Transcript שקופית 1 - Technion moodle

Muscle Diseases
Muscle Diseases
Clinical patterns of muscle disease
• Weakness: Proximal; Symmetric;
Persistent
• Weakness > Wasting
• Sensory: Normal
• Tendon reflexes: Decreased only in
areas of prominent weakness
• Other features in some myopathies
– Myotonia
– Rhabdomyolysis
– Cardiomyopathy
Laboratory Tests
•
•
•
•
•
Muscle enzymes
EMG
Muscle Pathology
Muscle Imaging
Genetic Evaluation
MUP - MOTOR UNIT
POTENTIAL
Recruitment and Interference
Pattern
EMG - NEUROGENIC
PATTERN
Positive Sharp Waves
Fibrillation
Fasciculations
Complex Repetitive Discharge
EMG – MYOPATHIC PATTERN
Short, Thin and Polyphasic
Early Recruitment
Early Interference
Muscle Pathology - Normal
Muscle
Muscle Pathology
• Fiber Size
H&E stain – Small Fibers
ATPase pH 9.4 stain - Large fibers
Muscle Pathology
• Necrotic Fibers
H&E
Muscle Pathology
• Ragged red muscle fiber
Gomori trichrome stain
Muscle Pathology Histochemistry
• Fiber Type
Muscle Pathology Inflammation
Congo red stain
Esterase stain
CD68 stain
Muscle Pathology – ImmunoHistrochemistry
Muscle Pathology – Electron
microscopy
559781160004923
Muscle Imaging
The Muscular Dystrophies
progressive hereditary degenerative
diseases of skeletal muscles.
Duchenne muscular dystrophy
Guillaume-Benjamin
Duchenne de Boulogne
DMD – Clinical Features
• Onset 3 to 5 yrs
• Weakness: Proximal > Distal; Symmetric;
Legs & Arms
• Steady decline in strength: After 6 to 11
years
• Waddling gait
• Failure to walk: 9 - 13 years; Later with
steroid treatment
DMD – Clinical Features
• Gowers sign:
Standing up with
the aid of hands
pushing on knees
DMD – Clinical Features
• Muscle hypertrophy
–
–
–
–
Especially calf
May be generalized
Increases With age
Due to muscle fibrosis,
not enlarged muscle
fibers
DMD – Clinical Features
• Contractures
• Scoliosis after loss of ambulation
• Cardiomyopathy: Dilated; Especially > 15
years
• Mental retardation: Mean IQ ~ 88
• Night blindness
Progression: Death 15 - 25 years due to
respiratory or cardiac failure
DMD - Dystrophin gene
• Chromosome Xp
• 79 Exons
– Exons are only 0.6% of gene
• Dystrophin mRNA
– Size: 14kb
– Encodes 3685 amino acid 427kDa protein
• 7 different dystrophin transcripts with
– Muscle, Cortical, Purkinje Cell, Retinal ,Schwann Cells
– Genotype: Dystrophin
• 96% with frameshift mutation
• 30% with new mutation
DMD - Dystrophin
• Dystrophin Localization: Subsarcolemmal
region in skeletal and cardiac muscle
• Dystrophin functions
– Stabilizaton of membrane during contraction
& relaxation
– Part of link between intracellular cytoskeleton
& extracellular matrix
DMD - Laboratory features
• Serum
– CK: Very high
– Troponin I: Elevated above normal but not to
levels in cardiac ischemia
– Liver enzymes: High AST & ALT
• EMG
– Myopathic pattern
DMD – Muscle Pathology
Biopsy from 5 yr old
boy
Biopsy from 10 yr old
boy
Endomysial connective tissue.
Variable fiber size.
Small fibers are rounded.
Markedly connective tissue.
Many hypercontracted muscle
fibers
DMD – Muscle Pathology
Dystrophin staining
Normal dystrophin
staining
around the rim of muscle
fibers.
Absent dystrophin: Duchenne muscular
dystrophy
Left: No staining around the rim of muscle
fibers.
Right: No staining of most muscle fibers.
