Myasthenia gravis (MG) is a chronic autoimmune disease of striated muscle that affects the neuromuscular junction. Most cases result from the production of autoantibodies toward postsynaptic acetylcholine receptors or, more rarely, through the production of antibodies against postsynaptic muscle-specific kinase (1). Other anti-muscle antibodies have also been identified (2). Immunoglobulin G has been the most abundant antibody detected at the neuromuscular junction. These antibodies result in impaired function and accelerated degradation of acetylcholine receptors as well as complement activation, which damages the postsynaptic surface. Thus, the end-plate potential may be disrupted, and synaptic transmission may be compromised (3).

MG affects twice as many women as men, with the peak incidence in women occurring in the third decade. MG affects approximately one in 20,000 pregnancies (4,5). The cardinal symptom of MG is weakness, worsening with activity and improving with rest. Patients frequently present with isolated ocular symptoms, commonly diplopia and ptosis. However, patients may also present with or ultimately develop bulbar symptoms. Bulbar involvement is characterized by dysarthria, dysphagia, and weakness of the neck and proximal muscles (1). The disease progresses in a craniocaudal fashion, and the majority of patients with bulbar symptoms develop generalized limb weakness. Weakness of the diaphragm and intercostal muscles may lead to dyspnea and myasthenic crisis. Respiratory failure occurs in few patients. The disease is characterized by relapses and remissions. The serum levels of antibodies do not always correlate with disease severity though decreased levels are usually associated with an improvement in the disease (2). Thymic abnormalities are common in patients with MG with most manifesting hyperplasia and 10% with thymomas. In addition, patients with MG often have other associated autoimmune diseases (6,7).

Anticholinesterases are used to treat MG. These are taken daily and act by increasing the amount of acetylcholine available to bind to the postsynaptic receptors. Pyridostigmine is commonly used to inhibit the enzyme responsible for hydrolysis of acetylcholine. The drug peaks within 2 hours and its duration is 3–6 hours. Commonly, doses are less than 120 mg every 3 hours. It is very important to follow levels of cholinesterase inhibitors during pregnancy because altered pharmacokinetics can lead to cholinergic crisis. Overdose of anticholinesterases causes cholinergic crisis, which is characterized by paralysis, respiratory failure, hypersalivation, miosis, sweating, vomiting, diarrhea, lacrimation, bronchospasm, and bradycardia. Myasthenic crisis is another event that may occur but this is due to an exacerbation of MG. Myasthenic crisis results in respiratory compromise requiring mechanical ventilation. There are a number of factors that may precipitate a crisis including pregnancy, infection, surgery, stress, medications, hyperthermia, and thyroid dysfunction (8).

Symptomatic patients with MG should be treated with anticholinesterases, immunosuppressant drugs, corticosteroids, plasmapheresis, and immunoglobulin (2). These therapies are directed at decreasing the levels of antibodies and increasing acetylcholine availability. Thymectomy is usually recommended as the thymus may generate autoantigen and house cells that secrete acetylcholine receptor antibody. Although remission occurs in nearly 50% of patients with MG within 1 to 5 years after a thymectomy (5), the impact that thymectomy has on pregnant women with MG has not been determined. Many long-term immunosuppressants are contraindicated during pregnancy. Methotrexate is contraindicated; folic acid antagonists lead to fetal skeletal and craniofacial abnormalities. Azathioprine can also lead to congenital anomalies and has been assigned to pregnancy category D by the FDA, though many women have taken this medication throughout pregnancy without any adverse outcome. Cyclosporine does not seem to carry any major teratogenic risk. Plasmapheresis removes acetylcholine receptor antibodies and immunoglobulin down-regulates the immune system (2).

