9. PATH- Peripheral Nervous System and Skeletal Muscle Flashcards
1
Q
What consists of the following: lower motor neuron with anterior horn of the spinal cord or cranial nerve motor nucleus in the brain stem, axon and muscle fibers innervated by the neuron?
A
Motor unit
2
Q
A peripheral nerve principle structural unit is the nerve fiber which is axon with its schwann cells and myelin sheath. What are numerous fibers grouped into fascicles by connective tissue sheaths?
A
Nerves
3
Q
Fascicles contain both myelinated and unmyelinated nerve fibers- unmyelinated axons are more numerous than myelinated, the cytoplasm of 1 schwann cell envelopes a variable number of unmyelinated fibers (5-10 axons). PNS axons are myelinated in SEGMENTS (internodes) separated by nodes of ranvier, single schwann cell supplies myelin sheath for?
A
each internode
4
Q
Epineurium encloses the entire nerve, perineurium is multilayered, concentric connective tissue sheath that encloses each fascicle, and what surrounds each individual nerve fiber?
A
Endoneurium
5
Q
Reactions of the motor units include segmental demyelination, axonal degeneration and muscle fiber atrophy, nerve regeneration and reinnervation of muscle, and reactions of muscle fibers. In neuromuscular disease you see a symptom of weakness and it is usually due to disorder of the?
A
Motor unit
6
Q
There are 2 main responses of peripheral nerve to injury determined by their target: 1) schwann cell damage leads to segmental demyelination with primary involvement of schwann cell and loss of myelin (just one cell/node), 2) axon damage causes axonal degeneration meaning primary involvement of neuron and its axon followed by axonal regeneration and?
A
Reinnervation of muscle
7
Q
There are two principle pathologic processes seen in muscle- 1) denervation atrophy which follows loss of axon and 2) what, which is primary abnormality of muscle fiber itself?
A
Myopathy
8
Q
In normal motor units, type I and type II myofibers are arranged in a “checker*board” distribution, and the internodes along the motor axons are uniform in thickness and length.Acute axonal injury (left axon) results in degeneration of the distal axon and its associated myelin sheath, with *atrophy of denervated myofibers. In contrast, acute demyelinating disease (right axon) produces random segmental degeneration of individual myelin internodes, while *sparing the axons.C,Regeneration of axons after injury (left axon) allows reinnervation of myofibers. The regenerated axon is myelinated by proliferating Schwann cells, but the new internodes are?
A
**shorter and the myelin sheaths are **thinner than the original ones.
9
Q
What occurs when dysfunction of schwann cell (hereditary or sensory) d/t damage to the myelin sheath like in guillain-barre, there is no primary axon abnl, does not* affect all schwann cells, and disintegrating myelin are engulfed by schwann cells and then mø?
A
Segmental Demyelination
axon AND myocytes remain intact
10
Q
The denuded axon in segmental demyelination is the stimulus for remyelination, precursor cells inside endoneurium have the capacity to replace injured schwann cells, newly myelinated internodes are SHORTER than normal, what are seen and are concentric layers of schwann cytoplasm and redundant basement membrane surrounding thinly myelinated axon?
A
Onion bulbs (schwann cell prolif where schwann wraps around an axon)
11
Q
With axonal degeneration, on EM one can see degenerating myelin with loosened myelin layers in the degenerating axon, in addition what can be seen as vacuoles derived from degenerating myelin /mø?
A
Lipid droplets
12
Q
What is a failure of outgrowing axons to find their distal target, can produce this, a non-neoplastic haphazard whorled proliferation of axonal processes and schwann cells, painful nodule that can happen when the transected ends of a peripheral nerve fail to be united after zon outgrowth?
A
Traumatic Neuroma
13
Q
Axonal degeneration is the result of destruction of the axon with secondary disintegration of the myelin sheath, what is focal or generalized trauma/ischemia affecting the whole neuron body (neuronopathy) or its axon (axonopathy)?
A
Axon damage
14
Q
In a focal lesion (traumatic transection of axon) the distal portion undergoes what, which is a prototypical pattern of injury in which the axons go in every direction?
