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5. HDS Neuro Psych > NMJ and Muscle Disorders > Flashcards

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.

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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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12
Q

LEMS

Treatment

A
  • Tx associated cancer ⇒ ↓ paraneoplastic Ab to VGCC
  • Symptomatic treatment with pyridostigmine (cholinesterase inhibitor)
  • Some response to immunosuppressants
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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
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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
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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
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16
Q

Myasthenia Gravis

Treatment

A
  • Cholinesterase inhibitor
    • Pyridostigmine (Mestinon)
    • Edrophonium (Tensilon)
  • Immunosuppressant treatment including steroids, azathioprine, mycophenylate, IVIG, and plasmapheresis
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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
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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)
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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
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20
Q

Botulism

Pathophysiology

A

Cleavage of proteins involved in docking of synaptic vesicles on the presynaptic NMJ

SNAP-25 or synaptobrevin

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21
Q

Botulism

Symptoms

A
  • Descending paralysis
  • Non-reactive pupils
  • Dry mouth, blurred vision
  • Respiratory distress or complete paralysis
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22
Q

Botulism

Diagnosis and Treatment

A

EMG: Fast RNS(2-50Hz) ⇒ incremental response similar to LEMS

Treatment is supportive, antitoxin

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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”
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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
25
Q

Muscular Dystrophies

Inheritance Patterns

A

Genetic, progressive weakness

  • X–linked:
    • Duchenne and Becker’s Muscular Dystrophies
    • Most Emery-Dreifuss
  • Autosomal dominant:
    • Myotonic Dystrophies
    • Fascioscapulohumeral Muscular Dystrophy
  • Autosomal Recessive:
    • Most Limb Girdle Muscular Dystrophies
26
Q

Muscular Dystrophies

Cardiac Effects

A

Cardiac issues including cardiac conduction defects and cardiomyopathies

Monitor w/ EKGs, echocardiograms, cardiac MRI

Cause of death in most pts

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
31
Q

Duchenne Muscular Dystrophy (DMD)

Treatment

A
  • Prednisone ⇒ prolongs ability to walk by a few years
  • Interdisciplinary support for respiratory, cardiac, skeletal complications
  • Genetic trials are ongoing
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
36
Q

Limb-Girdle Muscular Dystrophies

A
  • Mostly autosomal recessive
  • Comprises a large number of types
  • Shoulder and hip girdle weakness
  • May be asymmetric
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

42
Q

Hypokalemic Periodic Paralysis

A
  • Calcium or sodium channel mutations
  • Age is 1st or 2nd decade
  • Duration of attacks ⇒ hours to days
  • < 3.0 mEq/L K+
  • Triggers: Rest after exercise, cold and food (carbohydrate load) induce attacks
43
Q

Hyperkalemic Periodic Paralysis

A
  • Sodium channel mutation
  • Earlier age of onset (1st decade)
  • Duration of attacks ⇒ hours
  • Triggers: Rest after exercise, K+ rich foods, hunger, or cold can precipitate attacks
  • K+ is high or normal
44
Q

Anderson-Tawil

A
  • Potassium channel mutation
  • Age is 1st or 2nd decade
  • Duration of attacks ⇒ hours to days
  • Triggers: prolonged rest after exercise
  • K+ can be low, normal, or high
  • Associated w/ cardiac conduction and skeletal muscle abnormalities
45
Q

Inborn Errors of Metabolism

Associated Myopathies

A
  • Glycogen synthesis and degradation disorders
  • Lipid Myopathies
    • Accumulation of lipid within myocytes
  • Mitochondrial function disorders
    • Nuclear and mitochondrial genes (ox/phos)
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
  • Some have interstitial lung disease, vasculitis, myocarditis
  • ↑ Risk of developing visceral cancers
49
Q

Dermatomyositis

Associations

A
  • Look for an underlying cancer!
  • Anti-Jo Ab seen w/ interstitial lung disease
  • Esophageal involvement ⇒ dysphagia
  • Cardiac problems
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
55
Q

Infectious Inflammatory Myopathy

A
  • Trichinosis ⇒ most common
  • Follows ingestion of inadequately cooked pork
  • Adult female worm enters circulation and gets to skeletal muscle
  • Causes acute muscle pain and tenderness with local swelling, fever, and eosinophilia
  • Can see the encysted parasite in muscle biopsy, surrounded by lymphocytes and eosinophils
56
Q

Ethanol Myopathy

A
  • Binge drinking of alcohol: rhabdomyolysis with myoglobinuria that may lead to renal failure
  • Pain is either generalized or confined to a single muscle group
  • Swelling of myocytes, fiber necrosis, myophagocytosis, and regeneration
  • There may also be evidence of denervation
57
Q

Thyrotoxic Myopathy

A
  • Acute or chronic proximal muscle weakness
  • May precede the onset of other signs of thyroid dysfunction: increased T3/T4
  • Myofiber necrosis, regeneration, and interstitial lymphocytosis, fatty infiltration of muscle is seen in severe cases
  • Another dysfunction is thyrotoxic periodic paralysis
    • Characterized by episodic weakness that is often accompanied by hypokalemia
58
Q

Corticosteroid Myopathy

A
  • Proximal muscle weakness and atrophy
  • Severity of clinical disability is variable
  • Predominantly atrophy of type 2 muscle fibers
  • Bimodal distribution of fiber sizes:
    • Type 1 fibers of nearly normal caliber
    • Markedly atrophic type 2 fibers

5. HDS Neuro Psych (46 decks)

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