Pregnancy has a variable and unpredictable effect on MG. Our knowledge is limited by a paucity of literature on this subject. Approximately 30% to 40% of patients will have an exacerbation at some time during pregnancy, and 30% will enjoy a remission (2,9). Relapse seems to occur most commonly in the first trimester (8). However, one-third of all patients have exacerbations in the postpartum period (10). Neither the disease severity nor pregestational medication use before conception determines the relapse rate during
pregnancy. Remissions may be due to increased α-fetoprotein in the second and third trimesters leading to decreased antibody binding to the acetylcholine receptor. Women who become pregnant within the first year of MG diagnosis may have a worse outcome compared to those that postpone pregnancy; disease duration is inversely related to disease severity (10). Thus, it is recommended that women delay pregnancy for at least 1 year after diagnosis. The overall maternal mortality is estimated at 3.4% to 4%. Mortality risk factors include myasthenic and cholinergic crises (5,9,10).

There is no convincing evidence that MG alone has adverse effects on pregnancy (2). However, should the patient with MG develop pregnancy-related or myasthenic-related complications, then significant maternal and fetal morbidity may occur. Complications such as acute respiratory distress, weakness, and iatrogenic myasthenic crisis can adversely affect both the mother and fetus. If the mother develops preeclampsia, the use of magnesium (to prevent eclampsia) can precipitate myasthenic crisis. Magnesium inhibits the release of acetylcholine at the neuromuscular junction and decreases the motor end-plate sensitivity to acetylcholine (2,11). Some authors report an increased number of preterm births and premature rupture of membranes though further studies are needed to confirm these findings. There is a report of an increased perinatal death rate in babies born to mothers with MG, and there is a higher death rate due to fetal anomalies (2).

The fetus of patients with MG may develop transient neonatal myasthenia and, rarely, arthrogryposis multiplex congenital, contractures caused by decreased movement secondary to acetylcholine receptor antibodies (2,8,12). Other neonatal complications include Potter’s sequence, hyperbilirubinemia, and pulmonary hypoplasia. Ten to twenty percent of neonates born to mothers with MG will have neonatal MG. The infants usually display symptoms 12 to 48 hours after delivery which may last for up to 4 months. The infants may have poor sucking, hypotonia, and respiratory distress (2,5,8). Some infants will require anticholinesterases and respiratory support. The severity of disease in the mother does not predict the occurrence of neonatal MG. Maternal thymectomy may protect against neonatal MG (2,12,13).

Parturients with MG should attempt to have a vaginal delivery (10). Surgical intervention presents several risks to parturients with MG (infection and crisis) and should be reserved for obstetrical reasons or for patients in crisis. These patients should be seen in consultation with an anesthesiologist prior to the onset of labor in order to rule out other associated diseases that could further complicate the patient’s course. Diseases associated with MG include systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, diabetes, multiple sclerosis, myocarditis, dysrhythmias, cardiomyopathy, and Crohn’s disease (6,7). It is important to determine the duration, medication dose, and severity of the disease. Pulmonary function tests can help to determine which patients are at increased risk for needing respiratory support.

Labor and delivery may be a difficult time for the patient with MG. Cholinesterase inhibitors should be continued. Stress, pain, and exertion during the first stage of labor can exacerbate myasthenic symptoms and should be controlled with early epidural analgesia. Both epidural and combined spinal–epidural have been used successfully. Epidural analgesia curtails opioid-induced respiratory depression. Furthermore, titration of the analgesic level to T10 can help maintain good respiratory function during labor. In addition, the epidural can be extended should a cesarean delivery become necessary. This is especially important given that regional anesthesia is preferred to general anesthesia. Since the first stage of labor primarily involves smooth muscle, parturients tend to tolerate this stage well. However, neuraxial analgesia may exacerbate skeletal muscle weakness (4). A more dilute solution of local anesthetic may be used to reduce the extent of motor block (10). Some recommend a local anesthetic such as ropivacaine in order to reduce the extent of motor block (9,10). Amide local anesthetics should be used because ester local anesthetic duration can be prolonged by anticholinesterases (14,15). The second stage of labor may pose a problem for the patient as the expulsive effort required from the mother may lead to myasthenic crisis. This stage does require use of striated muscles. For this reason, assisted delivery with forceps or vacuum under epidural analgesia may be necessary. Several studies have shown an increase in assisted delivery in these parturients (15). All anesthetics that could cause respiratory depression or affect neuromuscular transmission should be avoided. Thus, most sedatives and opioids should not be given to these patients.

