INTRODUCTION
The term myopathy refers to a muscle fiberdisorder that can have a variety of etiologies. Myopathies present as pure motor syndromes without any disturbance of sensory or autonomic function. Deep tendon reflexes are usually preserved. In most myopathies, symptoms tend to be bilateral and affect proximal muscles preferentially, although there are exceptions. Because many myopathies cause progressive impairment of patients’ daily functioning, supportive therapy is often necessary to address the physical and psychological effects of these disorders. The final section of this chapter outlines strategies that are often used in rehabilitation of patients with myopathies.
EVALUATION OF MYOPATHIC DISORDERS
By far the most frequent symptom of patients presenting with myopathic disease is weakness. Clinically, it is important to differentiate weakness from easy fatigability. A hallmark of myopathy is the inability to generate a forceful contraction. It is important to observe patients performing activities such as walking, climbing stairs, and arising from a sitting, kneeling, squatting, or reclining position or using the arms overhead. Difficulty in performing these tasks signifies weakness rather than fatigue. Patients with complaints of fatigue often describe a subjective loss of energy. In myopathic disorders, objective muscle weakness and loss of function usually accompany fatigue. Pathologic fatigue not accompanied by muscle cramps upon exercise testing or repetitive electrophysiologic testing usually suggests a disorder of the neuromuscular junction (such as myasthenia gravis or Lambert-Eaton myasthenic syndrome), rather than a myopathy. If the patient develops fatigue along with frank swelling and cramps with exercise, then certain metabolic myopathies may be suspected.
Myalgias (muscle pain) and muscle aches may be a presenting complaint in patients being evaluated for myopathy. Most myopathies and muscle diseases are not associated with severe myalgias or muscles that are very tender to palpation. Severe myalgias and tenderness often accompany fasciitis, infectious myositis, and some metabolic myopathies.
Myopathies can be classified as hereditary or acquired. Information about the progression of the disease process is very important in helping to classify the specific etiology of myopathy. In patients who have deteriorating strength, it is important to make note of whether the rate of progression is over days, weeks, months, or years. A detailed family history and pedigree chart is very useful in clarifying suspected hereditary myopathies. Table 18–1 contrasts the key features of various hereditary and acquired myopathies.
| Hereditary Myopathies | ||
| Muscular Dystrophies | Congenital | Metabolic |
Dystrophinopathies:
Limb-girdle Fascioscapulohumeral Myotonic Emery-Dreifuss | Central core Nemaline rod Fiber-type disproportion Multicore–minicore Centronuclear | Glycogen storage diseases:
Channelopathies:
|
| Acquired Myopathies | ||
| Inflammatory | Toxic | Associated with Systemic Disease |
Dermatomyositis Polymyositis Inclusion body myositis Sarcoid Infectious:
| Alcohol Cocaine Medication-induced:
| Critical illness myopathy Endocrine:
|
Generally, myopathic electromyogram (EMG) findings will reveal low-amplitude, short-duration motor units. There can, however, be exceptions to this general rule. Early recruitment is another feature of myopathies. Nerve conduction velocities will be normal with normal sensory responses. Compound muscle action potentials (CMAPs) can be small in amplitude. Muscle biopsy may be necessary to confirm a diagnosis of myopathy and ascertain the specific type. Additionally, genetic testing has become an important tool in diagnosis, as advances in the field of genetics have yielded a more detailed understanding of the pathophysiology of myopathies.
HEREDITARY MYOPATHIES
MUSCULAR DYSTROPHIES
Muscular dystrophies are a progressive, heterogeneous group of neuromuscular disorders. They are often hereditary. These disorders are characterized by histologic abnormalities that include extensive muscle necrosis and fibrosis, with fat and connective tissue infiltration. Table 18–2 compares the key features of the major classifications of muscular dystrophies.
