Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

CHAPTER 9 – Muscle Diseases

Michael K. Urban, MD, PhD,
Salim Lahlou, MD

  

 

Muscular Dystrophies

  

 

Pathophysiology

  

 

Diagnosis and Differential Diagnosis

  

 

Anesthetic Considerations

  

 

Myotonias

  

 

Myotonic Dystrophy

  

 

Myotonia Congenita

  

 

Myotonia Fluctuans

  

 

Metabolic Myopathies

  

 

Glycogen Storage Myopathies

  

 

Myoglobinuria

  

 

Glycogenosis Type I (von Gierke's Disease)

  

 

Glycogenosis Type II (Pompe's Disease)

  

 

Mitochondrial Myopathies

  

 

Oxidative Phosphorylation Disorders

  

 

Luft's Disease

  

 

Complex I Deficiency

  

 

Complex IV Deficiency

  

 

Coenzyme Q Deficiency

  

 

Disorders of Fatty Acid Metabolism

  

 

Carnitine Deficiency

  

 

Acyl-Coenzyme A Dehydrogenase Deficiency

  

 

CPT Deficiency

  

 

Disorders of Pyruvate Metabolism

  

 

Muscle Channelopathies

  

 

Malignant Hyperthermia

  

 

Hyperkalemic Periodic Paralysis

  

 

Hypokalemic Periodic Paralysis

  

 

Myasthenias

  

 

Acquired Myasthenia Gravis

  

 

Eaton-Lambert Myasthenic Syndrome

  

 

Inflammatory Myopathies

  

 

Dermatomyositis

  

 

Polymyositis

  

 

Inclusion Body Myositis

  

 

Overlap Syndromes

  

 

Infective and Toxic Myopathies

  

 

Human Immunodeficiency Virus

  

 

Necrotizing Myopathy

  

 

Thyrotoxic Myopathy

Since the writing of this chapter by J. D. Miller and H. Rosenbaum, the genetic defects and molecular mechanisms involved in many of the muscle diseases have been elucidated. In some cases this makes the management of patients with these diseases easier. However, it still requires an astute clinician to make the diagnosis of a muscle disease and assess the magnitude of the compromise in normal physiologic functions. Complaints of fatigue, weakness, and polymyalgias are commonly reported symptoms. These are nonspecific symptoms whose etiology may extend from neuromuscular disorders through rheumatologic problems to psychiatric conditions. A detailed neuromuscular physical examination and routine diagnostic testing, including electromyography (EMG), serum electrolytes, thyroid function tests, and serum creatine kinase evaluation may not provide a definitive diagnosis. In fact, many of these patients may have a final nonspecific diagnosis of “fibromyalgia” or chronic fatigue syndrome, but some will have life-threatening muscle disorders that must be recognized if they are to have any chance of effective treatment.

Perioperative respiratory complications are a major concern for patients with muscular diseases. General anesthesia and surgery, particularly abdominal and thoracic, result in postoperative pulmonary changes, specifically a loss of lung volumes and an increase in the alveolar-arterial gradient. This is the reason for a postoperative pulmonary complication rate of 25% to 48%. Patients with chronic respiratory muscle weakness have a higher incidence of postoperative respiratory complications because of the loss of respiratory reserve. In addition, their inability to take deep inspirations and cough makes them more susceptible to atelectasis and pneumonia. However, a preoperative diagnosis of respiratory compromise may be difficult in patients with skeletal muscle weakness, because their respiratory reserve is rarely challenged. Preoperative pulmonary function testing of these patients provides an assessment of the severity of the pulmonary disease and potential pulmonary risk of undergoing the planned procedure. Patients with deteriorating skeletal muscle strength can also develop kyphoscoliosis with concomitant restrictive lung disease.

If possible, the administration of muscle relaxants should be avoided and, when required, a long-acting agent should be avoided. Hypomotility of the gastrointestinal tract may lead to delayed gastric emptying and increase the risk of pulmonary aspiration. This would favor securing the airway via rapid-sequence induction with succinylcholine; however, in some muscle diseases this has been associated with ventricular fibrillation, rhabdomyolysis, and malignant hyperthermia.

Because some of these patients will also have a cardiomyopathy, the depressant effects of volatile anesthetics may provoke congestive heart failure. The respiratory depressant effects of a narcotic anesthetic may, however, require prolonged postoperative respiratory support. In all cases, after general anesthesia one must anticipate the possibility of postoperative ventilation and, once extubated, the need for intensive respiratory therapy. Regional anesthesia avoids some of the complications of general anesthesia and may provide a vehicle for postoperative analgesia without employing narcotics. However, even if regional techniques are employed to reduce anesthetic requirements and provide postoperative pain management, it may still be necessary to protect the airway and ensure adequate oxygenation during the procedure through the use of general endotracheal anesthesia.

These points are all common considerations when anesthetizing patients with muscle diseases. In this chapter our goal is to delineate the characteristics of specific muscle diseases and how these diseases will impact on our perioperative plans.

MUSCULAR DYSTROPHIES

Muscular dystrophies are a group of hereditary myopathic diseases characterized by progressive weakness. Clinical presentation is heterogeneous, from severe fatal childhood forms to relatively benign adult forms. They are all best characterized by painless degeneration and atrophy of skeletal muscles without evidence of muscle denervation.[1] Originally these diseases were characterized on the basis of their clinical presentation, for example, limb-girdle myopathy. The discovery of dystrophin and related molecules has given “muscular dystrophy” a molecular biologic basis for diagnosis, genetic mapping, and treatment.[2] Dystrophin is a large (427-kb) rod-shaped protein, which comprises about 5% of the membrane-associated cytoskeletal protein [3] [4]; its gene is located on the short arm of the X chromosome. Dystrophin, with several other sarcolemmal proteins, stabilizes the muscle surface membrane during contraction and relaxation ( Fig. 9-1 ). The dystrophin-associated complex binds intracellular actin to the extracellular basal lamina, which mechanically stabilizes the sarcolemma during muscle contraction.

 
 

FIGURE 9-1  Schematic illustration of the principal extrajunctional molecules that are relevant to muscular dystrophy.  (Reprinted from Molnar MJ, Karpati MJ: Muscular dystrophies related to deficiency of sarcolemmal proteins. In Schapira AH, Griggs RC [eds]: Muscle Diseases. Boston, Butterworth-Heinemann, 1999, p 84.)

 

 

 

Pathophysiology

Muscular dystrophies are characterized by degeneration of the skeletal muscle fibers and replacement with fibrous and fatty connective tissue, without accumulation of metabolic intermediate 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.

Duchenne's dystrophy (DMD, also called pseudohypertrophic 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, with most of the reported cases being male. However, there are well-documented cases in females with a severity ranging from full Duchenne's 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 Duchenne's dystrophy 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 the disease. It is unclear whether heterozygotic females pose the same anesthetic risks as males with DMD.[5]

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Diagnosis and Differential Diagnosis

Progressive and symmetrical skeletal muscle weakness and wasting are the prominent features of DMD.[6] The initial clinical presentation involves a waddling gait, frequent falling, and difficulty climbing stairs owing to proximal muscle weakness in the pelvic girdle. There is also weakness in the shoulder girdle and trunk erectors, leading to thoracolumbar scoliosis. Certain muscles, particularly the calves, demonstrate early hypertrophy. The pelvic girdle and proximal leg muscle weakness is responsible for Gowers' sign, the child climbing up his or her legs to stand up. However, usually until age 3 to 5 the child's condition goes undiagnosed. 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 disappear in half of the cases by age 10. The earlier the onset, the more rapid the downhill course. Usually the child is unable to walk by age 9 to 11 years. Joint contractures appear during this period, due to the uneven loss of agonist and antagonist muscle groups. Degeneration of cardiac muscle leads to a dilated cardiomyopathy. Scarring of the posterobasal portion of the left ventricle produces tall right precordial R waves and deep left precordial Q waves in the electrocardiogram. Mitral regurgitation may also be present due to papillary muscle dysfunction. Respiratory muscle weakness is detectable by age 10, but the diaphragm is usually spared. Inability to cough and clear secretions predisposes these patients to pneumonia, which is often fatal by about the third decade. These patients also have lower than average intelligence and mild cerebral atrophy, presumably due to the lack of normal brain dystrophin. About 15% of patients have a much slower disease course, which stabilizes about the time of puberty. Some clinicians believe that exercise enhances muscle destruction; however, physical therapy that involves passive movement to prevent contractures and resistive exercises for the lungs to increase endurance may be helpful. Because contractures represent a major disability for DMD patients, they often have elective operative procedures to relieve these contractures. Hence, perioperative complications that prolong their inactivity may actually exacerbate their condition by preventing the important postoperative physical therapy.

The plasma muscle enzymes aldolase and creatine kinase (CK) levels are elevated severalfold early in the progression of the disease. 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, owing to the destruction of regenerating skeletal muscle in DMD. [7] [8] CK levels are highest (50 to 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, lactate dehydrogenase); however, liver damage has not been described in DMD, suggesting a skeletal origin. 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. Although DNA testing can detect multiple deletions, duplications, and point mutations in the dystrophin gene, proximal limb muscle biopsy remains the standard for diagnosis.

In Table 9-1 we have listed the other less common forms of muscular dystrophy and their clinical course. Becker 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, so that affected males are able to procreate, increasing the number of individuals with the disease. However, it is usually fatal from respiratory or cardiac complications between ages 30 to 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 (LGMD) are a heterogeneous grouping of sarcoglycanopathies, a class of transmembrane proteins that associate with dystrophin in a glycoprotein complex.[9] 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 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.

