The noninflammatory myopathies are a diverse group of diseases, some of which may mimic the autoimmune-mediated idiopathic inflammatory myopathies in their clinical presentation. They include certain metabolic, toxic, and infectious myopathies, as well as muscular dystrophies. In addition to muscle weakness, these forms of myopathy may present with exercise intolerance and muscle pain. Special testing techniques are often required to establish the diagnosis. This review focuses on those noninflammatory myopathies that should be included in the differential diagnosis of idiopathic inflammatory myopathy.
Key points
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Noninflammatory myopathies have diverse causes, including inherited or acquired metabolic abnormalities, toxins and drugs, and infections, as well as heritable defects in structural proteins (muscular dystrophies).
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This group of diseases should be considered in the differential diagnosis of autoimmune-mediated idiopathic inflammatory myopathies, because they can present with proximal muscle weakness, increased serum levels of muscle enzymes, and in some cases, endomysial inflammation.
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The primary metabolic myopathies are inherited disorders of muscle glycogen, lipid, or mitochondrial metabolism characterized by episodic exercise intolerance, occasionally with myoglobinuria, or progressive proximal muscle weakness.
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Drugs commonly used in rheumatology practice, including statins, antimalarials, and colchicine, can induce myopathies via diverse mechanisms.
The noninflammatory myopathies are a diverse group of diseases distinct from the autoimmune-mediated idiopathic inflammatory myopathies. They include the metabolic, toxic, and infectious myopathies, as well as the muscular dystrophies. Certain forms of these diseases can present with muscle weakness or pain and thus must be considered in the differential diagnosis of a patient being evaluated for polymyositis or other autoimmune-mediated muscle disease ( Table 1 ). The term noninflammatory is a misnomer, because some forms of muscular dystrophy and a variety of infectious myopathies may have inflammatory muscle infiltrates, and some forms of statin-induced myopathies may involve autoimmune mechanisms. In addition, inclusion body myositis is traditionally categorized as an idiopathic inflammatory myopathy but may not be autoimmune in origin. For the purposes of this review, the focus is on those noninflammatory myopathies that may mimic adult or pediatric forms of idiopathic inflammatory myopathy.
| Idiopathic Inflammatory Myopathy | Myophosphorylase Deficiency | CPT2 Deficiency (adult form) | Mitochondrial Myopathy | Dysferlinopathy | Fascioscapulohumeral Muscular Dystrophy | Proximal Myotonic Dystrophy Type 2 | |
|---|---|---|---|---|---|---|---|
| Typical age of onset | Childhood Midadult life | Childhood and adolescence | Young adulthood | Most often childhood, young adulthood | Adolescence and young adulthood | Before age 20 y | Young adulthood |
| Muscle symptoms | Proximal weakness | Pain early during exercise, especially if intense Late proximal weakness | Pain ± myoglobinuria, triggered by prolonged exercise or fasting | Premature fatigue with submaximal exercise Ocular muscle weakness | Proximal weakness | Facial and shoulder weakness; Eventual pelvic girdle weakness | Minimal or absent myotonia on examination Proximal weakness |
| Rash | Photosensitive Gottron Heliotrope Mechanic’s hands | None | None | Lipomas | None | None | Hyperhidrosis |
| Other extramuscular involvement | Fever Arthritis Interstitial lung disease Raynaud Cardiomyopathy | None | None | Axonal neuropathy Ataxia Seizures Pigmentary retinopathy Sensorineural hearing loss | None | Retinal vasculopathy Sensorineural hearing loss | Cardiomyopathies and conduction defects Cataracts Diabetes Testicular failure |
| Family history | Autoimmunity | Same syndrome | Same syndrome | Possible symptoms in mother (mtDNA disorders) | Same syndrome | Same syndrome | Same syndrome in forebearers but more severe in proband (anticipation) |
| CK levels | Usually 2–30 × normal | Always increased | Normal between attacks | Less than 1500 IU/mL | 10–70 × normal | 2–7 × normal | Normal or slightly increased |
Diagnostic evaluation
The evaluation of a suspected muscle disease begins with a careful patient history, focusing on the temporal pattern of onset and characteristics of the muscle symptoms, presence and distribution of muscle weakness, other organ system involvement, and family history. The physical examination should include an assessment of proximal and distal muscle strength and a search for neurogenic signs, such as spasticity, altered deep tendon reflexes, impaired sensation, muscle fasciculation, and atrophy. Subsequent testing usually involves measurement of serum levels of muscle enzymes, electromyography (EMG), magnetic resonance imaging (MRI), and muscle biopsy. The evaluation of metabolic myopathies often requires additional tests, including measurement of serum lactate and other metabolic intermediates, exercise testing, quantitative analysis of enzyme activity in muscle or blood lymphocytes, and molecular genetic analyses. An increasing number of metabolic myopathies and muscular dystrophies may now be diagnosed with molecular genetic testing, thereby obviating a muscle biopsy.