| Duchenne Muscular Dystrophy (DMD) | Becker Muscular Dystrophy (BMD) | Limb-Girdle Muscular Dystrophy (LGMD) | Facioscapulohumeral Muscular Dystrophy (FHS) | Myotonic Dystrophy | Emery-Dreifuss Muscular Dystrophya | |
|---|---|---|---|---|---|---|
| Etiology | X-linked recessive (xp21), spontaneous Most common form of muscular dystrophy, affecting 1 in 3500 male infants | X-linked recessive | Two forms: autosomal dominant (LGMD1), autosomal recessive (LGMD2) | Two forms: FHS1 and FHS2 (classic form) Autosomal dominant | Two forms: DM1 and DM2 Autosomal dominant | Two forms: EMD1 and EMD2 X-linked recessive |
| Onset | Early childhood (3–5 y) | Adulthood | LGMD1: later onset, in adulthood LGMD2: childhood or adolescence | FSH1: infantile form, < 2 y FSH2: early adulthood (2nd–3rd decade) | DM1: infancy through adulthood DM2: 20–60 y | Usually in teenage years, but can vary from neonatal period to adulthood |
| Symptoms and signs | Proximal muscle weakness (pelvic girdle) Abnormal muscle stretch reflexes Increased lumbar lordosis Ambulation difficulties: toe walking (< 5 y), clumsy running (< 7 y) Gower’s sign: difficulty rising from floor due to hip and knee extensor weakness Calf pseudohypertrophy with fat and fibrous tissue Contractures: iliotibial band (first), Achilles tendon Scoliosis, causing cardiomyopathy and restrictive lung disease Possible mental retardation Wheelchair by age 12 y Extraocular muscles are spared | Proximal weakness Calf pseudohypertrophy Cardiomyopathy Less mental retardation than DMD | Pelvic and shoulder girdle weakness Distal muscles, facial muscles, and extraocular muscles are spared Atrophy of affected muscle groups Contractures of elbow or heel cords, depending on subtype May develop cardiomyopathies Normal intellect | Proximal muscle weaknessb Facial droop Weak eye closing Weak forehead wrinkling Arm atrophy with deltoid and forearm sparing (Popeye arm) Cataracts (dry sclera) Retinopathy Lip protrusion Transverse smile Frontal balding Testicular atrophy Extraocular muscles are spared Inability to whistle | Weakness: distal > proximal myotonia with sustained grip “Hatchet face” (wasting of the temporalis and masseter) Frontal balding Poor vision Ptosis Impotence Hypertrichosis Mental retardation Cardiac abnormalities Endocrine abnormalities Congenital myotonic dystrophy—”shark mouth” appearance, facial diplegia, possible clubfoot | Early involvement of biceps, triceps, tibialis anterior and peroneal muscles Later involvement of shoulder and pelvic girdle muscles Contractures in elbows and ankles Rigid spine with neck extension contractures By 2nd decade, a dilated cardiomyopathy with conduction defects can occur Cardiac arrhythmias may lead to death |
| Laboratory findings | Muscle biopsy: no dystrophin; internal nuclei variation in fiber size Blood: increased CK and aldolase ECG: abnormal | Muscle biopsy: decreased dystrophin (15–85%) Blood: increased CK | Muscle biopsy: Elevated sarcolemmal proteins Blood: CK levels are often high | Muscle biopsy: scattered fiber necrosis and regeneration; inflammatory infiltrate may be noted | Muscle biopsy: type I fiber atrophy with type II hypertrophy; no dystrophin involvement | Muscle biopsy: fiber atrophy Blood: CK normal or mildly elevated ECG: Sinus bradycardia or conduction blocks |
| Electrodiagnostic findings | NCS— • SNAP: normal • CMAP: (+/–) decreased amplitude EMG—AA, ER, small MUAP at first | NCS— • SNAP: normal • CMAP: (+/-) decreased amplitude EMG—AA, ER, small MUAP at first | NCS— • SNAP: normal • CMAP: decreased EMG—AA, ER, small MUAP | NCS— • SNAP: normal • CMAP: decreased amplitude in the involved muscle EMG—AA, ER, small MUAP | NCS— • SNAP: normal • CMAP: (+/-) decreased amplitude EMG—AA, ER, small MUAP | NCS: • SNAP: normal • CMAP: decreased amplitude in affected muscles EMG: AA, ER, small MUAP |
| Treatment | Rehabilitation, scoliosis surgery before vital capacity drops below 35% (usually due to curvature of > 30 degrees) | Rehabilitation, bracing, tendon lengthening, possible scoliosis surgery | Physical and occupational therapy to manage weakness, contractures | Rehabilitation, bracing, ADL management | Rehabilitation, bracing, pharmacotherapy (procainamide, Dilantin, and quinine [PDQ]) May require a pacemaker | Monitoring and treatment of cardiac arrhythmias, physical therapy for joint mobility and contracture prevention May require pacemaker |
| Prognosis | Severely progressive (death by 20s) | Slowly progressive | Slowly progressive | Spreads to other muscles FSH1 (infantile) is rapidly progressive | Progressive; risk of sudden death increases with male sex, duration of disease, and age | Slowly progressive |
The dystrophinopathies encompass a spectrum of hereditary muscle diseases in which insufficient dystrophin is produced in the muscle cells. Dystrophin is a large, rodlike cytoskeletal protein on the inner surface of muscle fibers. It is part of the dystrophin–glycoprotein complex, which bridges the inner cytoskeleton and the extracellular matrix in muscle. Mutation of the gene leads to the muscle disorders, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).
