Causes of Myopathy
Myopathies are broadly categorized into inflammatory and noninflammatory causes, with the differential diagnosis requiring systematic evaluation to distinguish between immune-mediated, genetic, metabolic, endocrine, drug-induced, and infectious etiologies 1.
Major Categories of Myopathy
Inflammatory Myopathies (Idiopathic Inflammatory Myopathies)
The idiopathic inflammatory myopathies represent a distinct group of autoimmune muscle diseases 1:
Polymyositis (PM): Characterized by CD8+ cytotoxic T cells invading nonnecrotic muscle fibers, presenting with symmetric proximal muscle weakness 1
Dermatomyositis (DM): Features characteristic skin manifestations (Gottron papules, heliotrope rash, shawl sign) along with proximal muscle weakness, elevated muscle enzymes, and potential extramuscular involvement including interstitial lung disease and cardiac manifestations 1
Immune-Mediated Necrotizing Myopathy (IMNM): A severe myopathy with minimal inflammatory infiltrate on biopsy, triggered by viral infections, medications (particularly statins), and malignant neoplasms 1. Statin-induced necrotizing myopathy is associated with antibodies against HMGCR protein 1
Sporadic Inclusion Body Myositis (sIBM): Has degenerative features with muscle fiber vacuolization and abnormal accumulation of amyloid-β and phosphorylated tau proteins 1
Juvenile Dermatomyositis (JDM): Affects children under 18 years with proximal muscle weakness, calcinosis cutis, cutaneous vasculitis, and gastrointestinal vasculopathy 1
Noninflammatory Myopathies
The differential diagnosis of noninflammatory myopathies is extensive and must be systematically excluded when evaluating proximal muscle weakness with elevated muscle enzymes 1:
Genetic/Hereditary Causes
- Muscular dystrophies: Late-onset muscular dystrophy, limb-girdle dystrophy (dysferlinopathies) with adult onset, myotonic dystrophy type 2 1
- Mitochondrial myopathies: Show classic "ragged red fibers" on Gomori trichrome stain with subsarcolemmal and interfibrillar mitochondrial accumulation 1
- Adult-onset nemaline myopathy: Associated with monoclonal gammopathy 1
Drug-Induced Myopathy
- Statins are the most clinically significant medication trigger, capable of causing both toxic myopathy and immune-mediated necrotizing myopathy 1
- Other medications can trigger IMNM 1
Endocrine Myopathies
Metabolic Myopathies
- Various metabolic derangements affecting muscle function 1
Infectious Myopathies
Malignancy-Associated
- Cancer can trigger immune-mediated necrotizing myopathy 1
- Paraneoplastic myopathy syndromes
Critical Diagnostic Distinctions
Muscle biopsy remains the gold standard for differentiating inflammatory from noninflammatory myopathy and for subclassification 1. Key histopathologic features distinguish these entities:
- Muscular dystrophy: Reduction or absence of dystrophin with degenerating/regenerating fibers and replacement with fat or connective tissue 1
- Mitochondrial myopathy: Ragged red fibers with reduction or absence of cytochrome c oxidase 1
- Inflammatory myopathy: Endomysial mononuclear inflammatory infiltrate 1
Common Pitfall
A critical error is assuming all proximal weakness with elevated CK is inflammatory myositis. Muscular dystrophy and mitochondrial myopathies must be included in the differential diagnosis, as they can present identically with proximal muscle weakness and elevated muscle enzymes 1. Genetic testing for dystrophin gene and specialized staining techniques are essential when clinical suspicion exists.