eMedicine Specialties > Neurology > Neuromuscular Diseases
Myasthenia Gravis: Treatment & Medication
Updated: Jan 15, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
- Even though no rigorously tested treatment trials have been reported and no clear consensus exists on treatment strategies, myasthenia gravis is one of the most treatable neurologic disorders. Several factors (eg, severity, distribution, rapidity of disease progression) should be considered before initiating or changing therapy. Immunomodulation can be achieved by various medications, such as commonly used corticosteroids. Other medications that are used to treat more difficult cases include azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab. However, the effectiveness of many of these medications are far from proven and caution should be advised against use of them lightly.10,11,12
- AChE inhibitors and immunomodulating therapies are the mainstays of treatment. In the mild form of the disease, AChE inhibitors are used initially. Most patients with generalized myasthenia gravis require additional immunomodulating therapy.
- Plasmapheresis and thymectomy are important modalities for treating myasthenia gravis. They are not traditional medical immunomodulating therapies, but they function by modifying the immune system.
- Plasmapheresis or plasma exchange
- Plasma exchange (PE) is an effective treatment for myasthenia gravis, especially in preparation for surgery or as short-term management of an exacerbation. Improvement in strength may help to achieve rapid postoperative recovery and to shorten the period of assisted ventilation.
- Weakness improves within days, but the improvement lasts only 6-8 weeks.
- PE usually is used as an adjunct to other immunomodulatory therapies and as a tool for crisis management.
- Long-term regular PE on a weekly or monthly basis can be used if other treatments cannot control the disease.
- Complications of PE are limited primarily to complications of intravenous access (eg, central line placement), but also include less commonly hypotension and coagulation disorders.
- PE is thought to act by removing circulating humoral factors (ie, AChR Ab and immune complexes).
Surgical Care
- Thymectomy
- This is an important treatment option in myasthenia gravis, especially if a thymoma is present.
- It has been proposed as a first-line therapy in most patients with generalized myasthenia.
- The beneficial effect of thymectomy was reported as early as the 1930s and 1940s in a variety of case reports and small series.
- Even though no controlled trial to assess the efficacy of thymectomy in myasthenia gravis has been reported, thymectomy has become the standard of care and should be done in all patients with thymoma and in patients aged 10-55 years without thymoma but with generalized myasthenia gravis.
- Thymectomy may induce remission. This occurs more frequently in young patients with a short duration of disease, hyperplastic thymus, and high antibody titer.
- Remission rate increases with time: at 7-10 years after surgery, it reaches 40-60% in all categories of patients except those with thymoma.
Consultations
Coordinate care with the primary care physician.
Diet
- Patients with myasthenia gravis may experience difficulty chewing and swallowing because of oropharyngeal weakness. It may be difficult for the patient to chew meat or vegetables because of masticatory muscle weakness.
- If dysphagia develops, it is usually most severe for thin liquids because of weakness of pharyngeal muscles. To avoid nasal regurgitation or frank aspiration, liquids should be thickened.
Activity
Educate patients about the fluctuating nature of weakness and exercise-induced fatigability. Patients should be as active as possible but should rest frequently and avoid sustained physical activity.
Medication
AChE inhibitors are considered to be the basic treatment of myasthenia gravis. Long-term corticosteroid therapy and immunosuppressive drugs are also effective.
Anticholinesterase inhibitors
These agents inhibit AChE, raising the concentration of ACh at the NMJ and increasing the chance of activating the AChR. Any medication that increases the activity of the AChR can have an effect on myasthenia gravis.
Pyridostigmine bromide (Mestinon)
An intermediate-acting agent, preferred in clinical use to shorter-acting neostigmine bromide (Prostigmin) or longer-acting ambenonium chloride (Mytelase). Starts working in 30-60 min; effects last 3-6 h.
Also available as time span tablet, whose effects last 2.5 times longer. Time span form useful adjunct to regular pyridostigmine for nighttime control of myasthenic symptoms. Absorption and bioavailability of timespan vary among subjects. It should be used only at bedtime, and patients need close monitoring for cholinergic adverse effects.
