Histology & Pathology of Skeletal Ms

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Histology & Pathology of Skeletal Ms
2013-07-12 15:53:30

Histology & Pathology of Skeletal Ms
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  1. Indications of muscle biopsy
    Clinically sick muscle 

    Neuromuscular disease

    Systemic (autoimmune) disorders

    Treatment related biopsy:

    Repeat biopsy:
  2. Indications of muscle biopsy: neuromuscular disease
    - Myopathy (inflammatory, metabolic, congenital, muscular dystrophies)

    •   - Peripheral nerve damage (Neuropathy) or
    • motor neuron disease  

    •   - Distinction of an atypical neurogenic
    • disorder from a primary myopathy
  3. Indication of ms biopsy: treatment related biopsy
    - The risk of treatment is high enough that the diagnosis should be confirmed before therapy is started (e.g. high dose steroids,       immunosuppressive agents)
  4. Indication of ms biopsy: repeat biopsy
    -Hunting pathology!

    - Or follow up:

      Evaluate efficacy of the treatment

      Atypical presentation of a rare metabolic disorder not ordinarily suspected before biopsy
  5. Exceptions: Muscle biopsy is not indicated in
    A genetic testing is available

    • No visible prestation in the biopsy:
    • Myasthenia gravis: AB block ACh receptor
    • Periodic Paralysis: abnormality in the ion channels of the ms fiber
    • Endocrine myopathies: features of thyroid, parathyroid and adrenal disorder.
  6. Lab processing: cryostat
    - Immediately after the biopsy

    - Preserves integrity of DNA, RNA and proteins (enzymes)

    - Study of skeletal muscle pathology relies heavily on cryostat enzyme histochemistry
  7. Lab procressing: Fixed tissue
    - GTA – Electron microscopy

    - Formaldehyde: Paraffin processing and routine histology

    - Neutraldehyde: another way to fix which travel slowly
  8. Muscle Cryostat Histochemistry: HE stain
    Morphology of ms fiber pathology; nuclei
  9. Normal structure of ms
    polygonal (not elongate)

    Minimal size variation

    uniformly pink

    multi-nucleated and peripheral nuclei (not much endonucleated) 

    Endomysium around the fascicle 

    Perimysium around multiple fascicle
  10. Normal ms - spindle fiber and tendon insertions site
    Spindle fiber: smaller, receive innervation

    tendon insertions site:
  11. Denervation = Neurogenic atrophy
    Refers to damage of Motor neuron (CNS), axon (PNS) or motor end-plates in the skeletal muscle

    no anatomic location indication
  12. Myopathy
    Primary damage of the muscle (autoimmune, congenital, metabolic)
  13. Denervation: histological presentation and EM
    Biopsy - Angular atrophy: Neurogenic dysfunction axons (neuropathy), neurons (motor neuron disease)

    EM - empty sleeves of basement membrane

    Morular formation (nuclear clumps

    Sharp-angle and small ms fiber
  14. motor neuron neuropathy localization
    lower motor neuron --> lower extremity or parts

    uper motor neuron --> upper extremity and more global
  15. Motor neuron disease (ALS or Lu Gehrig disease): histology presentation
    group angular atrophy 

    large neuropathies
  16. Ms Cryostate Histochemistry: NSE stain
    Hydrolytic enzyme for NMJ
  17. NSE stain (nonspecific esterase) histology slide characteristic
    normal: mosaic presentation 

    disease: enlarged and atrophy ms with angular presentation
  18. Stain to recognize ms type (using myofibrillar ATPase)
    • pH 9.4 type II
    • pH 4.6 type I, IIa, IIb
    • pH 4.2 type I, IIc
  19. Fiber type differentiation
    Mosaic Fiber

    • Fiber type differentiation
    • - Type I fibers: Slow twitch sustained contraction, mitochondria and lipid rich,
    • predominant in postural/continually active muscles (Soleus)

    •  - Type II fibers (IIA/IIB): Fast twitch,
    • glycogen rich (Biceps, Quadriceps, Deltoid)
    • -->ATPase: pH acid: type I
    •                  pH alkaline type II
  20. Architectural Mosaicism: normal
    The normal profile of the muscle mosaicism depends on:

      - Type of muscle activity

      - Nervous stimulation (motor neuron dependent)
  21. Architectural Mosaicism: Loss of mosaicism
    Congenital type fiber predominance

