NMJ and Muscle Disorders Flashcards
1
Q
NMJ
A
Motor nerve axon terminal contains synaptic vesicles w/ Acetylcholine
Voltage-gated Ca2+ channelsactivated by presynaptic depolarization ⇒↑Ca2+intracellularly ⇒ synaptic vesicles fusion w/ presynaptic membrane ⇒ release of ACh into synapse ⇒AChRon postsynaptic membrane of NMJ activated ⇒ depolarization of muscle endplate ⇒ muscle fibercontraction
Any problem in this junction or in the muscle fibers themselves will causes weakness.
2
Q
Skeletal Muscle
Structure
A
- Divided by CT septae into fascicles
- Within the fascicles, large syncytial muscle fibers
- Cytoplasm of muscle fibers is filled with myofilaments ⇒ form the contractile apparatus
3
Q
Skeletal Muscle
Fiber Types
A
- Type I ⇒ slow twitch fiber
- Mainly responsible for posture
- High conc. of myoglobin, oxidative enzymes, and mitochondria
- ID using histochemistry for NADH
- Type II ⇒ fast twitch fiber
- Involved in more rapid phasic contractions
- High conc. of glycolytic enzyme
- ID using histochemistry for ATPase at pH 9.4
4
Q
Skeletal Muscle
Fiber Organization
A
- Mix of Type I and Type II fibers ⇒ checkerboard pattern
- Individual motor neuron innervates only Type I OR Type II fibers
- Checkerboard composed of the interlacing of fibers from different neurons
- All the fibers from one single neuron are referred to as a motor unit
5
Q
Skeletal Muscle
Reaction to Injury
A
- Initial degeneration muscle fibers: loss of the striations, ↑ eosinophilia, and mild inflammation around muscle fibers
- High regenerative capacity ⇒ d/t satellite (stem) cells
- Regenerating muscle ⇒ central enlarged, nuclei with prominent nucleoli in a basophilic cytoplasm
6
Q
Muscle Atrophy
A
- Acquired process ⇒ distinguish from dystrophy
- Clinically characterized by weakness and decreased muscle tone and bulk
-
Causes of atrophy include:
- Systemic problems
- Malnutrition
- Immobilization with disuse
- Endocrinologic disease
- Ex. Pan-hypopituitarism
- Anatomic causes
- Denervation of muscles secondary to trauma
- Polio with secondary denervation
-
Histology
- Reduction in myofiber size
- Angulated on cross section
7
Q
Denervation Muscle Atrophy
A
- Axonal degeneration ⇒ loss of neural input to muscle fibers within motor unit ⇒ denervation atrophy
- Breakdown of myosin and actin ⇒ ↓ cell size and resorption of myofibrils
- Small angulated fibers
- Some cells undergo cytoskeletal reorganization ⇒ central rounded zone of disorganized filaments (target fiber)
-
Fiber type grouping occurs ⇒ loss of the checkerboard pattern ⇒ new pattern w/ large areas of Type I or Type II staining
- As innervation lost, collateral sprout from adjacent nerve fibers to reinnervate now denervated muscles
- Useful in dx of denervation vs. other causes of muscle atrophy
8
Q
Neuromuscular Junction Disorders
A
-
Neuromuscular junction
- Pre-synaptic: Lambert-Eaton Syndrome, botulinum toxin
- Post-synaptic: Myasthenia Gravis
- Muscle membrane and muscle fibers: muscular dystrophies and myotonic dystrophies, periodic paralyses, Malignant Hyperthermia, Inflammatory myopathies, metabolic myopathies, toxic or infectious myopathies
9
Q
Myasthenic Disorders
A
Myasthenic - describes fatigable muscle weakness
Lambert-Eaton Syndrome & Myasthenia Gravis
- Caused by autoantibodies
- Fluctuate markedly
- Proximal muscles
- Bulbar muscles (face, OP)
- Respiratory muscles (diaphragm)
10
Q
Lambert-Eaton Myasthenic Syndrome (LEMS)
Overview
A
Paraneoplastic disorder which occurs in 2-3% small-cell lung cancer cases.
