PNS/Muscle 2 Flashcards
(87 cards)
1
Q
PACKET I
A
2
Q
What are the two main nerve responses to injury?
A
- Segmental demyelination
- Schwann cell dysfunction or sheath damage
- denuded axon indues remyelination by stimulating Schwann stemm cell proliferation
- Axonal degeneration
- primary destruction of the axon with the myelin sheath being secondary
- Wallerian degeneration
- Schwann cell catabolizes myelin and then macrophages “clean up”
- chromolysis (loss of nissl bodies) and perikaryon swelling
3
Q
With attempt at remyelination what occurs with the schwann cells? Myelin? Axon?
A
- Schwann cells
- proliferate and with multiple attempts to remyelinate they form an “onion bulb”
- Myelin
- thinner than previously
- Axon
- shorter internodal spaces
4
Q
What is the growth cone of the axon?
A
Multiple filopodia and lamellapodia that lead small, closely aggregated, thinnly myelinated axons along the cord of schwann cells. Very slow growth (1mm/day)
5
Q
Electrophysiology of axonal neuropathy?
Electrophysiology of demyelinating neuropathy?
A
- Axonal
- reduced signal strength due to axon dropout
- Demyelinating
- reduction in conduction velocity due to decreased myelin
6
Q
Guillan Barre Syndrome:
Cause? What occurs to the nerve?
A
- 2/3 are preceeded by influenza like illness
- Campylobacter jejuni
- Prior vaccinations
- However, it is due to immune response
- Inflammation and demyelination of roots and nerves
- perivenular and endoneural infiltration of lymphocytes, macrophages, and few plasma cells
- Macrophages penetrate at nodes and peel away myelin layers
7
Q
Guillain Barre:
Clinical?
Cause of death?
A
- Clinical concern is motor with ascending paralysis
- Elevation in CSF protein
- Altered vaso-permeability, especially in spinal roots
- Prominent segmental demyelination
- COD: due to respiratory paralysis, autonomic instability, cardiac arrest, or complication of treatment
8
Q
What is Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)?
A
- Chronic or subacute radiculoneuropathy
- no preceeding infection
- Often symmetric
- Mixed sensorimotor polyneuropathy
- Well developed “onion bulbing” due to ongoing injury
- Remissions may occur with steroids of plasmapharesis
9
Q
Neuropathy associated with systemic autoimmune disease:
Type of neuropathy?
Diseases associated?
A
- Polyneuropathy
- Distal sensory or sensorimotor
- RA
- SLE
- Sjogren
10
Q
What does neuropathy associated with vasculitis present as? What occurs?
A
- Mononeuritis multiplex
- mononeuritis or polyneuropathy possible
- Patchy axonal degeneration and loss
- Perivascular inflammatory infiltrates
11
Q
Leprosy:
How is morphology determined?
What are the two types?
A
- Morphology determined by cellular immune response
- Types
- Lepromatous
- Tuberculoid
12
Q
What occurs in lepromatous leprosy?
A
- Schwann cell invaded by bacteria
- segmental demyelination and remyelination
- Loss of both myelinated and unmyelinated fibers
- Endoneurial fibrosis
- Thickening of perineural sheaths
Overall: symmetric polyneuropathy with primary sensory loss in cooler extremities
13
Q
How does tuberculoid leprosy present?
A
- Active cell mediated response
- nodular granulomatous inflammation in dermis
- injury to cutaneous nerves
- perineural and endoneural fibrosis
- T cell response
- More localized nerve damage of axons, schwann cells, perineural and endoneural layers
14
Q
Lyme disease presentation?
A
- Due to dorrelia burgdorferi (spirochete)
- Variable presentation
- asceptic meningitis
- mild encephalopathy
- Polyradiculoneuropathies
- Facial nerve palsies
- either unilateral or bilateral
15
Q
In HIV what occurs in the early stage versus what occurs in the late stage?
