AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by weakness and fatigue of the skeletal muscles of the face and extremities. It affects people of both sexes and all ages, but twice as many female patients are affected as male patients. MG usually strikes in women in their third decade of life.

Pathophysiology

The underlying pathology is the production of autoantibodies against human acetylcholine receptors (AChRs), usually immunoglobulin G, which can be detected in as many as 90% of patients. These antibodies interfere with the conduction of impulses across myoneural junctions by decreasing the number of available AChRs at neuromuscular junctions. Patients with milder symptoms tend to have lower antibody titers. Patients with thymoma and more severe disease have higher titers. Some MG patients may not have detectable antibody levels.

MG typically affects females during their reproductive years. Difficulties specific to pregnant patients can be concerning, and the course of MG during pregnancy is hard to predict. Patients may have disease exacerbation, crisis, or, interestingly enough, remission. Although the disease course is variable, pregnant patients face risks of exacerbation, respiratory failure, adverse drug response, crisis, and death.

Mitchell and Bebbington reviewed the performance of MG patients during pregnancy at the Vancouver Salvation Army Grace Hospital. Four of 9 patients experienced antepartum exacerbations ranging from muscle weakness to respiratory failure. Three of the 4 patients had undergone previous thymectomy, and the patient with the worst symptoms (respiratory failure) had a prior thymectomy.¹ These findings negate studies that concluded that thymectomy leads to fewer exacerbations.

In a large study from 1991, Plauche found that exacerbations occurred in approximately 41% of patients during pregnancy and in 29.8% of patients postpartum. Approximately 4% of patients died because of worsening of the disease or because of treatment complications.²

A study by Batocchi et al reported that the disease worsened in 10 (19%) of 54 patients. Approximately 60% of exacerbations occurred during the first trimester, and approximately 28% of patients deteriorated immediately after delivery. Premature delivery occurred in 4 (7.4%) of 54 patients. Cesarean delivery was performed in 16 pregnancies (30%). The study concluded that no correlation exists between MG severity before and during pregnancy.³

Frequency

International

Worldwide prevalence is approximately 40 cases per million population, and the incidence is 1 case in 20,000-40,000 population per year.

Race

Persons of all races are affected.

Sex

Both sexes are affected, and the female-to-male ratio is 2:1.

Age

Persons of any age are affected, but MG usually affects women in their third decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients with myasthenia gravis present with symptoms such as ptosis, diplopia, breathing and swallowing difficulties, and weak limbs. Intermittent ptosis and diplopia are usually the initial reported symptoms. Symptoms usually become generalized within 1 year. Symptoms fluctuate in severity; they worsen with exertion and are relieved with rest. Fatigue upon exertion is essential to making the diagnosis. Despite these common presenting symptoms, some patients have atypical presentations.

Physical

Upon physical examination, muscle strength should be assessed by having the patient squeeze the examiner's hand repeatedly or having the patient flex her arm against resistance. Facial weakness can be evaluated by asking the patient to smile. A snarling expression may be evident when the patient attempts to smile. Although muscles are weak, deep tendon reflexes are preserved. Diplopia and ptosis should also be addressed.

Causes

The underlying pathology is the production of autoantibodies against human AChRs, usually immunoglobulin G, which can be detected in as many as 90% of patients.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The differential diagnosis of myasthenia gravis includes conditions associated with weakness of muscles, such as Lambert-Eaton myasthenic syndrome, botulism, hyperthyroidism, neurasthenia, intracranial mass lesion, progressive external ophthalmoplegia, and drug-induced MG.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Screen for other autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, pemphigus, Hashimoto thyroiditis, scleroderma, dermatitis herpetiformis, autoimmune hemolytic anemia, polymyositis, and sarcoidosis.

Imaging Studies

Obtain CT scans to study the thymus, or obtain MRIs to evaluate the mediastinum.