TABLE 9-1   -- Comparison Between Duchenne's and Other Forms of Muscular Dystrophies

 

Inheritance

Clinical Course

Comorbidities and Anesthetic Concerns

Becker's Dystrophy

X-linked, same locus as Duchenne's Reduced amount and abnormal dystrophin

Later onset (age 12 years) More benign course

Cardiac involvement less frequent and less severe but heart failure common cause of death

 

 

Death in early 40s, most commonly due to pneumonia

Pseudohypertrophy common Reports of cardiac arrests intraoperatively and postoperatively (patients at risk for rhabdomyolysis)

Emery-Dreifuss Dystrophy

X-linked

  

 

Slow progression

  

 

Early contractures in elbow, ankles, and neck

  

 

Significant cardiac risk common sudden death between ages 30 and 60 years

  

 

Early atrial arrhythmias progressing to asystole: prophylactic ventricular with pacemaker suggested

  

 

Possible cardiomyopathy, ventricular fibrosis and cardiomegaly

  

 

Possible difficult intubation secondary to limitation of neck motion (although flexion is more limited than extension)

Rigid Spine Syndrome

X-linked?

Slow progression

Severe restrictive lung disease

 

 

Painless limitation of neck and trunk motions

Weakness of respiratory muscles

 

 

 

Cardiomyopathy

 

 

 

Scoliosis

 

 

 

Difficult intubation

Facioscapulohumeral (Landouzy-Dejerine) Dystrophy

Autosomal dominant inheritance

Onset in adolescence

Rare cardiac involvement

 

 

Weakness of pectoral, orbicularis shoulder and pelvic muscles (less than Duchenne's)

Abnormal vital capacity

 

 

Life span minimally affected

Normal CO2 response curve

 

 

 

Frequent upper respiratorytract infections

 

 

 

Postoperative respiratory complications

Limb Girdle Dystrophy

Five subtypes

Two most common subtypes:

Variable cardiac involvement

 

Predominantly autosomal recessive

Erb's type (early onset, shoulder girdle primarily involved)

Sinus tachycardia and right bundle branch block most common ECG abnormalities

 

Severe childhood autosomal recessive dystrophy gene located on 17q12-21

Leyden-Möbius (late onset, pelvic girdle involvement)

Early severe diaphragmatic weakness (hypoventilation, hypercarbia)

 

 

Severity between Duchenne's and fascioscapulohumeral dystrophy5

Heart transplant in severe childhood autosomal recessive dystrophy6

Distal Myopathies

Autosomal dominant

Welander's myopathy: onset after age 30 years, seen mostly in Sweden, affects hands most frequently

Possible cardiomyopathy secondary to interstitial fibrosis of the heart muscle in Markesberry's dystrophy6

 

 

Markesberry's dystrophy: onset in fifth decade, feet involvement Early adult-onset myopathy: involvement of anterior or posterior compartment of legs

 

Oculopharyngeal Muscular Dystrophy

 

Onset after age 30 years, slow progression

Common dysphagia, dyscoordination of posterior pharynx and involvement of esophagus causing aspiration and inanition6

 

 

Weakness of pharyngeal muscles, ptosis, limbs, extraocular muscles (rare diplopia)

Sensitivity to muscle relaxants13,14; anticipate mechanical ventilation postoperatively

 

 

Similar symptoms to ocular myasthenia gravis13,14

Anticholinesterase agents do not reverse weakness

 

 

No dysarthria, dyspnea

Normal sensitivity to vecuronium in a case report15

Congenital Muscular Dystrophy

Fukuyama form, autosomal recessive

Onset at birth

Seizures and mental retardation in Fukuyama form

 

 

Proximal more than distal muscles involved

 

 

 

Slow progression Creatine kinase slightly elevated Death by age 10 years in Fukuyama form (seen frequently in Japan)

 

 

 

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

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 ( Table 9-2 ). The operative risk is the lowest early in the course of the disease, before the patient has significant comorbidities. Hence, it is imperative to determine the severity of the disease and the associated comorbidities. Fifty to 70 percent of the patients with muscular dystrophy 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 emotional trauma. Complex ventricular premature beats correlate with both abnormal left ventricular function and an increased incidence of sudden death.[10]

TABLE 9-2   -- Anesthetic Issues in Muscular Dystrophy

Potent Inhalational Anesthetics

Use is not recommended because they may trigger a malignant hyperthermia–like syndrome in patients with Duchenne's muscular dystrophy and depress myocardial contractility.

Hypnotics

Pentothal when used should be given in small increments. Propofol has been recommended as the preferred hypnotic, but higher than expected doses may be required for induction. Consideration should also be given to the myocardial status of the patient,[21] because some of these patients have significant cardiomyopathy, and the reduction in heart rate and decreased contractility with an induction dose of propofol may lead to profound hypotension and reduced end organ perfusion.

Opioids

The use of narcotics eliminates the use of myocardial depressants or inhalational agents; however, consideration should be given to the use of short-acting opioids and/or the need for postoperative ventilation.

Muscle Relaxants

The administration of nondepolarizing muscle relaxants is usually followed by an increased response, both in maximal effect and duration of action.[20] The recovery from neuromuscular blockade in muscular dystrophy patients has been reported to be three to six times longer than in healthy adults. In addition, postoperative pulmonary complications have been associated with the use of long-acting neuromuscular blocking agents.

 

The combined effects of primary smooth muscle abnormalities, inactivity, and general anesthesia induces gastric dilatation, delayed gastric emptying, and the risk of pulmonary aspiration.

 

Regional anesthesia may be a good alternative to general anesthesia to avoid the risk of triggering agents, respiratory depression, and the ability to use local anesthetics for postoperative analgesia.

 

 

Patients for operative procedures should have a recent echocardiogram. Echocardiography will demonstrate mitral valve prolapse in 10% to 25% of the 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.[11] 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 and associates[12] have advocated 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 to have 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. [13] [14] In addition, EDMD patients may prove difficult to intubate and careful assessment with cervical radiography should be undertaken preoperatively. A total intravenous anesthetic or a nitrous/narcotic technique that omits volatile anesthetics and depolarizing agents (to avoid malignant hyperthermia [MH] triggering agents) would seem appropriate if a general anesthesia technique cannot be avoided.[13] To date, however, MH 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 may appear to have returned to its 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, has been shown to be 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 MH-like findings during general anesthesia.[15] Breucking and colleagues[16]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 6 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 consisting 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,[17] in 1964, and Richards,[18] in 1972, did not note any temperature rise or cardiac arrest after using virtually all anesthetic agents available at that time in DMD patients. Richards reported the use of halothane 37 times and that of succinylcholine 12 times, all without subsequent problems. Nevertheless, since those publications there have been several case reports describing 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,[16] 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 and coworkers[19] reported that 48% of pediatric patients with cardiac arrest during anesthesia had an unrecognized myopathy, and 67% of them were associated with succinylcholine-induced hyperkalemia. It is speculated that an inherent membrane defect in DMD renders the muscle more susceptible to injury induced by anesthetics and depolarization with succinylcholine. Recent case reports [20] [21] 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.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

MYOTONIAS

Myotonias are a group of muscle diseases in which the pathognomonic finding is muscle stiffness., The process consists of slowed muscle relaxation after vigorous contraction. In some patients the stiffness may resolve with repeated muscle contractions, whereas in others it may be exacerbated. It is usually worse if a period of rest is followed by a period of exercise, and it can be provoked by cold. Myotonia results from an abnormality in the electrical properties of the sarcolemma, predisposing the muscle membrane to becoming easily depolarized. This results in a characteristic EMG pattern of repetitive discharges (myotonic runs). A diagnostic clinical sign of myotonia is percussion myotonia: after being struck by a percussion hammer, the muscle continues to contract for a period of time and becomes transiently indented.

Myotonic Dystrophy

Myotonic dystrophy (DM, Steinert's disease) is extremely variable in presentation, from asymptomatic cases to congenital DM with respiratory insufficiency and mental retardation ( Table 9-3 ).[22] It is an autosomal dominant worldwide disease with an estimated frequency 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, since within a family one can detect both minimally affected and severely affected individuals.

TABLE 9-3   -- Clinical Features of Myotonic Dystrophy

Neuromuscular

Myotonia, weakness

 

Reduced deep tendon reflexes

Eye

Cataract, ptosis

 

Ophthalmoparesis, retinal pigmentation

Endocrine

Testicular atrophy, diabetes, pituitary dysfunction, hyperparathyroidism

Skin

Frontal balding, pilomatrixoma

Cardiovascular

Hypotension, syncope, palpitations, mitral valve prolapse, sudden death

Gastrointestinal

Dysphagia, pseudo-obstruction

Central Nervous System

Mental retardation

Immune System

Reduced immunoglobulins

 

 

The characteristic sign of DM is myotonia; however, myotonia is absent in congenital myotonia and gradually appears during childhood. In the congenital variant hypotonia, respiratory distress and cranial muscle weakness occur at birth. In these infants motor development is delayed and is often accompanied by mental retardation. In the adult form of DM symptoms appear during the second and fourth decades of life, with progressive muscular weakness. This 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., Deep tendon reflexes are usually reduced or absent. Weakness of the muscles of the vocal cord apparatus results in a nasal speech and the propensity to aspiration pneumonia. The limb muscles first affected lead to footdrop and weak handshake.

DM 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). The cardiac conduction abnormalities are common and may cause sudden death. In one report 57% of the DM patients had conduction defects, with one third with first-degree atrioventricular block unresponsive to atropine. Many of these patients also have an associated cardiomyopathy, and congestive heart failure can also 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 hypotonia, chronic aspiration, and central hypoventilation. Weakness of the respiratory muscles will result in alveolar hypoventilation, hypercapnia, and hypoxemia and increasing somnolence. In some cases 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 in some cases leads to chronic pulmonary damage such as bronchiectasis. The hypersomnolence seen with DM is often associated with CO2 retention and appears to be primarily a central nervous system (CNS) manifestation of the disease.