A
- Early stage
- mononeuritis multiplex and demyelinating disorders
- similar to acute or chronic demyelinating diseases
- Late stage
- distal sensory neuropathy, often painful
- Loss of myelin integrity
16
Q
Diptheria:
What is it caused by/what does it look like?
Main cause of damage? Result?
A
- Corynebacterium diphtheriae
- G+ rod with clubbed ends
- Exotoxin
- initially causes paresthesia/weakness
- early loss of proprioception/vibratory sense
17
Q
Diphtheria:
How does the toxin get to the NS?
A
- Enters sensory ganglia due to incomplete blood nerve barrier
- Demyelination extends into adjacent anterior and posterior roots
- Mixed sensorimotor nerves
- The toxin blocks protein synthesis
18
Q
What is VZV?
A
- Latent infection of sensory ganglia of the SC and brainstem
- Reactivation causes painful vesicular skin eruptions along a dermatome
- thoracic and trigeminal nerves are most common
- Ganglia show neuronal destruction and loss
- Nerves show axonal degeneration after death of a sensory neuron
- May have persistant postherpetic neuralgia syndrome
19
Q
4 types of acquired metabolic and toxic neuropathies?
A
- Diabetes
- Metabolic, hormonal, and nutritional
- Toxic
- Tumor associated syndromes
20
Q
Diabetic neuropathy:
Mechanism?
2 most common neuropathies?
A
- Mechanism: non-enzymatic glycation of proteins and a change in function
- mass reaction due to abundance of glucose
- Ascending Distal symmetric sensorymotor neuropathy (most common)
- primarily axonal of small fibers
- endoneurial arterioles show vascular thickening
- Autonomic neuropathy (20-40%)
- Nearly always with distal symmetric sensory or sensorimotor neuropathy
- Postural htn, incomplete emptying of bladder (increased infections), sexual dysfunction
21
Q
PNS/MUSCLE II
A
22
Q
What occurs in uremic neuropathy?
A
- Axonal damage with secondary demyelination
- Distal symmetric neuropathy
- fine motor
- Some recover with dialysis
23
Q
What neuropathies are associated with thyroid dysfunction?
A
- Hypothyroidism
- carpal tunnel syndrome
- distal symmetric sensory polyneuropathy
- Hyperthyroidism
- GB type syndrome
- demyelination
24
Q
Alcohol’s effect on nerves?
A
- Primarily axonal
- Directly toxic to nerves
- Independent from possible related thiamine deficiency
25
In regards to nerves what could a pancoast tumor cause? Pelvic tumor?
* Pancoast
* brachial plexopathy
* Pelvic
* obturator palsy
26
In regards to compression what can tumors in the head cause? What about the cauda equina involvment in minengral carcinomatosis?
* Tumors in head
* cranial nerve palsy
* Bell's palsy
* Cauda equina
* polyradiculopathy of lower limb
27
Paraneoplastic neuropathy is typically associated with what cancer? What are the two types of lesions?
* Small cell lung carcinoma
* Slowly progressive sensorimotor lesion
* most common
* diffuse and symmetric
* Pure sensory with degeneration of DRG neurons
* less common
28
Neuropathy associated to IgM paraprotein? Mechanism?
* Binding of antibody to myelin associated glycoprotein
* Demyelinating neuropathy
29
Neuropathys associated with IgG or IgA?
Syndrome associated?
* Demyelinating neuropathy
* deposition in uncompacted myelin
* POEMS syndrome
* Polyneuropathy
* Organomegaly
* Endocrinopathy
* Monoclonal gammopathy
* Skin change
30
Role of light chain amyloid in neuropathy?
* Vascular insufficiency or direct toxicity to axons
31
4 types of hereditary neuropathies?
