Pathophysiology

Muscular dystrophies are characterized by degeneration of the skeletal muscle fibers and replacement with fibrous and fatty connective tissue, without accumulation of intermediate metabolic substrates. There is no evidence for direct neurologic involvement. The breakdown of the muscle fiber sarcolemma occurs early in the disease, with an influx of calcium and the activation of proteases, and the eventual destruction of tissue by inflammatory elements. The absence of dystrophin results in a loss of skeletal muscle membrane integrity and subsequent breakdown of the sarcolemma with an influx of extracellular calcium, activation of cellular proteases, inflammation, necrosis, and replacement fibrosis.

Duchenne’s muscular dystrophy (DMD, also called pseudohypertrophic muscular dystrophy) is the most common form, seen in 1 per 3500 births. The myopathy is associated with mutations of the dystrophin gene located in the Xp21 stripe, inherited as a sex-linked recessive trait; most of the reported cases are male. However, well-documented cases in females range in severity from full DMD to mild weakness. Transmission of this disease in female offspring of normal fathers can occur when there is early inactivation of the normal X chromosome (Lyon hypothesis). Only one X chromosome is active in any cell, with inactivation of the other X-chromosome occurring early in embryogenesis. Some heterozygotic females with DMD would then be expected to carry the abnormal X chromosome as the only active dystrophin gene in most cells. Female children with Turner’s syndrome (XO) would also present with DMD. It is unclear whether heterozygotic females pose the same anesthetic risks as males with DMD. Although DNA testing can detect multiple deletions, duplications, and point mutations in the dystrophin gene, proximal limb muscle biopsy remains the standard for diagnosis. Skeletal muscle biopsy early in the disease process may demonstrate necrosis and phagocytosis of muscle fibers, as well as areas of vigorous muscle regeneration. Immunostaining reveals the complete lack of dystrophin at the surface of the muscle fibers.

Diagnosis and Differential

Progressive and symmetric skeletal muscle weakness and wasting with histologic evidence of dystrophic muscle changes are diagnostic of DMD. The initial clinical presentation involves a waddling gait, frequent falling, and difficulty climbing stairs because of proximal muscle weakness in the pelvic girdle. Also, weakness in the shoulder girdle and trunk erectors leads to thoracolumbar scoliosis. Certain muscles, particularly the calves, demonstrate early hypertrophy. The pelvic girdle and proximal leg muscle weakness is responsible for Gowers’ sign, with the child climbing up the legs to stand up. However, the child’s condition usually goes undiagnosed until age 3 to 5 years. This is rapidly followed by atrophy of the other proximal muscles. All muscles are ultimately involved except for the cranial muscles and the external anal sphincter. Because of lack of denervation, there is intact sensation, but the proximal deep tendon reflexes (DTRs) disappear in half of patients by age 10. The earlier the onset, the more rapid is the downhill course. Usually the child is unable to walk by age 9 to 11 years. Joint contractures appear during this period because of the uneven loss of agonist and antagonist muscle groups.

In the heart, loss of dystrophin affects l -type calcium channels with increased intracellular calcium. The excess calcium activates proteases that degrade the contractile proteins, leading to inflammation and myocardial cell death and fibrosis, producing a dilated cardiomyopathy. Cardiomyopathy is the major cause of death in DMD patients. The timing and severity of the cardiomyopathy in DMD is unrelated to the severity of skeletal muscle degeneration. Although all patients with DMD will eventually develop cardiomyopathy, symptoms may not become apparent because of their inability to exercise. Uncharacteristic symptoms of CHF in this population may include sleep disturbances, loss of appetite, nausea, abdominal pain, cough, or increased secretions. These patients will have a resting tachycardia. Physical findings of a cardiomyopathy on examination may include jugular venous distention, displacement of the point of maximal impulse (PMI), and S ₃ /S ₄ gallop. Scarring of the posterobasal portion of the left ventricle produces tall, right precordial R waves and deep, left precordial Q waves in the electrocardiogram (ECG). Mitral regurgitation may also be present because of papillary muscle dysfunction.