A
Wallerian Degeneration
15
Q
IN axonal degen and muscle fiber atrophy, schwann cells catabolize myelin and later engulf axon fragments, producing small oval compartments known as what? which then after mø are recruited for clean up- proximal stump of severed nerve shows degen changes in distal most 2-3 internodes, then undergoes regeneration?
A
Myelin Ovoids
16
Q
Axonal degeneration leads to muscle fibers in the motor unit to lose neural input and undergo denervation atrophy, may see target fibers which are rounded zone of disorganized myofibers in CENTER of fiber, and what which are atrophic fibers- smaller and triangular* shap when denervation atrophy occurs?
A
Angulated Fibers = triangular shaped
17
Q
Schwann cells vacated by degenerating axons provide guide for growth cone of regenerating fibers, a regenerating cluster is a closely aggregated, thinly myelinated small-caliber group of axons, reinnervation of skeletal m changes its composition* altering the checker board distribution of the 2 major fiber types, fiber type is determined by neuron of the motor unit, WHAT determines fiber type?
A
Motor Neuron - all muscle fibers of a single unit are the SAME type
-slow growth at 1mm/day- marrow stromal cell transplants can help
18
Q
Axonal degeneration: The axon and its myelin sheath undergo anterograde degeneration (shown for the green neuron), with resulting denervation atrophy of the myocytes within its motor unit (pale-pink myocytes). Reinnervation of muscle: *Sprouting of adjacent (red) uninjured motor axons leads to fiber type grouping of myocytes, while the injured axon attempts axonal sprouting. What is known as the following: Scattered myocytes of adjacent motor units are small (degenerated or regenerated), whereas the neurons and nerve fibers are normal.
A
Myopathy
19
Q
What type of fiber? Action: sustained force Strength: weight bearing Lipids: abundant Glycogen: scant Phys: slow twitch Color: red
A
Type 1 - high in myoglobin and oxidative enzymes and MANY mT = tonic contractions
ONE SLOW FAT RED OX
20
Q
What type of fiber? Action: Sudden movements Strength: purposeful motion Lipids: scant Glycogen: abundant Phys: fast twitch Color: white
A
Type 2- rich in glycolytic enzymes, rapid phase contractions
21
Q
Axons of unaffected neighboring motor unit extend sprouts to reinnervate the denervated myocytes and incorporate them into the healthy motor unit, newly adopted reinnervated fibers assume *fiber type of their new *sibilings, what is a patch of contiguous myocytes having the same histochemical type?
A
Type grouping (as seen after axon damage and neighboring axon takes over dead axon’s muscles)
22
Q
Group atrophy is when type group becomes denervated, what type fiber atrophy occurs due to *inactivity or disuseor neurodegenerative disease, and also occurs during glucocorticoid therapy- known as steroid myopathy, NOT trauma?
A
Type 2 fiber atrophy
23
Q
Many diseases affect muscle, but myocytes only have a few pathologic reactions. What is destruction of a portion of myocyte, followed by myophagocytosis (mø infiltrate region) loss of muscle fiber leads to deposition of collagen and fat?
A
Segmental necrosis
24
Q
Along with segmental necrosis, vacuolization, alterations in structural proteins or organelles and accumulation of intraxytoplasmic deposits are seen in many disease, along with regerenation and what, which is muscle fiber splitting?
A
Hypertrophy
25
What occurs via satellite precursor cells proliferate and reconstitute the destroyed portion of fiber, regenerating portion has larger internalized (Central) nuclei- should be at periphery- with prominent nucleoli, cytoplasm laden with RNA is RED (trichome stain)?
Muscle fiber regeneration
26
Hypertrophy is a response to increase in load, either through exercise or pathologic conditions (fibers injured), what then occurs and is when large fibers may divide longitudinally, on cross section you see single large fiber with a *cell membrane traversing* its diameter, often with adjacent nuclei?
Muscle Fiber Splitting
27
Patients with peripheral neuropathy (PN) generally describe the pain as tingling, stabbing, burning or pins and needles. What type affects a single nerve, with deficits in a restricted distribution, due to trauma, entrapment infections, etc?
Mononeuropathies
28
Polyneuropathy affects many nerves, and is usually symmetric, deficits start at the feet and ascend with disease progression, hands usually have deficits at the same time as the knees = stocking and glove distribution. What damages several nerves in a *haphazard fashion, such as pt with right wrist drop and left foot drop, usually due to vasculitis commonly seen in PAN-polyarteritis nodosum?
