What is the appropriate work‑up for a patient presenting with proximal muscle weakness (proximal myopathy)?

Work-up for Proximal Myopathy

Begin by measuring serum creatine kinase (CK), thyroid-stimulating hormone (TSH), and electrolytes (potassium, phosphate, calcium), as these tests identify the most common treatable causes and guide all subsequent evaluation. 1, 2, 3

Initial Laboratory Assessment

• CK is the single most important initial test because it distinguishes inflammatory/dystrophic myopathies (typically elevated) from endocrine, toxic, and some metabolic causes (often normal or minimally elevated). 1, 4, 3

• CK >3× upper limit of normal strongly suggests inflammatory myositis, muscular dystrophy, or immune-mediated necrotizing myopathy and requires urgent evaluation for life-threatening complications including myocarditis. 4, 2

• CK normal or <2× normal directs evaluation toward thyroid disease, steroid-induced myopathy, electrolyte disorders, or certain metabolic/mitochondrial myopathies. 1, 4, 2

• Measure aldolase, AST, ALT, and LDH as these muscle enzymes provide additional diagnostic clues and can be elevated even when CK is normal in some myopathies. 5, 1

Endocrine and Metabolic Screening

• TSH should be checked in all patients because both hypothyroidism and hyperthyroidism cause proximal weakness with normal or mildly elevated CK, and symptoms completely resolve with thyroid replacement. 2, 3, 6, 7

• Measure serum potassium, phosphate, calcium, and 25-OH vitamin D levels as severe hypokalemia, hypophosphatemia, and osteomalacia directly cause respiratory and proximal muscle weakness through cellular ATP depletion. 2, 3, 7

• Check inflammatory markers (ESR, CRP) because normal values argue against inflammatory myositis and support steroid-induced or endocrine myopathy, while elevated markers suggest inflammatory or infectious causes. 5, 4, 3

Autoimmune and Inflammatory Evaluation (When CK Elevated)

• Obtain myositis-specific autoantibodies (anti-Jo-1, anti-Mi-2, anti-SRP, anti-HMGCR, anti-NXP2, anti-TIF1γ) to define disease subgroups, predict pulmonary and cardiac involvement, and differentiate autoimmune inflammatory myopathy from immune-mediated necrotizing myopathy. 5, 1

• Antinuclear antibody (ANA) testing helps screen for connective tissue diseases that can present with myositis. 8, 3

• Troponin, ECG, and echocardiogram are mandatory because cardiac involvement (myocarditis, cardiomyopathy, arrhythmias) is a major determinant of mortality in inflammatory myopathies and muscular dystrophies. 5, 1, 2

Neurophysiologic Studies

• Electromyography (EMG) with nerve conduction studies should be performed to confirm a myopathic process (polyphasic motor unit action potentials of short duration and low amplitude with fibrillation potentials) versus neurogenic patterns (spinal muscular atrophy, peripheral neuropathies). 5, 1, 2, 8

• EMG helps target the optimal muscle for biopsy by identifying affected muscles while avoiding those with severe end-stage changes. 5, 1

Advanced Imaging

• Muscle MRI (T1-weighted, T2-weighted, and STIR sequences) should be obtained to detect inflammation, guide biopsy site selection, establish baseline for monitoring therapeutic response, and differentiate infectious myositis (ring-enhancing abscesses) from inflammatory myopathy. 5, 1, 9

• MRI is particularly valuable in children with suspected juvenile dermatomyositis as it can avoid invasive testing like EMG or muscle biopsy in straightforward cases. 5

Muscle Biopsy

• Muscle biopsy is the gold standard for confirming inflammatory myopathy diagnosis and differentiating inflammatory from noninflammatory causes including muscular dystrophy (dystrophin reduction/absence, fiber degeneration, fat/connective tissue replacement) and mitochondrial myopathy (ragged red fibers on Gomori trichrome stain, cytochrome c oxidase deficiency). 5, 1, 2, 8

• Biopsy the contralateral muscle to the one studied by EMG to avoid sampling artifact from needle trauma. 5

• Choose a weak muscle with EMG abnormalities but not end-stage atrophic muscle to maximize diagnostic yield. 5

Genetic Testing

• Genetic testing for dystrophin gene and other muscular dystrophy panels should be pursued when biopsy shows dystrophic features or when family history suggests hereditary myopathy. 5, 2

• Mitochondrial DNA testing and nuclear gene panels are indicated when ragged red fibers or cytochrome c oxidase deficiency are found on biopsy. 5, 2

Malignancy Screening

• Screen for malignancy in patients with dermatomyositis features (heliotrope rash, Gottron papules, photosensitive erythema) or positive anti-TIF1γ or anti-NXP2 antibodies, as paraneoplastic myositis requires identification of the underlying cancer. 5, 1, 3

Critical Pitfalls to Avoid

• Distinguish true weakness from subjective fatigue by objective strength grading; muscle weakness is more typical of myositis than pain, while pain predominance suggests neuropathy or radiculopathy. 5, 2

• Immune-mediated necrotizing myopathy (anti-HMGCR, anti-SRP positive) presents with marked CK elevation (often >10× normal) and requires immunosuppression, not steroid withdrawal, despite minimal inflammatory infiltrate on biopsy. 4, 2

• Checkpoint inhibitor myositis has 20% mortality and requires immediate high-dose steroids plus urgent cardiology evaluation, as concomitant myocarditis carries an ominous prognosis. 5, 4, 2

• Assess respiratory and pharyngeal muscle involvement because respiratory failure is a leading cause of mortality and requires prompt intervention. 1, 2, 3

• Infectious myositis (most often Staphylococcus aureus) can mimic inflammatory myopathy but requires antibiotics rather than immunosuppression; MRI showing ring-enhancing abscesses and positive urine/blood cultures are diagnostic clues. 9