The “gold standard” for assessing cardiac function in DMD patients is the two-dimensional echocardiogram. However, cardiac magnetic resonance imaging (MRI) has been shown to be a more reliable noninvasive measure of cardiac function in DMD patients. In some cases, gadolinium contrast has been used in conjunction with cardiac MRI to visualize fibrotic areas. Several studies have shown the benefits of steroid therapy on skeletal, respiratory, and cardiac muscle function; steroid treated DMD children maintained normal cardiac function longer than untreated DMD children. In addition, angiotensin-converting enzyme (ACE) inhibitors slow the progression of cardiac dysfunction in DMD patients.

Duchenne’s dystrophy produces respiratory muscle weakness, which places these patients at increased risk for perioperative pulmonary complications . Respiratory muscle weakness is detectable by age 10, but the diaphragm is usually spared. There is a progressive decrease in total lung capacity and vital capacity. Inability to cough and clear secretions predisposes these patients to pneumonia, which is often fatal by about the third decade. However, about 15% of patients have a much slower disease course, which stabilizes about the time of puberty. These patients also have lower-than-average intelligence with mild cerebral atrophy, presumably from the lack of normal brain dystrophin; initiating perioperative incentive spirometry may therefore prove difficult. Some clinicians believe that exercise enhances muscle destruction; however, physical therapy that involves passive movement to prevent contractures and resistance exercises for the lungs to increase endurance may be helpful. Because contractures represent a major disability, DMD patients often have elective procedures to relieve these contractures. Thus, perioperative complications that prolong their inactivity may actually exacerbate their condition by preventing the important postoperative physical therapy.

The American College of Chest Physicians 2009 consensus statement on the respiratory management of patients with DMD recommends preoperative assessment of oxygenation, lung volumes, and cough strength ( Table 9-1 ). Oxygen (O ₂ ) saturation below 95% on room air by pulse oximetry is considered a “clinically significant abnormality” and warrants further assessment, which may include arterial blood gas (ABG) analysis. Assessment of lung volumes involves measuring forced vital capacity (FVC) in the seated, upright position. DMD patients with FVC less than 50% should receive preoperative training with noninvasive positive-pressure ventilation (NPPV) to facilitate postoperative extubation. In addition, because the coughing and clearing of secretions are important aspects of pulmonary toilet after surgery, preoperative measurement should include maximum expiratory pressure (MEP) and peak cough flow (PCF). Using these values as guidelines, patients should receive preoperative training in the postoperative use of manual and mechanically assisted cough devices.

In addition to the cardiac and pulmonary manifestations, DMD effects are systemic with the possible need for neurologic, GI, nutritional, and physical therapy support. Many of these patients have elevated plasma muscle enzymes aldolase and creatine kinase (CK) levels early in disease progression. The MB fraction of CK, normally present only in heart muscle, cannot be used as a guide to cardiac injury because it is also elevated as a result of the destruction of regenerating skeletal muscle in DMD. CK levels are highest (50-100 times normal) up to age 3 years and then decrease by about 20% per year as muscle atrophies. Increased plasma levels of liver enzymes have also been noted (aminotransferases/transaminases, lactate dehydrogenase); however, liver damage has not been described in DMD, suggesting a skeletal origin.

Table 9-2 lists the other, less common forms of muscular dystrophy and their clinical course. Becker’s muscular dystrophy (BMD) is an allelic variant of DMD in which the mutated dystrophin gene produces a reduced amount of a truncated dystrophin protein. The pace of muscle destruction in BMD is much slower than in DMD, with symptoms usually appearing in early adolescence. Most BMD patients will develop a cardiomyopathy by age 30, which may not correlate with the degree of skeletal muscle destruction. BMD is usually fatal from respiratory or cardiac complications between ages 30 and 60 .

Facioscapulohumeral dystrophy (FSHD) is the third most common muscular dystrophy, with a pattern of progressive muscular weakness involving the face, scapular stabilizers, proximal arm, and fibula. Patients with FSHD usually present with shoulder weakness and scapular winging. FSHD is also associated with retinal abnormalities and hearing loss, but the cardiac muscle is usually spared.

The limb-girdle muscular dystrophies (LGMDs) are a heterogeneous grouping of sarcoglycanopathies, a class of transmembrane proteins that associate with dystrophin in a glycoprotein complex. Common clinical features include early involvement of the proximal muscles of the legs, followed by shoulder muscles with scapular winging. Affected individuals have a characteristic stance of lordosis, abducted hips, and hyperextended knees. The facial and ocular musculature is usually spared. There are usually no associated cognitive or cardiac abnormalities. Onset of LGMD is in late childhood, with slow progression. In contrast to most muscular dystrophies that affect the proximal musculature, the distal myopathies affect the forearms, hands, and lower legs.

