Medication Summary
There is no cure for myasthenia gravis (MG). Medication is used to manage symptoms and control immune system activity. Acetylcholine esterase (AChE) inhibitors are considered to be the basic treatment of MG. Edrophonium is primarily used as a diagnostic tool owing to its short half-life. Pyridostigmine is used for long-term maintenance. Consider treatment with eculizumab for patients who are anti-acetylcholine receptor antibody-positive refractory.
High doses of corticosteroids commonly are used to suppress autoimmunity. Patients with MG also may be taking other immunosuppressive drugs (eg, azathioprine or cyclosporine). Adverse effects of these medications must be considered in assessment of the clinical picture. Bronchodilators may be useful in overcoming the bronchospasm associated with a cholinergic crisis.
Anticholinesterase Inhibitors
Class Summary
Anticholinesterase inhibitors interfere with the degradation of acetylcholine (ACh) by AChE, thereby increasing the amount of ACh available at the neuromuscular junction (NMJ) and increasing the chance of activating the acetylcholine receptors (AChRs). Any medication that increases the activity of the AChRs can have an effect on MG.
AChE inhibitors continue to be used as first-line treatment of MG. The improvement is usually partial and frequently decreases after many weeks to months of treatment. Besides, these agents are not as beneficial for ocular MG as for generalized MG. Hence, they often are complemented (and sometimes replaced) with immunosuppressive therapy.
Pyridostigmine bromide (Mestinon, Regonol)
Pyridostigmine acts in smooth muscle, the central nervous system (CNS), and secretory glands, where it blocks the action of ACh at parasympathetic sites. An intermediate-acting agent, it is preferred in clinical use to the shorter-acting neostigmine bromide and the longer-acting ambenonium chloride. It starts working in 30-60 minutes; effects last 3-6 hours.
Individualize the dose; MG does not affect all skeletal muscles similarly, and all symptoms may not be controllable without adverse effects. In critically ill or postoperative patients, administer the drug intravenously (IV).
In the United States, pyridostigmine is available in 3 forms: 60-mg scored tab, 180-mg timespan tablet, and 60-mg/5 mL syrup. Dose should not typically exceed 600 mg a day in adults and 7 mg/kg in children. Dosing half hour before meals may help in swallowing and reduce the risk of aspiration. The effects of the timespan tablet last 2.5 times longer. The timespan form is a useful adjunct to regular pyridostigmine for nighttime control of myasthenic symptoms. The absorption and bioavailability of the timespan tablet vary among subjects. It should be used only at bedtime, and patients need close monitoring for cholinergic adverse effects.
Patients can develop cholinergic side effects secondary to the accumulation of ACh at muscarinic and nicotinic receptors. Muscarinic side effects include nausea, vomiting, abdominal cramping, diarrhea, increased oral and bronchial secretions, bradycardia, and sometimes confusion or psychosis. When patients develop significant side effects, pretreatment with anticholinergic medications is recommended (eg, propantheline, glycopyrrolate, or diphenoxylate with atropine) 30 minutes before taking pyridostigmine.
Neostigmine (Bloxiverz)
Neostigmine inhibits the destruction of ACh by AChE, thereby facilitating the transmission of impulses across the NMJ. It is a short-acting AChE inhibitor that is available in an oral form (15 mg tablet) and a form suitable for IV, intramuscular (IM), or subcutaneous (SC) administration. Its half-life is 45-60 minutes. It is poorly absorbed from the gastrointestinal (GI) tract and should be used only if pyridostigmine is unavailable. Individualize the dose for all patients.
Edrophonium (Enlon)
Edrophonium is primarily used as diagnostic tool to predict the response to longer-acting cholinesterase inhibitors. Like other cholinesterase inhibitors, it decreases the metabolism of ACh, increasing the cholinergic effect at the NMJ. It was used in the past to distinguish between cholinergic and myasthenic crisis. If IV edrophonium resultsed in worsening of symptoms, the increased weakness in patients is probably due to overdosing the anticholinesterase medication. If weakness, on the other hand, improves following edrophonium, the weakness is due to the underlying MG.
