Myasthenia Gravis Medication
- Author: Aashit K Shah, MD, FAAN, FANA; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE more...
Acetylcholine esterase (AChE) inhibitors are considered to be the basic treatment of myasthenia gravis (MG). Edrophonium is primarily used as a diagnostic tool owing to its short half-life. Pyridostigmine is used for long-term maintenance.
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 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 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. 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.
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 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.
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. 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 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.
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.
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 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 6-12 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.
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 A 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 A 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.
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, 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, 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 onset of action is variable and usually starts between 1 and 12 months.
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.
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.
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.
Beta-agonists are used to alleviate the respiratory distress and bronchospasm resulting from the cholinergic medications used to treat MG.
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 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 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 acts in smooth muscle, the central nervous system (CNS), and secretory glands, where it blocks the action of ACh at parasympathetic sites.
Strauss AJL, Seigal BC, Hsu KC. Immunofluorescence demonstration of a muscle binding complement fixing serum globulin fraction in Myasthenia Gravis. Proc Soc Exp Biol. 1960. 105:184.
Patric J, Lindstrom JM. Autoimmune response to acetylcholine receptor. Science. 1973. 180:871.
Jaretzki A 3rd, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000 Jul 12. 55(1):16-23. [Medline].
Padua L, Stalberg E, LoMonaco M, Evoli A, Batocchi A, Tonali P. SFEMG in ocular myasthenia gravis diagnosis. Clin Neurophysiol. 2000 Jul. 111(7):1203-7. [Medline].
Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct. 14 (10):1023-36. [Medline].
Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. 2004 Apr. 29(4):484-505. [Medline].
Saperstein DS, Barohn RJ. Management of myasthenia gravis. Semin Neurol. 2004 Mar. 24(1):41-8. [Medline].
Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007 Mar 13. 68(11):837-41. [Medline].
Mandawat A, Kaminski HJ, Cutter G, Katirji B, Alshekhlee A. Comparative analysis of therapeutic options used for myasthenia gravis. Ann Neurol. 2010 Dec. 68(6):797-805. [Medline].
Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008 Feb. 37(2):141-9. [Medline].
Bershad EM, Feen ES, Suarez JI. Myasthenia gravis crisis. South Med J. 2008 Jan. 101(1):63-9. [Medline].
Evoli A, Tonali PA, Padua L. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003 Oct. 126(Pt 10):2304-11. [Medline].
Sanders DB, Howard JF, Massey JM. Seronegative myasthenia gravis. Ann Neurol. 1987. 22:126.
Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2008 Jan 23. CD002277. [Medline].
Martignago S, Fanin M, Albertini E, Pegoraro E, Angelini C. Muscle histopathology in myasthenia gravis with antibodies against MuSK and AChR. Neuropathol Appl Neurobiol. 2009 Feb. 35(1):103-10. [Medline].
Keller DM. Late-Onset Myasthenia Gravis Linked to Higher Cancer Risk. Medscape Medical News. Jul 2 2013. [Full Text].
Liu CJ, Chang YS, Teng CJ, et al. Risk of extrathymic cancer in patients with myasthenia gravis in Taiwan: a nationwide population-based study. Eur J Neurol. 2012 May. 19(5):746-51. [Medline].
Harding A. Pediatric Myasthenia Diagnosis Can Be Challenging, Study Shows. Medscape Medical News. Available at http://www.medscape.com/viewarticle/811117. Accessed: September 23, 2013.
Vanderpluym J, Vajsar J, Jacob FD, Mah JK, Grenier D, Kolski H. Clinical Characteristics of Pediatric Myasthenia: A Surveillance Study. Pediatrics. 2013 Sep 9. [Medline].
Engel AG. Acquired autoimmune myasthenia gravis. In: Engel AG, Franzini-Armstrong C, eds. Myology: Basic and Clinical. 2nd ed. 1994. 1769-1797.
J P Sieb. Myasthenia gravis: an update for the clinician. Clin Exp Immunol. March 2014. 175(3):408–418. [Full Text].
Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve. 2011 Jul. 44 (1):36-40. [Medline].
Qureshi AI, Choundry MA, Mohammad Y, et al. Respiratory failure as a first presentation of myasthenia gravis. Med Sci Monit. 2004 Dec. 10(12):CR684-9. [Medline].
Tindall RS. Humoral immunity in myasthenia gravis: biochemical characterization of acquired antireceptor antibodies and clinical correlations. Ann Neurol. 1981 Nov. 10(5):437-47. [Medline].
Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001 Mar. 7(3):365-8. [Medline].
Stickler DE, Massey JM, Sanders DB. MuSK-antibody positive myasthenia gravis: clinical and electrodiagnostic patterns. Clin Neurophysiol. 2005 Sep. 116(9):2065-8. [Medline].
