Publisher Summary
Myasthenia gravis (MG) is a chronic autoimmune disorder in which autoantibodies against the acetylcholine receptor (AChR Abs) at the neuromuscular junction impair neuromuscular transmission, causing weakness of skeletal muscles. It is considered a rare disease in the general population and also in pregnancy. Women are more affected than men at a ratio of 6:4. Main signs and symptoms include diplopia and ptosis that represent involvement of extrinsic ocular muscles. Fifteen percent of patients will only have this ocular involvement, but it may progressively affect the bulbar muscles used for swallowing. In addition, when limbs are affected, fluctuating weakness and easy fatigability of skeletal muscles are seen. The onset of MG can be triggered during pregnancy or postpartum. In pre-existing MG, exacerbations are frequently unpredictable and not unusual during pregnancy, labor, or the postpartum period. So it is recommended to myasthenic patients considering pregnancy should seek preconception counseling in order to improve their clinical condition, minimize the use of immunosuppressive drugs, and address the need for thymectomy.
Myasthenia gravis (MG) is a chronic autoimmune disorder in which autoantibodies against the acetylcholine receptor (AChR Abs) at the neuromuscular junction impair neuromuscular transmission, causing weakness of skeletal muscles. The main signs and symptoms include diplopia and ptosis that represent involvement of extrinsic ocular muscles. Limbs can also be affected, and there is weakness that has a proximal distribution, worsens with sustained exertion, and improves after rest. The onset of MG can be triggered during pregnancy or the postpartum period. In preexisting MG, exacerbations are frequently unpredictable and not unusual during pregnancy, labor, or the postpartum period. The clinical state at the beginning of pregnancy does not predict the occurrence of exacerbation or remission. However, pre-conception care is essential to optimize treatment before pregnancy. Considerations concerning MG include first trimester vomiting that may influence drug absorption, and respiratory tract involvement that may worsen in pregnancy. It is also important to consider the higher incidences of pregnancy complications such as preterm birth, preeclampsia, and polyhydramnios. Most of all, care of a myasthenic pregnant woman has some challenging considerations, and requires a multidisciplinary approach with neurologists, obstetricians, and neonatologists.
Introduction
Myasthenia gravis (MG) is a chronic autoimmune disorder in which autoantibodies against the acetylcholine receptor (AChR Abs) at the neuromuscular junction impair neuromuscular transmission, causing weakness of skeletal muscles. It is considered a rare disease in the general population and also in pregnancy. The overall incidence ranges from 50 to 125 cases per million population . Women are more affected than men at a ratio of 6:4. It may occur at any age, but female incidence peaks in the third decade of life, whereas the male mean age of onset is at 42 years . Thus, like other autoimmune diseases, MG occurs commonly in women in childbearing age.
Clinical Features
Main signs and symptoms include diplopia and ptosis that represent involvement of extrinsic ocular muscles. Fifteen percent of patients will only have this ocular involvement, but it may progressively affect the bulbar muscles used for swallowing. In addition, when limbs are affected, fluctuating weakness and easy fatigability of skeletal muscles are seen. Weakness has often a proximal distribution, worsens with sustained exertion, and improves after rest. The disease typically has periods of remission and exacerbations that may be triggered by certain medications, intercurrent infections, surgery, general anesthesia, emotional stress, menses, pregnancy, and puerperium ( Box 3.1 ). A myasthenic crisis occurs when there is involvement of respiratory muscles requiring mechanical ventilation. It is not unusual for patients with MG to have other autoimmune diseases such as hypothyroidism (13%), systemic lupus erythematosus, rheumatoid arthritis (5–6%), or polymiositis (1%) . Box 3.2 shows clinical features of MG.
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Physical exertion
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Hot temperature
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Drugs—e.g., aminoglycosides, phenytoin, local anesthetics
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Emotional upsets
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Surgery
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Infections
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Menses
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Hyperthyroidism
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Pregnancy
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Hypokalemia
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Can present at any age, typically bimodal peak, with first peak in the third decade and the second peak in sixth and seventh decades (“young women and old men”).
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Weakness and fatigue of the voluntary muscles are the most important features. Symptoms worsen or appear on exertion and improve at rest or with anticholinesterases. Typically there is a diurnal variation, with worsening of symptoms in the later part of the day.
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Ocular muscle weakness is usually the initial presentation and may be the only feature through the course in about 10% of patients. The ptosis (and diplopia) is exacerbated by the prolonged upward gaze toward a fixed target for 1 min.