Because DM is a systemic disease, anesthetic management must include consideration of the multiple manifestations of the disease. All of these patients must be treated as though they have both a cardiomyopathy and cardiac conduction defects. Medications that increase vagal tone or anesthetic plans that result in hypoxia may result in high cardiac conduction blocks. Hence, transthoracic pacing and antiarrhythmic medications should be readily available. If possible, inhalational agents should be avoided, owing to their myocardial depressant and conduction system effects.[23] Because these patients are at risk for aspiration, they should be kept at NPO status and relatively rapid protection of the airway should be achieved with an endotracheal tube. However, succinylcholine will produce contractures lasting for several minutes, rather than relaxation, and these contractures can be severe enough to prevent intubation and ventilation. These contractures are not, inhibited by nondepolarizing agents. Other agents may also induce myotonic contractures, including methohexital and etomidate, as well as a case report with propofol. The reversal of neuromuscular blockage by neostigmine could precipitate a myotonic response; thus it is advisable to use shorter-acting nondepolarizing muscle relaxants or avoid relaxation. Myotonic contractions can occur, however, in the presence of neuromuscular blocking agents and neuraxial anesthesia, because direct stimulation of the muscle (surgical stimulation) may result in contraction. The combination of central respiratory depression and weak respiratory musculature makes these patients vulnerable to the respiratory depressants effects of most sedatives, hypnotics, and narcotics. Therefore, when possible, regional anesthesia would be the preferred anesthetic and when general anesthesia is required the patients must be monitored postoperatively. The myotonic responses to DM can be treated with phenytoin (4-6 mg/kg/day) or quinine (0.3 to 1.5 g/day).

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

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Myotonia Congenita

This is a distinct entity from the congenital onset of DM, which usually presents with severe systemic involvement. There are two forms of this disease, one described by Thomsen in 1876 as a autosomal dominant trait and one described by Becker in the 1950s whose inheritance is recessive. Both forms are the result of mutations in the gene that codes for the major chloride channel.[24] The Thomsen variant is a mild disease with generalized myotonia, usually recognized in early childhood due to frequent falling. Cranial and upper limb musculature is the 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 owing to muscle hypertrophy. Many patients have lid lag and blepharospasm, which is 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 10 years) 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).

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

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, are not sensitive to cold, and do have stiffness (myotonia) that is provoked by exercise after an interval of rest. The stiffness that occurs after heavy exercise may last 30 minutes to 2 hours with periods of days or weeks between incidents.[25] There have been several reports of adverse anesthetic events with the use of succinylcholine in these patients.[26] A variant of this disorder 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, owing to 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 DM.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

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METABOLIC MYOPATHIES

For muscles to contract they require energy (adenosine triphosphate [ATP]), which is provided from the metabolism of glycogen, glucose, and fatty acids. The metabolic pathways of all three converge into acetyl coenzyme A (acetyl-CoA), which within the mitochondrion is oxidized through the Krebs cycle and respiratory chain to ATP ( Fig. 9-2 ). With regard to myopathies, defects in this process are substrate use defects (involving glycogenoses) or disorders of lipid metabolism. Tsujino and colleagues contend that patients with muscle substrate use diseases present with two major clinical presentations: (1) acute, recurrent, reversible muscle dysfunction that manifests as exercise intolerance or myalgia and (2) fixed, often progressive weakness.[27] Those disorders presenting as acute reversible muscle weakness can usually be differentiated into defects in glycogen or lipid metabolism based on their presentation. Because glycogen metabolism is important for intense aerobic exercise, patients with defects in glycogen metabolism experience muscle cramping and weakness after strenuous exercise, whereas patients with lipid metabolic defects often complain of muscle cramping or weakness after prolonged moderate exercise. Prolonged fasting can exacerbate these conditions and lead to respiratory muscle fatigue and myoglobinuria.

 
 

FIGURE 9-2  Schematic representation of substrate metabolism. Respiratory chain complexes encoded exclusively by nuclear DNA are solid; complexes encoded by both nuclear and mitochondrial DNA are cross-hatched.  (Reprinted from Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL [eds]: The Molecular and Genetic Basis of Neurological Disease. Boston, Butterworth-Heinemann, 1997, p 201.)

 

 

 

Metabolic myopathies of infancy or early childhood, however, usually present as multisystem disorders. The floppy infant syndrome, is the simplified clinical description for children with different metabolic myopathies. These children are at risk for respiratory complications because they have diminished cough reflex and regularly aspirate. The metabolic defects are likely to result in developmental defects in the CNS, cardiomyopathy, and cardiac conduction defects. In addition, the progressive atrophy of skeletal musculature will lead to contractures and scoliosis.[28]

Glycogen Storage Myopathies

These disorders are the result of muscle enzymatic defects in glycogenolytic or glycolytic pathways leading to the accumulation of glycogen. The myopathy is not, however, caused by the accumulation of glycogen but by the block in energy production, substrate use disease., 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 ). We will discuss these myopathic nonlysosomal glycogenoses in their enzymatic sequential order. [28] [29]

 
 

FIGURE 9-3  Scheme of glycogen metabolism and glycolysis. Roman numerals refer to glycogenosis enzymatic defects.  (From Tsujinao S, Nonaka I, DiMauro S: Glycogen storage myopathies. Neurol Clin 2000;18:127.)

 

 

 

Debranching Enzyme Deficiency (Type III, Cori-Forbes Disease)

This is a disease of childhood with hepatomegaly and liver dysfunction, growth retardation, and fasting hypoglycemia that often resolves spontaneously around puberty. The enzyme has two catalytic functions, a transferase that transfers a glucosyl unit to the acceptor chain of the phosphorylase-limit dextrin (PLD) and then the glucosyl unit is hydrolyzed. Infusion of fructose, as well as a high-protein diet, will increase blood glucose levels, since gluconeogenesis is not affected. Those cases that do not resolve at puberty have early evidence of muscle involvement, both skeletal and cardiac. However, clinical myopathy is not common and usually manifests later (third and fourth decade), after the liver symptoms have remitted. Serum CK is increased in patients with myopathy. The myopathy presents as weakness rather than exercise intolerance, cramps, or myoglobinuria. There can be wasting of the distal leg and intrinsic hand muscles, which can lead to a diagnosis of motor neuron disease. The course is slowly progressive and usually not incapacitating.

Branching Enzyme Deficiency (Type IV, Anderson's Disease)

The branching enzyme catalyzes the last step in glycogen biosynthesis by attaching short glucosyl chains to a peripheral chain of the nascent glycogen. In the enzyme-deficient state the abnormal unbranched glycogens precipitate and are no longer available for glucose production. The clinical manifestations include hepatosplenomegaly, cirrhosis, hypotonia, muscle wasting, and cardiomegaly. Most individuals affected with the disease die early. Patients who survive to maturity may also exhibit central and peripheral nervous system dysfunction.

Myophosphorylase Deficiency (Type V, McArdle's Disease)

Patients typically exhibit exercise intolerance with myalgia, cramping, stiffness, and weakness of the muscles exercised. The exercise intolerance usually develops during the teenage years, but weakness is usually not manifested until later decades. Most patients learn to adapt to their limited exercise tolerance and only later in life does the fixed proximal weakness impose significant limitations in lifestyle. If exercise continues with cramping, myoglobinuria may occur with subsequent renal failure. In this disease, as well as some of the other muscle glycolygenoses, the three to five times normal increase in venous lactate levels observed when an isolated muscle is made ischemic does not occur.

A distinct variant exists that exhibits severe generalized weakness, respiratory insufficiency, and death in infancy. Type V deficiency may also be associated with some cases of sudden infant death syndrome (SIDS).

Phosphorylase initiates glycogen degradation by removing 1,4-glucosyl residues from the outer branches of the glycogen molecule, leaving a phosphorylase-limit-dextran (PLD) molecule with four glucosyl units, which are then degraded by the debranching enzyme leading to glucose-1-phosphate. There are three isoenzymes expressed in muscle, brain, and liver. The brain contains both muscle and brain isoenzymes, which is why specific brain defects have not been characterized. The disease is transmitted as an autosomal recessive trait with localization on chromosome 11.

Because prolonged muscle ischemia can lead to permanent muscle weakness with atrophy and myoglobinuria with renal failure, tourniquets should be avoided. Since experimentally limited muscle exercise tolerance has been extended with glucose infusions, glucose-containing solutions should be infused intraoperatively. Adequate hydration and mannitol infusions when urine output decreases should be employed to prevent myoglobinuria. Succinylcholine should be avoided to prevent muscle fasciculations and breakdown. For the same reason, postoperative shivering should be avoided by using a warmer for intravenous fluids and warming blankets.

Muscle Phosphofructokinase Deficiency (Type VII, Tauri's Disease)

Phosphofructokinase (PFK) deficiency is similar to myophosphorylase deficiency in its clinical presentation and diagnosis. This enzyme converts fructose-6 and fructose-1-phosphate to fructose-1,6-diphosphate, with the defect thus blocking the metabolism of glycogen, glucose, and fructose. As with myophosphorylase deficiency, prolonged ischemic exercise in PFK may result in muscle necrosis and myoglobinuria. However, renal failure is not as common in PFK as it is in myophosphorylase. Because the enzyme defect also effects erythrocytes, some patients also exhibit increased hemolysis with jaundice. PFK is a tetrameric enzyme that is under the control of three structural genes (M, L, P), but only the M gene subunit is expressed in mature muscle, whereas erythrocytes express both the M and L subunits. The absence of anemia in PFK patients is related to the fact that erythrocytes can synthesize a functional enzyme with the L subunit. The defect in the M gene is transmitted as an autosomal trait on chromosome 1.