Serum creatine kinase (CK) concentrations are 10–20 times the upper limit of normal in patients with both DMD and BMD and peak at around age 3 years. Serum CK is also mildly increased in 70% percent of DMD and 50% of BMD female carriers.
Electrodiagnostic testing in dystrophinopathies is of limited value, especially when there is a family history of the disorder. Diagnosis requires genetic testing for identifiable mutations in the dystrophin gene and, if this is unsuccessful, a muscle biopsy. Evaluation and treatment of pediatric patients with Duchenne and Becker muscular dystrophies is described in detail in Chapter 20, and readers are referred to that chapter for additional information. An overview of each condition is presented here, along with other disorders in this group, to facilitate comparison of key features of the various dystrophinopathies.
(see also chapter 20)
ESSENTIALS OF DIAGNOSIS
X-linked recessive disorder, more common in males.
Weakness and hypotonia are often present at birth.
Child may attain developmental milestones until age 4 or 5 years, then experience difficulty running and jumping.
Weakness is proximal and manifests with positive Gower’s sign and lumbar lordosis.
Muscle biopsy specimens show damage to muscle fibers.
Western blot test shows reduced or absent dystrophin (0–3%).
DMD is an X-linked disorder caused by an abnormality in the Xp21 gene locus. It is the most common of the muscular dystrophies, affecting up to 1 in 3500 male infants at birth, and only rarely affecting female infants.
Affected infants may manifest weakness and hypotonia or have no obvious abnormality at birth. Symptoms and signs become more apparent as the child develops, which usually prompts diagnosis by age 4 or 5 years. Toe walking is common; this is a compensatory adaptation to knee extensor weakness. A lordotic posture of the lumbar spine is adopted to compensate for hip extensor weakness. Calf pseudohypertrophy and calf pain are other common findings. Gower’s sign, which involves the patient using hands and arms to walk up the body in order to stand up, is another symptom. Patients have varying degrees of cognitive impairment.
The earliest signs of weakness are seen in the neck flexors during the preschool years. The child is often wheelchair bound by the age of 12. Pulmonary function declines gradually. Tachyarrhythmias and cardiomyopathies may develop. Smooth muscle is often involved, with patients developing gastroparesis.
Very high CK levels and reduced or absent dystrophin are characteristic findings. Muscle biopsy findings reveal scattered necrotic and regenerating muscle fibers. The Western blot test reveals 0–3% of the normal amount of dystrophin present in muscle tissue.
Treatment with prednisone helps maintain strength and prolongs ambulation by 2 years. The optimal dose of prednisone is 0.75 mg/kg per day, and benefits may continue for up to 3 years. Supportive therapy is necessary to address the physical and psychological effects of the disease: contracture management requires splinting and bracing; ambulatory decline requires assistive devices; spinal weakness requires appropriate assistance such as proper seating. Half of all DMD patients develop scoliosis between 12 and 15 years of age, which correlates with the adolescent growth spurt. For curvature that has progressed past 20–40 degrees, spinal arthrodesis has been shown to be the only effective treatment. Spinal orthoses are generally not used for prevention of scoliosis in those with DMD. Unfortunately, most patients with DMD die in their late teens or early 20s from ventilatory or cardiac failure.
(see also Chapter 20)
ESSENTIALS OF DIAGNOSIS
X-linked recessive disorder.