* Hereditary motor and sensory neuropathy (HMSN)
* mutations in genes for formation/maintenance of myelin
* Hereditary sensory neuropathy w/ or w/o autonomic neuropathy
* limited to numbness, pain, and autonomic dysfunction
* Familial amyloid polyneuropathy
* amyloid deposition due to mutation in transthyretin gene (AD)
* Peripheral neuropathy accompanying inherited metabolic disorder
* ALD (x-linked), porphyria (AD)... etc
32
Charcot-Marie Tooth 1:
Inheritance?
When does it present?
What occurs to the nerves and body?
* AD in childhood or early adulthood
* Repeated segmental demyelination (onion)
* Hypertrophy of individual peripheral nerves
* may be palpable
* Distal leg weakness
* Progressive muscular atrophy of the calf (peroneal muscular calf atrophy)
* Pes cavus: characteristic look of calf and foot
33
Charcot-Marie Tooth 1:
CMT1A genetics versus CMT1B?
* CMT1A
* duplication of C17 (segmental trisomy)
* Encodes for peripheral myelin protein 22
* Transmembrane protein involved in compact myelin
* CMT1B
* mutation on C1
* Gene for myelin protein zero (MPZ)
34
CMT2:
What is the form?
Inheritance?
What happens to the nerves?
* Neuronal form: affects the axon (no onion)
* AD
* _NO_ nerve enlargement
* Loss of myelinated axons
* No segmental demyelination
* normal conduction velocity
35
Most common subtype of Charcot Marie Tooth 2? Genetics involved?
* CMT2A
* Mutations in MFN gene involved in normal mitochondrial fusion
* Presents in early childhood
36
X linked Charcot marie tooth genetic mutation?
Mutation in GJB1 gene that codes for connexin 32
37
Hereditary neuropathy with pressure palsy:
What is the mutation?
Type of neuropathy?
* Deletion of the gene for PMP22
* Transient motor and sensory neuropathy triggered at sites prone to entrapment
* resolves in weeks to months
* may progress to chronic neuropathy
* Swollen, bulbous myelin sheath near nodes
38
What happens to the nerve with a laceration or avulsion?
* Axon degenerates distally
* Regeneration depends on the continuity of the nerve
* If cell body is preserved it will attempt to regenerate
* Neuroma may develop
* Disorganized axons with CT
39
Types of compression neuropathies?
* Carpal tunnel syndrome
* median nerve numbness/parasthesia
* frequently bilateral
* frequently due to repetitive motion
* Ulnar
* Radial - saturday night palsy
* Mortons neuroma
* intermetatarsal sites
* in women who wear heals
40
Disease of the neuromuscular junction?
* Myasthenia gravis
* Eaton-Lambert myasthenic syndrome
* Congenital myasthenic syndromes
* Disorders caused by toxins
41
Myasthenia gravis:
2 causes?
Diagnosis?
* Autoantibodies to acetylcholine receptors on postsynaptic membrane (85%)
* Antibodies against muscle specific receptor tyrosine kinase
* interference with trafficking/clustering
* no compliment involved
* Both result in decreased ACh receptor function
* Tensilon test: anticholinesterase given to help diagnose
42
Myasthenia gravis:
Who is targeted?
Muscle response?
Symptoms?
* Younger women and older men
* Decreased muscle response with repeated stimulation
* Symptoms/signs
* General weakness
* Extraocular muscles usually involved with drooping ptosis and diplopia
43
Eaton-Lambert:
Causes?
Presentation?
* Due to paraneoplastic syndrome with antibodies against pre-synaptic voltage gated Ca++ channels (lung cancer)
* Patients without a tumor often have other autoimmune features/diseases
* Presentation
* weakness in extremities
* INCREASED muscle response with repeated stimulation
44
Congenital myasthenic syndromes:
Inheritance pattern?
Type of mutations?
When do they present?
* AR
* Loss of function in genes of presynaptic, synaptic, or postsynaptic proteins
* Severe forms present in infancy
* Milder forms present later
45
Toxin that affects the neuromuscular junction? Mechanism of action? REsult?