- Can occur w/o malignancy
-
Symptoms:
- Gait problems
- Autonomic dysfunction including orthostatic hypotension, constipation, and dry mouth
- Proximal muscle weakness - legs > arms
- Less bulbar weakness than in Myasthenia Gravis
-
Pathophysiology:
- Voltage-gated calcium channels (VGCC) in the presynaptic neuromuscular junction targeted by autoantibodies
11
Q
LEMS
Diagnosis
A
- VGCC antibodies in serum
-
EMG:
-
Slow Repetitive Nerve Stimulation ⇒ ↓ response
- Depletion of ACh in synapse
-
Fast RNS or post exercise ⇒ ↑ response
- ↑ Presynaptic intracellular Ca2+ ⇒ repletion of ACh in synapse
-
Slow Repetitive Nerve Stimulation ⇒ ↓ response
12
Q
LEMS
Treatment
A
- Tx associated cancer ⇒ ↓ paraneoplastic Ab to VGCC
- Symptomatic treatment with pyridostigmine (cholinesterase inhibitor)
- Some response to immunosuppressants
13
Q
Myasthenia Gravis (MG)
Overview
A
- Prevalence of up to 200/1 million
- Bimodal distribution
- Women ⇒ 20’s
- Men ⇒ late adulthood
-
Ab to ACh receptor most common
- Binding or blocking Ab
- Accelerated degradation of AChR
- Complement-mediated lysis of the of the postsynaptic membrane
- Other Ab identified, mostly anti-muscle-specific tyrosine kinase (MuSK)
- Associated with other autoimmune diseases
- Associated with thymomas
14
Q
Myasthenia Gravis
Symptoms
A
- Ocular subtype: involvement of the extraocular and eyelid muscles only: may cause double vision
- Generalized type: involvement of the face, limbs and chest: may be life-threatening due to asphyxiation
- 50% of pts present w/ ocular symptoms first
-
Ptosis often unilateral
- Will worsen as pt tries to look up for a prolonged period of time
- Hypophonia (low volume of voice)
- Slurred speech (dysarthria)
- Coughing on liquids (dysphagia) and possibly aspiration
-
Respiratory dysfunction during severe myasthenic crisis
- Requires frequent measurement of Negative Inspiratory Force (NIF) and Forced Vital Capacity (VC)
- Might need intubation and ventilator
15
Q
Myasthenia Gravis
Diagnosis
A
- AchR Ab in serum (binding or blocking) ⇒ if ⊖, check MuSK Ab (muscle skeletal receptor tyrosine kinase)
- Edrophonium (aka Tensilon) test (less common)
- Ice pack test
- EMG:
-
Slow RNS ⇒ ↓response
- ↓response to ACh in synapse, sensitive to depletion of AChR after repeated stimulations
- Fast RNS ⇒ NO increment
- Single fiber EMG if above are negative
-
Slow RNS ⇒ ↓response
16
Q
Myasthenia Gravis
Treatment
A
- Cholinesterase inhibitor
- Pyridostigmine (Mestinon)
- Edrophonium (Tensilon)
- Immunosuppressant treatment including steroids, azathioprine, mycophenylate, IVIG, and plasmapheresis
17
Q
Myasthenia Gravis
Thymectomy
A
- CT of chest recommended to rule out thymoma
- Thymectomy indicated for pts w/ thymomas
- RCT found improved outcomes for non-thymoma pts who underwent thymectomy
18
Q
Myasthenia Gravis
Contraindicated Medications
A
Some medications can worsen myasthenic crisis:
- Some antibiotics: aminoglycosides and fluoroquinolones
- Botulinum toxin
- Quinine
- Procainamide
- Betablockers
- Magnesium
- Steroids (although used as treatment)
19
Q
Botulism
Overview
A
- Clostridium botulinum toxin
- Spores found in soil, fish, home canned goods
- Infantile botulism: honey
-
Iatrogenic: Botulinum toxin injections are done in high concentrations for cervical dystonia or spasticity (i.e. for cerebral palsy or stroke-contractures)
- Rarely a problem w/ cosmetic procedures or for chronic migraine
20
Q
Botulism
Pathophysiology
A
Cleavage of proteins involved in docking of synaptic vesicles on the presynaptic NMJ
SNAP-25 or synaptobrevin
21
Q
Botulism
Symptoms
A
- Descending paralysis
- Non-reactive pupils
- Dry mouth, blurred vision