Individualize dose because myasthenia gravis does not affect all skeletal muscles similarly, all symptoms may not be controlled without producing adverse effects.
In critically ill or postoperative patients, administer IV.
In US, available in 3 forms: 60 mg scored tab, 180 mg time span tab, and 60 mg/5 mL syrup.
Adult
Adjust dose to needs of individual patient
60-960 mg/d PO in divided doses
2 mg IV/IM q2-3h or 1/30th PO dose; IV form best given as IV drip, infusing 1/30th of total daily dose over 24 h; avoid IM route if possible because of erratic absorption
Pediatric
7 mg/kg/d PO in divided doses
Increases effects of depolarizing neuromuscular blockers; increases toxicity of edrophonium
Documented hypersensitivity, peritonitis, mechanical obstruction of GI or GU tract
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Overdose may cause cholinergic crisis, which may be fatal; IV atropine should be readily available to treat cholinergic reactions
Use cautiously in patients with bronchial asthma and those receiving a cardiac glycoside; adverse effects stem from dose-related, excessive stimulation of muscarinic AChR and include excessive salivation, abdominal cramps, diarrhea, blurring of vision, and flushing; adverse GI effects are common and can be controlled by anticholinergic drugs preferentially affecting muscarinic AChR, such as diphenoxylate hydrochloride (Lomotil) and atropine sulfate
Neostigmine (Prostigmin)
This short-acting AChE inhibitor is available in PO form (15 mg tab) and form suitable for IV/IM/SC administration. Half-life is 45-60 min. Poorly absorbed from GI tract, should be used only if pyridostigmine unavailable.
Individualize dose for all patients.
Adult
15 mg/dose PO q3-4h
0.5-2.5 mg IV/IM/SC q1-3h or 1/30th PO dose; not to exceed 10 mg/d
Pediatric
2 mg/kg/d PO divided q3-4h
0.01-0.04 mg/kg IV/IM/SC q2-4h or 1/30th PO dose
Muscarinic effects antagonized by atropine; increases effects of neuromuscular agents; pyridostigmine may decrease response to nondepolarizing neuromuscular blockers
Documented hypersensitivity to drug or bromides; peritonitis, mechanical obstruction of GI or GU tract
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use caution in patients with asthma, bradycardia, hyperthyroidism, cardiac arrhythmias, or peptic ulcer; AChE insensitivity can develop for brief or prolonged periods
Immunomodulatory therapy
Myasthenia gravis 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 myasthenia gravis, several uncontrolled trials and retrospective studies support use of such therapies. The therapies used in myasthenia gravis include prednisone, azathioprine, IVIg, plasmapheresis, and cyclosporine.
Prednisone (Deltasone, Sterapred, Orasone)
Corticosteroids were among first immunomodulating agents used to treat myasthenia gravis and still are used frequently and effectively. Prednisone is most commonly used corticosteroid in US. 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.
Significant improvement, which may be associated with decreased Ab titer, usually occurs in 1-4 mo.
Alternate-day regimen may minimize adverse effects. Trial of steroid withdrawal may be attempted, but most patients on long-term corticosteroid therapy relapse and require re-institution of steroids.