Corticosteroids
Class Summary
Corticosteroids are anti-inflammatory and immunomodulating agents used to treat idiopathic and acquired autoimmune disorders. They were among the first immunomodulating agents used to treat MG and still are used frequently and effectively. They are typically used in moderate or severe cases that do not respond adequately to AChE inhibitors and thymectomy. Long-term treatment with corticosteroids is effective and may induce remission or cause marked to moderate improvement in most patients.
Transient worsening might occur initially; clinical improvement then shows after 2-4 weeks with maximal effect in 5-6 months. These agents are usually given over 1 or 2 years before tapering is begun. Remissions are noted in 30% and marked improvement in 40%.
Corticosteroids act in both ocular MG and generalized MG. They can be combined with other immunosuppressive medications for better effect with lesser dose and shorter duration of administration. Pulsed IV steroids might be beneficial in refractory patients.
Prednisone (Deltasone, Rayos)
Prednisone is most commonly used corticosteroid in the United States. Some experts believe that the long-term administration of prednisone is beneficial, but others use the drug only during acute exacerbations to limit the adverse effects of chronic steroid use.
Prednisone is effective in decreasing the severity of MG exacerbations by suppressing the formation of autoantibodies. However, clinical effects often are not seen for several weeks. Significant improvement, which may be associated with a decreased antibody titer, usually occurs in 1-4 months. An alternate-day regimen may minimize adverse effects. A trial of steroid withdrawal may be attempted, but most patients on long-term corticosteroid therapy relapse and require re-institution of steroids.
Chronic administration of corticosteroids is associated with numerous serious side effects. The risk of infection, diabetes mellitus, hypotension, glaucoma, osteoporosis, steroid myopathy, and aseptic necrosis of the joints are some examples. It is prudent to obtain chest X-ray, PPD skin test, and a detailed history of exposure to tuberculosis, strongyloides, or other organisms that may grow as a result of the chronic administration of corticosteroids. Measurement of DEXA at baseline and every 6-12 months while the patient is on corticosteroids is recommended. If the bone density shows evidence of osteopenia or osteoporosis, calcium supplementation (1 g/day), vitamin D (400-800 IU daily), and biphosphonates are started prophylactically for steroid-induced osteoporosis. Prophylactic treatment with histamine-H2 receptor blockers are usually not required.
BP monitoring, periodic eye exam to check for glaucoma and cataracts is recommended. Fasting blood glucose, serum potassium levels should be periodically checked. Potassium may be supplemented if the patient becomes hypokalemic.
High dose steroids and lack of physical activity can lead to type 2 muscle fiber atrophy with proximal muscle weakness. Distinction from myasthenic weakness is important and is challenging. Patients who become weaker during a prednisone taper, and show craniobulbar, and upper extremity muscle weakness, and demonstrate worsening of their decremental response on RNS are more likely to experience worsening of their myasthenia gravis symptoms. In contrast, patients who are continued on high doses of corticosteroids, normal RNS, and other evidence of steroid induced toxicity (i.e., Cushingoid features), increasing leg weakness, or have type 2 muscle fiber atrophy could benefit from physical therapy and steroid dose reduction.
Methylprednisolone (Solu-Medrol, Medrol, A-Methapred)
Methylprednisolone may be used in place of prednisone in patients who are intubated and in those unable to tolerate oral intake. It decreases inflammation by suppressing the migration of polymorphonuclear (PMN) leukocytes and reversing increased capillary permeability.
Immunomodulators
Class Summary
MG is an autoimmune disease, and immunomodulatory therapies have been used for these disorders since introduction of steroids. Although no rigorous clinical trials have established the efficacy of immunomodulatory therapies in MG, several uncontrolled trials and retrospective studies support use of such therapies. The therapies used in MG include prednisone, azathioprine, IV immunoglobulin (IVIg), plasmapheresis, and cyclosporine.
