Diagnosis of Myopathies

Myopathies are primary disorders of skeletal muscle causing weakness, wasting, or myalgia due to a defect intrinsic to the muscle fiber (as opposed to nerve, neuromuscular junction, or motor neuron disease). Diagnosis requires an integrated approach combining clinical evaluation, laboratory tests, electrophysiology, imaging, muscle biopsy, and molecular/genetic testing.

1. Clinical Evaluation

Pattern of weakness: proximal and symmetric (limb-girdle, hip/shoulder) favors myopathy, versus distal weakness seen in most neuropathies (exceptions: myotonic dystrophy, inclusion body myositis, distal myopathies).
Onset and course: acute (toxic, inflammatory), subacute (inflammatory myopathy, endocrine), chronic progressive (muscular dystrophy), episodic (metabolic/channelopathies with exercise-induced cramps/myoglobinuria).
Associated features: myalgia, cramps, myoglobinuria (metabolic myopathies), skin rash (dermatomyositis), ptosis/ophthalmoplegia (mitochondrial, OPMD), cardiac or respiratory involvement (dystrophinopathies, myotonic dystrophy), family history (inherited dystrophies).
Drug/toxin history: statins, corticosteroids, alcohol, colchicine, zidovudine (toxic myopathies).
Deep tendon reflexes are typically preserved until late (unlike neurogenic disease where they are lost early).

2. Laboratory Investigations

Serum creatine kinase (CK) is the most sensitive marker of muscle fiber damage; marked elevation (>2000 U/L) strongly suggests a myopathic process, though not all myopathies raise CK (e.g., many endocrine and chronic/cachectic myopathies have normal CK) - Harrison's Principles of Internal Medicine, 22E.
Other enzymes: aldolase, AST, ALT, LDH (less specific).
Myositis-specific/associated autoantibodies (anti-Jo-1, anti-Mi-2, anti-SRP, anti-HMGCR) support autoimmune/inflammatory myopathies.
Metabolic work-up: lactate/pyruvate (mitochondrial disease), forearm exercise test, electrolytes (K+, Ca2+, PTH, thyroid function) to screen endocrine causes.
Genetic/molecular testing (see below).

3. Electrophysiology (EMG/NCS)

Nerve conduction studies are typically normal in pure myopathy, helping exclude neuropathy.
Needle EMG in myopathy shows: small-amplitude, short-duration, polyphasic motor unit action potentials with early/full recruitment - the classic "myopathic pattern," in contrast to the large-amplitude, long-duration units with reduced recruitment and fibrillations/fasciculations seen in neurogenic (denervating) disease.
Myotonic discharges point to myotonic dystrophy or channelopathies; fibrillations and complex repetitive discharges can be seen in inflammatory myopathies.
EMG can be normal in many metabolic myopathies - Goldman-Cecil Medicine.

4. Imaging

Muscle MRI: detects edema (active inflammation), fatty replacement/atrophy (chronic dystrophic change), and helps select an unaffected-but-involved site for biopsy; useful in dystrophies and inflammatory myopathies.
Muscle ultrasound is a rapid bedside adjunct for detecting atrophy/echogenicity changes.
ECG/echocardiogram is recommended in muscular dystrophies to screen for associated cardiomyopathy/conduction defects.

5. Muscle Biopsy (Histopathology) - the gold standard for tissue diagnosis

A biopsy from a clinically affected but not end-stage muscle is examined by light microscopy, histochemistry, immunohistochemistry, and sometimes electron microscopy. Key patterns include:

Pattern	Typical Cause
Fiber necrosis and regeneration, with variable inflammatory infiltrate	Muscular dystrophies, inflammatory myopathies
Endomysial inflammatory infiltrate (CD8+ T cells surrounding non-necrotic fibers)	Polymyositis
Perifascicular atrophy, perivascular/perimysial inflammation, microangiopathy	Dermatomyositis
Necrosis with minimal inflammation, macrophage-predominant	Immune-mediated necrotizing myopathy (e.g., anti-HMGCR, statin-associated)
Rimmed vacuoles, endomysial inflammation, congophilic inclusions	Inclusion body myositis
Fiber-type grouping and grouped atrophy (loss of the normal checkerboard fiber-type mosaic)	Neurogenic (denervating) disease - important negative finding that argues against a primary myopathy - Robbins, Cotran & Kumar Pathologic Basis of Disease
Type 2 fiber atrophy (selective)	Disuse, corticosteroid (steroid) myopathy, cachectic/critical illness myopathy
Ragged red fibers (subsarcolemmal mitochondrial accumulation, seen with trichrome stain), COX-negative fibers	Mitochondrial myopathies (MELAS, MERRF, KSS)
Central cores on oxidative enzyme stains	Central core disease
Vacuoles with glycogen/lipid accumulation	Glycogen storage disease, lipid storage myopathy
Absence of dystrophin on immunostain	Duchenne muscular dystrophy

Histochemical stains (ATPase for fiber typing, NADH-TR, SDH/COX for mitochondrial enzymes, PAS for glycogen, oil red O for lipid) and immunohistochemistry (dystrophin, sarcoglycans, MHC class I upregulation in inflammatory myopathy) refine the diagnosis. Electron microscopy can further characterize mitochondrial abnormalities, tubular aggregates, or storage material.

6. Genetic/Molecular Testing

For suspected inherited myopathies (dystrophinopathies, limb-girdle dystrophies, myotonic dystrophy, metabolic and mitochondrial myopathies), targeted gene panels or next-generation sequencing have increasingly replaced muscle biopsy as the first-line diagnostic tool once a specific phenotype is suspected - Bradley and Daroff's Neurology in Clinical Practice.

7. Diagnostic Algorithm (Summary)

History and examination -> establish myopathic pattern of weakness and exclude neurogenic/NMJ causes.
Serum CK and basic metabolic/endocrine screen.
EMG/NCS to confirm a myopathic electrical pattern and exclude neuropathy/motor neuron disease.
Autoantibody panel if inflammatory myopathy suspected.
Muscle MRI to localize disease activity and guide biopsy site.
Muscle biopsy with histochemistry/immunohistochemistry (+/- electron microscopy) for definitive tissue diagnosis, especially in inflammatory, mitochondrial, and structural myopathies.
Genetic testing, particularly when a hereditary dystrophy, channelopathy, or metabolic/mitochondrial myopathy is suspected clinically.

Recent evidence check: A quick search for recent systematic reviews/meta-analyses on myopathy diagnosis did not return results directly updating this diagnostic algorithm; the approach above remains consistent with current major textbook references (Harrison's 22E, Robbins Pathologic Basis of Disease, Bradley and Daroff's Neurology).

This structure (clinical -> biochemical -> electrophysiological -> imaging -> histopathological -> genetic) is exactly how examiners expect a 10-mark answer to be organized, since it demonstrates a stepwise, rational diagnostic workflow rather than listing tests randomly.

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