Adult
No single regimen accepted for corticosteroid treatment of myasthenia gravis; some regimens start with low dose and increase gradually; others, use high dose initially to achieve quicker response
No consensus exists on dosing schedule among physicians using initial low-dose regimen
Authors use starting dose of 15 mg/d PO, increasing by 5 mg q2-3d until satisfactory clinical response achieved or maximum dose of 50-60 mg/d reached; taper should begin after 3-6 mo of treatment and documented response
Starting with high doses (20-30 mg/d PO, increasing by 5-10 mg q2-3d to maximum 60 mg/d) may improve weakness more rapidly; some start with 60-80 mg/d and others 100 mg qod
Initial deterioration in weakness before improvement is common and serious concern within first 3 wk; this potential complication warrants initiation of high doses in supervised setting
Pediatric
4-5 mg/m2/d PO; alternative: 1-2 mg/kg PO qd; taper over several mo as symptoms resolve
Clearance may be decreased by estrogens; with concurrent digoxin, may increase digitalis toxicity secondary to hypokalemia; metabolism may be increased by phenobarbital, phenytoin, and rifampin (consider increasing maintenance dose); patients taking concurrent diuretics should be monitored for hypokalemia
Documented hypersensitivity; systemic viral, fungal, or tubercular infections
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Long-term use may predispose patients to various problems, including hyperglycemia; manifestations of latent diabetes mellitus; nonketotic hyperosmolar state; osteoporosis; avascular necrosis of the hip; peptic/gastric ulcer disease; GI bleeding; cataracts; glaucoma; steroid myopathy; cushingoid appearance; weight gain; suppression of pituitary-hypothalamic axis; growth suppression in children; water retention, which may precipitate congestive heart failure and hypertension; hypokalemia; unmasking of latent infections (such as TB or herpes zoster), predisposition to fungal and parasitic infection, and increased susceptibility to opportunistic infections
Due to suppressed pituitary-hypothalamic axis, additional steroid dosing may be necessary at times of stress (eg, systemic infections or surgery)
Azathioprine (Imuran)
Second most commonly used immunosuppressive medication in myasthenia gravis, reserved for steroid failure or unacceptable effects from prolonged steroid use. Can be used for steroid-sparing effects to lower steroid dose. One drawback is that onset of action is 6-12 mo.
Adult
1 mg/kg/d PO initial dose; increase gradually to desired effect, usually 2-3 mg/kg/d qd; may be divided ac if adverse GI effects are bothersome
Some experts advocate dose increases until RBC MCV >100 fL; do not increase dose if patient develops leukopenia
Pediatric
Maintenance: 1-2 mg/kg/d PO
Toxicity increased by allopurinol; concurrent ACE inhibitors may induce severe leukopenia; may increase plasma levels of methotrexate metabolite; may decrease effects of anticoagulants; may decrease cyclosporine plasma levels
Documented hypersensitivity, severe flulike reaction to drug (20-30%), inability to tolerate medication, pregnancy or nursing
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Monitor CBC regularly for development of leukopenia, thrombocytopenia, or macrocytic anemia; rarely causes hepatotoxicity, but 2- to 3-fold elevation of hepatic enzymes common (decrease dose should this occur); may increase risk of serious infections and neoplasia
Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin)
High-dose IVIg successfully treats myasthenia gravis. Like plasma exchange, has rapid onset of action, but effects last only short time. Best used in crisis management (eg, myasthenic crisis and perioperative period).
Adult
2 g/kg slow IV infusion over 2-5 d
Pediatric
Administer as in adults
None reported
Allergy to immunoglobulins, IgA deficiency, presence of antibodies to IgA, renal insufficiency or renal artery stenosis (ie, increased risk of renal failure)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Check serum IgA before administering; use IgA-depleted product (G-Gard-SD); may increase serum viscosity and thromboembolic events; watch for fluid overload or hypotension; carefully and frequently monitor vital signs during and immediately after administration; headaches frequent during or after infusion; rarely, aseptic meningitis may develop; flulike syndrome may occur
Cyclosporine A (Neoral, Sandimmune)
Fungal peptide with potent immunosuppressive activity. Has been shown effective in patients with myasthenia gravis in prospective, double-blind, placebo-controlled clinical trial. Does have some significant adverse effects, which usually preclude its use as first-line immunosuppressive therapy. However, in patients who are at high risk for adverse steroid effects, CsA can be used as initial therapy. Onset of action within a few wk to mo, similar to that of prednisone.