Azathioprine (Imuran, Azasan)
Azathioprine is an imidazolyl derivative of 6-mercaptopurine (6-MP). Many of its biological effects are similar to those of its parent compound. Both compounds are eliminated rapidly from the blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or 6-MP is detectable in urine 8 hours after being taken.
Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. The mechanism whereby it affects autoimmune diseases is unknown. It works primarily on T cells, suppresses hypersensitivities of the cell-mediated type and causing variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses.
Azathioprine is the second most commonly used immunosuppressive medication in MG. It is reserved for patients with either steroid failure or unacceptable effects from prolonged steroid use. Furthermore, it can be used for steroid-sparing effects to lower steroid doses. One drawback is that it works very slowly; it may require 12-18 months to exert its therapeutic effect. Up to 10% of patients may have idiosyncratic reaction disallowing use. Do not allow the white blood cell (WBC) count to drop below 3000/µL or the lymphocyte count to drop below 1000/µL.
Azathioprine is available in tablet form for oral administration or in 100-mg vials for IV injection.
Administer 2-3 mg/kg PO daily or BID; begin with a low initial dose. Maximal effect is 1-2 years.
The disadvantage of using this product is that it increases the risk of eoplasia, immunosuppression, pancytopenia, pancreatitis, and hepatotoxicity.
It is not for use in pregnant patients.
The drug causes flu-like symptoms, bone marrow suppression, and LFTs abnormalities. About 10% of patients do not tolerate the drug.
Check TPMT (thiopurine methyltransferase) enzyme activity. If the individual is homozygous for TPMT (1:300), do not give azathioprine as these individuals are unable to metabolize azathioprine and may have myelosuppression. Heterozygous individuals for TPMT are given azathioprine in smaller doses and monitored carefully.
Not to be used with allopurinol as the combination can result in bone marrow suppression and liver toxicity. Concurrent administration of allopurinol can increase azathioprine toxicity by interfering with its metabolism by xanthine oxidase, an important degradative pathway. Reduce azathioprine dose by as much as 75% in patients who take allopurinol.
Perform a CBC to check WBC for the first few months of starting treatment. Azathioprine is a useful and generally well-tolerated agent in MG. The usual dosage is 2-3 mg/kg/day. Approximately 5-10% of individuals have idiosyncratic reaction with fever, nausea, and vomiting, sometimes accompanied by eosinophilia or increased hepatocellular enzymes at the initiating dose. Obtain a baseline CBC and differential, platelet count, and LFTs (ALT, AST, and ALP). If the patient is not already receiving corticosteroids, obtain an anergy panel, including a PPD, and check that a recent x-ray film has been taken.
Therapy starts with 50 mg/day for 5 days, blood tests are checked, and the dosage is increased by 50 mg/day every 5 days, with blood tests checked before each increase. After reaching 150 mg/day, increase 25 mg/day every 5 days, checking the blood studies. At 2 to 2.5 mg/kg/day, observe the patient for 3-4 months. If the patient has not started to show clinical improvement and an increase in red blood cell (RBC) mean cell volume (MCV; increase in MCV of >100 fL is a useful indicator of a therapeutic dose, in the absence of concomitant iron deficiency), increase dose again by 25 mg/day to 3 mg/kg/day.
CBC and LFTs are monitored every 2 weeks for several months, until a stable dose of azathioprine is achieved. Patients who have been receiving a stable dose for greater than 2 years and who have shown no signs of toxicity can be monitored 2 to 3 times per year. Upward adjustment of dose or signs of toxicity require returning to weekly monitoring and going through the same cycle.