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In most cases, weakness progresses from ocular muscles to involve other muscles in a craniocaudal direction. The weakness of intercostal muscles and diaphragm leads to dyspnea on exertion or at rest. The orthopnea with rapid resolution on sitting up and diaphragmatic paradox are important clinical signs of neuromuscular breathlessness.
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Deep tendon reflexes are intact or may be brisk.
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There are no objective sensory deficits.
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In severe cases, respiratory failure may ensue, requiring intubation and mechanical ventilation.
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Symptoms may fluctuate and there may be remissions of variable periods, particularly in early stages.
Diagnosis
Diagnosis of MG should start with a complete history and physical examination. Other neuromuscular conditions including mitochondrial myopathy, thyroid ophthalmopathy, and Lambert–Eaton myasthenic syndrome must be excluded. Serum AChR Abs is present in 70–90% of patients with general involvement, and 50% of patients with purely ocular MG. It confirms clinical diagnosis . Other antibodies may be present, such as those against the muscle-specific receptor tyrosine kinase that may be useful in seronegative patients . Electronic testing is also used for diagnosis and to assess severity. Typical pattern includes an abnormal decline in the size of evoked potentials noted on repetitive supermaximal muscle motor nerve stimulation . Abnormal jitter and blocking are detected virtually in all patients who have MG and a weak muscle is tested. The method is especially interesting in seronegative patients.
Approximately 75% of patients have thymic abnormalities, and 10% have thymomas . Thymomas are more frequent in patients over the age of 30. Because 30% are invasive at the time of diagnosis, all thymomas should be surgically removed. Women of childbearing age who have MG have an enlarged thymus and circulating autoantibodies in most cases.
General Aspects of Preconception Care
The onset of MG can be triggered during pregnancy or postpartum. In pre-existing MG, exacerbations are frequently unpredictable and not unusual during pregnancy, labor, or the postpartum period. Although a good outcome is possible, there are some important clinical considerations for the myasthenic patient planning a pregnancy. Pregnancy is associated with important hemodynamic changes essential for fetal growth and well-being. These include a rise in blood volume and renal clearance that interfere with absorption of oral medications that may need dosage adjustments. The growing fetus many times restricts the diaphragm and compromises the respiratory function in normal pregnancy. Symptoms may be worse in MG, especially with previous respiratory involvement.
Myasthenic patients considering pregnancy should seek preconception counseling in order to improve their clinical condition, minimize the use of immunosuppressive drugs, and address the need for thymectomy. It is also important to maximize treatment to concomitant disorders, such as arterial hypertension, diabetes mellitus, and hypothyroidism, as all add risk to the future pregnancy.
All issues and risks should be made clear to patients to enable them to make a conscious decision based on the most current information available. Those with involvement of the respiratory muscles should be advised not to get pregnant until improvement of their clinical condition. They should also be aware that the effects of pregnancy in MG is often unpredictable, and so is the opposite: the effects of the disease in pregnancy cannot be predicted.
Effect of Pregnancy on MG
Pregnancy may change the course of MG, often in an unpredictable way. The clinical state at the beginning of pregnancy does not predict the occurrence of exacerbation or remission . It is also interesting to notice that each pregnancy has its effect on MG. The course of future pregnancies cannot be predicted by the ongoing pregnancy. In one review of 322 pregnancies in 225 myasthenic patients, exacerbation, remission, and no change in disease occurred in 41%, 29%, and 30%, respectively . Additionally, postpartum exacerbations were noted in 30% of all patients. It seems that the first trimester and the postpartum period are the times of highest risk of exacerbation . Despite these findings, the long-term outcome of MG is not altered by pregnancy . The maternal mortality risk is inversely related to the duration of the disease with the highest risk being in the first year. It is thus recommended that myasthenic women postpone pregnancy for the first year or two after diagnosis .
Normal physiologic changes associated with pregnancy, especially the hemodynamic changes and alteration in gastrointestinal absorption, may affect the clinical course of MG. Besides, common symptoms of the first trimester, such as nausea and vomiting, can lead to subtherapeutic levels of medication, sometimes requiring parenteral therapy. Another important consideration concerns infections in the myasthenic pregnant woman. Infections should be treated aggressively because they can precipitate severe exacerbations. Special attention is required for respiratory infections. When diaphragmatic muscle weakness is present, it may become more symptomatic during pregnancy because of the respiratory restriction caused by increase in abdomen. A simple upper respiratory tract infection can lead to a life-threatening respiratory crisis in need of mechanical ventilation . Complaints of cough or dyspnea should be evaluated promptly.
