Myopathy

• Myopathy 💪 : skeletal muscle disease due to:

• Clinical 💪 : objective weakness resulting in visible functional deficits (e.g. falls, inability to stand, inability to hold objects) vs. subtle deficits related to skeletal muscle damage elsewhere (e.g. dysphagia, constipation); ⊕ cramps, myalgias, stiffness, myotonia; ⊖ muscle atrophy

• Exam 💪 : proximal > distal muscle strength (i.e. the presence of distal-predominant weakness points toward particular diseases e.g. IBM, facioscapulohumeral MD, type 1 MD); muscles may be tender or non-tender; reflexes are generally normal or ↓ in-proportion to degree of weakness; of note, the weakness should be stable throughout a single bedside exam (i.e. presence of worsening weakness during exam suggests NMJ disease); sensory deficits should not be present unless unrelated superimposed neuropathy (e.g. diabetes) vs. related neuromyopathy (e.g. toxin vs. autoantibody-mediated nerve and muscle damage)

• Labs 💪 : ↑ CK & aldolase → ↑ AST > ALT if severe; UA showing ⊕ blood but microscopy showing discordantly low RBCs

• EMG ⚡: MUAPs show ↓ amplitude, ↓ duration, & ↑ complexity. Due to lesser force elicited by remaining myofibers, myofibers also compensate by activating adjacent myofibers (rapid/early recruitment). (Note: in advanced myopathy, myofiber loss is so profound there are no adjacent myofibers available, & recruitment is therefore reduced, thus mimicking neuropathic disease.)

• NCS ⚡ : routine NCS involves measuring summated action potential from the nerve (”sensory NCS,” which is expectedly normal in myopathy) or the muscle (”motor NCS”), particularly the distal muscles. Given most myopathies are proximal-predominant, routine motor NCS will therefore be falsely reassuring (unless the study is performed in the affected musculature)

⚪ Myotonia: describes symptoms related to ↓ muscle relaxation after a forceful voluntary contraction (e.g. unable to release handgrip after handshake, unable to open eyes after forcefully shutting eyelids), which often improves after repeated contractions & worsens in the cold

Injury = Rhabdomyolysis

• Uncomplicated fall → Compartment syndrome
• Diffuse ischemia (e.g. post-shock)

Atraumatic = Myopathy

• CK < 5000 → entire myopathy DDx, & notably, low-grade CK elevations can still carry clinical significance (e.g. inflammatory myopathy)
• CK > 5000 → necrotizing myopathies (autoimmune/paraneoplastic & toxic), metabolic myopathy (acquired)

Note ⚪ : of the MSAs, NXP-2 dermatomyositis is the only antibody disease (in one study) that has been shown when detected at low ⊕ levels to correlate with more diagnostic accuracy, relative to high ⊕ levels being more predictive in every other MSA. This can be easily remembered as it is the dermatomyositis subtype that also is less likely to have typical dermatologic findings (e.g. heliotrope rash, shawl sign, Gottron’s papules)

• Dermatomyositis (DM): muscle biopsy shows perifascicular distribution of atrophic, degenerating, & regenerating myofibers with perivascular B-cell predominant infiltrate (see below). On skin biopsy, there is more than expected MxA expression, which is the most sensitive & specific histologic marker for DM, whose origin is felt to be derived from IFN-1 secretion by local dendritic cells

• Polymyositis (PM): muscle biopsy shows a strong inflammatory infiltrate of CD8+ T-cells & macrophages surrounding, entering, & destroying normal-appearing myofibers in an unlimited distribution

• Inclusion-Body Myositis (IBM): as many patients initially diagnosed with PM via histopathology go on to develop IBM pathology on repeat biopsy, IBM should be considered in treatment-refractory PM patients. Pathology is notable for inflammatory infiltrate identical to PM, but with additional specific findings (sarcoplasmic “rimmed” facuoles red-rimmed on modified trichrome stain & blue-rimmed on H&E, abundant COX ⊖ fibers, Congo red ⊕ amyloid deposits in vacuolated fibers, EM finding of tubulofilamentous inclusions in sarcoplasm & nuclei). IBM is associated with T-LGL & some have posited that it is the muscular invasion of neoplastic T-LGL cells lacking normal apoptotic mechanism that causes PM & IBM patients to be so treatment-refractory

• Immune-mediated Necrotizing Myopathy (IMNM): due to anti-HMGCR vs. anti-SRP antibody vs. seronegative disease. Pathology is non-specific with findings compatible with both toxic myopathies as well as early muscular dystrophies. When inflammatory infiltrate is present, there is no CD8+ T-cell invasion & macrophages are the predominant finding, more so being involved in the tissue repair process of necrotic fibers

• Regional Ischemic Immune Myopathy (RIIM): a finding of paraneoplastic disease owing to myovasculopathy & leading to a poor prognosis. Pathology shows well-demarcated areas of ischemia involving adjacent fascicles with necrotic fibers showing diffuse sarcoplasmic C5b-9 deposition, as well as prominent MxA immunostaining similar to that of dermatomyositis. Overall, can be viewed as a pathologic descriptor of paraneoplastic DM, or less formal finding of “monomyopathy multiplex”

• Episodic Pain/Weakness (Rhabdomyolysis): if patient without underlying myopathy is inactive but is suddenly required to do overwhelming amount of exercise, this syndrome can be accounted for as the “couch potato” syndrome. However, if patient is quite active, exercise-induced episodic rhabdomyolysis suggests an underlying metabolic myopathy (e.g. McArdel’s). If episodes are delayed or unrelated to exercise, the pattern suggests a genetic channelopathy, secondary periodic paralysis (e.g. thyrotoxic), or Andersen-Tawil syndrome

• Myotonia: if improvement with exercise, likely Cl- channelopathy or Na+ channelopathy; if worsens with exercise or cold, likely Na+ channelopathy (”paramyotonia congenita”) or Brody’s disease; if accompanied by fixed weakness, likely myotonic dystrophy, proximal myotonic myopathy, or Becker’s disease; others include Rippling muscle disease, neuromyotonia, & mimicker (Stiff-person syndrome)

• Scapuloperoneal: highly suggestive of facioscapulohumeral MD, but also seen in acid maltase deficiency, congenital myopathies, Emery-Dreifuss dystrophy, & others

• Ptsosis: oculopharyngeal muscular dystrophy if ⊕ dysphagia, mitochondrial myopathies if ⊖ dysphagia. (The finding of diplopia is very rare in these patients & should prompt consideration of NMJ disease.)

• Prominent Neck Extensor: isolated neck extensor myopathy vs. myopathy-mimicker (ALS & myasthenia). (Otherwise, neck extensor weakness is usually found in the context of accompanying proximal extremity weakness.)

• Bulbar: oculopharyngeal muscular dystrophy

• Diagnostic approach to patients with suspected muscle disorders (myopathies) (UpToDate)

• Takotsubo cardiomyopathy and cardiogenic shock due to hypokalaemic rhabdomyolysis (Andrew's Case Report)

• Myositis-Specific Antibodies Identified

• Paraneoplastic dermatomyopathy (Arkana Lab)

• Pattern Recognition Approach to Myopathy

• Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis

• Dermatomyositis and polymyositis: Clinical presentation, autoantibodies, and pathogenesis

• Dermatomyositis and type 1 interferons

• Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis

• Inclusion body myositis: clinical and pathological boundaries

• Mitochondrial pathology in inclusion body myositis

• Association of inclusion body myositis with T cell large granular lymphocytic leukaemia

• Diagnosis and Management of Immune-Mediated Myopathies

• A Shifting Frame (NEJM CPS Case)