    Neurogenic conditions (introducing “grouping”)
  22. Architectural Mosaicism: Loss of mosaicism
    -Fiber type grouping in chronic denervation
    sign of chronic reinnervation

    • Fiber
    • type grouping represents recovering neurogenic damage
  23. How does the body compensate for denervation?

    the ms fiber type that is innervated by the dying neuron is now innervated by the adjacent neuron which could be the innervation of another ms fiber type --> grouping of the same type of ms fiber
  24. Myopathies
    • ØHereditary myopathic disease:
    •   -Duchenne muscular dystrophy
    •   - Centronuclear myopathy

    ØInflammatory/autoimmune: dermatomyositis, inclusion body myositis

    ØMitochondrial Myopathy
  25. Primary Myopathy: biopsy presentation
    • scar tissue that separate the ms fiber 
    • loss of normal variation in size
  26. Primary myofiber disease (Myopathy)
    ØIncreased space in peri- & endomysium (scar tissue): Chronicity of the disease

    ØIncreased myofiber size variation

    ØRound atrophy

    ØInternal nucleation

    • ØRegen/degen changes: Small fibers with
    • abnormal cytoplasmic reactivity and nuclear features (signifies the intensity
    • of turn over in the muscle)

    • ØInflammatorycells:
    •   - Primary lymphohistiocytic
    •   - Secondary histiocytic (clean up and repair signal)
  27. Hallmark of primary myopathy disease
    regeneration and degeneration in histologic slide
  28. Duchenne Muscular Dystrophy
    ØDystrophin deficiency

    ØChromosome Xp21; Recessive

    ØOnset 3 to 5 yrs

    • ØWeakness Proximal > Distal
    • •Symmetric 
    • •Legs & Arms 
    • •Most involved muscles: Adductor magnus
    • in legs
    • •Relatively spared muscles: Gracilis
    • & Sartorius

    • ØCourse
    • •Reduced motor function by 2 to 3
    • years
    • •Steady decline in strength: After 6
    • to 11 years

    ØFailure to walk: 9 - 13 years
  29. Muscular Dystrophy - etiology
    lacking dystrophy protein (using western blot)
  30. Centronuclear Myopathy: histologic presentation
    single internal nuclei
  31. hallmark of dermatomyositis
    perifascicular atrophy
  32. Dermatomyositis
    ØClinical rash/cutaneous necrosis

    ØSlowly progressive pelvic and femoral weakness

    ØChronic inflammation – (T-CD4)

    ØMembrane attack complex
  33. Dermatomyositis: inflammation
    Myoinvasion (Lymphocytes attacking muscle fibers): perimesyum attacking 

    Lymphohistiocytic: endomesyum attacking
  34. How to differentiate myopathic changes vs neurogenic process? (stain? and presentation?)
    Stain: HE

    • Presentation: 
    • -Myopathic changes: 
    • ØRandom
    • myofiber size variation

    • ØRound
    • atrophy

    • ØRegenerating
    • / degenerating fibers

    • ØMyositis:
    • Inflammation

    • -neurogenic process:
    • ØAngular fiber atrophy

    ØMorular formations

    Fiber type groupin
  35. Gormori Trichrome stain
    Morphology of Fibrosis, nemaline, rods, ragged red fibers, inclusions
  36. inclusion body myositis under Gormori stain
    rimmed vacuoles
  37. mitochondrial myopathies under Gomori stain
    Ragged Red fibers
  38. How to stain mitochondria?
    stain oxidative enzyme NADH, SDH, COX2
  39. how is NADH stain different from SDH and COX2
    NADH can stain RER core, Tub agg in addition to Mt

    SDH and COX2 is specific for Mt

    Could provide mean for differential dxn
  40. how to see turn-over in the ms? (stain?)
    Alkaline phosphatase: generation, microvascular

    Acid phosphatase: lysosomes, macrophages
  41. Dermatomyositis: Alkaline phosphatase activity
    Regenerating muscle fibers


    Immune disease of connective tissue 

    Exclude present of Scar tissue
  42. Dermatomyositis: Acid phosphatase activity
    Indicates site of lysomomal activity:

    • -Macrophages engaged in phagocytosis
    • of dead fibers (degeneration)

    -Lysosomal storage disease
  43. Myopathy with acid phosphatase activity
    • Acid phosphatase – Lysosomal activity:
    • Macrophages, degen fibers