Anesthetic Considerations

Patients with muscular dystrophies often require surgery for muscle biopsy, the correction of scoliosis, the release of contractures, and exploratory laparotomy for ileus ( Box 9-1 ). The surgical risk is the lowest early in the disease course, before the patient has significant comorbidities. Thus, it is imperative to determine the severity of the disease and the associated comorbidities. Among patients with muscular dystrophy, 50% to 70% demonstrate some cardiac abnormality, although these are clinically significant in only 10% of patients and often in the terminal phase of the disease. No correlation has been established between the severity of the cardiac disease and the severity of the skeletal disease. Necrosis and fibrosis of the myocardium in DMD is typically limited to the posterobasal and lateral free walls of the left ventricle, whereas in the other muscular dystrophies the fibrosis may be more diffusely dispersed. Dysrhythmias occur frequently, even after minor trauma. Complex ventricular premature beats correlate with both abnormal left ventricular function and an increased incidence of sudden death. These patients probably have impaired cardiac autonomic function with increased sympathetic tone, explaining the resting tachycardia and the propensity to develop arrhythmias.

Patients undergoing surgery should have a recent echocardiogram. Echocardiography will demonstrate mitral valve prolapse in 10% to 25% of patients. It may also show posterobasilar hypokinesis in a thin-walled ventricle and a slow relaxation phase with normal contraction, characterizing the cardiomyopathy seen in DMD. However, preoperative echocardiography may not always reflect the ability of the diseased myocardium to respond to perioperative stress. Heart failure can occur during anesthesia for major surgery even with normal preoperative echocardiography and electrocardiography, and sudden death can occur even in patients with fully compensated cardiac status. Angermann et al. advocate the use of stress echocardiography using angiotensin to detect latent heart failure and identify inducible contraction abnormalities.

Atrial and atrioventricular conduction defects with bradycardia are common in Emery-Dreifuss muscular dystrophy (EDMD), and again, the severity of heart disease does not correlate with the degree of skeletal muscle involvement. Several anesthesiologists have recommended preoperative prophylactic cardiac pacing in EDMD patients undergoing general anesthesia and having emergency pacing available when any form of anesthesia is used. Regional anesthesia has been used successfully in EDMD patients for lengthening of both Achilles tendons; in one case a temporary transvenous pacemaker was inserted before administration of the anesthetic. In addition, EDMD patients may prove difficult to intubate and careful assessment with cervical radiography should be undertaken preoperatively. A total intravenous anesthetic (TIVA) or a nitrous/narcotic technique that omits volatile anesthetics and depolarizing agents, to avoid malignant hyperthermia–triggering agents, would seem appropriate if a general anesthesia technique cannot be avoided. To date, however, malignant hyperthermia has not been described in EDMD.

Perioperative respiratory complications are a major concern when anesthetizing patients with muscular dystrophy. As previously discussed, at the end of the first decade of life, reductions in inspiration, expiration, vital capacity, and total lung capacity become prominent and reflect the weakness of respiratory muscles. Decreased ability to cough and the accumulation of oral secretions predispose muscular dystrophy patients to postoperative respiratory tract infections. Respiratory insufficiency, however, may not be apparent because impaired skeletal muscle function prevents these patients from exercising enough to exceed their limited breathing capacity. Preoperative pulmonary function studies are valuable in determining the postoperative course of these patients. Patients with a vital capacity of greater than 30% of the predicted value can usually be extubated immediately after surgery. With progression of the disease (vital capacity less than 30% of predicted) and the added morbidity of kyphoscoliosis, which can contribute to a restrictive respiratory pattern, postoperative ventilatory support will be required. Delayed pulmonary insufficiency may occur up to 36 hours postoperatively, even if the patient’s skeletal muscle strength apparently returned to preoperative level. Sleep apnea may also compound the respiratory problems and may contribute to development of pulmonary hypertension. Preoperative introduction to chest physiotherapy and nasal continuous positive airway pressure (CPAP) and their use early in the postoperative period have been effective in decreasing the incidence of respiratory complications.