Macrocytosis is not an indication of discontinuation of therapy. WBC 3-4K/mm3 is a safe endpoint. If WBC falls <2.5K/mm3 or the absolute neutrophil count is less than 1000/mm3, azathioprine should be briefly discontinued, then reintroduced at a lower dose. Leukopenia can present within a week or as late as 2 years after intiating azathioprine. This measure cannot be used in patients receiving prednisone, because of the steroid-induced leukocytosis. In that situation, an absolute lymphocyte count of 5-10% is an appropriate target. If LFTs show transaminases trend upwards of 2-3 times of normal values, the medication is held. This can be typically seen within a month of starting the medication. Side effects that may respond to lowering of the dose or dividing the daily dose to twice or three times a day include epigastric distress, nausea and vomiting, stomatitis, oral thrush, increased susceptibility to infections, marrow suppression, or increase in hepatocellular or obstructive liver chemistries. The majority of patients benefit from the drug and tolerate it long term (years). Generally, leucopenia reverses within 1 month and hepatotoxicity usually takes several months to resolve.
Very little evidence has shown an increased incidence of neoplasm from azathioprine in the doses generally used in MG. The major disadvantage of azathioprine is the delay in therapeutic effect; it takes 3-4 months to see a clinical effect, and it may take more than 12 months for maximal effect.
An adequate therapeutic trial with azathioprine should last at least 1-2 years, since the lag to onset of effect may range from 3-12 months, and the point of maximum benefit may be delayed 1-3 years.
Cyclosporine (Gengraf, Neoral, Sandimmune)
Cyclosporine A is an 11-amino acid cyclic peptide that is a natural product of fungi. It acts on T-cell replication and activity. It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle is suggested.
Cyclosporine binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin (IL)–2 and subsequent recruitment of activated T cells. It has about 30% bioavailability, but there is marked individual variability. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.
Cyclosporine suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.
Cyclosporine is used as a second-line immunosuppressive agent and has been shown effective in patients with MG in prospective, double-blind, placebo-controlled clinical trial. This agent does have some significant adverse effects (more serious than those of azathioprine), which usually preclude its use as first-line immunosuppressive therapy. However, in patients who are at high risk for adverse steroid effects, it can be used as initial therapy. The onset of action is within a few weeks to months, similar to that of prednisone.
Administer 2.5-4 mg/kg/day divided BID with a fat-containing meal or snack.
The onset of action for this agent is 2-4 months with optimum effect to be observed in 7 months.
The advantage of this product is that it is a steroid-sparing immunosuppression; not cytotoxic but selectively immunomodulatory.
Disadvantages include increased risk of neoplasia, skin malignancy, HTN, renal failure, immunosuppression, hepatotoxicity, seizures, PRES (posterior reversible encephalopathy syndrome), increased ICP, and tremor. It also has a broad range of interactions with many drugs.
Metabolized in liver CYP450 system, and excreted in bile; potentiates risk of necrotizing myopathy or myoglobinuria due to lovastatin, which also depends on biliary excretion. It is lipid soluble.
Corticosteroids increase plasma cyclosporine levels.
MG improvement noted in about 2 weeks, with maximal improvement by 4 months, correlating with reduction in AChR antibody levels.
Monitor plasma cyclosporine trough levels every 3 weeks until stable, then monthly. Trough levels are measured in the morning 12 hours after last dose. Trough levels should be maintained between 100–200 ng/mL. Decrease dose if Cr rises above 1.4 times the baseline level.
Common side effects include HTN, PRES (posterior reversible encephalopathy syndrome), and nephrotoxic (especially elderly). Facial hirsutism, GI disturbances, headache, tremor, convulsions, and hepatotoxicity are related to drug levels and are reversible with dose reduction. When used concurrently, NSAIDs will potentiate cyclosporine nephrotoxicity.
Cyclophosphamide
Cyclophosphamide is an alkylating agent that interferes with cell proliferation. It is more effective against B cells than against T cells, which makes it a good choice in an antibody-mediated disease such as MG. Because of potential for serious side effects (ie, gastrointestinal upset, bone marrow toxicity, alopecia, hemorrhagic cystitis, teratogenicity, sterilization, and increased risk of infections and secondary malignancies), it is usually reserved for more severe cases where more routinely used immunotherapy has failed because of lack of efficacy or intolerable adverse effects.