Phosphorylase B Kinase Deficiency (Type VIII)

Phosphorylase B kinase has a pivotal role in both the degradation and synthesis of glycogen. The enzyme phosphorylates glycogen phosphorylase to an active form while at the same time phosphorylating glycogen synthase to an inactive form; thus, when glycogen degradation is turned on, synthesis is turned off. Phosphorylase B kinase deficiency can be classified into different groups dependent on clinical presentation: liver disease of childhood exhibiting hepatomegaly, growth retardation, delayed motor development, hyperlipidemia, and fasting hypoglycemia, inherited as either a X-linked recessive or an autosomal recessive trait; liver and muscle disease characterized by hepatomegaly and nonprogressive myopathy of childhood, inherited as an autosomal recessive trait; muscle disease in which the patients exhibit weakness of exercising muscles with myalgias, cramps, and myoglobinuria, inherited as a X-linked recessive trait; and fatal infantile cardiomyopathy, inherited as an autosomal recessive trait. The anesthetic considerations would be similar for the previously mentioned deficits, except where the degree of liver disease required modifications.

Phosphoglycerate Kinase Deficiency (Type IX)

Phosphoglycerate kinase (PGK) catalyzes the formation of 3-phosphoglycerate and ATP. Because the enzyme is transcribed from a single gene that is expressed in all tissues except sperm, there is considerable clinical variability. The major clinical presentations include hemolytic anemia, CNS dysfunction (mental retardation, behavioral abnormalities, seizures, stroke), and exercise myopathies. These major clinical features occur with equal frequency in enzyme-deficient patients, but rarely do all appear in the same patient. It is inherited as a X-linked trait.

Phosphoglycerate Mutase Deficiency (Type X)

Phosphoglycerate mutase (PGAM) catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglycerate. Clinical features include myopathy with exercise intolerance, cramps, and myoglobinuria. It is inherited as an autosomal trait, manifesting variable heterozygotic symptoms.

Muscle Lactate Dehydrogenase Deficiency (Type XI)

Lactate dehydrogenase (LDH) is a tetramer that is composed of two distinct subunits, M and H, which can be arranged into five isoenzymes. The M subunit is the predominant form in skeletal muscle. Hence, patients with the M-type deficit exhibit exercise weakness and recurrent myoglobinuria but not other tissue pathology.

Aldolase Deficiency (Type XII)

Aldolase is present as three isoenzymes in skeletal muscle and erythrocytes; liver, kidney, and small intestine; and neural tissue. Patients with myopathy consisting of exercise intolerance also exhibit hemolytic anemia.

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Myoglobinuria

Myoglobinuria is a common metabolic abnormality among the substrate use muscle diseases. Due to an enzymatic blockage in glycogen metabolism and glycolysis, the muscle becomes starved for energy, leading to ischemia, necrosis, and the release of myoglobin into the circulation. However, the most common cause of recurrent myoglobinuria is a lipid metabolism disorder, carnitine palmitoyltransferase II (CPT II). Myoglobin is a 17,000-dalton protein with a heme prosthetic group present in muscle at a concentration of about 1 g/kg and is released during ischemia and cell death. The normal serum myoglobin concentration is about 20 ng/mL, and a serum concentration of 300 ng/mL is required for renal excretion. Visible brown discoloration of the urine with myoglobin suggests massive muscle destruction (rhabdomyolysis). Hemolysis is distinguished from myoglobinuria by a positive urine benzidine test (greater than 500 ng/mL of myoglobin) without microscopic red blood cells. Furthermore, if hemolysis is not a factor, a serum sample should be free of hemolysis. Hypovolemia and acidosis in combination with myoglobinuria increase the probability of acute renal failure. The exaggerated response of muscle fasciculations to succinylcholine, seen in children and adults with myopathies, places them at risk for myoglobinuria and renal failure. Arrhythmias may develop due to the effects of hyperkalemia, acidosis, and hypocalcemia (owing to the uptake of calcium by injured muscle). The hypocalcemia will also be exacerbated by the intravenous administration of sodium bicarbonate and the hyperventilation in patients on respirators. In these instances calcium should then be administered.

Treatment is aimed at reversing muscle destruction (rest, in many cases) and the maintenance of adequate urine output. Early vigorous fluid resuscitation reduces the incidence of renal failure during myoglobinuria. Mannitol should be administered to promote an osmotic diuresis and to scavenge the free oxygen radicals produced after reperfusion of the ischemic kidney. Alkalinization of the urine with sodium bicarbonate may prevent the precipitation of myoglobin acid hematin in the renal tubules and also reduce the risk of renal failure.

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Glycogenosis Type I (von Gierke's Disease)

Patients with this disease lack glucose-6-phosphatase, which acts primarily in the liver to convert glucose-6-phosphate to glucose, where it can be utilized by the brain and other tissues that require glucose.[27] Hence, this is not primarily a muscle disease but involves a lack of energy supply for muscles and other tissues. Because glycogen synthesis continues without glycogen degradation and glucose utilization, there is excess liver glycogen deposition with hepatomegaly. Because fasting hypoglycemia can be severe and is associated with acidosis, frequent small carbohydrate feedings are required. The disease is usually accompanied by seizures, mental retardation, and growth retardation; children rarely survive beyond 2 years. However, some patients have survived into their teenage years through portocaval shunts where intestinal uptake of glucose will bypass the liver, with the administration of thyroxine and glucagons to limit glycogen synthesis. Patients for surgery should be permitted to take oral glucose solutions up to 4 hours before surgery, followed by a glucose infusion. Frequent monitoring of both blood glucose and pH is required throughout the perioperative period. Lactate-containing solutions should be avoided, because these patients lack the ability to convert lactic acid to glycogen.

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Glycogenosis Type II (Pompe's Disease)

This is a lysosomal acid maltase deficiency that results in the deposition of glycogen in smooth, skeletal, and cardiac muscle. The clinical presentation takes three forms. The first is an infantile form that primarily involves cardiomegaly with congestive heart failure and death, usually before age 2. The next is a juvenile form resulting in severe proximal, truncal, and respiratory muscle weakness. An echocardiogram may reveal cardiac hypertrophy with subaortic stenosis. Muscle glycogen deposition may lead to an enlarged protruding tongue, making the patient prone to upper airway obstruction. Respiratory muscle weakness may predispose the patient to prolonged postoperative ventilatory support. Once extubated, aggressive pulmonary toilet is required to prevent pneumonia. These patients often die during the second and third decade. Finally, there is a milder adult-onset variant simulating limb-girdle dystrophy. Muscle weakness in these patients is unclear but may involve the rupture of hypertrophied lysosomes, causing muscle destruction.

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MITOCHONDRIAL MYOPATHIES

The mitochondrion is an intracellular organelle that is responsible for the majority of the energy-producing pathways. The genetics of mitochondria are complex in that the enzymes and proteins of the organelle are coded for by either mitochondrial genes or cellular genes. In addition, the mitochondrial DNA is exclusively maternally inherited and heterogeneous, such that multiple different copies of mitochondrial DNA may exist within the cell. Genetic defects in these mitochondrial enzymes are devastating to normal muscle action because the enzymes are responsible for ATP production from the mitochondrial respiratory chain and oxidative phosphorylation ( Fig. 9-4 ).[30] Luft reported the first case of a mitochondrial disorder in 1962 in a Swedish woman with evidence of hypermetabolism, but with normal thyroid function.[31] The woman was subsequently found to have a loose coupling of oxidation and physophorylation with abnormal mitochondrial structure. The following year the morphologic criteria for mitochondrial myopathy were described (RRF, ragged-red appearance with a modification of the Gomori trichrome stain).[32] It has since been discovered that not all RRF mitochondrial diseases involve myopathy, and RRF is not always present in mitochondrial myopathies. Mitochondrial myopathies can be divided into (1) “pure” mitochondrial myopathies; (2) mitochondrial encephalomyopathies; (3) oxidative phosphorylation disorders; (4) disorders of fatty acid metabolism; and (5) disorders of pyruvate metabolism. [33] [34] [35] [36] [37]

 
 

FIGURE 9-4  The mitochondrial respiratory chain and oxidative phosphorylation system.  (From Cooper JM, Clark J: The structural organization of the mitochondrial respiratory chain. In Shapira AH, Di-Mauro S [eds]: Mitochondrial Disorders in Neurology. Oxford, UK, Butterworth-Heineman. International Medical Reviews, Neurology 1994, vol 14, pp 1-30.)

 

 

 

For an in-depth discussion of mitochondrial myopathies, please see Chapter 14 , Mitochondrial Diseases.

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OXIDATIVE PHOSPHORYLATION DISORDERS

The list of neuromuscular disorders associated with mitochondrial abnormalities and specifically with defects in oxidative phosphorylation (OxPhos) continually increases.[38] In addition, defects in OxPhos have the potential to affect every tissue in the body. The major cardiac manifestation of an OxPhos deficit is hypertrophic cardiomyopathy. One of the specific metabolic defects in this process has been identified, a translocase that exchanges mitochondrial ATP for cytosolic adenosine diphosphate (ADP). Hematologic manifestations have also been associated with OxPhos lesions, specifically sideroblastic anemia in the Pearson marrow pancreas syndrome. Proximal tubular defects can also be a common kidney manifestation of pediatric OxPhos diseases. Diabetes mellitus is fairly common in pediatric OxPhos disorders and has been described in the mitochondrial disorders Kearns-Sayre, Pearson, Wolfram, and MELAS. Preoperative evaluation of these patients must include their tendency to develop lactic acidosis, feeding habits, and the utility of a glucose infusion in maintaining normal metabolism. Patients with cardiac involvement should have an echocardiogram, and patients with a history of respiratory problems (e.g., recurrent pneumonias, asthma, dyspnea) should have pulmonary function studies. Barbiturates that inhibit the respiratory chain should be avoided. Succinylcholine should also be avoided, owing to the small risk of inducing MH and lactic acidosis in myopathic patients.