Sometimes the first indication that a child has muscular dystrophy is an unexplained cardiac arrest or myoglobinuria with malignant hyperthermia–like findings during general anesthesia. In patients with muscular dystrophies, do inhalational agents and succinylcholine trigger malignant hyperthermia? In 2000, Breucking et al. investigated 200 families with muscular dystrophy of the Duchenne and Becker types who had received a total of 444 anesthetics. Sudden cardiac arrests occurred in six patients with undiagnosed disease at the time they received a general anesthetic of an inhalational agent and/or succinylcholine. There were also nine, less severe incidents of fever, rhabdomyolysis, and masseter spasm. The authors recommended the avoidance of the triggering agents—succinylcholine and volatile anesthetics—to decrease the risk of severe anesthetic complications. In earlier reports, Cobham and Davis (1964) and Richards (1972) found no temperature rise or cardiac arrest after using virtually all anesthetic agents available at that time in DMD patients. Richards reported using halothane 37 times and succinylcholine 12 times, all without subsequent problems.

Nevertheless, since those publications, several case reports have described life-threatening complications (dysrhythmias, cardiac arrest, rhabdomyolysis) after anesthesia with muscle relaxants and inhalational agents. The anesthetic complications often seemed to parallel the severity of the muscle disease. Succinylcholine has been involved in the majority of lethal complications in patients with unsuspected DMD, leading the U.S. Food and Drug Administration in 1992 to issue a warning with regard to the administration of succinylcholine in young children and adolescents. Larach et al. reported that 48% of pediatric patients with cardiac arrest during anesthesia had an unrecognized myopathy, with 67% of these associated with succinylcholine-induced hyperkalemia. An inherent membrane defect in DMD may render the muscle more susceptible to injury induced by inhalational anesthetics and depolarization with succinylcholine. Patients with DMD may have an upregulated isoform of the acetylcholine receptor that is more sensitive to the effects of succinylcholine. These agents probably trigger rhabdomyolysis and nonspecific hypermetabolic responses in DMD patients rather than malignant hyperthermia. Case reports have documented the use of propofol, narcotics, and nondepolarizing muscle relaxants in DMD patients without complications, but as with the earlier series of uneventful anesthetics with triggering agents, large series are required to document their safety. In patients with DMD, onset of nondepolarizing neuromuscular blockade may be significantly delayed, which must be considered when rapid-sequence induction is required. However, the prolonged recovery from neuromuscular blockade may require postoperative ventilation.

Myotonic Dystrophy

Myotonic dystrophy (dystrophia myotonia, DM; Steinert’s disease) is extremely variable in presentation, from asymptomatic cases to congenital DM with respiratory insufficiency and mental retardation ( Table 9-3 ). It is an autosomal dominant inherited neuromuscular disorder with a worldwide prevalence of 1 in 8000. The genetic defect is a result of the abnormal expansion of the nucleotide CTG on chromosome 19, which codes for a serine-threonine protein kinase. The relationship between the genetic defect and the clinical findings is still unknown. However, knockout mice that completely lack this enzyme develop normally. Expressivity of the genetic defect must also be variable; both minimally affected and severely affected individuals may be seen within a family.

Four types of myotonic dystrophy are described: congenital (CDM), juvenile or early onset (JDM), adult onset , and late onset . The most severe form is CDM, which presents as hypotonia rather than myotonia. CDM has a high mortality during the neonatal period from respiratory distress. Cranial muscle weakness occurs at birth, which gives these infants a characteristic tent-shaped mouth. JDM children may have some facial weakness early in life, but major muscle weakness is often delayed and accompanied by some mental retardation. In adult-onset DM, symptoms appear during the second and fourth decades of life, with progressive muscular weakness. Muscle weakness and wasting are the most disabling features of DM. Wasting is usually most prominent in the cranial musculature and distal limb muscles. Temporalis and masseter muscle atrophy leads to the classic appearance of the “hatchet face.” DTRs are usually reduced or absent. Weakness of the muscles of the vocal cord apparatus results in nasal speech and propensity for aspiration pneumonia. The distal limb muscles first affected lead to footdrop and weak handshake.

Myotonic dystrophy is a multisystem disease and can affect the heart (conduction system), smooth muscle (impaired intestinal motility), eye (cataracts), brain (mental retardation), and endocrine system (e.g., testicular atrophy, insulin resistance, hypometabolism). Cardiac conduction abnormalities are common and may cause sudden death. In one report, 57% of DM patients had conduction defects, one third of whom had first-degree atrioventricular block unresponsive to atropine. Many of these patients also have an associated cardiomyopathy, and CHF can be a cause of death. Because anesthetics can increase vagal tone or induce arrhythmias, transthoracic pacing should be readily available.