Adult
Clinical and immunological effects correlate with serum concentration; dose usually adjusted to achieve trough serum level of 100-200 ng/mL (as determined by HPLC)
4-10 mg/kg/d PO divided bid/tid has been used
Pediatric
Administer as in adults
Several drugs may act synergistically to enhance nephrotoxicity of CsA, including gentamicin, tobramycin, vancomycin, amphotericin B, ketoconazole, melphalan, diclofenac, cimetidine, ranitidine, trimethoprim with sulfamethoxazole, and azapropazone
CsA metabolized by liver microsomal enzymes; concurrent diltiazem, verapamil, nicardipine, ketoconazole, fluconazole, or itraconazole may increase serum level of CsA, while phenytoin, phenobarbital, carbamazepine, and rifampin may decrease serum level
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Two most significant adverse effects are hypertension, which is easily treated with antihypertensive medication; more important is nephrotoxicity—careful monitoring of renal function mandatory
Like azathioprine, CsA can lower blood counts, predispose to opportunistic infections, and may increase incidence of malignancy in patients on long-term therapy
Cyclophosphamide (Cytoxan, Neosar)
Alkylating agent that interferes with cell proliferation. More effective against B cell compared to T cells, making it a good choice in an antibody-mediated disease such as myasthenia gravis. Because of potential for serious side effects, usually reserved for more severe cases where more routinely used immunotherapy has failed due to lack of efficacy or intolerable side effects.
Adult
Variable dosages used
Standard oral dosages used in clinical trials include 1-2 mg/kg/d in one series and 3-5 mg/kg/d in another; some patients treated with 200-250 mg IV for 5 d; IV doses ranging from 350-1000 g/m2 administered
Pediatric
Not established
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity
Documented hypersensitivity; preexisting bone marrow depression
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Mycophenolate mofetil (CellCept, Myfortic)
Inhibitor of de novo purine synthesis by blocking the enzyme inosine monophosphate dehydrogenase. Very effective against proliferative lymphocytes, which do not make use of purine salvage pathway.
Adult
1-3 g PO qd or divided bid
Pediatric
No data available on pediatric patients with myasthenia gravis
Based on pharmacokinetic and safety data in pediatric patients after renal transplantation, recommended dose of CellCept oral suspension is 600 mg/m2 bid
In combination with either acyclovir or ganciclovir may result in higher levels for both interacting drugs due to competition for renal tubular excretion; aluminum/magnesium present in some antacids, and cholestyramine containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates and azathioprine may increase toxicity; may decrease levonorgestrel AUC; may decrease live-virus vaccine immune response; when administered in combination with theophylline may increase free fraction levels of theophylline
Documented hypersensitivity to drug or components
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Increases risk for infection (monitor blood count); severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increase free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with that reported for other immunosuppressants (0.9%); commonly causes constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis; rare reports include interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus; do not chew, crush, or cut Myfortic tab
More on Myasthenia Gravis |
| Overview: Myasthenia Gravis |
| Differential Diagnoses & Workup: Myasthenia Gravis |
 Treatment & Medication: Myasthenia Gravis |
| Follow-up: Myasthenia Gravis |
| Multimedia: Myasthenia Gravis |
| References |
| « Previous Page | Next Page » |
References
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. [Medline].
Patric J, Lindstrom JM. Autoimmune response to acetylcholine receptor. Science. 1973;180:871. [Medline].
Evoli A, Tonali PA, Padua L. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. Oct 2003;126(Pt 10):2304-11. [Medline].
Sanders DB, Howard JF, Massey JM. Seronegative myasthenia gravis. Ann Neurol. 1987;22:126. [Medline].
Engel AG. Acquired autoimmune myasthenia gravis. In: Engel AG, Franzini-Armstrong C, eds. Myology: Basic and Clinical. 2nd ed. 1994;1769-1797. [Medline].
Jaretzki A, Barohn RJ, Ernstoff RM. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. Jul 12 2000;55(1):16-23. [Medline].
Tindall RS. Humoral immunity in myasthenia gravis: biochemical characterization of acquired antireceptor antibodies and clinical correlations. Ann Neurol. Nov 1981;10(5):437-47. [Medline].
Stickler DE, Massey JM, Sanders DB. MuSK-antibody positive myasthenia gravis: clinical and electrodiagnostic patterns. Clin Neurophysiol. Sep 2005;116(9):2065-8. [Medline].
