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
25
Muscular Dystrophies
Inheritance Patterns
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
Muscular Dystrophies
Cardiac Effects
Cardiac issues including **cardiac conduction defects and cardiomyopathies**
Monitor w/ EKGs, echocardiograms, cardiac MRI
Cause of death in most pts
27
Duchenne Muscular Dystrophy (DMD)
Overview
* **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
Becker’s Muscular Dystrophy
* **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
Duchenne Muscular Dystrophy (DMD)
Clinical presentation
* 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
Duchenne Muscular Dystrophy
Pathology
* **Degeneration and regeneration of muscle fibers**
* **Necrosis** and **phagocytosis** of muscle fibers
* **Fatty and fibrous tissue deposition**
* Fiber type grouping is not seen
31
Duchenne Muscular Dystrophy (DMD)
Treatment
* **Prednisone** ⇒ prolongs ability to walk by a few years
* **Interdisciplinary support** for respiratory, cardiac, skeletal complications
* Genetic trials are ongoing
32
Myotonic Dystrophy
Overview
* **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
Myotonic Dystrophy
Clinical Presentation
* **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
Myotonic Dystrophy
Pathology
* Variation in fiber size
* ↑ # of internal nuclei
* **Ring fibers**
* Sub-sarcolemmal band of cytoplasm that appears distinct from the center of the fiber
35
Facioscapulohumeral
Muscular Dystrophy
* **Autosomal dominant**
* **Scapular winging**
* Facial weakness
* Hearing loss
* Retinopathy
36
Limb-Girdle Muscular Dystrophies
* **Mostly autosomal recessive**
* Comprises a large number of types
* **Shoulder and hip girdle weakness**
* May be asymmetric
37
Emery-Dreifuss
Muscular Dystrophy
* **Mostly X-lined**
* **Contractures prominent**, unlike other muscular dystrophies
* Mostly **upper extremities**
* (Biceps and triceps affected more than shoulders)
38
Malignant Hyperthermia
* **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
Distal Myopathies
**Affect hands and feet**
Welander, Nonaka and Miyoshi forms
40
Congenital Myopathies
* _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
Periodic Paralysis
**Hereditary transient weakness**
_Channelopathies_ of the **sodium or calcium channels**
42
Hypokalemic Periodic Paralysis
* **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
Hyperkalemic Periodic Paralysis
* **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
Anderson-Tawil
* **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
Inborn Errors of Metabolism
Associated Myopathies
* **Glycogen synthesis and degradation disorders**
* **Lipid Myopathies**
* Accumulation of lipid within myocytes
* **Mitochondrial function disorders**
* Nuclear and mitochondrial genes (ox/phos)
46
Mitochondrial Myopathies
* 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
Non-infectious Inflammatory Myopathies
* 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
Dermatomyositis
Clinical Manifestations
* _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
Dermatomyositis
Associations
* **Look for an underlying cancer!**
* **Anti-Jo Ab** seen w/ _interstitial lung disease_
* Esophageal involvement ⇒ **dysphagia**
* **Cardiac problems**
50
Dermatomyositis
Diagnosis and Treatment
* Diagnosis:
* Muscle biopsy shows **inflammatory infiltrates** w/ **_perifascicular_ atrophy and vascular lesions**
* Treatment:
* **Steroids, IVIG, methotrexate, mycophenolatemofetil**
51
Polymyositis
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
Inclusion Body Myositis
* **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
Statin Induced Myopathy
* **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
Critical Illness Myopathy
* _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
Infectious Inflammatory Myopathy
* **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
Ethanol Myopathy
* 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
Thyrotoxic Myopathy
* **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
Corticosteroid Myopathy
* **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