Cesarean delivery should be reserved for obstetric indications, as surgery itself is a trigger for myasthenic crisis (2,10,13). Cesarean delivery has been accomplished with both spinal and general anesthesia. Should a cesarean delivery become necessary in a patient with an epidural already in place, the regional anesthetic blockade can be extended with amide local anesthetics. Chloroprocaine should be avoided given the impaired hydrolysis of ester local anesthetics in the setting of anticholinesterase therapy (2,10). However, patients who have preexisting respiratory compromise may not be able to tolerate a high level of neuraxial anesthesia (10). Maternal hypoxemia may be caused by the decrease in forced vital capacity (FVC) and forced expiratory volume in 1 minute (FEV₁) from neuraxial anesthesia combined with the supine position, decreased functional residual capacity (FRC) of pregnancy, and myasthenia-induced intercostal muscle and diaphragm weakness. In order to maintain a level below T₄, many anesthesiologists prefer epidural to spinal anesthesia (10). Several authors have reported neuraxial anesthetic success with supplemental use of noninvasive ventilatory support such as bilevel positive airway pressure (BiPAP) (16,17).

General anesthesia should be avoided in MG patients, but if general anesthesia and neuromuscular blockade becomes necessary, there are several important considerations. Due to the reduction in functional acetylcholine receptors, patients with MG exhibit resistance to succinylcholine. A higher dose may overcome this resistance but can lead to a phase II block. In addition, chronic anticholinesterase therapy can decrease plasma cholinesterase levels which may lead to prolonged neuromuscular block with succinylcholine (11,18). For these reasons, routine use of depolarizing muscle relaxants in these patients is not recommended. However, some believe that the dose of succinylcholine commonly used is large enough that resistance should not pose a significant problem. Furthermore, the inhibition of plasma cholinesterase by anticholinergics may not have a clinical effect (19). Since parturients should undergo a rapid sequence induction given the risk of aspiration, rocuronium offers an alternative medication for neuromuscular blockade. However, the response to nondepolarizing neuromuscular relaxants is markedly exaggerated in MG patients, which can lead to a prolonged neuromuscular blockade. Even a defasciculating dose of a nondepolarizer can produce profound weakness. When these nondepolarizing muscle relaxants are used, the dose should be greatly reduced (10% to 25% of ED₉₅ and monitored with a peripheral nerve stimulator) or avoided altogether if possible. Of
note, in Europe, success has been reported with the use of rocuronium for a rapid sequence induction followed by sugammadex reversal (18). Volatile agents also contribute to neuromuscular relaxation, necessitating extreme caution on emergence (2,4,10,11). Given this property of volatile anesthetics, some have advocated induction and intubation with volatile agents alone (10). Reversal with cholinesterase inhibitors in MG can lead to a cholinergic crisis which mimics a myasthenic crisis, with paralysis and respiratory failure (10) (Fig. 32-1).

Due to the risk of prolonged weakness and respiratory depression, postoperative mechanical ventilation may be necessary. The duration of disease, presence of coexisting respiratory disease, and the peripartum pyridostigmine dose all influence the need for prolonged mechanical ventilation (4). Additional factors which are used to assess the need for postoperative ventilation in MG include: A forced expiratory flow 25% to 75% <3.3 L and <78% predicted, a FVC <2.6 L, and a maximum expiratory flow 50% <3.9 L/s and <80% predicted (16). All patients undergoing general anesthesia should be informed about the possibility of prolonged intubation. All patients with MG should be carefully observed in the postpartum period for an exacerbation of the disease.