OxPhos disorders can be classified according to the specific site of the biochemical defect.[39] However, patients may have an isolated defect in one complex or the genetic defect may affect several complexes. In addition, the clinical pictures of these defects often overlap. Furthermore, because the genes for OxPhos subunits may originate in either mtDNA or nuclear DNA, the specific biochemical defect does not point to the mode of inheritance. A discussion of a few of the more important syndromes associated with mitochondrial OxPhos defects follows.

Luft's Disease

As discussed earlier, in 1962 Luft described a 35-year-old woman with symptoms of hyperthyroidism (hyperhidrosis, polydipsia, polyphagia, weight loss) with normal thyroid function.[31] She was nonetheless treated for hyperthyroidism, including thyroidectomy, without the expected results. She was subsequently found to have mitochondria of variable size with increased numbers of cristae. The biochemical defect was a loose coupling of oxidative phosphorylation; for every oxidation of hydrogen an ATP was not, produced from ADP. Hence, more oxygen expenditure was required to achieve a normal amount of energy production. Perioperatively these patients would be at risk for hyperthermia, increased oxygen utilization, metabolic acidosis, and hypovolemia.

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Complex I Deficiency

Complex I deficiency ( Fig. 9-4 ) is one of the most common OxPhos deficits. The presentation may include isolated myopathy with exercise intolerance and lactic acidosis or a multisystemic disease.[40]The multisystemic disease includes a fatal infantile lactic acidosis with cardiomyopathy and CNS impairment.

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Complex IV Deficiency

This defect usually presents before age 3 as severe infantile myopathy with failure to thrive, weakness, hypotonia, severe lactic acidosis, and associated hepatic, cardiac and renal involvement.[41] There have been reports of the myopathy improving spontaneously after age 3. This “benign” reversible infantile myopathy may be caused by a developmentally regulated OxPhos subunit.

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Coenzyme Q Deficiency

Coenzyme Q is responsible for shuttling electrons between complexes I, II, and III.[41] The clinical presentation has included progressive muscle weakness starting in childhood, with associated CNS disorders. The patients improved clinically when administered 150 mg of coenzyme Q daily.

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DISORDERS OF FATTY ACID METABOLISM

Muscles use long-chain fatty acids as a source of energy (Figs. 9-1 and 9-5 [1] [5]). The fatty acids are esterified with coenzyme A (CoA) and then transported across the inner mitochondrial membrane through three steps: (1) esterification to carnitine with carnitine palmityl transferase (CPT I); (2) translocation across the membrane with carnitine acylcarnitine translocase; and (3) release as CoA by CPT II. Inherited defects have been described for each of these enzymes as well as the enzymes involved in β oxidation. [42] [43] Presentation is usually in infancy as hypoketotic hypoglycemia triggered by fasting or a hypermetabolic state (infection), which may be associated with encephalopathy, hepatocellular dysfunction, and cardiomegaly.

 
 

FIGURE 9-5  The transport of fatty acids into muscle mitochondria.

 

 

Carnitine Deficiency

Carnitine is synthesized in the liver and then transported to skeletal muscle, where it facilitates the transport of long-chain fatty acids into the mitochondrion. Medium-chain fatty acids do not require carnitine for transport. Because skeletal and cardiac muscle derives most of its resting, fasting, and endurance energy from fatty acid metabolism, carnitine deficiency results in weak muscles and the deposition of lipid granules. Childhood carnitine deficiency myopathy includes progressive dilated cardiomyopathy. In addition, Reye's syndrome has been associated with the deficiency, which includes vomiting, stupor, and coma. Because carnitine and medium-chain fatty acids will ameliorate the muscle weakness, they should be administered perioperatively. Corticosteroids should also be administered, because they provide an alternative transport mechanism for long-chain fatty acids. Prolonged fasting must be avoided, and glucose-containing infusions should be used.

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Acyl-Coenzyme A Dehydrogenase Deficiency

The dehydrogenases break down the mitochondrial fatty acid CoA to acyl-CoA; hence, defects in these enzymes lead to the accumulation of fatty acyl-CoA and fatty carnitine acyl-CoA. The most common form is the medium-chain acyl-CoA dehydrogenase deficiency, with an incidence of 1 in 10,000. It usually presents as hypoketotic hypoglycemia during the first or second year, after fasting or a metabolic stress. The deficiency has been linked to a number of deaths from sudden infant death syndrome (SIDS). In addition, patients who survive the childhood crisis often acquire a myopathy and cardiomyopathy.

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CPT Deficiency

CPT II is more common than CPT I deficiency, usually presenting in late adolescence as exercise-induced muscle cramping and myoglobinuria. Prolonged metabolic stress can result in respiratory insufficiency and renal failure from rhabdomyolysis. Serum levels of muscle CK are elevated during attacks but are usually normal between episodes. These patients exhibit normal work and oxidative capacity as long as a carbohydrate substrate is available; it is only during fasting or when glycogen stores (glucose) have been depleted that these patients have a metabolic crisis. Hence, as with several other substrate deficiency disorders, glucose should be administered perioperatively. Severe shivering and muscle contractions (succinylcholine) should also be avoided.

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DISORDERS OF PYRUVATE METABOLISM

These include pyruvate dehydrogenase (PDHC) and pyruvate carboxylase (PCD) deficiency. PDHC is one of the most common presentations of congenital lactic acidosis.[44] Clinical presentation can occur in the newborn as severe persistent lactic acidosis, usually resulting in death; can occur as a form that manifests later in infancy, associated with developmental delay, hypotonia, seizures, dysmorphic features, and intermittent episodes of lactic acidosis; and can occur in older childhood in males with ataxia, precipitated by carbohydrate meals and treated with high-fat, low carbohydrate diets.

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MUSCLE CHANNELOPATHIES

This is a group of disorders that have a common molecular basis in the impairment of voltage gated skeletal muscle.[45]

Malignant Hyperthermia

Still a cause of a fatal event under anesthesia, MH was first described in 1960 by Denborough and Lovell.[46] The incidence is reported to be from 1 in 15,000 anesthetics in children to 1 in 50,000 to 100,000 anesthetics in adults. The MH syndrome is characterized by generalized muscle rigidity, unexplained increased CO2 production, metabolic acidosis, rhabdomyolysis, elevated CK levels, hyperkalemia, and hyperthermia.[47] An increase in core temperature of 1°C every 5 minutes with elevation up to 46°C has been reported. Although the degree and duration of core temperature elevation has an effect on outcome, hyperthermia may be a late sign in the development of MH.

Pathogenesis.

The syndrome is triggered by the administration of volatile anesthetics and the depolarizing muscle relaxant succinylcholine.[48] The initial presentation may be masseter spasm after the administration of succinylcholine. If succinylcholine is not administered to facilitate endotracheal intubation, the syndrome may not be recognized until later into an uncomplicated inhalational anesthetic.[49] At that point in the anesthetic, the tachycardia, hypertension, and rigid muscles might be attributed to “light” anesthesia, leading the anesthesiologist to increase the concentration of the delivered anesthetic. Only after the patient becomes red and hot, and the ETco2 has risen significantly, is the problem recognized. Muscle rigidity may make ventilation difficult, which in association with increased CO2 production leads to both respiratory and metabolic acidosis. Furthermore, the CO2 absorbance of the breathing circuit will become hot and exhausted, exacerbating the hyperthermia and acidosis. Cardiac arrhythmias, including ventricular tachycardia and fibrillation, the result of acidosis, hyperthermia, and catecholamine surges, are common. Bleeding may occur from the surgical site owing to the development of coagulopathies (e.g., DIC, thrombocytopenia). Acute renal failure ensues from hypotension and rhabdomyolysis. Coma will follow as a result of extreme hyperthermia and cerebral edema. The syndrome is almost always fatal if not appropriately treated. MH has also been reported in humans in response to stress or exercise.[50]

MH is a defect in the regulation of myoplasmic calcium concentration. The triggering event leads to a release of calcium from the sarcoplasmic reticulum via a voltage-dependent muscle ryanodine (RYR1) channel.[51] The RYR1 channel is regulated by calcium, ATP, calmodulin, and magnesium. Micromolar concentrations of calcium activate the RYR1 channel, whereas calcium concentrations tenfold higher (10 μM) inhibit the channel. Mutations in the RYR1, gene on human chromosome 19q13.1 have been linked to MH-susceptible individuals.[52] The mutant RYR1 channel is activated by lower than normal concentrations of calcium and is inhibited by higher than normal concentrations of calcium. In addition, modulation of the RYR1 receptor via calmodulin was altered such that its activating properties were dramatically increased. This ultimately leads to excess sarcoplasmic calcium with persistent contracture of myofibrils, depletion of ATP, uncoupling of oxidative phosphorylation, metabolic acidosis, and muscle necrosis. Genetic linkage studies have demonstrated that about 50% of the cases of MH can be linked to mutations in the RYR1, gene. The RYR1, mutation has also been linked to central core disease (a rare congenital myopathy) and to the King-Denborough syndrome. In one report it was demonstrated that in 124 MH-susceptible individuals, 23% had mutations in the RYR1, gene.[53] In other analysis MH susceptibility was linked to the dihydropyridine (DHP) receptor gene on chromosome 7q, which also regulates skeletal muscle calcium flux.[54]

Thus, although the inheritance of MH is autosomal dominant, the molecular genetics of MH susceptibility may involve more than one genetic locus.