Less common than DMD, with later onset (usually after 12 years of age) and slower progression.
Like DMD, Becker muscular dystrophy affects only boys with rare exceptions.
Western blot test shows 20–80% of the normal levels of dystrophin.
BMD is an X-linked disorder with an incidence of 5 per 100,000 people. In 10% of cases, the genetic defect is the result of a spontaneous mutation. The same gene locus is affected as in DMD (ie, Xp21), and expression is allelic.
BMD is a less severe form of muscular dystrophy than DMD, with a slower rate of progression. Patients typically present after age 12 years, when increasing weakness and disability prompt evaluation. Great variability in phenotypic expression exists, and a wide spectrum of clinical phenotypes can be seen. In contrast to DMD, many patients remain ambulatory past the age of 15 years. Nonetheless, 50% of patients lose the ability to ambulate independently by the fourth decade. Cardiac abnormalities are similar to those described earlier for DMD.
Characteristic findings are seen on muscle biopsy evaluation. Muscle is replaced with fat and connective tissue. Reduced levels of dystrophin are noted on the Western blot test (20–80% of normal).
The approach to treatment is similar to that for DMD, discussed earlier. Many patients survive beyond 30 years of age.
ESSENTIALS OF DIAGNOSIS
Equal occurrence in males and females.
Autosomal-dominant (LGMD1) or autosomal-recessive (LGMD2) mode of inheritance.
Predominantly affects the pelvic or shoulder girdle musculature, or both.
Limb-girdle muscular dystrophy (LGMD) is a hereditary dystrophy that affects males and females equally. Inheritance may be either autosomal dominant or autosomal recessive, designated LGMD1or LGMD2, respectively. Genotypic subtypes of each are given alphabetical subclasses, as LGMD1A, LGMD1B, etc. In patients with LGMD1 subtypes, disease onset is usually later, in adulthood. Patients with LGMD2 subtypes usually have onset during childhood or adolescence. Many of the LGMD2 subtypes have been linked to gene defects causing abnormalities of the sarcolemmal-associated proteins.
Pelvic and shoulder girdle weakness are common presenting symptoms among patients with all forms of LGMD. Distal muscles are spared as well as facial and extraocular muscles. The rate of progression is slower in LGMD than in DMD. The age of onset can vary from childhood through adulthood, depending on the type. Cardiomyopathies are associated with many types. Pseudohypertrophy of the calf muscles may occur. Atrophy of affected muscle groups along with early contractures of the elbow and heel cords may develop, depending on the subtype. Low back pain may be a prominent symptom in affected patients. Intellect is usually normal.
CK levels are often very high but can vary according to the subtype. Muscle biopsy evaluation can help evaluate different sarcolemmal-associated proteins, including sarcoglycans, dystroglycans, calpain-3, dysferlin, fukutin-related protein, telethonin, and titin, which can help determine subtypes.
Treatment consists of supportive care, which may include physical therapy and occupational therapy to support activities of daily living (ADLs) and ambulation. Splinting and stretching are required for contracture management. The course of disease is slowly progressive and may lead to significant disability, depending on the mode of inheritance and subtype.
ESSENTIALS OF DIAGNOSIS
Autosomal-dominant inheritance linked to chromosome 4q35 locus.
Caused by a DNA fragment deletion of D4Z4 at the telomere region.
Second most common inherited muscular dystrophy in adults.
Patients usually become symptomatic before age 20.
Predominantly affects the facial and shoulder girdle muscles.
Fascioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy, after DMD and BMD, and the second most common form in the adult population. The disease has two forms: a rapidly progressive infantile form, which manifests within the first two years of life, and the classic form, with onset usually in the second or third decade.
Infantile-onset FSHD is associated with severe weakness that leads to diagnosis within the first 2 years of life. For patients with the classic form of the disease, the onset of weakness is highly variable, ranging from 3 to 44 years, although presentation is generally before age 20. Weakness of the facial muscles may be asymmetric. Shoulder girdle weakness causes scapular winging. Humeral weakness and wasting can occur with sparing of the forearm muscles. In the leg, the tibialis anterior muscle is often affected and may cause a drop foot.