Other Tests

• Diagnosis is based on clinical history and signs, improvement with anticholinesterase injection, serum anti-AChR antibody titers, and electromyographic signs of impaired neuromuscular transmission. The combination of test results helps the physician confirm the diagnosis.
• Intravenous injection of edrophonium (Tensilon) is a routine test when symptoms and signs suggest MG. This cholinesterase inhibitor increases the amount of acetylcholine available, which increases the probability of acetylcholine binding to the receptor. It is the test of choice because it is fast and inexpensive. Initially, the patient is injected with 1-2 mg of edrophonium. If this dose does not yield expected results and no adverse effects are observed, another 4-5 mg is administered. Clinical improvement occurs in 10-60 seconds and lasts for approximately 10 minutes. Test muscles that do not require patient cooperation so that results are more reliable. Edrophonium test results are positive in approximately 90% of myasthenic patients.
• Anti-AChR antibody titration is usually performed by radioimmunoassay. This is the most specific test for MG. High antibody titers usually correlate with severe disease.
• Low-rate repetitive nerve stimulation is also used to demonstrate problems with neuromuscular transmission. A decremental pattern (>10% difference in compound muscle action potential amplitude between the first and fourth or fifth stimulus) is the usual finding. Single-fiber electromyography produces the most sensitive data to support the diagnosis. Findings are abnormal in more than 90% of patients. This test shows abnormalities in neuromuscular transmission as increased jitter and blocking.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Many medications can adversely affect patients with myasthenia gravis (MG). The following drugs must be avoided:
• • Narcotics
  • Tranquilizers
  • Barbiturates
  • Inhalation anesthetics (ie, halothane, trichloroethylene, ether)
  • Magnesium and lithium salts
  • Penicillamine
  • Beta-adrenergic agents
  • Quinidine
  • Aminoglycoside antibiotics
  • Colistin
  • Neomycin
  • Tetracycline drugs
  • Lincomycin
  • Polymyxin
  • Quinacrine
  • Chloroquine
• MG is associated with many other autoimmune disorders. Patients must be checked for the following conditions:
• • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Pemphigus
  • Hashimoto thyroiditis
  • Scleroderma
  • Dermatitis herpetiformis
  • Autoimmune hemolytic anemia
  • Polymyositis
  • Sarcoidosis
• Thymic abnormalities are also associated with MG. As many as 50-60% of patients have lymphofollicular hyperplasia, and 10-20% have a thymoma.
• Therapy should be individualized, and each patient must be followed closely by a neurologist and an obstetrician/gynecologist during pregnancy. Although medical therapy is effective, the patient's condition may worsen. Crisis can occur as a result of a worsening disease processes, reduced effects of anticholinesterase drugs, or overdose of anticholinesterase medication. Management of myasthenic crisis requires careful monitoring. Arterial blood gas values must be monitored in patients with increasing weakness.
• Plasmapheresis is an expensive procedure used in patients in myasthenic crisis. Together with steroids, plasmapheresis is a very effective treatment. It consists of 3-6 exchanges of 2-3 L over 1-2 weeks. It is safe during pregnancy and has even saved patients during fulminant crises. As the etiology of preterm delivery is unknown, plasmapheresis is (or may be) associated with preterm delivery. Other complications can occur from hypovolemic reactions or allergies. Large hormone shifts may cause preterm delivery. Patients undergoing plasmapheresis should be monitored.
• Intravenous immunoglobulin is also useful in patients in myasthenic crisis. It is thought to interfere with anti-AChR antibodies. It is infused at 0.4 g/kg/d for 5 consecutive days. Improvement is noticeable in 3-21 days and lasts as long as 3 months.
• Monitoring patients for infection is important, especially those on steroids. Serial ultrasonography, nonstress tests, and biophysical profiles should be used for kids at risk as per the usual obstetrical management protocol.
• Many patients develop depression or comorbid depressive episodes. Bupropion (Wellbutrin XL) has been studied extensively and may be a good addition for these patients.