- Respiratory distress or complete paralysis
22
Q
Botulism
Diagnosis and Treatment
A
EMG: Fast RNS(2-50Hz) ⇒ incremental response similar to LEMS
Treatment is supportive, antitoxin
23
Q
Myopathies
Overview
A
Diseases of the muscle fibers
Symptoms:
- Weakness ⇒ dysfunction of muscle fibers
- Muscle tenderness ⇒ inflammation of muscles
- Cramps (myotonia) ⇒ abnormal activation of muscle fibers
-
Myoglobinuria
- Breakdown of muscle enzymes
- Creatinine Kinase (CK) elevated in blood
- “Tea colored urine”
24
Q
Muscular Dystrophies
Overview
A
- Genetic diseases characterized by: progressive muscular atrophy and degeneration
- Various forms of inheritance
- Weakness and extra-skeletal features
- Advanced cases are characterized by the replacement of muscle fibers by fibro-fatty tissue
- Distinguishes dystrophies from myopathies, which also present with muscle weakness
27
Q
Duchenne Muscular Dystrophy (DMD)
Overview
A
- DMD gene on X chromosome codes for Dystrophin Protein
- Connects the contractile apparatus to the extracellular membrane
- Absent in Duchenne’s Muscular dystrophy
- Reduced in number in Becker’s muscular dystrophy
28
Q
Becker’s Muscular Dystrophy
A
- DMD gene on X chromosome codes for Dystrophin Protein
- Connects the contractile apparatus to the extracellular membrane
- Reduced in number in Becker’s muscular dystrophy
29
Q
Duchenne Muscular Dystrophy (DMD)
Clinical presentation
A
- Affects boys
- Toe walking at young ages
-
Calf Pseudohypertrophy
- Destruction of calf muscle & replacement by fat/fibrous tissue
- Elevated creatinine kinase
- Gowers sign ⇒ indicative of proximal muscles weakness
- Foot contractures
- Scoliosis
- Severe pelvic and shoulder weakness
- Eventually requires wheelchair
- Ventilator support
- Usu. death by age 20
30
Q
Duchenne Muscular Dystrophy
Pathology
A
- Degeneration and regeneration of muscle fibers
- Necrosis and phagocytosis of muscle fibers
- Fatty and fibrous tissue deposition
- Fiber type grouping is not seen
32
Q
Myotonic Dystrophy
Overview
A
- Most common dystrophy in adults
- Involuntary contraction of a group of muscles
-
Autosomal dominant, shows anticipation
- Genes: DM1, DM2
- Type 1 may be seen at birth
- ↑ Risk for Malignant Hyperthermia
- Often presents in late childhood with abnormalities in gait
33
Q
Myotonic Dystrophy
Clinical Presentation
A
-
Weakness of hands and feet
- Grip myotonia ⇒ when gripping hand, hand cramps when trying to relax and let go
- Cataracts
- Cardiac involvement
- Cognitive problems
- Frontal balding
- Long facies
- Temporal wasting
34
Q
Myotonic Dystrophy
Pathology
A
- Variation in fiber size
- ↑ # of internal nuclei
-
Ring fibers
- Sub-sarcolemmal band of cytoplasm that appears distinct from the center of the fiber
35
Q
Facioscapulohumeral
Muscular Dystrophy
A
- Autosomal dominant
- Scapular winging
- Facial weakness
- Hearing loss
- Retinopathy
37
Q
Emery-Dreifuss
Muscular Dystrophy
A
- Mostly X-lined
- Contractures prominent, unlike other muscular dystrophies
- Mostly upper extremities
- (Biceps and triceps affected more than shoulders)
38
Q
Malignant Hyperthermia
A
- Inherited susceptibility to anesthesia
- Common w/ muscle disorders
- Triggered by inhaled anesthetics
- Increased intracellular calcium
- Symptoms: Fever > 38.8°C, myoglobinuria, tachycardia, acidosis
- Emergency ⇒ treat w/ dantrolene
39
Q
Distal Myopathies
A
Affect hands and feet
Welander, Nonaka and Miyoshi forms
40
Q
Congenital Myopathies
A
-
Most conditions share common clinical features:
- Onset in early life
- Non-progressive or slowly progressive course
- Proximal or generalized muscle weakness
- Hypotonia ⇒ “Floppy babies”