Increased serum levels of creatine kinase (CK), aldolase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (LDH) characterize many forms of myopathy, both inflammatory and noninflammatory. An increased CK level is the most sensitive of these tests. Some noninflammatory myopathies, including certain metabolic myopathies and electrolyte disorders, may develop without an increase in muscle enzymes. Myositis-specific autoantibodies support the presence of an idiopathic inflammatory myopathy. A diagnostic test for statin-associated autoimmune necrotizing myopathy will also be available soon.
EMG can facilitate the differentiation of myopathic or neuropathic processes, determine the distribution of a myopathy, and pinpoint an affected muscle group for biopsy. The signs of a myopathy include spontaneous electrical activity at rest from single muscle fibers (fibrillation potentials and positive sharp waves); short, small-amplitude polyphasic motor unit action potentials during muscle contraction; and the inability to identify individual motor unit potentials (interference pattern) with lower than normal forces of contraction (early recruitment). The presence of abnormal spontaneous electrical activity in the resting muscles indicates an irritable myopathy and is postulated to reflect the presence of an active necrotizing myopathic process or unstable muscle membrane potential. However, this finding has poor sensitivity and specificity for predicting the presence of an inflammatory myopathy on biopsy.
MRI of patients with inflammatory myopathies shows increased muscle signal on fast spin echo T2 fat-saturated or short-tau inversion recovery sequences, which indicates edema. In the noninflammatory myopathies, MRI is normal or may show atrophy, sometimes of characteristic musculature. MRI and spectroscopy of the brain often show findings that help establish a diagnosis of mitochondrial disease.
A muscle biopsy remains a critical test, unless the diagnosis can be secured with genetic testing. The best specimen is obtained from muscle that is moderately weak but not affected by end-stage atrophy, fibrosis, or replacement by fat, as judged by clinical examination, EMG, or MRI. The tissue should be analyzed in a reference muscle histopathology laboratory, where a comprehensive panel of immunohistochemical and histochemical stains can be performed. The histologic analyses depend in part on the clinical history, so it is important that this information be forwarded to the laboratory. The protocol for handling the tissue should be made available to the surgeon and the local pathologist in advance. If a metabolic myopathy is suspected, a portion of the specimen should be snap frozen in liquid nitrogen and stored at –70°C for future quantitative enzyme analyses at a reference laboratory.
Mitochondrial myopathies are often associated with defects in multiple metabolic pathways, and assays of these provide diagnostic information. An increased fasting plasma lactate level may be a useful indicator of a mitochondrial myopathy, but it is not uniformly present. Assays of plasma and cerebrospinal fluid (CSF) amino acids and urinary organic acids can also provide useful information in the diagnosis of mitochondrial disorders, primarily in pediatric patients with profound metabolic disturbances. A decrease in plasma levels of free carnitine and a relative increase in acylcarnitine species are often observed in fatty acid oxidation disorders and mitochondrial myopathies related to mutations in mitochondrial DNA (mtDNA).
The forearm ischemic exercise test screens for defects in the glycogenolysis, glycolysis, and myoadenylate deaminase pathways ( Box 1 , Fig. 1 ). When normal skeletal muscle becomes ischemic, anaerobic glycolysis and the purine nucleotide cycle become essential sources of energy. Both lactate and ammonia levels increase 3-fold to 5-fold. Individuals with myophosphorylase (McArdle disease) and phosphofructokinase deficiency can increase ammonia but not lactate production. Patients with debrancher, phosphoglycerate mutase, phosphoglycerate kinase, and LDH deficiencies have a blunted increase in lactate, whereas patients with deficiencies of acid maltase, branching enzyme, and phosphorylase b kinase have normal responses. Patients with myoadenylate deaminase deficiency increase their serum lactate but not ammonia. Because exercise under ischemic conditions can cause painful muscle contractures and occasional rhabdomyolysis in patients with myophosphorylase deficiency, a forearm exercise test without tourniquet occlusion of blood flow is now advocated by some investigators. The Forearm Ischemic Exercise Test (FIET) may yield false-positive results in individuals who cannot or do not exercise vigorously enough to increase lactate production. Accordingly, any positive test must be followed by biochemical analysis of muscle or molecular studies of blood cells to identify the putative enzyme defect.
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