Alpha-fetoprotein (AFP) has been studied as a factor influencing MG in pregnancy. AFP has been identified as a factor inhibiting binding of antiacetylcholine receptor antibodies to acetylcholine receptors, with a level of 60,000 ng/mL inhibiting 93% of autoantibodies from binding . Varying levels of AFP could partially explain variations in clinical course during pregnancy.
Effect of MG in Pregnancy
Preterm delivery is a major complication of pregnancy, responsible for high neo-natal morbidity and mortality. It is defined by births occurring at less than 37 weeks gestation. Its etiology in the general population and a possible association with MG are not completely understood. The overall incidence of preterm delivery is 10% and reported incidence in MG is variable. In one case series evaluating clinical outcome in myasthenic patients, 36.5% of pregnancies ended before 37 weeks . This group also found a high rate of perinatal death, 68 per 1000 live births. Another large series found no increase in preterm deliveries in MG . However, their population had increased incidence of fetal anomalies, which were responsible for a death rate of 18 per 1000 live births, higher than the general population (2.2 deaths per 1000 live births).
Another common medical problem in obstetrics is pre-eclampsia. Pre-eclampsia is a hypertensive syndrome that complicates 5% of pregnancies, and is considered a major cause of maternal and perinatal death. Maternal complications include hypertensive crisis, cerebral events such as convulsions and hemorrhage, hepatic involvement in HELLP syndrome, and renal lesions. Because there is no treatment for pre-eclampsia, management options focus on preventing these severe complications and anticipating delivery. Damage to the central nervous system is prevented by administration of magnesium sulfate. Despite being a first-line drug in treatment of pre-eclampsia, its use is contraindicated in myasthenic patients. Excess magnesium at the neuromuscular junction causes a relative depression of muscle fiber excitability, which may further exacerbate weakness and fatigability. In one case report, an undiagnosed myasthenic patient treated with magnesium sulfate for pre-eclampsia experienced severe proximal muscle weakness approximately 15 min after magnesium administration . Another report suggests that the administration of magnesium sulfate for seizure prophylaxis precipitated a myasthenic crisis . Narcotics and sedatives may be used under careful supervision as anticonvulsive agents. Seizure prophylaxis may be achieved by administration of phenobarbital.
Myasthenic pregnant women who develop pre-eclampsia are also at increased risk if they use corticosteroids. High-dose corticosteroids may increase fluid retention and aggravate hypertension in patients with severe pre-eclampsia. These patients are at increased risk for developing pulmonary edema and should be monitored closely for worsening respiratory status. Decreased urine output commonly seen in severe pre-eclampsia calls for frequent need of dose adjustment of medications to avoid toxicity. In addition, cholinergic side effects can mimic symptoms of pre-eclampsia. Severe hypertension should be treated with a regime that includes hydralazine. Management of pre-eclampsia in the myasthenic pregnant woman is challenging with less therapeutic options and increased maternal risk.
Preterm birth and pre-eclampsia are not the only concerns in myasthenic pregnant women. Other life-threatening risks include respiratory failure and cholinergic crisis due to overmedication. It is of use to monitor pulmonary function as the patient progresses through gestation. In addition, an electrocardiogram is indicated for the reported risk of focal myocardial necrosis in some patients with MG . Care includes evaluation of thyroid function to rule out coexisting thyroid disease.
Fetal assessment tests that rely on alterations of fetal movement or heart rate response to fetal movement are not always reliable in the myasthenic patient. This includes the patient’s perception of fetal movement. During a myasthenic crisis, continuous fetal monitoring of a viable fetus is indicated because the patient and fetus may be hypoxic.
Polyhydramnios as a severe complication resulting from impaired fetal swallowing has been described in several case reports. In extreme cases, fetal arthrogryposis multiplex congenita may be observed in pregnant myasthenic patients. In these cases, lack of fetal movement causes joint contractures and paralysis of the fetal diaphragm results in the development of pulmonary hypoplasia . In some studies evaluating arthrogryposis multiplex congenita, high maternal antiacetylcholine receptor autoantibody titers appear related to the occurrence of fetal/neonatal symptoms . Decreased fetal breathing and total body movements were observed on ultrasound with increasing antibody titers ( Table 3.1 ). Passive placental transfer of antiacetylcholine receptor IgG can be responsible for symptoms in the fetus pre-natally and may cause transient neonatal MG after delivery.