Surgical Care

• Surgery is very stressful; therefore, delivery via cesarean delivery is reserved only for necessary cases. Also, the hazards of anesthesia must be kept in mind because patients are sensitive to sedatives and narcotics. Not depressing respiration is important. In 1978, Rolbin and colleagues reported on their evaluation of the safety of anesthesia for MG patients.⁴ They concluded that regional anesthesia is good for abdominal delivery. They stated that epidural anesthesia could be used to decrease the requirements of systemic medications and provide anesthesia for outlet forceps. Amide-type local anesthetics are thought to be safe when large doses of drugs are needed. The group recommended general endotracheal anesthesia for cesarean delivery in patients with respiratory problems. Depolarizing anesthetics must always be avoided.
• Thymectomy is recommended for most young patients. It improves the disease course and can improve remission. Thymectomy is thought to remove an antigen source and reduce an anti-AChR antibody source. A thymoma, which is a potentially invasive tumor that must be removed, is found in few cases. In 1999, Batocchi et al reported that 4 of 44 patients had thymomas.³ To avoid any postoperative problems, thymectomy is performed when the disease is in control. Plasmapheresis can be used for disease control. In 1986, Ip et al used thymectomy as a treatment for myasthenic crisis during pregnancy.⁵ The patient improved, and although she had to receive large doses of pyridostigmine, she delivered her baby at 39 weeks' gestation.

Activity

Rest is very important to restore muscle strength, especially during pregnancy.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Combination drug therapy is reported to be safer and more effective than monotherapy. Pharmaceutical treatment for myasthenia gravis (MG) is very effective.

Drug Category: Anticholinesterase muscle stimulants

Preferred treatment for MG and reportedly are safe in pregnancy. Increase the amount of acetylcholine available to bind to receptors. Neostigmine was the first drug used for MG.

Drug Category: Corticosteroids

Immunosuppressants useful in treatment of MG. Deoxycorticosteroids (DOCs) for severely ill patients. Work by decreasing antibody synthesis and inhibiting CD4⁺ T-cell proliferation. Johns' regimen is the accepted regimen for steroid use in MG. Prednisone is fairly safe during pregnancy. Patients who wish to become pregnant are recommended to get pregnant while in steroid-induced remission. Cleft lip and palate in newborns of patients on steroids were noted in a few instances. High-dose corticosteroids can lead to premature rupture of membranes. Weight gain and cushingoid appearance are common complications.

Drug Category: Antimetabolites

Azathioprine is used when response to corticosteroids is not adequate or when corticosteroid dosage must be decreased. Also, this drug added if symptoms are not controlled satisfactorily with acetylcholinesterase. It is converted to the metabolite mercaptopurine and inhibits T-cell reactivity. Azathioprine is found to reduce serum anti-AChR antibody titers. Cyclosporine is a strong immunosuppressant and inhibits T-cell activation. It is restricted to patients who do not respond well to other medications.

Drug Category: Immunoglobulins

Useful in myasthenic crisis. Neutralize circulating myelin antibodies through antiidiotypic antibodies. Down-regulate proinflammatory cytokines (including INF-gamma), block Fc receptors on macrophages, suppress inducer T and B cells and augment suppressor T cells, block complement cascade, and promote remyelination.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Follow-up consists of evaluating patients for adverse effects of pharmaceuticals and preventing infection. Observing the patient for signs of respiratory deterioration is necessary. The postanesthetic period is very important because postpartum exacerbation is common. Arterial blood gases should be checked often; thus, a surgical ICU is the best place for postoperative myasthenic patients.
• Rest periods should be emphasized in the months after delivery. Caring for a newborn is difficult, and maternal exhaustion may occur. The disease course is variable and unpredictable during pregnancy and after delivery. One pregnancy without exacerbations does not necessarily mean that future pregnancies carry no risk. Pregnancy can lead to many complications; therefore, the physician must be vigilant.