Romi F, Skeie GO, Gilhus NE. Striational antibodies in myasthenia gravis: reactivity and possible clinical significance. Arch Neurol. Mar 2005;62(3):442-6. [Medline].
Drachman DB, Jones RJ, Brodsky RA. Treatment of refractory myasthenia: "rebooting" with high-dose cyclophosphamide. Ann Neurol. Jan 2003;53(1):29-34. [Medline].
Meriggioli MN, Ciafaloni E, Al-Hayk KA. Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability. Neurology. Nov 25 2003;61(10):1438-40. [Medline].
Lisak RP. Myasthenia Gravis. Curr Treat Options Neurol. Jul 1999;1(3):239-250. [Medline].
Oh SJ, Dhall R, Young A, Morgan MB, Lu L, Claussen GC. Statins may aggravate myasthenia gravis. Muscle Nerve. Aug 21 2008;38(3):1101-1107. [Medline].
Argov Z, Wirguin I. Drugs and the neuromuscular junction: Pharmacotherapy of transmission disorders and drug-induced myasthenic syndromes. In: Lisak RP, ed. Handbook of Myasthenia Gravis and Myasthenic syndromes. 1994:295-319.
Grob D, Brunner NG, Namba T. The natural course of myasthenia gravis and effect of therapeutic measures. Ann N Y Acad Sci. 1981;377:652-69. [Medline].
Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Rey A, Blesa R, et al. Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients. J Neuroimmunol. Jul 22 2008;[Medline].
Kurtzke JE, Kurland LT. Epidemiology of neurologic disease. In: Baker AB, Baker LH, eds. Clinical Neurology. Philadelphia: Harper & Row;1982:47-49. [Medline].
Lewis RA, Lisak RP. "Rebooting" the immune system with cyclophosphamide:taking risks for a "cure"?. Ann Neurol. 2003;53:7-9. [Medline].
Limburg PC, The TH, Hummel-Tappel E. Anti-acetylcholine receptor antibodies in myasthenia gravis. Part 1. Relation to clinical parameters in 250 patients. J Neurol Sci. Mar 1983;58(3):357-70. [Medline].
Mantegazza R, Beghi E, Pareyson D. A multicenter follow-up study of 1152 patients with myasthenia gravis in Italy. J Neurol. 1990;237:339-44. [Medline].
Massey JM. Acquired myasthenia gravis. Neurol Clinics. 1997;15(3):577-595. [Medline].
Medical Economics. 2005 Physicians' Desk Reference (PDR). Thomson Healthcare;2004.
Oh S. Single fiber electromyography in various diseases. In: Oh SJ, ed. Electromyography: Neuromuscular Transmission Studies. Baltimore;254. [Medline].
Oosterhuis HJ, Limburg PC, Hummel-Tappel E. Anti-acetylcholine receptor antibodies in myasthenia gravis. Part 2. Clinical and serological follow-up of individual patients. J Neurol Sci. Mar 1983;58(3):371-85. [Medline].
Osserman KE. Myasthenia Gravis. New York: Grune and Stratton;1958:78-79,86-87. [Medline].
Osserman KE, Genkins G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. Mt Sinai J Med. Nov-Dec 1971;38(6):497-537. [Medline].
Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology. Dec 23 2003;61(12):1652-61. [Medline].
Sanders DB, El-Salem K, Massey JM, et al. Clinical aspects of MuSK antibody positive seronegative MG. Neurology. Jun 24 2003;60(12):1978-80. [Medline].
Wittbrodt ET. Drugs and myasthenia gravis. An update. Arch Intern Med. Feb 24 1997;157(4):399-408. [Medline].
Further Reading
Keywords
myasthenia gravis, autoimmune neuromuscular disease, skeletal muscle weakness, fatigability on exertion, muscle weakness, acetylcholine receptor, AChR, seronegative myasthenia gravis, SNMG, muscle-specific kinase, MuSK, MG