Diagnosis.

The diagnosis of MH is based on the presentation of the clinical syndrome or the in-vitro contracture test (IVCT). The IVCT is specific for MH, but its lower sensitivity eliminates it as a practical screening test for the general surgical population. Furthermore, because many clinical scenarios can produce a hypermetabolic state and mimic MH, the diagnosis is usually made in individuals with both appropriate clinical criteria and a positive IVCT. Larach and colleagues[55] developed a clinical grading scale to assess the probability of MH susceptibility ( Table 9-4 ). This MH scale incorporates six clinical criteria, such that the probability of MH susceptibility increases the more criteria manifested by the patient. When an individual manifests enough criteria consistent with MH, it is important that the individual undergo an IVCT, because many will be found to be non–MH susceptible. This information is important for family counseling.

TABLE 9-4   -- Criteria for the Clinical Grading Scale for Malignant Hyperthermia

Process

Clinical Criteria

Muscle rigidity

Generalized rigidity; masseter muscle spasm

Muscle breakdown

Creatine kinase > 20,000 U/L; myoglobinuria; plasma K > 6 mEq/L

Respiratory acidosis

End-tidal CO2 > 55 mm Hg; PaCO2 > 60 mm Hg

Temperature increase

Rapidly increasing; T > 38.8°C

Cardiac involvement

Unexplained sinus tachycardia, V-tach, V-fib

Family history

Familial history of malignant hyperthermia

 

 

The IVCT is performed at only two centers in Canada and six in the United States (see www.mhaus.org, for the addresses of MH diagnostic centers). The patient should have the muscle biopsy performed at the IVCT diagnostic center, because the test must be performed within 4 hours of excision of the muscle. The caffeine-halothane contracture test (CHCT) requires 2 g of muscle, usually harvested from the vastus lateralis or vastus medialis muscle. Regional anesthesia with sedation is preferable for the procedure, but direct infiltration of the muscle with local anesthetic is contraindicated. In the North American protocol, six longitudinal strips of muscle are hooked to force transducers and three are exposed to 3% halothane and three to caffeine. The development of a contracture of greater than or equal to 0.7g for halothane and greater than or equal to 0.3g for caffeine is considered positive for MH.[56] The specificity of this test is about 98% for tested individuals who have had an unequivocal MH episode, but the sensitivity is only 85% to 90%. Hence, with a low prevalence of the MH syndrome and 10% to 15% of normal patients testing positive, the IVCT cannot be used for routine screening. An ideal testing solution for MH would utilize a simple DNA-based test to screen surgical patients. However, as noted earlier, more than one genetic locus has been identified as being associated with MH susceptibility, and at this time our detection rate for gene mutations in known MH susceptible patients is only 23%.[53]

What about patients with masseter muscle spasm (MMS) during the induction of anesthesia? Sudden cardiac arrest after the administration of succinylcholine has been reported in normal patients with MMS but is considerably more frequent in patients with myopathies.[57] Children with muscle diseases may have a myotonic response to succinylcholine (MMS), which also includes elevated CK levels, metabolic acidosis, hyperkalemia, and dysrhythmias. This does not, however, necessarily imply that these individuals are MH susceptible. Can MMS occur in “normal” individuals after induction with succinylcholine and inhalational agents? In a study of 5000 anesthetized children, not a single child induced with pentothal developed MMS whereas the incidence of MMS was 0.5% with succinylcholine and halothane.[58] None of these patients developed MH. However, others have reported that 60% of patients with MMS tested IVCT positive for MH.[59] Because the development of the MH syndrome is potentially fatal, a non-triggering anesthetic should be used for the operation after the observation of MMS alone during anesthetic induction. The development of generalized myotonic contractions and other sequelae after succinylcholine and/or inhalational agents is abnormal, and in these cases, if possible, the anesthetic should be terminated, the patient hospitalized for observation, and the possibility of MH susceptibility investigated. Even if the patient is not MH susceptible, significant rhabdomyolysis that may occur in some muscle diseases could progress to severe metabolic acidosis, renal failure, and sudden death.

Treatment.

The mortality from an MH syndrome has fallen from almost 100% to low levels due to vigilance, supportive care, withdrawal of triggering agents, and administration of dantrolene. When an MH response is suspected, dantrolene should be administered at 1 to 2 mg/kg intravenously with additional doses every 15 to 30 minutes until evidence of the acute episode has subsided. After the initial episode, the dantrolene should be continued at 1 mg/kg intravenously every 6 hours or 0.25 to 0.5 mg/kg/hr intravenously until the treatment has produced stable, normal vital signs (possibly for 24 hours, depending on the severity of the episode). Evidence of an MH relapse has been reported in about 25% of patients within 24 hours of the initial episode.[60] Each 20-mg vial of dantrolene contains 3 g of mannitol, and the vials are reconstituted in water. The most common complication of dantrolene administration is muscle weakness.

Additional responses to an MH episode should include correction of the metabolic acidosis with bicarbonate (1/2 to 2 mEq/kg), hyperventilation with 100% oxygen, and an initial fluid bolus of 10 to 20 mL/kg of cooled or room temperature normal saline. Continued fluid management will depend on the patient's urine output, electrolytes, and hemodynamic stability. Aggressive alkaline diuresis to maintain a urine output of 1 to 2 cc/kg may be required to prevent renal failure from myoglobinuria. The administration of glucose and insulin will drive potassium intracellularly and provide a substrate for maintenance of cerebral functions. Arterial blood samples and blood samples for electrolytes and CK levels should be sent regularly. It may be necessary to lavage body cavities (stomach and bladder) with cooled saline to prevent dangerous levels of hyperthermia. Muscle compartments must be evaluated to allow early treatment of compartment syndrome.

Management of the MH-Susceptible Patient.

MH-susceptible patients can safely be administered general anesthesia with nitrous oxide, intravenous anesthetics, and nondepolarizing muscle relaxants. Regional anesthesia with any local anesthetic is also considered safe for MH-susceptible patients. The anesthetic circuit should not have been exposed to inhalational agents, a new CO2 absorbent, and flushing of the anesthesia machine with a continuous flow of oxygen at 10 L/min for 20 minutes. Prophylactic loading with dantrolene appears unnecessary, because MH may still develop and effective serum dantrolene levels can be achieved after acute intravenous loading.[61] Because stress can theoretically trigger an MH response, patients should be appropriately treated with anxiolytics before their arrival in the operating room, and patients receiving a regional anesthetic should also be sedated. An MH kit with enough dantrolene to administer 10 mg/kg to a large adult, several ampules of bicarbonate, equipment for lavaging body cavities, intravenous fluids, and ice for topical cooling should be readily available.

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Hyperkalemic Periodic Paralysis

Hyperkalemic periodic paralysis is inherited as an autosomal dominant trait with complete penetrance. The paralytic attacks usually begin infrequently during the first decade of life and then increase in frequency with age until they may recur daily. They often occur in the morning or after a period of rest after strenuous exercise. The attacks never occur during exercise and may be aborted if the individual begins mild exercise. The muscle weakness is accompanied by hyperkalemia, with levels up to 6 mM and a concomitant decrease in serum sodium levels. With resolution of the weakness the serum potassium level returns to normal and the patient may experience a water diuresis, creatinuria, and myalgias. The attacks can be precipitated by potassium intake, the cold, stress, glucocorticoids, and pregnancy. There are three clinical variants of the disease: with myotonia, without myotonia, and with paramyotonia. Lowering the patient's body temperature will induce weakness but not myotonia in any of the clinical variants. The myotonia that does occur in some patients is mild and rarely interferes with movement. In the paramyotonia variant the attacks include generalized weakness and paradoxical myotonia. In paramyotonia congenita, the myotonia is induced by cold and includes hyperkalemia, but differs in that the myotonia appears during exercise and worsens with continued exercise. These individuals have the characteristic lid-lag phenomenon.[45]

The diagnosis of hyperkalemic periodic paralysis can be made via an exercise stress test. Individuals are exercised for 30 minutes to a heart rate greater than 120 beats per minute, followed by absolute rest. In normal individuals the serum potassium value will rise during the exercise phase and then decline to baseline during the rest phase. In the periodic paralysis patients, the serum potassium value will start to decline at rest but then rise again in 10 to 20 minutes with accompanying weakness.[62]

The pathogenesis of the disease involves abnormal activation of sarcolemmal sodium channels.[63] The mutation has been linked to the skeletal muscle sodium channel gene on chromosome 17q23. The mutant sodium channel responds to elevated potassium levels by increased influx of sodium and prolonged depolarization. This renders the muscle inexcitable (paralyzed) and results in a compensatory release of potassium from the cells, which may then activate more sodium channels.

Individuals with the disease may be able to attenuate attacks by ingestion of carbohydrates, continuation of mild exercise, and administration of a potassium-wasting diuretic. Preventive therapy also includes the use of potassium-wasting diuretics (hydrochlorothiazide).

Preoperative carbohydrate depletion should be avoided, if possible, by carbohydrate loading the night before surgery or starting an infusion of a glucose-containing solution. Intravenous solutions free of potassium should be administered. The electrocardiogram may show evidence of peaked T waves before a paretic attack. At that time glucose, insulin, and inhaled β agonists should be administered in an attempt to abort the paralysis. Of course the patient must be kept warm and relaxed, because both the cold and stress can trigger paralysis.

