do not alter disease progression or outcome. Pyridostigmine is the most commonly used drug. It has a rapid onset of action within 15 to 30 minutes reaching peak activity in about two hours.
The effect lasts for about three to four hours. Adverse side effects of Pyridostigmine are mostly due to the cholinergic properties of the drug such as abdominal cramping, diarrhea, increased salivation and bronchial secretions, nausea, sweating, and bradycardia. Nicotinic side effects are also frequent and include muscle fasciculation and cramping. Plasma exchange and intravenous immunoglobulin have rapid onset of action with improvement within days, but this is a transient effect.
They are used in certain situations such as myasthenic crisis and preoperatively before thymectomy or other surgical procedures. They can be used intermittently to maintain remission in patients with MG who are not well controlled despite the use of chronic immunomodulating drugs.
Typically one exchange is done every other day for a total of four to six times. Adverse effects of plasmapheresis include hypotension, paresthesias, infections, thrombotic complications related to venous access, and bleeding tendencies due to decreased coagulation factors [ 59 ].
It involves isolating immunoglobulins isolated from pooled human plasma by ethanol cryoprecipitation and is administered for 5 days at a dose of 0. The mechanism of action of IVIg is complex. Factors include inhibition of cytokines competition with autoantibodies, and inhibition of complement deposition. Skip to main content. Search MDA. Search Donate. Myasthenia Gravis MG. Myasthenia Gravis MG What is myasthenia gravis? Myasthenia gravis is characterized by autoantibodies against the acetylcholine receptor AChR-Ab , or against a receptor-associated protein called muscle-specific tyrosine kinase MuSK-Ab There are two clinical forms of myasthenia gravis: ocular and generalized.
What are the symptoms of MG? What causes MG? What is the progression of MG? What is the status of research on MG? Parsippany, NJ. Carr, A. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. Increased risk for clinical onset of myasthenia gravis during the postpartum period. Neurology
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