Myotonia refers to an abnormal delay in muscle relaxation after contraction, which is caused by skeletal muscle membrane hyperexcitability and inappropriate firing. This results in contracture states common to a number of muscle diseases that are collaboratively called myotonic disorders (20). Myotonia can be mild or severe; if severe, it interferes with activities of daily living such as walking and climbing stairs. Repeated contraction and relaxation may improve myotonia, which is called the “warming up” phenomenon. Medications used to treat myotonia include sodium channel antagonists such as procainamide, phenytoin, and mexiletine, tricyclic antidepressant drugs, benzodiazepines, calcium channel antagonists, and prednisone (21).

The most common disease within the myotonias is myotonic dystrophy. Myotonic dystrophy (DM) is currently divided into two types: Type 1 (DM1 or Steinert’s disease) and type 2 (DM2 or proximal myotonic myopathy [PROMM]). Both are genetically inherited in an autosomal dominant manner and are trinucleotide repeat disorders. DM1 is caused by an abnormal repetition of CTG on chromosome 19 in the DM protein kinase gene, and DM2 is caused by a CCTG repeat on chromosome three in the ZNF9 gene (21). The severity of the disease generally depends on the amount of extra genetic material. DM1 severity seems to worsen in subsequent generations (22). Patients suffer from weakness, atrophy (face, neck, fingers, and limbs), cardiac conduction defects, cognitive dysfunction, cataracts, hypersomnia, insulin resistance, and muscle pain (20). DM2 is not as common as DM1, usually has less severe muscle weakness than DM1, and demonstrates less genetic anticipation (21).

Myotonia congenita (CM) is a less common myotonia and also has two main forms: The autosomal dominant form called Thomsen’s disease and the autosomal recessive form called Becker’s disease. These diseases are caused by a mutation in CLCN1, which is the skeletal muscle chloride channel that suppresses muscle membranes after potentials. In Thomsen’s disease, the myotonia is more severe in the upper limbs and is often associated with muscular hypertrophy. Patients suffer from painless muscle stiffness. Becker’s disease tends to be more severe and affects the lower limbs first (20).

DM is associated with an increased rate of obstetric complications. During pregnancy, some patients experience increased weakness while others remain undiagnosed until pregnancy when they become symptomatic. In pregnant patients with DM1, there is an increased incidence of fetal loss, premature delivery, and polyhydramnios (22). Some studies show that the incidence of preterm birth is as high as 50% in patients with DM1 who had clinical signs of the disease prior to pregnancy. These patients also have an increased risk of placenta previa (23). Since DM is an autosomal dominant disease, many fetuses are affected. One study has shown that the pregnancies with affected fetuses have a higher risk of preterm labor and polyhydramnios compared to those with unaffected fetuses (24). It is not known why the fetus influences preterm labor, but polyhydramnios is due to reduced swallowing of amniotic fluid by the affected fetus.

The disease may affect uterine smooth muscle, requiring forceps or other assisted delivery methods (22). The rate of cesarean delivery in these patients is twice as high as in unaffected patients (23). The risk of uterine atony is also increased. Tocolytic treatment with β-adrenergic agonists may precipitate myotonia and rhabdomyolysis, and magnesium may cause severe weakness and respiratory compromise. Women with DM2 do not seem to have a higher risk of
fetal loss or polyhydramnios, but they may have worsening of symptoms during pregnancy and an increased risk of preterm labor (5). Pregnancy does not cause a worsening of the overall disease course in DM (22).

Patients with DM1 are also at increased risk of anesthetic and surgical complications. Triggers of myotonia, such as hypothermia and shivering, should be avoided; if laryngeal and respiratory muscles are involved, intubation can be challenging. Myotonic patients are at increased risk for aspiration due to laryngeal muscle weakness and poor esophageal motility (25). Myotonic contractions during surgical manipulation and electrocautery may interfere with surgical access (26). Laboring women may have decreased pulmonary reserve and are at increased risk for respiratory depression from intravenous opioids (5). Patients with DM1 have an increased sensitivity to induction agents and other sedatives (22). Due to the risk of cardiac arrhythmias, electrocardiographic monitoring should be used.