Mycophenolate mofetil (CellCept)
Mycophenolate mofetil, a derivative of mycophenolic acid (MPA), blocks the de novo pathway of guanosine nucleotide synthesis by inhibiting the activity of inosine monophosphate dehydrogenase and thus inhibiting de novo purine synthesis. Both T and B lymphocytes are highly dependent upon the de novo pathway, whereas other cells use the purine salvage pathway of nucleotide synthesis. As a result, MPA selectively inhibits lymphocyte activity.
Mycophenolate mofetil has been shown to be effective in MG and is recommended as a steroid-sparing immune modulator.
The starting dose is 250 mg PO BID for 5 days, then 500 mg PO BID for 5 days, then 1 g PO BID
Its onset of action is 2-4 months with maximal effect observed at 5-6 months.
The advantage to using this agent is that it acts through steroid-sparing immunosuppression.
The disadvantages include increased risk of lymphoma, immunosuppression, teratogenicity risk, pancytopenia, GIB, renal failure, acute ILD, and HTN. It may also cause nausea, diarrhea, abdominal pain, fever, leukopenia, and edema.
Mycophenolate mofetil is an immunosuppressive drug with a mode of action similar to azathioprine. Its major advantage is that its effect seems to be limited to lymphocytes. Thus, although lymphocytes may be reduced in function and number, there is no effect on liver function tests and no effect on either RBC or PMN counts. Several uncontrolled studies have reported efficacy, and some also suggest that mycophenolate mofetil has a quicker mode of onset than azathioprine, particularly at 1 g BID.
Begin with 500 mg BID, and if the drug is tolerated, increase the dose to 1 g bid after 4 weeks. If diarrhea occurs, try 1 to 1.5 g/day. Other side effects include gastrointestinal hemorrhage and perforation; increased susceptibility to infections is a consideration with all of these agents, particularly in combination with corticosteroids. Neutropenia is generally associated with doses of 2 g/day or greater. Mycophenolate mofetil eventually may replace azathioprine as the first-line immunosuppressive drug in patients with MG, but further studies are required.
Monitor blood tests weekly for the first month of treatment, twice monthly for the second and third months, and then monthly thereafter.
It is used sometimes as an adjuvant drug in combination with cyclosporine and prednisone. It is the preferred drug for elderly myasthenics.
Methotrexate (Otrexup, Rasuvo, Trexall)
Methotrexate is not used frequently in myasthenia gravis, although it may be effective. It has an earlier onset of action compared to azathioprine. It may be initiated orally at 7.5 mg/week given in three divided doses 12 hours apart. It is gradually increased by 2.5 mg a week up to 25 mg/week as necessary. Major side effects include alopecia, stomatitis, interstitial lung disease, teratogenicity, oncogenicity, risk of infection, pulmonary fibrosis, renal, liver, and bone marrow toxicities. Doses of over 50 mg a week are rarely used for MG as this may require leukovorin rescue. Patients are given folate along with methotrexate.
Immune Globulins
Class Summary
Immunoglobulins are commonly used in admitted patients and rarely administered in the emergency department (ED).
IVIg is recommended for MG crisis, in patients with severe weakness poorly controlled with other agents, or in lieu of plasma exchange at a dose of 1 g/kg. IVIg is effective in moderate or severe MG worsening into crisis but does not exhibit value in mild disease. Data do not support or exclude a role for IVIg in chronic MG. The use of IVIg in a seronegative patient is not supported by the literature.
Immune globulin intravenous (Carimmune, Gammunex, Gammagard, Octagam)
High-dose IVIg successfully treats MG, though the mechanism of action is unknown. It is used in crisis management (eg, myasthenic crisis and the perioperative period) instead or in combination with plasmapheresis. Like plasmapheresis, it has a rapid onset of action, but the effects last only a short time.
Monoclonal Antibodies
Class Summary
Monoclonal antibodies are used to bind to one specific substance in the body (eg, molecules, antigens). This binding is very versatile and can mimic, block, or cause changes to enact precise mechanisms (eg, bridging molecules, replacing or activating enzymes or cofactors, immune system stimulation).