Pasnoor M, Wolfe GI, Nations S, et al. Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience. Muscle Nerve. 2010 Mar. 41(3):370-4. [Medline].
Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology. 2003 Jun 24. 60(12):1978-80. [Medline].
Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012 Apr. 69 (4):445-51. [Medline].
Romi F, Skeie GO, Gilhus NE. Striational antibodies in myasthenia gravis: reactivity and possible clinical significance. Arch Neurol. 2005 Mar. 62(3):442-6. [Medline].
Phillips LH 2nd, Melnick PA. Diagnosis of myasthenia gravis in the 1990s. Semin Neurol. 1990 Mar. 10(1):62-9. [Medline].
Toth L, Toth A, Dioszeghy P, Repassy G. Electronystagmographic analysis of optokinetic nystagmus for the evaluation of ocular symptoms in myasthenia gravis. Acta Otolaryngol. 1999. 119(6):629-32. [Medline].
Yang Q, Wei M, Sun F, Tian J, Chen X, Lu C. Open-loop and closed-loop optokinetic nystagmus (OKN) in myasthenia gravis and nonmyasthenic subjects. Exp Neurol. 2000 Nov. 166(1):166-72. [Medline].
Movaghar M, Slavin ML. Effect of local heat versus ice on blepharoptosis resulting from ocular myasthenia. Ophthalmology. 2000 Dec. 107(12):2209-14. [Medline].
Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscul Disord. 2006 Jul. 16(7):459-67. [Medline].
Pascuzzi RM. Pearls and pitfalls in the diagnosis and management of neuromuscular junction disorders. Semin Neurol. 2001 Dec. 21(4):425-40. [Medline].
Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology. 2003 Dec 23. 61(12):1652-61. [Medline].
Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev. 2005 Apr 18. CD002828. [Medline].
Drachman DB, Jones RJ, Brodsky RA. Treatment of refractory myasthenia: "rebooting" with high-dose cyclophosphamide. Ann Neurol. 2003 Jan. 53(1):29-34. [Medline].
Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al. Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability. Neurology. 2003 Nov 25. 61(10):1438-40. [Medline].
Lisak RP. Myasthenia Gravis. Curr Treat Options Neurol. 1999 Jul. 1(3):239-250. [Medline].
Gold R, Schneider-Gold C. Current and future standards in treatment of myasthenia gravis. Neurotherapeutics. 2008 Oct. 5(4):535-41. [Medline].
[Guideline] Benatar M, Kaminski HJ. Evidence report: the medical treatment of ocular myasthenia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007 Jun 12. 68(24):2144-9. [Medline].
Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev. 2007 Oct 17. CD005224. [Medline].
Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004 May 19. 291(19):2367-75. [Medline].
Zinman L, Bril V. IVIG treatment for myasthenia gravis: effectiveness, limitations, and novel therapeutic strategies. Ann N Y Acad Sci. 2008. 1132:264-70. [Medline].
Díaz-Manera J, Martínez-Hernández E, Querol L, Klooster R, Rojas-García R, Suárez-Calvet X, et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012 Jan 17. 78 (3):189-93. [Medline].
Leite MI, Strobel P, Jones M, et al. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol. 2005 Mar. 57(3):444-8. [Medline].
Takanami I, Abiko T, Koizumi S. Therapeutic outcomes in thymectomied patients with myasthenia gravis. Ann Thorac Cardiovasc Surg. 2009 Dec. 15(6):373-7. [Medline].
Nieto IP, Robledo JP, Pajuelo MC, et al. Prognostic factors for myasthenia gravis treated by thymectomy: review of 61 cases. Ann Thorac Surg. 1999 Jun. 67(6):1568-71. [Medline].
Goldstein SD, Yang SC. Assessment of robotic thymectomy using the Myasthenia Gravis Foundation of America Guidelines. Ann Thorac Surg. 2010 Apr. 89(4):1080-5; discussion 1085-6. [Medline].
Marulli G, Schiavon M, Perissinotto E, et al. Surgical and neurologic outcomes after robotic thymectomy in 100 consecutive patients with myasthenia gravis. J Thorac Cardiovasc Surg. 2013 Mar. 145(3):730-5; discussion 735-6. [Medline].
Brooks M. PLEX and IVIG both effective maintenance options in juvenile MG. Reuters Health Information. March 6, 2014. [Full Text].
Liew WK, Powell CA, Sloan SR, et al. Comparison of plasmapheresis and intravenous immunoglobulin as maintenance therapies for juvenile myasthenia gravis. JAMA Neurol. 2014 Mar 3. [Medline].
|Osserman MG Class*||Mean Anti-AChR Titer (× 10–9 M)||Positive Results, %|
|AChR = acetylcholine receptor; MG = myasthenia gravis.
*Osserman classification: R = remission, I = ocular only, IIA = mild generalized, IIB = moderate generalized, III = acute severe, IV = chronic severe.