Mononeuritis Multiplex
PAN: Patients usually present with asymmetric peripheral neuropathy, such as multiple mononeuropathy (mononeuritis multiplex) with signs of motor and sensory involvement of the peroneal, median, or ulnar nerves. As additional nerve branches are affected, patients may appear to have a distal symmetric polyneuropathy.
29
What neuropathy affects nerve roots as well as peripheral nerves, causing diffuse, symmetric signs and symptoms in proximal and distal parts of the body?
Polyradiculoneuropathies
30
What mononeuropathy causes facial muscle paralysis in 15-60s, usually resolves spontaneoously, assoc with *URI* or DM, sx include facial tingling, mid severe headache/neck pain, balance issues, ipsilateral limb paresthesias and weakness, and sense of clumsiness... Ddx includes stroke, brain tumor, lyme disease and ramsay hunt syndrome?
CN VII Bell's Palsy, usually unilateral
*Ramsay Hunt syndrome is defined as an acute peripheral facial neuropathy associated with erythematous vesicular rash of the skin of the ear canal, auricle (also termed herpes zoster *oticus), and/or mucous membrane of the oropharynx.*
31
Neurogenic bladder (over/underactive) is a number of urinary conditions in people who lack bladder control due to a brain, SC, or nerve problem. Nerve damage can be a result of MS, parkinsons or diabetes*, can also be due to infection of brain/SC, stroke or people who are born with problems in the SC such as?
Spina Bifida
32
What is an acute inflammatory demyelinating* polyneuropathy, life threatening, weakness begins in distal limbs and ascendings with paralysis, deep tendon reflex disappear, there is inflam and demyelination of spinal nerve roots and peripheral nerves (radiculoneuropathy) and is an acute onset immune mediated neuropathy that is treatable?
Guillain-Barre Syndrome
33
2/3 of Guillain-Barre Syndrome preceded by acute influenza-like illness, most commonly campylobacter jejuni, cytomegalovirus, EBV, mycoplasma penumoniae or prior vaccination, can see perivenular and endoneurial infiltration by lymps, mø and plasma cells in peripheral nerves, see segmental demyelination = primary lesion what what abs?
Anti-Myelin antibodies
34
Guillain-Barre Syndrome has cytoplasmic processes of mø that penetrate the basement membrane of schwann cells - near nodes of ranvier, and extend between myelin lamellae, stripping myelin sheath from axon, CSF see increased protein, no pleocytosis (because inflam cells are confined to roots) , what are the two treatments for this syndrome?
*Plasmapheresis and then IViG (if no access)
2-5% mortality from 25% due to improved respiratory care and support (most died from respiratory paralysis)
35
What is the MC acquired inflammatory peripheral neuropathy assoc w symmetrical mixed sensorimotor polyneuropathy which persists for *>2months*, may be seen with relapses and remissions, tx with immunosuppressive (glucocorticoid, IViG, plasmapheresis), DDX: time course and RESPONDS to steroids (GB does not), see complement- IgG and IgM on myelin sheath, and sural nerve bx shows ONION BULBS?
Chronic Inflammatory demyelinating Poly(radiculo)neuropathy
36
What disease causes invasion of schwann cells by mycobacterium, bacteria proliferates and infects other cells, see segmental demyelination and remyelination and loss of both myelinated and unmyelinated axons, endoneurial fibrosis and multilayered thickening of perineural sheaths*, with symmetric polyneuropathy affecting COOL extremities (extensors and hand/feet)?
Lepromatous Leprosy (Hansen Disease) = Mycobacterium Leprae= Th2 humoral response
*Acid fast staining with slender bacilli, stained + for AFP**** = leprosy
37
Leprosy involves pain fibers and loss of sensation contibutes to injury, there are large traumatic ulcers because patient is unaware, what kind of faces is seen?
Leonine Facies
38
What type of leprosy is Th1 cell mediated, less severe cutaneous than other form, seen with granulomatous nodules in the dermis, localized* nerve involvement, injures cutaneous nerves, axons schwann cells and myelin is lost and there is fibrosis of perineurium and endoneurium?