Rituximab (Rituxan)
Rituximab is a genetically engineered chimeric murine-human monoclonal antibody (mAb) directed against the CD20 antigen found on the surfaces of normal and malignant B cells. The antibody is an IgG1κ immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. Risk of progressive multifocal leukoencephalopathy associated with use.
Eculizumab (Soliris)
Eculizumab is a complement inhibitor. Its precise mechanism in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. It is indicated for the treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor (AchR) antibody-positive.
Fc Receptor Antagonists
Class Summary
This class of drugs inhibits FcRn, which accelerates the destruction of IgG. The reduction of tissue and serum IgG concentrations may be beneficial for patients with IgG autoantibody-mediated diseases.
Efgartigimod (Efgartigimod alfa-fcab, Vyvgart)
Efgartigimod alfa is a human IgG1 antibody Fc fragment that binds to neonatal Fc receptor (FcRn), which reduces the circulating IgG. The FDA approved efgartigimod for the treatment of gMG in adults who test positive for AchR antibody.
Beta2 Agonists
Class Summary
Beta-agonists are used to alleviate the respiratory distress and bronchospasm resulting from the cholinergic medications used to treat MG.
Albuterol (Proventil-HFA, Ventolin-HFA, ProAir-HFA)
Standard unit doses of beta-agonist nebulizer treatment may improve respirations in a cholinergic crisis. Continuous beta-agonist nebulizer treatment may be indicated in severe cases. Otherwise, the standard dosing regimen of 2 puffs from a metered dose inhaler or 2.5-5 mg nebulized every 4-6 hours often will suffice in achieving bronchodilation.
Anticholinergic agents
Class Summary
Anticholinergic bronchodilators cause the reversal of cholinergic medication effects that induce bronchospasm. These drugs can act synergistically or independently with beta-agonists to produce bronchodilation. They are quaternary amines, and they are poorly absorbed across the pulmonary epithelium. As a result, they have minimal systemic side effects.
Ipratropium (Atrovent)
Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from the serous and seromucous glands lining the nasal mucosa.
Glycopyrrolate (Robinul, Cuvposa)
Glycopyrrolate acts in smooth muscle, the central nervous system (CNS), and secretory glands, where it blocks the action of ACh at parasympathetic sites.
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Normal neuromuscular junction showing a presynaptic terminal with a motor nerve ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.
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Acetylcholine receptor. Note 5 subunits, each with 4 membrane-spanning domains forming a rosette with a central opening. The central opening acts as an ion channel.
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CT scan of chest showing an anterior mediastinal mass (thymoma) in a patient with myasthenia gravis.
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Increasing left ptosis developing upon sustained upward gaze in patient with 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.
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Cogan sign. Patient changes gaze from downward position (A) to primary position (B). Both lids are seen to overshoot in twitch (B) before gaining their initial ptotic position (D). In this case, Cogan sign is seen more obviously on right, whereas left lid is more ptotic.
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CT scan of chest and mediastinum showing thymoma in patient with myasthenia gravis.
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Repetitive nerve stimulation at frequency of 2 Hz showing increasing decrement in amplitude of compound muscle action potential up to fourth response (42% amplitude loss), after which it stabilizes.
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Single-fiber electromyography showing so-called jitter phenomenon (second action potential wave group).
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What is myasthenia gravis? Myasthenia gravis is an autoimmune disease that's categorized as a type II hypersensitivity that involves autoantibodies binding acetylcholine receptors on skeletal muscle cells. Courtesy of Osmosis.org (https://www.osmosis.org/).
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Motor end plate and innervation. Courtesy of Wikimedia Commons.
Tables
| Distribution of Weakness | Percentage of Patients |
|---|---|
| Localized ocular | 17% |
| Ocular and generalized | 50% |
| Ocular and bulbar | 13% |
| Ocular and limb | 20% |