* Botox (clostridum botulinum)
* Prevents ACh release at presynaptic membrane
* Flaccid paralysis
46
What is collateral reinnervation? What occurs to muscle cell types?
* When there is axonal degeneration and healthy axons then take over and innervate the muscle
* The muscle cell type changes to match the new axon resulting in _Fiber type grouping_
* Should that fiber become damaged and no healthy axons are there to re-innervate the result is _Group atrophy_
47
What occurs as a result of segmental myocyte degeneration?
* Release of creatine kinase
* Results in phagocytosis and activation of satellite cells to regenerate
* Continuity of original myofiber may be resorted or lead to deposition of collagen and fatty infiltrate
48
What occurs during regeneration of myocytes?
* cells are recruited from satellite precursor cells
* they have large internalized nuclei and prominent nucleoli
* basophilic cytoplasm due to increased synthesis and RNA content
49
What are the signs/symptoms of dermatomyositis?
* Eyelid rash most common
* increased capillary loops
* Scaling erythematous eruptions
* Gottron's papules at points of contact
* Symetric weakness affecting proximal muscles first and distal later
* Dysphagia
* ILD, vasulitis, myocarditis
* Juvenile form: calcinosis and GI involvment
50
Dermatomyositis:
Where is inflammatory infiltrate found?
Type of muscle atrophy?
* Infiltrate around small vessels and in perimysial CT
* Muscle atrophy
* perifascicular
* hypoperfusion and fibrosis possible cause for perifascicular atrophy
* small vessel damage is a key contributor
51
Dermatomyositis:
3 autoantibodies involved and associations?
* Anti-Mi2 helicase
* involved in nucleosome remodeling
* Gottren's lesions
* Anti-Jo1 to histidyl t-RNA synthetase
* intersitial lung disease
* Anti-P155/P140 to transcriptional regulators
* perineoplastic
* juvenile
52
Polymyositis:
Onset?
Signs/symptoms?
* Adult onset
* no juvenile form like dermatomyositis
* Proximal symmetric weakness
* NO RASH
* NO cutaneous involvement
53
Polymyositis:
Gross and micro findings?
* Direct injury to myofibers by CD8+ cell in endomysium
* Necrotic and regenerative fibers present
* No evidence of vascular injury
54
Inclusion body myositis:
Onset?
Signs/symptoms?
* Late adulthood: most common type 65+
* Involvement of DISTAL muscles
55
Inclusion body myositis:
Micro and EM findings?
* Rimmed vacuoles
* basophilic granules at the periphery
* Vacuolated fibers stain with congo red
* EM: tubular and filamentous inclusions
* Beta amyloid
* TDP-43
* Ubiquitin
56
What are the two drug induced toxic myopathies?
* Statins: unrelated to dose or subtype
* Chloroquine and Hydrochloroquine
* proximal myopathy
* lysosomal storage myopathy
* vacuoles within myocytes
* predominantely TI
57
What is ICU myopathy?
Complications?
* Weakness associated with treatment involving steroid treatment
* May have selective loss of myosin (thick fil.)
* Complication: problems weaning from ventilators
58
4 Steroid mypathies? What do they cause?
* Endogenous
* cushings, adrenal tumors
* Exogenous
* treatment of asthma, COPD, RA
* Acute - less common
* rhabdomyolysis
* Chronic
* proximal limb weakness as well as neck flexors
* recovery in weeks to months following reduction/discontinuation
59
What occurs in thyrotoxic myopathy?
* Acute or chronic proximal muscle weakness
* Exophthalmic ophthalmoplegia
* Myofiber damage with regeneration
* Focal myofibril degeneration with fatty infiltrates
60
Hypothyroid effects on muscle?
* Cramps with slow reflexes and movements
* Fiber atrophy and increased internal nuclei
* Accumulation of glycogen aggregates or mucopolysaccharides
61
Binge/Acute alcohol myopathy involves?