Complications

• Some rare problems may occur during pregnancy. Maternal complications are discussed as follows:
• • In 2000, Ellison and colleagues reported a rare case of bone marrow suppression in a patient who experienced leukopenia and thrombocytopenia during all 3 of her pregnancies.¹⁰ Her third pregnancy was the most serious. Her platelet count was 48 X 10⁹/L, and her WBC count dropped to 1.5 X 10⁹/L at 35 weeks' gestation. She improved after receiving 65 mg of human immunoglobulin (1 mg/kg for 2 d). Labor was induced, and she delivered a boy. Interestingly, 1 day after each delivery, her platelet and WBC counts increased. On the third postnatal day, her platelet count increased to 128 X 10⁹/L from 82 X 10⁹/L after immunoglobulin transfusion, and her WBC count increased to 2.5 X 10⁹/L from 2.2 X 10⁹/L. Bone marrow suppression has been observed in other pregnant MG patients. In 1992, Igarashi et al reported that suppression could be due to megakaryocyte colony-forming unit suppressive factor produced by autoimmune mechanisms.¹⁵
  • Some exacerbations can be linked to the anxiety and physiological stress of pregnancy. Hypoventilation is a risk during pregnancy because respiratory muscles are weakened from MG. Also, the lungs do not become fully inflated because the diaphragm is elevated during pregnancy. Approximately 20% of patients experience respiratory crises that require mechanical ventilation. This is one of most severe complications.
  • Infections due to decreased immunity play a very important role in the exacerbation of MG during pregnancy.
  • Labor also may be complicated. Although smooth muscle is not affected by autoantibodies and the uterus is not compromised, the second stage of labor involves striated muscle. The patient may become exhausted during labor and may require assistance. Forceps delivery has been recommended.
  • In 1979, Duff and colleagues described an association between MG and preeclampsia.⁹ They observed preeclampsia in 3 patients and reasoned that altered immune status could be an etiologic factor in preeclampsia. Preeclampsia also may be problematic from a pharmacological standpoint because magnesium sulfate is contraindicated in myasthenic patients.
• Not only is the mother at risk, her baby also faces significant risks, including neonatal MG, prematurity, severe malformation, and death.
• • Rates of neonatal MG are as high as 10-20%. Affected babies show respiratory distress and inadequate suck. Babies are affected by transient myasthenia, which is self-limited and lasts approximately 3 weeks. This is due to the transplacental transfer of antibodies. This is puzzling because no close correlation exists between maternal disease severity and neonatal myasthenia, nor is there a correlation between the occurrence of neonatal MG and maternal anti-AChR antibody titers. These unpredictable results could be due to the protective role of alpha-fetoprotein in neonatal MG. Alpha-fetoprotein has been shown to inhibit the binding of MG antibody to its receptor.
  • More severe neonatal problems have been reported, including death from malformations attributable to MG. In 1991, Carr and colleagues reported that the most common fetal abnormalities are pulmonary hypoplasia and arthrogryposis.⁸ They reported the case of a patient whose 2 previous births were followed by neonatal death due to malformation. During the patient's third pregnancy, they decided to decrease her antibody titer, which was very high (400 nmol/L), by using plasmapheresis and prednisone. They found that fetal breathing increased when antibody levels were low and it decreased with increasing antibody titers. The presence of abnormalities in this case coincided with the presence of AChR antibodies of high avidity. The hypothesis was that these antibodies inhibited fetal diaphragmatic motion, which resulted in a lack of stimulation of normal fetal lung development.
  • Prematurity is also a concern. In 1991, Plauche compiled the results from various studies and found that premature delivery occurs in approximately 36.5% of cases.²