Some patients with FSHD have only mild weakness over the course of their lifetime. Other patients appear to experience a late exacerbation of muscle weakness. After having mild weakness for years, they suddenly develop a marked increase in weakness in the typical distribution over several years, leading to significant disability.
CK levels range from normal to mildly elevated. Muscle biopsy findings may show necrosis. Genetic testing may reveal abnormalities at the D4Z4 region.
Treatment of patients consists of supportive care, which may include physical therapy and occupational therapy to support ADLs and ambulation. Splinting and stretching are required for contracture management. The use of prednisone has not been found to be helpful. Ankle-foot orthotics may be helpful in cases of drop foot. Affected individuals with classic FSHD usually have a normal lifespan.
ESSENTIALS OF DIAGNOSIS
Autosomal-dominant inheritance.
The most common inherited neuromuscular disorder of adults.
Limb weakness starts distally then progresses to the proximal muscles.
Atrophy and weakness of the facial muscles leads to a “hatchet face” appearance.
Molecular genetic testing reveals an unstable CTG trinucleotide repeat in the MPK gene.
Myotonic dystrophy is the most common inherited neuromuscular disorder of adults. Myotonia refers to a state of delayed relaxation or sustained contraction of skeletal muscle. There are two common types, designated DM1 and DM2. DM1 can present at any age, including infancy. Most patients with DM2 become symptomatic between the ages of 20 and 60 years, although the onset can occur in childhood. Age of onset is inversely correlated with the number of repeat links, and exhibits genetic anticipation.
DM1, the congenital form of the disease, is associated with severe weakness. However, weakness may not be evident in the adult-onset form. Other clinical signs include delayed relaxation of the fingers after grip, and characteristic facial features, seen in adults with longstanding DM1. These patients have a long thin face with temporal and masseter wasting, sometimes referred to as a “hatchet face. “Adult males often have frontal balding.
DM1 is a systemic disorder affecting the gastrointestinal tract, ventilatory muscles, cardiac muscles, the eyes, and the endocrine system. Cardiac abnormalities are common, and 90% of patients have conduction defects. Neurobehavioral abnormalities are also common.
Molecular genetic testing reveals unstable CTG trinucleotide repeats within the region of the myosin–protein kinase (MPK) gene at 19q13.3. CK levels can be normal or mildly elevated. On muscle biopsy evaluation less necrosis is seen than in the other dystrophies. EMG reveals waxing and waning discharges.
Symptomatic, painful myotonia can be treated with agents such as mexiletine or membrane stabilizers such as carbamazepine or phenytoin sodium. These agents have been shown to reduce the symptoms, although with little functional gain. Risk of sudden death increases with male sex, duration of disease, and age.
ESSENTIALS OF DIAGNOSIS
Two variants, one of which is X-linked recessive.
Affects males and females equally.
Patients usually become symptomatic in the teenage years, but age of presentation can vary.
Weakness occurs in the biceps brachii, triceps, anterior tibialis, and peroneal muscles.
Elbow flexion contractures are a hallmark of the disease.
Emery-Dreifuss muscular dystrophy (EMD), also known as humeroperoneal muscular dystrophy, refers to a group of muscular dystrophies characterized by weakness of shoulder and pelvic girdle muscles, contractures, and cardiac conduction abnormalities. There are two main types, EMD1 and EMD2.
Age of presentation can vary from the neonatal period to the third decade; however, patients usually become symptomatic by the teenage years. There is early involvement of the humeroperoneal muscles (eg, biceps, triceps, tibialis anterior, and peroneal muscles). Severe contractures of the elbow (flexion) are a hallmark of the disease. Ankle (equinus) contractures, along with spinalrigidity and neck extension, are also characteristic.
Weakness is slowly progressive, and eventually the shoulder and pelvic girdle muscles become involved. A dilated cardiomyopathy often develops in affected individuals by age 20, along with various conduction defects.
Serum CK levels range from normal to mildly elevated. Muscle biopsy findings reveal muscle fiber atrophy in more than 95% of patients. Electrocardiography may show sinus bradycardia or conduction blocks. EMG shows myopathic motor unit action potentials (MUAPs).
Physical therapy may help maintain joint mobility and prevent contractures. Cardiac arrhythmias in early adult life can lead to death. Careful monitoring is essential as EMD patients with arrhythmias may require pacemaker placement.
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