* Rhabdomyolysis and myoglobinuria
* dark urine and possible RF
* Acute pain (general or local)
* Swelling of myocytes, necrosis, myophagocytosis, and regeneration
* Type I more suceptible
62
Chronic alcoholic myopathy damage?
* Type II fiber atrophy
* Painless weakness
63
DMD:
Genetics and gene product damage?
* DMD gene on Xp21 - X-linked
* Loss of Dystrophin
* protein interface between intracellular contractile apparatus and the ECM
* leads to weakness of the cell cytoskeleton
* Due to deletions with a frameshift mutation most commonly
64
Clinical manifestation of DMD?
* Early motor milestones met on time but slowly develops clumsiness and mental retardation
* Weakness begins in pelvic girdle muscles and extends to shoulder. Use of arms to get up =
* GOWER'S SIGN
* Enlargement of calf muscles: PSEUDOHYPERTROPHY
* increase in the size of muscle fibers and later replacement by fat and CT
* Death in 20s due to resp/cardiac complications
65
DMD:
Gross and micro morphology?
* Both TI and TII fibers as well as both small and large fibers involved
* Increased internalized nuclei
* Degeneration/necrosis/phagocytosis --\> regeneration (basophilic cyto) --\> proliferation of endomysial CT
* this cycles and in later stages the muscle is replaced by fat and CT
66
Becker MD:
Inheritance?
Symptoms and onset?
* Also X-linked recessive but less common and less severe
* Begins later: childhood or adolescnece
* Involves changes but not loss of dystrophin
* abnormal molecular weight
* truncated (?) but still ahs some function
* Nearly normal life span
67
Myotonic dystrophy:
Inheritance pattern?
Pathogenesis?
* Autosomal Dominant
* CTG repeats in protein kinase gene DMPK
* C19
* normal - 30 repeats
* Several thousand in severely affected
* Trait demonstrates anticipation
68
Myotonic dystrophy:
Micro and gross morphology?
* Variable fiber size; mostly TI
* Increased internal nuclei
* Ring fibers
* subsarcolemma band of cyto around myofibrils
* Myofibrils oriented in CIRCULAR manner
* Dystrophic muscle spindle fibers
* splitting, necrosis, regeneration
* ONLY dystrophy to involve spindles
69
Myotonic dystrophy:
Clinical presentation?
* Patients complain of stiffness
* Late childhood gait difficulty
* Progresses to hand/wrist weakness
* Face muscle atrophy
* ptosis
* cataracts
* Frontal balding
* Gonadal atrophy
* cardiomyopathy
* abnormal glucose tolerance
* dementia
* sudden involuntary contractures
70
Emery Dreifuss muscular dystrophy:
Clinical findings?
Pathological finding?
* Clinical
* slowly progressive onset
* prominent contractures
* Path
* normal gene products localize to inner face of nuclear membrane
71
Facioscapulohumeral muscular dystrophy:
Clinical?
Pathological findings?
* Clinical
* variable onset
* weakness of face, neck, and shoulder
* Path
* dystrophic myopathy often with inflammatory infiltrate
72
Congenital muscular dystrophy:
types? Clinical findings?
* Congenital musuclar dystrophy
* neonatal hypotonia
* respiratory insuff
* delayed milestones
* With CNS malformation
* neonatal hypotonia and MR
* With CNS and ocular malformation
* neonatal hypotonia and MR
* cerebral and ocular malformations
73
Type 1 Limb girdle dystrophies:
Inheritance?
3 types?
Autosomal dominant
* Myotilin: facial sparing, dysrthric speech
* Lamin A/C: arrhythmia and cardiomyopathy
* Caveolin 3 - mild course
74
Type 2 Limb girdle dystrophies:
Inheritance?
Main type?
* Autosomal recessive
* Sarcoglycan: severe course
* duchenne like
75
Limb Girdle muscular dystrophies:
Typical onset?
Clinical?