Tuberculoid Leprosy
39
What has an exotoxin that affects peripheral nerves and begins with paresthesias and weakness- imcomplete immunization and waning adult immunity is why its caused, early loss of proprioception and vibratory sensation due to sensory ganglia, selective demyelination of axons that extend into adjacent anterior and posterior roots* and into mixed sensorimotor nerves, periph neuropathy assoc with prominent bulbar and respiratory muscle dysfunction causing death?
Diptheria
40
What is the MC viral infection of the PNS, latent infection of sensory ganglia of the SC and brainstem in dorsal root ganglia, reactivation of latent infection causes painful vesicular skin eruption in distribution of sensory dermatomes= shingles, neuronal destruction and loss of affected ganglia?
Varicella-Zoster Virus
41
Varicella-Zoster Virus shows abudant mononuclear infiltrate, regional necrosis and hemorrhage may also be found, axon degeneration of peripheral nerves after death of sensory neurons is seen, focal destruction of large motor neurons in the anterior horn or what may be seen at corresponding levels?
cranial nerve motor nuclei
42
What is assoc with various neurologic manifefstations occuring in the 2nd and 3rd stage of the disease including polyradiculoneuropathy, unilateral or bilateral facial nerve palsies and is spread via ticks and is associated with erythema chronica migrans?
Lyme Dz due to B. Borgurllai
43
What virus causes mononeuritis multiplex, a demyelinating DO that resembles Guillain barre or chronic inflam demyelinating polyneuropathy, and in late stages of the virus can see distal sensory neuropathy which is painful?
HIV
44
What is the MCC of peripheral neuropathy, MC pattern is ascending distal symmetric sensorimotor polyneuropathy, prevalence of complications depends on the duration, with >15 years with disease =80%, see numbness, loss of pain sensation, difficulty with balance, paresthesias and dysesthesias (pain), neuropathy leads to chronic skin ulcers and diffuse vascular injury?
Diabetes Mellitus
45
Diabetes Mellitus is associated with segmental demyelination with a DEC in axons, degen of myelin sheaths and regenerative axonal clusters, relative loss of small myelinated and unmyelinated fibers, large fibers are also affected, endoneurial arterioles show thickening*, hyalinization* and intense?
PAS positivity
46
Diabetes Mellitus is also associated with dysfunction of autonomic nervous system in 40% almost always assoc with distal sensorimotor neuropathy, sx include postural hypotension, incomplete emptying of bladder, increased infections and sexual dysfunction, on EM see thickening of endoneurial vessel wall, marked loss of myelinated fibers and?
thinly myelinated fibers
47
What ocurrs in most people with renal failure have periph neuropathy, showing distal symmetric neuropathy- may be asymptomatic, muscle cramps, distal dysesthesias and dec in DTRs, axonal degeneration usually primary even, regeneration and recover common after dialysis?
UREMIC Neuropathy
48
What dysfunction can cause compression mononeuropathies such as carpel tunnel, distal symmetrical predominantly sensory polyneuropathy?
```
Thyroid Dysfunction (hypothyroid)
Hyperthyroid rarely causes guillain barre
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49
What deficiency causes subacte combine degeneration with damage to long tracts in the spinal cord and peripheral nerves?
VitB12 cyanocobalamin
50
Peripheral neuropathies may appear after exposure to industrial or environmental chemicals, biologic toxins, or therapeutic drugs. Important causes of toxic peripheral nerve damage include alcohol (independent of associated nutritional deficiencies), heavy metals (*lead*, mercury, arsenic, and thallium), and organic solvents. Various medications can cause toxic nerve damage, but the most notorious are what? These include vinca alkaloids and taxanes, microtubule inhibitors that interfere with axonal transport, and cisplatin, which may cause a neuronopathy.
chemotherapeutic agents
51
Neuropathies from local effects of malignancy, complications of its treatment, paraneoplastic effects or tumor derived Ig (B cell tumors). Direct infiltration of compression of peripheral n. can cause obturator palsy (pelvic tumor) or what from neoplasms of the apex of the lung?
Brachial Plexopathy
52
Neuropathies associated with monoclonal gammopathies (b-cell neoplasms), POEMS syndrome is common: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes, deposition of paraprotein between noncompacted myelin lamellae is seen, What paraneoplastic neuropathy is the MC and causes sensorimotor neuronopathy, which is distal, asymmetric and multifocal?