Local and regional anesthesia and analgesia are preferable to general anesthesia, but neither prevents myotonia from occurring (23). Epidural and spinal anesthesia have both been used successfully in DM, but a high thoracic block may not be tolerated for cesarean delivery in a patient with decreased cardiac or pulmonary reserve. Combined spinal–epidural has also been used successfully in DM for cesarean delivery (27,28). Patients with DM2 are not at risk from anesthesia to the same extent as patients with DM1 (29,30).

Succinylcholine should not be administered to patients with myotonia due to hyperkalemia and total body rigidity. The latter can cause difficulty with intubation and ventilation. Nondepolarizing neuromuscular relaxants should be used with caution because of their potentially long duration of action given the patient’s preexisting weakness (25). Although nondepolarizing neuromuscular relaxants usually do not cause a prolonged block, they do not counteract a succinylcholine-induced myotonia (20). Anticholinesterase medications may cause myotonia in patients with CM (21).

There are rare case reports of hyperthermia and acidosis in patients with CM undergoing general anesthesia. It is not certain that these were definitive cases of malignant hyperthermia (MH); one case was described without the administration of triggering agents. A recent review states: “It is highly unlikely that patients with any of the chloride channel myotonias have a risk of developing MH above that of the general population” (20) (Table 32-1). There are no case reports of MH in the setting of DM. It may be very difficult to make the diagnosis of MH when a patient has generalized skeletal muscle rigidity after receiving succinylcholine. Although quite unlikely, it is possible for a patient to have two genetic defects making them susceptible to both MH and myotonia (20).

Muscular dystrophies (MDs) are a heterogeneous group of inherited neuromuscular disorders including Duchenne MD, Becker MD, limb-girdle MD, congenital MD, and facioscapulohumeral MD (FSHD). Some are X-linked and have a male preponderance, while others have an autosomal inheritance. These diseases all cause muscle weakness and are characterized pathologically by muscle fiber degeneration, necrosis, fibrosis, and sometimes inflammation. Traditionally, they have been classified based on pathologic, clinical, and inheritance patterns, but currently molecular diagnostic techniques are available to differentiate the many different forms of the disease (31).

FSHD is an autosomal dominant disease; women tend to be less severely affected than men. The disease is characterized by progressive weakness and wasting of the facial, shoulder girdle, and upper arm muscles (32). The progression of weakness is slow in this disease with only 20% of patients ever becoming wheelchair bound (22). This type of MD is not associated with a shortened life expectancy (33).

There is very little information regarding pregnancy and anesthesia for women with MD, especially since many women with these diseases decide against having children. Vaginal delivery may be attempted if there is no obstetric contraindication. One study involving a postal questionnaire of women with FSHD found an increased incidence of low birth weight babies (33) (Table 32-2). Cesarean delivery and forceps delivery were more common in patients with FSHD compared to national birth data (Fig. 32-2). This was thought to be due to abdominal and truncal weakness affecting the second stage of labor. Twenty-four percent of the women with FSHD reported worsening symptoms of weakness and falling that did not resolve postpartum (33).

Limb-girdle MD refers to a myopathy that involves progressive weakness of the limb-girdle musculature. There are many different forms described: Autosomal dominant, autosomal recessive, some with early onset in childhood, and others with a later onset. These patients have difficulty with walking, climbing stairs, and rising from a seated position. An older postal questionnaire that included nine women with limb-girdle MD suggests that these patients also have an increased incidence of operative deliveries but may suffer from a more marked progression of disease during pregnancy compared to those with FSHD (32).

Respiratory complications may be increased in patients with MD, especially if there is restrictive lung disease due to kyphoscoliosis (5). In severe forms of FSHD, patients may have weakness of accessory muscles of respiration and reduced vital capacity. Patients with limb-girdle MD may have weakness of the diaphragm (34). A recent case report describes a woman with limb-girdle MD who had severe restrictive lung
disease during pregnancy. She was treated with noninvasive positive pressure ventilation at 34 weeks’ gestation and had a combined spinal–epidural placed for her emergency cesarean delivery without complications (35).