* Onset as adolescents or young adults
* Weakness proximal in upper and lower extremities
* Variable findings and progression of dystrophic myopathy
76
Central core disease:
Inheritance and genetics?
Clinical?
Pathologic?
* AD Ryanodine receptor 1 mutation
* Clinical:
* Floppy infant
* Early hypotonia, weakness, skeletal deformities
* may develop malignant hyperthermia
* Path:
* cytoplasmic cores are lightly eosinophilic
* decreased mitochondria
77
Nemaline myopathy:
Several causes - mostly what inheritance?
Clinical variation?
Pathologic findings?
* Autosomal recessive
* Majority either childhood weakness or floppy infant with hypotonia
* Path
* aggregates of subsarcolemmal spindle shaped rods
* nemoline rods
* Primarily affect TI fibers
* Rods are derived from Z-band material
* alpha actinin
78
Spinal muscular atrophy:
Also known as?
Inheritance?
Genetics?
* Infantile motor neuron disease
* AR
* Mutations in Survival Motor Neuron gene 1
* SMN1 on C5 (mostly deletions)
* Contiguous region has variable # of homologous SMN2 gene
* type of disease depends on variable copies of SMN2
79
Spinal muscular atrophy:
3 types?
* SMA1 - Werdnig Hoffman disease (severe)
* floppy infant and death within 3 yrs
* Severe loss of LMN
* Profound neurogenic atrophy
* SMA2
* 3-35month presentation and survives more than 4 years
* SMA3
* presents after 2 years - adult lifespan
* Least damage: so most SMN2
80
What is the result of carnitine palmitoyltransferase II deficiency?
* Lipid myopathy
* Carnitine transport system abnormalities or mitochondrial dehydrogenase deficiency blocks FATTY ACID OXIDATION
* Accumulation of lipid droplets in myocytes
* vacuoles primarily type I
81
Clinical presentation of lipid myopathies (aka carnitine palmitoyltransferase II deficiency)?
* Muscle pain, tightness, myoglobinuria following prolonged exercise or exercise with fasting
* rhabdomyolysis and RF possible
* Cardiomyopathy and fatty liver may also occur
82
Difference between McArdle disease and Pompe's disease?
* Both are glycogen storage diseases
* McArdle
* myophosphorylase deficiency
* more common
* episodic muscle damage with exercise
* Pompes
* Acid maltase deficiency
* Lysosomal accumulation of glycogen
* Severe - early presentation; mild - adult onset
83
Mitochondrial myopathy:
Clinical?
* Clinical: proximal weakness
* sometimes severe involvement of extraocular muscles
* neurological symptoms
* lactic acidosis
* cardiomyopathy
84
Mitochondrial myopathy:
Gross/micro findings?
* Aggregates of abnormal mitochondria
* typically under sarcolemma
* Ragged red fibers
* distorted myofibrils that are irregular in outline
* "Parking lot inclusions"
* abnormal cristae with paracrystalline pattern
85
Ion channel myopathies may have relapsing episodes of hypotonic paralysis:
What is this induced by?
Association with what channels?
* Induced by exercise, cold, or high-carb meals
* Associated with either hyper, hypo, or normaokalemia
* Hyperkalemic hypotonia: SCM4A (Na channel)
* Hypokalemic hypotonia: CACA1S voltage gated L-type calcium channel
86
Malignant hyperthermia:
Triggered by? Result?
* Triggered by anesthetics
* halogenated hydrocarbons
* succinylcholine
* Results in tachycardia, tachypnea, muscle spasm, and hyperpyrexia
87
Malignant hyperthermia:
Familial suceptibility with herditary muscle diseases affects withat receptor? Downstream effect?
Diagnosis?
* Ryanodine receptor 1
* mutant receptor allows uncontrolled efflux of Ca++ from sarcoplasm after exposure to anesthetic inducting contraction, tetany, increased muscle metabolism, and excessive heat production
* Diagnosis by contraction response of biopsied muscle to anasthetic or identification of gene mutation