The pulmonary complications of DM are the result of chronic aspiration and central hypoventilation. Weakness of the respiratory muscles causes alveolar hypoventilation, hypercapnia, and hypoxemia, resulting in increased somnolence. In some patients an increased respiratory effort is required in one group of respiratory muscles (diaphragm) to overcome the myotonia in other respiratory muscles (intercostals). Smooth muscle atrophy leading to poor gastric motility, coupled with a diminished protective cough reflex, promotes aspiration. Recurrent aspiration pneumonia can lead to chronic pulmonary damage such as bronchiectasis and pulmonary hypertension. The hypersomnolence seen with DM is often associated with carbon dioxide (CO ₂ ) retention and appears to be primarily a central nervous system (CNS) manifestation of the disease.

A recently recognized variant of DM is proximal myotonic myopathy (PROMM). This disorder has features in common with DM (e.g., facial muscle weakness, frontal balding), but the muscle weakness and stiffness is predominantly confined to proximal rather than distal muscles and usually appears in adolescence.

Myotonia Congenita

Myotonia congenita, a distinct entity from the congenital onset of DM, is characterized by two forms, one described by Thomsen in 1876 as autosomal dominant and the other by Becker in the 1950s as autosomal recessive inheritance. Both forms are the result of mutations in the gene that codes for the major chloride channel. The Thomsen variant is a mild disease with generalized myotonia, usually recognized in early childhood because of frequent falling. Cranial and upper-limb musculature is most severely affected, sometimes resulting in difficulty chewing. The myotonic responses occur after a rest interval and may result in the patient falling to the ground in a rigid state. Some patients have an athletic appearance as a result of muscle hypertrophy. Many patients have lid lag and blepharospasm, which involves myotonia of the lid musculature. The Becker recessive variant is similar to the dominant form, except that the myotonia is usually more severe and presents later in life (after age 10) and does not progress in severity beyond the third decade. These patients are usually handicapped in their daily activities because of leg muscle stiffness and generalized weakness. The stiffness of myotonia is treated with medications that reduce the increased excitability of the cell membrane by acting at the sodium channel (local anesthetics, antiarrhythmics).

Myotonia Fluctuans

Becker also described individuals with the dominant form of nondystrophic myotonia in which muscle stiffness fluctuated from day to day. These individuals do not experience muscle weakness, but rather have a prolonged time for relaxation after voluntary muscle contraction and external mechanical stimulation. The stiffness (contractures) that occurs after heavy exercise may last 30 minutes to 2 hours, with days or weeks between incidents. Succinylcholine has triggered myotonic crisis, with difficulty in ventilation and intubation, and thus should be avoided in these patients. The duration of neuromuscular blocker therapy will be increased in patients with myotonia fluctuans, but anticholinesterases should be avoided because they may trigger a myotonic crisis.

A variant of myotonia fluctuans has been described in which the myotonia occurs during exercise and is not relieved by warming a cold limb. In another variant, with persistent and sometimes severe myotonia, increased serum potassium will aggravate the myotonia. Children with this disorder may experience acute hypoventilation and coma after eating a meal rich in potassium, caused by myotonia of the thoracic muscles. Often these children are misdiagnosed as having a seizure disorder. Clearly, mutations of the sodium-chloride channels of muscle can result in several different clinical syndromes, including the systemic form found in myotonic dystrophy.

Glycogen Storage Myopathies

The glycogen storage disorders are the result of muscle enzymatic defects in glycogenolytic or glycolytic pathways leading to the accumulation of glycogen. The myopathy is not caused by the accumulation of glycogen, however, but rather by the block in energy production, and thus substrate use diseases. The glycogen storage diseases were assigned Roman numerals in the order of their discovery and classified as “muscle diseases of glycogenosis” by Cori ( Fig. 9-3 ). This section discusses these myopathic nonlysosomal glycogenoses in their enzymatic sequential order.

Glycogen metabolism and glycolysis.

Roman numerals refer to glycogenosis enzymatic defects.

(Redrawn from Tsujinao S, Nonaka I, DiMauro S: Glycogen storage myopathies, Neurol Clin 18:127, 2000.)

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