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Because many medications can adversely affect patients with myasthenia gravis (MG), the following drugs should be avoided:
• • Narcotics
  • Tranquilizers
  • Barbiturates
  • Inhalation anesthetics (ie, halothane, trichloroethylene, ether)
  • Magnesium and lithium salts
  • Penicillamine
  • Beta-adrenergic agents
  • Quinidine
  • Aminoglycoside antibiotics
  • Colistin
  • Neomycin
  • Tetracycline drugs
  • Lincomycin
  • Polymyxin
  • Quinacrine
  • Chloroquine

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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3. Batocchi AP, Majolini L, Evoli A, et al. Course and treatment of myasthenia gravis during pregnancy. Neurology. Feb 1999;52(3):447-52. [Medline].
4. Rolbin WH, Levinson G, Shnider SM, Wright RG. Anesthetic considerations for myasthenia gravis and pregnancy. Anesth Analg. Jul-Aug 1978;57(4):441-7. [Medline].
5. Ip MS, So SY, Lam WK, et al. Thymectomy in myasthenia gravis during pregnancy. Postgrad Med J. Jun 1986;62(728):473-4. [Medline].
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8. Carr SR, Gilchrist JM, Abuelo DN, Clark D. Treatment of antenatal myasthenia gravis. Obstet Gynecol. Sep 1991;78(3 Pt 2):485-9. [Medline].
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10. Ellison J, Thomson AJ, Walker ID, Greer IA. Thrombocytopenia and leucopenia precipitated by pregnancy in a woman with myasthenia gravis. BJOG. Aug 2000;107(8):1052-4. [Medline].
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12. Giwa-Osagie OF, Newton JR, Larcher V. Obstetric performance of patients with my asthenia gravis. Int J Gynaecol Obstet. Aug 1981;19(4):267-70. [Medline].
13. Hoff JM, Daltveit AK, Gilhus NE. Myasthenia gravis in pregnancy and birth: identifying risk factors, optimising care. Eur J Neurol. Jan 2007;14(1):38-43. [Medline].
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15. Igarashi S, Yamauchi T, Tsuji S, et al. [A case of myasthenia gravis complicated by cyclic thrombocytopenia]. Rinsho Shinkeigaku. Mar 1992;32(3):321-3. [Medline].
16. Johns TR, Howard FM. Symposium on therapeutic controversies. Myasthenia gravis. Steroids and immunosuppressive drugs. Trans Am Neurol Assoc. 1978;103:278-81. [Medline].
17. Kalidindi M, Ganpot S, Tahmesebi F, Govind A, Okolo S, Yoong W. Myasthenia gravis and pregnancy. J Obstet Gynaecol. Jan 2007;27(1):30-2. [Medline].
18. Levine SE, Keesey JC. Successful plasmapheresis for fulminant myasthenia gravis during pregnancy. Arch Neurol. Feb 1986;43(2):197-8. [Medline].
19. McNall PG, Jafarnia MR. Management of myasthenia gravis in the obstetrical patient. Am J Obstet Gynecol. Jun 15 1965;92:518-25. [Medline].
20. Newsom-Davis J, Willcox N, Schluep M, et al. Immunological heterogeneity and cellular mechanisms in myasthenia gravis. Ann N Y Acad Sci. 1987;505:12-26. [Medline].
21. Ramirez C, de Seze J, Delrieu O, et al. [Myasthenia gravis and pregnancy: clinical course and management of delivery and the postpartum phase]. Rev Neurol (Paris). Mar 2006;162(3):330-8. [Medline].
22. Sax TW, Rosenbaum RB. Neuromuscular disorders in pregnancy. Muscle Nerve. Nov 2006;34(5):559-71. [Medline].
23. Shehata HA, Okosun H. Neurological disorders in pregnancy. Curr Opin Obstet Gynecol. Apr 2004;16(2):117-22. [Medline].
24. Téllez Zenteno JF. Can we consider thymectomy before pregnancy in female patients with myasthenia gravis?. Eur J Cardiothorac Surg. Aug 2006;30(2):411-2; author reply 412. [Medline].
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Article Last Updated: Dec 13, 2007