- Severe joint contractures (arthrogryposis)
-
Diseases:
- Central Core disease ⇒ ryanodine receptor gene mutation
- Nemaline (“rod body”) myopathy ⇒ most distinctive
41
Q
Periodic Paralysis
A
Hereditary transient weakness
Channelopathies of the sodium or calcium channels
46
Q
Mitochondrial Myopathies
A
- Oxidative phosphorylation diseases
- Ex. MERRF (myoclonic epilepsy w/ ragged red fibers)
-
Mitochondrial myopathies caused by:
- Point mutations in mitochondrial DNA
- Deletions or duplications of mitochondrial DNA
- Mutations in genes for mitochondrial proteins that are encoded by nuclear DNA
- Muscle fiber contour becomes irregular on cross-section (ragged red fibers)
- Subsarcolemmal aggregates of abnormal mitochondria
- Some contain paracrystalline parking lot inclusions or ∆ mitochondrial structure
47
Q
Non-infectious Inflammatory Myopathies
A
- Heterogeneous group of disorders
- Immunologically mediated
- Characterized by injury and inflammation of skeletal muscle
-
Three relatively distinct disorders:
- Dermatomyositis
- Polymyositis
- Inclusion body myositis/myopathy
-
Common to all 3:
- Progressive proximal weakness
- ↑ Serum Creatinine Kinase
- Associated w/ autoimmunity
- Biopsy required for definitive dx
- Important to dx b/c immunosuppressive therapy beneficial in adult and juvenile dermatomyositis and polymyositis
48
Q
Dermatomyositis
Clinical Manifestations
A
-
Skin manifestations
- Grotton’s lesions ⇒ scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees
- Heliotrope rash ⇒ lilac or heliotrope discoloration of the upper eyelids with periorbital edema
- Chest and back rash ⇒ V sign, Shawl sign
- Calcinosis of joints and fingers
-
Muscle manifestations
-
Insidious, bilaterally symmetric, muscle weakness
- Affects proximal muscles first
- Often accompanied by myalgias
- ⅓ of pts have dysphagia 2/2 head and neck flexors/extensors weakness
- Cranial muscle sparing
-
Insidious, bilaterally symmetric, muscle weakness
- Some have interstitial lung disease, vasculitis, myocarditis
- ↑ Risk of developing visceral cancers
50
Q
Dermatomyositis
Diagnosis and Treatment
A
- Diagnosis:
- Muscle biopsy shows inflammatory infiltrates w/ perifascicular atrophy and vascular lesions
- Treatment:
- Steroids, IVIG, methotrexate, mycophenolatemofetil
51
Q
Polymyositis
A
Recently regrouped into anti-synthetase myopathy and immune-mediated necrotizing myopathy
-
Symmetric proximal muscle involvement
- Similar to dermatomyositis
- No cutaneous involvement
- Occurs mainly in adults
- Likely d/t CMI of myocytes
- No e/o vasculitis
-
Muscle biopsy:
- ⊕ Inflammatory infiltrates, necrosis and regeneration
- ⊖ vascular lesions or perifascicular atrophy
- Treatment: Steroids, IVIG, methotrexate, mycophenolatemofetil
52
Q
Inclusion Body Myositis
A
- Most common myopathy in > 50 age group
- Male predominant
- Pattern of weakness is unique ⇒ finger flexors and quadriceps weakness classic
- No treatment proven to improve or slow progression of weakness
- Muscle biopsy demonstrates rimmed vacuoles, intracellular inclusion bodies, lymphocytic infiltrates around muscle cells
53
Q
Statin Induced Myopathy
A
- Myalgia ⇒ normal serum CK
- Myositis ⇒ increased CK or muscle biopsy findings
- Rhabdomyolysis ⇒ CK levels >10 times upper limit of normal
- Likely multifactorial including mitochondrial dysfunction, apoptosis, membranolysis
54
Q
Critical Illness Myopathy
A
-
Multifactorial causes
- Sepsis
- Sedated on a ventilator
- Multiple courses of abx
- DKA
- Pt in ICU for days to weeks
- Prevention involves avoidance of hyperglycemia, limiting sedation and avoiding steroids when possible
- Treatment is rehabilitation