A rare variant of hyperkalemic periodic paralysis is normokalemic periodic paralysis, in which the serum potassium value does not increase during severe attacks. This condition includes urinary potassium retention, beneficial effects of sodium loading, and lack of beneficial effects in glucose loading. In one family the mutation was linked to the sodium channel gene on chromosome 17q.

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Hypokalemic Periodic Paralysis

As with the hyperkalemic variant, the attacks in hypokalemic periodic paralysis usually begin before age 16 with infrequent attacks, which then increase in frequency to a point where they may recur daily. The attacks usually occur in the second half of the night or early in the morning. The patient may awaken in the morning paralyzed except for the cranial muscles, which are usually spared. However, respiratory function is compromised during severe attacks and fatal respiratory failure has been reported. Attacks are triggered by preceding strenuous physical activity, high carbohydrate and sodium meals, stress, and the cold. During severe attacks the serum potassium level falls to abnormal levels. Attacks can be accompanied by oliguria, constipation, diaphoresis, and sinus bradycardia. In addition, many patients may develop a permanent myopathy.[64]

The diagnosis of hypokalemic periodic paralysis is made by establishing hypokalemia during attacks and normokalemia between attacks. If an abnormally low serum potassium level is sustained, then one should consider secondary reasons for paretic attacks, including renal or gastrointestinal potassium wasting and thyrotoxic conditions. The administration of glucose and insulin may provoke an attack by driving potassium intracellularly.

Hypokalemic periodic paralysis is inherited as an autosomal dominant trait, with higher penetrance in males. The disease is linked to the L-type calcium channel DHP receptor on chromosome 1q31-32, but the pathogenesis has not been well elucidated.

Attacks can be prevented or attenuated by ingesting 2 to 10 g of potassium chloride. Patients planning to undergo surgery should not ingest a meal high in carbohydrates the night before. Electrolytes should be measured preoperatively on the day of surgery, and appropriate corrections to serum potassium should be instituted. Some patients are treated with acetazolamide to induce a mild metabolic acidosis, preventing potassium from shifting into the cell. Hypothermia should be avoided. Because an episode may precipitate respiratory failure, these patients should be monitored postoperatively.

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MYASTHENIAS

These are disorders that affect the neuromuscular junction (NMJ) and are characterized by fluctuating muscle weakness and abnormal fatigability. The NMJ consists of the presynaptic and postsynaptic regions separated by the synaptic space. The nerve terminal contains acetylcholine (ACh) membrane-enclosed synaptic vesicles, which are released in response to a generated motor nerve action potential. The ACh molecules then bind to a postsynaptic receptor and induce a muscle action potential ( Fig. 9-6 ). In addition to acquired myasthenia gravis (MG) and the Eaton-Lambert syndrome, several toxins and medications can produce myasthenic-like syndromes that affect the NMJ, including botulism, tetanus, venom poisoning, aminoglycosides, hypermagnesemia, quinidine, and organophosphate poisoning.

 
 

FIGURE 9-6  Schematic diagram of the neuromuscular junction, depicting the density of ACh receptors on the folds of postjunctional muscle membranes. Compared with normal folds, the density of ACh receptors is greatly reduced in the presence of myasthenia gravis. (From Stoelting RK, Dierdorf SF: Anesthesia and Co-Existing Disease. New York, Churchill Livingstone, 1993, p 440.)

 

 

 

Acquired Myasthenia Gravis

The classic syndrome involves fluctuating weakness and fatigability involving the ocular and other muscles innervated by cranial nerves, with worsening symptoms during the day ( Table 9-5 ). There is considerable variation in the world prevalence, from 1.2 per 1 million in Japan to 14.2 per 100,000 in West Virginia; with a female-to-male ratio of 3 to 2. MG may occur at any age, but females are more commonly affected under 40 and males more commonly affected over 60.[65]


TABLE 9-5   -- Differential Diagnosis of Acquired Myasthenia Gravis

  

 

Symptoms

  

 

Fluctuating weakness

  

 

Fatigability of ocular and other muscles innervated by cranial nerves

  

 

Gender ratio

  

 

Female to male 3:2

  

 

Females ± age 40, males ± age 60

  

 

∼2/3 thymic hyperplasia; 10% thymomas

  

 

In 50% of patients initial symptoms involve extraocular muscles

  

 

Eyelid ptosis

  

 

Sustained upward gaze

  

 

Diplopia

  

 

Face appears expressionless

  

 

Speech is hoarse and slowed

  

 

Chewing and swallowing difficult; risk of aspiration

  

 

Dyspnea with mild to moderate exertion

 

 

The defect is the result of a decrease in the number of available receptors for ACh at the postsynaptic NMJ. The ACh receptors are inactivated by circulating antibodies, which block access of the receptor to ACh. Ultimately, the ACh receptor IgG complex institutes a complement-mediated lysis of the receptors in the junctional folds. Antibodies to ACh receptors are detectable in the serum in 74% to 94% of MG patients. About two thirds of the patients have thymic hyperplasia and 10% have thymomas. In about 10% of the cases MG is associated with another autoimmune disease, including hyperthyroidism, polymyositis, systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, ulcerative colitis, sarcoidosis, and pernicious anemia. In addition, MG has developed in patients receiving D-penicillamine and interferon therapy and after bone marrow transplantation ( Table 9-6 ).


TABLE 9-6   -- Secondary Causes of Myasthenia Gravis

  

 

Hyperthyroidism

  

 

Polymyositis

  

 

Systemic lupus erythematosus

  

 

Sjögren's syndrome

  

 

Rheumatoid arthritis

  

 

Ulcerative colitis

  

 

Sarcoidosis

  

 

Pernicious anemia

  

 

Has developed in patients:

  

 

Receiving D-penicillamine

  

 

Receiving interferon therapy

  

 

After bone marrow transplantation

 

 

In about 50% of the patients the initial symptoms involve extraocular muscles, but bulbar and limb muscles may also be included in the initial presentation. Levator palpebrae weakness leads to eyelid ptosis, which is often exacerbated by sustained upward gaze. Individuals often complain of diplopia. The face often appears expressionless with a snarling smile. Speech is usually hoarse and slowed. Chewing and swallowing of food is difficult, with a risk of aspiration. Dyspnea will occur with mild to moderate exercise. The proximal limb muscles are often more affected than the distal limb muscles. Muscle weakness is worse with repeated exercise and as the day progresses. However, the symptoms may vary daily or from week to week with periods of remission (see Table 9-5 ).

Although the initial symptoms are usually ocular, in about 90% of the patients the disease becomes generalized within the first year of diagnosis, with progression the most rapid during the first 3 years (Table 9-7 ). Prior to the 1990s the disease progressed to a complete systemic deterioration and death in one fourth of the affected patients. With the introduction of more effective therapy, the mortality from the disease has decreased dramatically. In a series of 100 patients reported by Beckman and colleagues,[65] there were no fatalities directly related to the disease. However, patients do experience episodes of respiratory failure due to bulbar involvement. A myasthenic, crisis is defined as an acute exacerbation of symptomswith respiratory compromise. In a series of 53 patients with a myasthenic crisis, 75% of the patients were extubated within 1 month of being placed on a respirator, with three deaths during the crisis and four deaths post extubation.[66] Independent risk factors associated with poor prognosis were identified, such that patients with no risk factors were all extubated within 2 weeks while patients with increasing risk factors required longer periods of respiratory support ( Table 9-8 ).


TABLE 9-7   -- Classification of Myasthenia Gravis

  

I.   

Ocular Myasthenia

  

II. 

Chronic Generalized

  

A.   

Mild

  

B.   

Moderate

  

III. 

Acute, Fulminating

  

IV. 

Late, Severe

 

 


TABLE 9-8   -- Risk Factors Associated with Prolonged Intubation After Myasthenia Gravis Crisis

  

 

Preintubation serum HCO3- > 30 mg/dL

  

 

Peak vital capacity < 25 mL/kg

  

 

Age > 50 years

  

 

Comorbidities: atelectasis, anemia, congestive heart failure, Clostridium difficileinfection

 

 

To define the severity of the disease and the clinical prognosis, a classification for MG was devised by Osserman in 1958 and then modified in 1971 (see Table 9-7 ).[67]

Patients in group I are medication responsive and are not at risk for a crisis. Patients in group IIB are moderately severe, poorly responsive to medications, and are at risk for a crisis. Patients in group III have a disease that rapidly progresses over 6 months with a high risk for a crisis and often have thymomas. Patients with group IV disease have had a milder form of the disease for more than 2 years and then develop a severe, progressive form of the disease.

Neonatal myasthenia develops in about 12% of infants born to mothers with MG due to the passive transfer of ACh receptor antibodies. The symptoms of poor feeding, generalized weakness, respiratory distress, and weak cry appear a few hours after birth and usually last only 18 days.

About 30% of women with MG experience a worsening of symptoms during pregnancy. If possible, pregnancy should be planned for periods of remission when the patient is no longer receiving immunosuppressants. If the symptoms during pregnancy become debilitating, these women can receive plasmapheresis and increased cholinesterase therapy.

The diagnosis of MG is usually based on the symptoms of easy fatigability and fluctuating weakness. An edrophonium chloride (Tensilon) test, however, is sometimes used to confirm the diagnosis. An initial 2 mg intravenous dose of edrophonium is administered to ascertain tolerance and then 6 to 8 mg is injected. The patient is then observed for an improvement in symptoms or the ability to complete repetitive functions. The improvement in MG symptoms is suggestive of a diagnosis of MG, and they usually last about 10 minutes. Side effects of edrophonium injection include fasciculations, sweating, nausea, abdominal cramps, and bradycardia. In addition, electrophysiologic studies can be performed, where in MG there is a decremental response of the compound action potential to repetitive electrical stimulation.