One "revertant" fiber with dystrophin
DMD: Therapy
• Drug treatment: Prolongs ability to walk by 2 to 3
years
– Prednisone
•
•
•
•
•
•
•
•
Prolongs walking by 2 to 3 years
Increased Strength
Falling reduced
Most beneficial while patient still ambulatory
Myoblast therapy
Gene therapy
Carrier Evaluation
Perinatal Consultation
Myotonia: General features
• Clinical: Delayed relaxation of skeletal
muscle following voluntary contraction
• Present with initial activity
• Usually abates after repeated muscle
activity
• Classification by ion channel disorder
• EMG: Myotonia
Myotonic Dystrophy: Clinical
features
• General
– Marked variation in severity within families
– Anticipation
– Strong relationship of clinical syndromes to
age of patient and age of onset
• Onset: Neonatal to late adulthood
Myotonic Dystrophy: Clinical
features
• Weakness
– Cranial
• Face: Superficial muscles; Temporalis
• Ptosis (Symmetric; Partial): Levator palpebrae
superioris;
• Masseter
• Palate ± Tongue: Indistinct speech
– Neck: Flexors & Sternomastoids
Myotonic Dystrophy: Clinical
features
• Myotonia
– Evoked by percussion or muscle contraction
– Onset: 5 to 25 years; Not congenital
– Rarely causes disability
– Treatment: Little functional benefit
Myotonic Dystrophy: Clinical
features
• CNS
– Personality: Avoidant; Apathy
– Hypersomnia
• Excessive daytime sleepiness
– Mental retardation (10% to 24%): Congenital;
Non-progressive
• PNS
– Mild sensory neuropathy (Rarely functionally
significant(
Myotonic Dystrophy: Clinical
features
• Face
–
–
–
–
Frontal balding
Temporal wasting
Ptosis
Hatchet face
• Eyes
–
–
–
–
Cataracts
Ptosis
Retinal degeneration
Ciliary body weakness (Low intraocular tension(
Myotonic Dystrophy: Clinical
features
• Cardiac:
– Conduction defects: Ectopic beats; Sudden death
– Tachyarrhythmias
– ± Cardiomyopathy
• Gastrointestinal: Dysphagia (Pharyngeal or
Esophageal); Megacolon; Cholelithiasis;
Constipation
• Skeletal
– Small sella turcica
– Frontal bossing
Myotonic Dystrophy: Laboratory
features
• CK: Normal to 3x
• EMG
– Myotonia
• After 1st decade
• Not present early in congenital MyD
– Myopathic potentials: Distal > Proximal
• Genetic testing
• Muscle biopsy
– Myopathic changes
Myotonia treatment
•
•
•
•
•
•
Quinine
Mexiletine
Dilantin
Procainamide
Carbamazepine
Acetazolamide
Dermatomyositis: Clinical
features
• Frequency: > 90% of
inflammatory
myopathies in
children
• Skin - Erythematous
rash: Heliotrope
Dermatomyositis: Clinical
features
Gottron's papules
Erythema
Dermatomyositis: Clinical
features
• Muscle weakness: Proximal; Dysphagia
• Joint contractures
• Other occasional systemic features
– Ocular: Retinopathy; Conjunctivitis; Iritis;
Uveitis
– Cardiac
Dermatomyositis:
Malignancy associated
• Females; Age related
• Neoplasms
– Ovarian advanced stage
– Small cell carcinoma, lung
Dermatomyositis: Laboratory
features
• Serum CK: Normal or High (up to 30 times
normal)
• Antibodies: Mi-2 & Jo-1
• Myoglobinuria (sustained): May be presenting
feature
• EMG: Irritative myopathy
– Motor units: Small amplitude; Brief; Polyphasic
– Spontaneous activity: Fibrillations; Positive sharp
waves
Dermatomyositis: Laboratory
features
• DM: Pathology
– Muscle fibers: Perifascicular pathology
• Myopathic changes: Necrosis + phagocytosis;
Regeneration
• Muscle fiber atrophy
– Vessels
• Microvascular deposits
– Inflammation - Usually perivascular
Dermatomyositis: Muscle
Pathology
Dermatomyositis: Treatment
options
• Prednisone
– Oral 100 mg q.d.; then taper
– Latency before benefit: 1 to 6 months
• Solumedrol (i.v.): Fewer side effects than oral
prednisone
• Azathioprine
– 2.5 - 3mg/kg/day
– Used to reduce Prednisone dose
– Latency before benefit: 6 to 12 months
• Methotrexate
• Cyclosporine
• IVIg
Dermatomyositis: Prognosis worse
•
•
•
•
•
•
Cardiac involvenment
Acute onset
Fever
Arthritis
Hypergammaglobulinemia
Lung fibrosis
IBM: Clinical features
• Muscles commonly spared
– Deltoid
– Pectoralis
– Interossei (Hands)
– Face
• Progression
– Slow over 5 to 20 years
– More rapid progression to disability with onset
after 60 years
IBM: Clinical features
• Dysphagia (30%): Upper 1/3 of
esophagus; Especially females
• Polyneuropathy
– Usually subclinical
– Sensory > Motor
– Loss of myelinated axons in sural nerve
IBM: Laboratory
• Serum CK: Mildly elevated 2 to 5 fold; May be
normal
• EMG: Irritable myopathy; Long duration
potentials may occur
• Barium swallow: Cricopharyngeus dysfunction
• Nerve conduction studies: Absent sural
potentials in some patients > 60 years
• Muscle MRI: Fatty infiltration of medial head of
gastrocnemius
IBM: Muscle Pathology
– Mitochondrial disorder: COX- muscle fibers &
multiple mDNA deletions in 50% of IBM
– Muscle fiber hypertrophy: More common than
in polymyositis
IBM: Muscle Pathology
• Rimmed vacuoles with granular material & filaments
– Histochemistry: Best visualized with Congo Red stain
– Contain
• Filaments: 15 to 18 nm
• Several proteins b-Amyloid, Desmin; Ubiquitin;
Transglutaminases 1 & 2
IBM: Electron Microscopy
IBM: Treatment
• None
• Few reports of response to IV Ig or
immunoabsorption
Hereditary IBM: Clinical
Features
•
•
•
•
Onset: 2nd or 3rd decade
Early: Peroneals
Distal & Proximal
Lower extremity
– Onset: Peroneal weakness (Anterior distal legs)
– Then: Hips & Hamstring
• Upper extremity: Shoulder girdle; Wrist
extension; Hands
• Sparing: Quadriceps; Deltoids
– Weak in some patients: Disease progression
Hereditary IBM: Clinical
Features
• Neck flexors may be weak
• Cranial nerves: Spared
– Rare ptosis
– No facial weakness
• Progression: slow
– Disability within 10 to 20 years of onset
– Often become wheel chair dependent
– Weakness may remain distal or involve
proximal muscles of arms legs or neck