Muscle lecture

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Muscle PathologyNovember 18, 2004Steven S.
Chin, M.D., Ph.D.
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Neuromuscular disease workup Clinical
history Family history Electrodiagnostic
studies Laboratory studies Muscle biopsy
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Muscle-related terms

• Muscle
• Fascicles
• Myofiber muscle fiber
• Myofibrils
• Myofilaments
• Myosin and actin filaments

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Connective tissue sheaths of muscle
Endomysium - surrounds individual
fibers Perimysium - surrounds each
fascicle Epimysium - surrounds groups of
fascicles Nerves, blood vessels, and muscle
spindles located in perimysium
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Muscle fibers bundled into fascicles Modified
Gomori trichrome stain
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Striated appearance of skeletal muscle. High
magnification, HE stain.
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Electron micrograph of normal skeletal muscle.
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Muscle spindle - mechanoreceptors
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Muscle biopsy

• Handle carefully to avoid distortions
• - excessive contraction
• Routine formalin-fixed, paraffin sections
• Cryosections
• - freeze to - 160 C
• - preserves enzymatic activities
• - preserves architecture
• Electron microscopy

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Special stains

• ATPase (pH 9.4, pH 4.6, pH 4.2)
• - differentiates type 1 and type 2 myofibers
• Modified Gomori's trichrome
• - collagen
• - mitochondria and other organelles
• - inclusions
• NADH-TR oxidative stain
• HE demonstrates myofiber degeneration and
  regeneration

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Type 1 and 2 muscle fibers

• Type 1
• - slow twitch, oxidative
• Type 2
• - fast twitch, mainly glycolytic
• Normal human muscle
• - mosaic pattern (checkerboard) of
• both fiber types

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Myosin ATPase stain of normal skeletal muscle
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Modified Gomori's trichrome stain on normal
skeletal muscle.
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Modified Gomori's trichrome stain on normal
skeletal muscle. Sarcoplasmic ?dots' -
mitochondria.
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NADH-TR (nicotinamide adenine dinucleotide -
tetrazolium reductase) Normal skeletal muscle.
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Normal muscle - HE stain
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Muscle pathology

• Two major types of pathology
• Neurogenic
• - loss of nerve stimulation
• Myopathic
• - intrinsic abnormality of muscle

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Neurogenic diseases

• Amyotrophic lateral sclerosis
• Spinal muscular atrophy (SMA)
• Hereditary neuropathies
• Trauma
• Vascular diseases
• Infections

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Neurogenic Pathology

• Grouped atrophy
• Small angulated fibers
• Both fiber types are atrophic
• Fiber type grouping reinnervation
• Nuclear clumps
• Target fibers

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Chronic neurogenic disorder
1. Normal
2. Early denervation
3. Reinnervation - fiber type grouping
4. Continued denervation - group atrophy
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Neurogenic atrophy - ?grouped' atrophy
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Target fibers - NADH-TR stain
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Large fiber type groups indicative of chronic
neurogenic disease. ATPase stain.
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Marked atrophy of clusters of myofibers. Wernig-Ho
ffmann disease.
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Myopathic Diseases

• Dystrophic muscle diseases
• Inflammatory myopathies
• Myasthenia gravis
• Congenital myopathies
• Metabolic myopathies

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Myopathic Pathology

• Wide variation in fiber size
• Degeneration and regeneration
• Inflammation
• Central nuclei
• Fibrosis
• Architectural changes

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Duchenne Muscular Dystrophy

• Affects 1 in 3500 live male births
• X-linked disease - Xp21
• Huge gene and huge protein
• up to 3 Mbases of DNA
• 79 exons
• 427 kD protein - dystrophin
• 50 of cases are sporadic

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Duchenne Muscular Dystrophy

• Boys usually present below age 5 with proximal
  weakness
• Waddling gait
• Difficulty getting up from the floor (Gower's
  maneuver)
• Difficulty with climbing stairs
• Enlarged calves (pseudo-hypertrophy)

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Duchenne Muscular Dystrophy

• Elevated creatinine kinase
• Loss of ambulation between 8 and 12 years
• Usually die in late teens from respiratory
  insufficiency or pneumonia

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Duchenne Muscular DystrophyPathology

• Variation in fiber size with large rounded fibers
  
• Marked endomysial fibrosis
• Some regeneration
• Eventually muscle replaced by fat and fibrous
  tissue

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Duchenne muscular dystrophy - HE stain
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Duchenne muscular dystrophy - modified Gomori's
trichrome stain
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Dystrophin