There are several therapeutic options for patients with MG, including cholinesterase inhibitors, immunosuppressants, plasma exchange, specific immunoglobulins, and thymectomy. Pyridostigmine (Mestinon), a cholinesterase inhibitor that prolongs the action of ACh at the NMJ receptor, is the first line of treatment for the symptomatic relief of MG. Pyridostigmine is dosed initially at 15 to 60 mg four times a day with resolution of symptoms within 15 to 30 minutes and a duration of 3 to 4 hours. Neostigmine bromide, a shorter-acting cholinesterase inhibitor, may be administered parenterally for acute episodes. Progressive weakness with increasing dosing of anticholinesterases may indicate the onset of a myasthenic or a cholinergic crisis. A cholinergic crisis is associated with muscarinic effects of abdominal cramps, nausea, vomiting, diarrhea, miosis, lacrimation, increased bronchial secretions, and diaphoresis. It is also possible to see significant bradycardia. These muscarinic symptoms should not be prominent during a myasthenic crisis and should be discriminated by a 2-mg edrophonium test. However, it is often difficult to distinguish these two crises and it is best to hold the anticholinesterase and support the patient with intubation and ventilation.

Thymectomy will improve the remission rate and ameliorate the progression of the disease. The best responders to thymectomy are females with hyperplastic thymus glands and high ACh receptor antibody titers. Alternate-day prednisone therapy induces remission and improves the clinical course of the disease in more than half of the patients. Azathioprine in doses of 150 to 200 mg/day in many cases also provides improvement in symptoms.

Patients for surgery and anesthesia should be warned that they may require postoperative ventilatory support. MG criteria that correlate with postoperative controlled ventilation include duration of disease greater than 6 years, presence of pulmonary disease, pyridostigmine dose greater than 750 mg/day, and preoperative vital capacity less than 2.9 L.[68] If possible, neuromuscular blocking drugs should be avoided, because the response to these medications is variable, owing to the nature of the disease and the treatment with anticholinesterases. However, patients with MG are usually resistant to succinylcholine and sensitive to nondepolarizing muscle relaxants. Hence, if rapid intubation is required, a larger dose (1.5 to 2 mg/kg) of succinylcholine should be administered. [69] [70] Chronic use of anticholinesterases will also impair the effect of plasma cholinesterase. This may result in prolonged neuromuscular blockade by succinylcholine and mivacuronium. It may also reduce the metabolism of ester local anesthetics. The use of any nondepolarizing muscle relaxant should be titrated with the use of a peripheral nerve stimulator. For maintenance of anesthesia, inhalational agents might be preferred because they can be eliminated by ventilation and would not have the depressant effects that narcotics would postoperatively. One approach is to hold the patient's anticholinesterase medication 4 hours before surgery and then begin neostigmine intravenously 1 hour before emergence from anesthesia, at 1/30 to 1-20/60 the daily pyridostigmine dose infused over 24 hours. Before extubation the patient should be fully awake, have a full return to a train of four if muscle relaxants were used, and a negative inspiratory force greater than 30 cm H2O.

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Eaton-Lambert Myasthenic Syndrome

Eaton-Lambert myasthenic syndrome (ELMS) was first described in 1956 in patients with fatigable weakness and pulmonary malignancies. The weakness usually affects the proximal limb muscles, predominantly the lower limbs, with sparing of the extraocular and bulbar muscles. Symptoms are usually worse in the morning on awakening and improve during the day. Unlike MG, deep tendon reflexes are usually reduced or absent. The patients also have autonomic symptoms of dry mouth, orthostatic hypotension, hyperhidrosis, and reduced papillary light reflex. ELMS is probably due to impaired release of ACh at the nerve terminal, produced by autoantibodies directed against the voltage-gated calcium channels. It is the calcium influx into the nerve terminal that stimulates the release of ACh vesicles.[71]Because malignancy is present in about 60% of the cases of ELMS, a diagnosis of the myasthenic syndrome should elicit a search for a neoplasm.

Therapy with cholinesterases alone is usually not very effective. Muscle strength and autonomic functions can be improved with 3,4-diaminopyridine (DAP) therapy. DAP causes peripheral paresthesias, palpitations, sleeplessness, cough, diarrhea, and rare seizures. Guanidine hydrochloride, which increases the release of ACh, has also proven effective, but the severe side effects of bone marrow depression, renal tubular necrosis, cardiac arrhythmias, liver failure, and ataxia have limited its use.

These patients are sensitive to both depolarizing and nondepolarizing muscle relaxants. In addition, because ELMS patients may be treated with both DAP and pyridostigmine, antagonism of the neuromuscular blockade at the end of the surgical procedure may prove ineffective. These patients often undergo diagnostic procedures in search of occult malignancies; and because they have reduced respiratory reserve, they are at risk for respiratory failure with only a minimum of anesthetics and sedatives.[72]

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INFLAMMATORY MYOPATHIES

Dermatomyositis

DM can present at any age, but usually the childhood cases present between 5 and 14 years and the adult form at 40 to 60 years. Women are usually affected more often than men. The neck flexors, shoulder girdle, and pelvic girdle muscles are the most severely affected, such that lifting their arms over the head, climbing stairs, or rising from a chair is difficult. Children usually also present with fatigue, low-grade fevers, and a rash that precedes the muscle weakness and myalgia. The classic rash includes a purplish discoloration of the eyelids with periorbital edema; papular erythematous scaly lesions over the knuckles; and a flat erythematous sun-sensitive rash over the neck, face, and anterior chest. Children also develop subcutaneous calcifications. Cardiac conduction abnormalities are common, as are congestive heart failure and myocarditis. About 10% of DM individuals also develop interstitial lung disease, with restrictive lung disease and reduced diffusing capacity. There may also be evidence of chronic pulmonary aspiration from oropharyngeal and esophageal weakness. Vasculitis of the gastrointestinal tract may result in ulcerations and perforations. In addition, necrotizing vasculitis may affect the eyes, kidneys, and lungs. Arthralgias involving all joints are a common complaint. Adult DM also is strongly associated with (up to 45%) underlying malignancies. Corticosteroids are the major therapy for DM, with the addition of more powerful immunosuppressants.[73]

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Polymyositis

PM usually presents in individuals older than 20 years, with women affected more often than men. The patient usually presents as neck flexor and proximal arm and leg weakness that develops over weeks and months, but without a characteristic rash as in DM. Dysphagia is also a common symptom of PM. These patients also have similar cardiac and pulmonary complications as in DM, but there is a much lower incidence of associated malignancies. Most patients with PM improve with immunosuppressive therapy.

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Inclusion Body Myositis

IBM presents with slowly progressive, distal and proximal muscle weakness, often with years from onset of symptoms to diagnosis. It is the most common inflammatory myopathy in men older than 50 years of age. Early signs of the disease include asymmetrical quadriceps and wrist/finger flexor weakness. At least 40% of the patients complain of dysphagia. IBM is not associated with cardiac abnormalities or an increased risk of cancer. The muscle biopsy demonstrates inflammation with atrophic fibers and eosinophilic cytoplasmic inclusions. Patients with IBM do not significantly improve with immunosuppressive therapy.

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Overlap Syndromes

These are a group of disorders in which an inflammatory myopathy occurs in association with a connective tissue disease. These diseases include scleroderma, Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and mixed connective tissue disease. Antinuclear antibodies are seen in many of these patients.

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INFECTIVE AND TOXIC MYOPATHIES

Infections, endocrine abnormalities, environmental toxins, and medications can all potentially produce myalgias and muscle weakness. In developing countries infections from parasitic infestations produce myositis and myopathies. Exogenous chemicals and the abnormal production of internal endocrine chemicals can have profound effects of skeletal muscle function. It is beyond the scope of this chapter to discuss in any detail the action of these agents on the skeletal muscle apparatus. Instead we have chosen three more common agents from each class that result in a myopathy.

Human Immunodeficiency Virus

The spectrum of findings with HIV spans asymptomatic CK elevation to generalized fatigue to severe proximal limb-girdle weakness. In one report, 18% of HIV-infected patients had muscle involvement, which included a PM-like myopathy and muscle atrophy.[74] These patients are also subject to bacterial and protozoal myopathies as a result of immunosuppressive therapy. The PM-like myopathy is progressive, is symmetrical, and usually affects the lower extremities. Dysphagia, respiratory weakness, and rashes are not part of the syndrome. HIV-infected patients also are subject to a poorly defined muscle wasting syndrome characterized by severe muscle wasting with normal or only mildly reduced muscle strength. This may be the result of generalized systemic infections, poor nutrition, and the toxins from antiviral medications.

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Necrotizing Myopathy

Cholesterol-lowering medications have a propensity to produce myopathy and necrotizing myopathy. Lovastatin in combination with other medications (cyclosporine) or in patients with hepatobiliary or renal dysfunction may risk severe myopathy with rhabdomyolysis. σ-Aminocaproic acid, which is used during surgery to inhibit fibrinolysis and reduce bleeding, has been implicated in a necrotizing myopathy that affects the axial musculature. The symptoms can begin 4 or more weeks after administration of the medication and may be the result of an ischemic insult to the muscle.[75]

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Thyrotoxic Myopathy

The incidence of myopathy among thyrotoxic patients has been reported to be as high as 82%. Common symptoms include myalgias, fatigue, and exercise intolerance. The weakness is predominantly proximal, and it may be associated with dysphagia and respiratory insufficiency. The sudden onset of generalized weakness with bulbar palsy has been described for thyrotoxic patients alone, but it should raise the suspicion of associated myasthenia gravis. CK levels are usually normal, except during thyroid storm, when rhabdomyolysis could lead to renal failure. The treatment of thyrotoxic myopathy is to reinstate a euthyroid condition.

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