• Muscle membrane protein
• Lacking in Duchenne muscular dystrophy
• Leads to breakdown in muscle fibers with use
• Lack of other membrane proteins are associated
  with other specific dystrophies

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After Kumar et al., Robbins Cotran Pathologic
Basis of Disease, 2004
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Normal immunohistochemical sarcolemmal staining
for dystrophin
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Dystrophin staining in a patient with DMD
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Diagnosis

• Blood tests to look for common deletions - 65
• Stain muscle with antibody to dystrophin
• In utero testing can also be done

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Inflammatory Myopathies

• Polymyositis
• Dermatomyositis
• Inclusion body myositis
• Sarcoidosis
• Trichinosis
• Viral myositis

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Polymyositis and DermatomyositisClinical

• Pain and aching in muscles
• Proximal weakness
• More common in females
• Elevated creatinine kinase
• Facial rash in dermatomyositis
• Respond to steroids

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PolymyositisDermatomyositisPathology

• Chronic inflammatory infiltrate
• Degeneration and regeneration
• Variation in fiber size
• Moth-eaten fibers
• Perifascicular atrophy - dermatomyositis

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Inflammatory myopathy - chronic inflammatory cell
infiltrate surrounding and infiltrating necrotic
muscle fibers. HE stain.
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Polymyositis - endomysial, chronic inflammatory
cell infiltrates and chronic myopathic changes.
HE stain.
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Necrotic and regenerating myofibers. HE stain.
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Regenerating myofiber. HE stain.
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?Moth-eaten' myofibers. NADH-TR stain.
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Dermatomyositis - perifasicular atrophy. Modified
Gomori's trichrome stain.
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Trichinosis

• Nematode Trichinella spp (spiralis)
• Clinical symptoms
• 2 weeks after ingestion of contaminated
• food (pork)
• Vomiting and diarrhea (enteric phase)
• Periorbital and facial edema, fever, myalgia and
  proximal weakness (acute systemic phase)
• Larvae encyst in skeletal muscle
• Lymphocytic and eosinophilic response
• Eosinophilia
• Eventually calcify

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Trichinella in host nurse cell.
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Myasthenia Gravis

• Neuromuscular transmission disorder
• Fluctuating weakness, principally abnormal
  fatiguability after repeated activity
• Improvement after rest
• More common in females
• Circulating antibodies to acetylcholine receptors
• Leads to lysis of postsynaptic membranes
• Clinical diagnosis - Tensilon test
• Inhibits acetylcholinesterase

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Congenital Myopathies

• Hypotonic (floppy) or weak infant
• Usually non-progressive or
• slowly progressive
• Unusual morphological changes in muscle fibers

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Central Core Disease

• Common congenital myopathy
• Autosomal dominant
• Delay in achieving motor milestones (walking)
• Mild non- progressive weakness of proximal limb
  musculature
• Central area in muscle fibers that lacks
  oxidative enzymes
• Affects type 1 muscle fibers
• Strong association with susceptibility to
  malignant hyperthermia

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Central core disease. NADH-TR stain.
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Central core disease - ultrastructural
disorganization (Z-band streaming).
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Mitochondrial Myopathy

• May develop symptoms later in life
• Increased numbers of abnormally formed
  mitochondria in muscle
• Maternal inheritance

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Ragged red fibers - modified Gomori's trichrome.
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Ragged red fiber - succinate dehydrogenase stain.
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Metabolic Myopathies

• Storage diseases
• Pompe's Disease
• Acid maltase (a1,4-glucosidase) deficiency
• Type II glycogenosis
• McArdle's Disease
• Myophosphorylase deficiency
• Type V glycogenosis
• Corticosteroid Myopathy

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Pompe's Disease Infantile-onset acid maltase
deficiency Autosomal recessive Generalized
progressive weakness, hypotonia, cardiomegaly
and hepatomegaly Death usually from
cardio-respiratory failure before age
2 Childhood-onset and adult-onset forms of acid
maltase deficiency Less severe than infantile
form
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Pompe's disease - HE stain
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Pompe's disease - PAS stain.
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Periodic Acid Schiff stain - normal muscle
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McArdle's Disease Myophosphorylase
deficiency Autosomal recessive Cramps and
muscular stiffness on exertion Myoglobinuria may
occur in 50 of cases No specific treatment Avoid
sudden strenuous exercise
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McArdle's disease - PAS stain.
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Type 2 myofiber atrophy - ATPase stain pH 9.4