Small Cell Lung Carcinoma
53
What type of neuropathy regenerates slowly and discontunity complicates its regrowth, axons continue to grow despite misalignment resulting in small bundles of axons randomly oriented but surrounded by organized layers of scwann cells, fibroblasts and perineural cells intermixed with connective tissue?
Traumatic Neuroma
54
In carpel tunnel syndrome, what nerve is compressed in the transverse carpal ligament seen frequently in women bilaterally, causes numbness and paresthesias at tip of thumb and first 2 digits, associated with tissue edema, pregnancy, inflammatory arthritis, hypothyroidism, amyloidosis, acromegaly, diabetes, and excessive repetitive motions?
Median N
55
Saturday night palsy is caused by compression of what nerve in the upper arm when one falls asleep awkwardly? other compression neuropathy is ulnar N at elbow and peroneal nerve at knee...
Radial nerve
56
What nueroma causes metatarsalgia (foot pain), histologically the lesion has perineural fibrosis usually at interdigital nerve at intermetatarsal sites, MC in Women?
Morton Neuroma
57
Inherited peripheral neuropathies are uncommon- must be considered in DDx of anyone presenting with peripheral neuropathy. What is the MC inherited PN, MC d/t AD chr 17, PMP22 mutation peripheral myelin protein22, in second decade of life, slowly progressive demyelination of motor and senosry nerves (also Xlinked and AD-MDN2 associated with early childhood onset)?
Charcot-Marie-Tooth CMT assoc with distal muscle atrophy, sensory loss and foot deformities + onion bulb formation
58
What is a hereditary polyneuropathy that is due to deposition of amyloid in peripheral nerves, due to germline mutation of transthyretin gene?
Familial Amyloid Polyneuropathy
59
Upon depolarization, presynaptic nerve terminals release acetylcholinesterase (ACh) into the synaptic cleft, AChR are responsible for initiation of signals leading to muscle contraction, regardless of the cause, DOs that impair function of the NM juction tend to be present with painless weakness**, either due to inherited defects, toxins or antibody mediated like myasthenia gravis (antib to AChR) and?
Lamber-Eaton Myasthenic Syndrome
60
What NMJ disease is common, with a bimodal age, more common in women, and in older adults mc in men, there is immune mediated loss of acetylcholine receptors (85%) have circulation Ab to AChR, remaining have Ab against sarcolemmal protein muscle specific receptor tyrosine kinase, with a strong association between AChR and thymic abnormalities**?
Myasthenia Gravis
61
Myasthenia Gravis is associated with a b9 thyroid tumor called a thymoma, and 30% of patients with MG have what, which is MC in younger and histo shows B cell follicles in the thymus possibly due to hyperplasia disrupting normal thymic function which promotes autoimmunity against AChRs expressed on thymic myoid cells?
Thymic Hyperplasia
62
Myasthenia Gravis is d/t autoabs at AChRs at NMJ, pts present with fluctuating generalized weakness that worsens with exertion and over the course of the day, weakness begins with *extraocular muscles- dropping eyelides (ptosis) and double vision (diplopia)*, there is characteristic diminshed responses after?
repeated stimulation
63
Myasthenia Gravis is treated with acetylcholinesterase inhibitors which increases the half life of ACH, a thymectomy may be performed for those with a thymoma which may benefit overall disease, and immunosupressives and what are the other option for treatment, to decrease the amount of autoabs?
Plasmapheresis
*neostigmine
64
What syndrome is assoc with ab that block acetylcholine release by inhibiting presynaptic calcium channels, is is usually a paraneoplastic process**, 50% are associated with small cell carcinoma of the lung***, sx may precede diagnosis of cancer by years, causes proximal muscle weakness and autonomic dysfunction, repeptitive stimulation INCREASES muscle response which is opposite of MG?
Lambert Eaton Myasthenic Syndrome
65
Skeletal muscle myofibers are arranged in fascicles each associated with a small pool of tissue stem cells which are what cells which contribute to muscle regeneration? myofibers are two main types- 1 and 2 and are admixed in checkerboard fashion, fiber type determined by signals received from innervating motor neurons
Satellite Cells**
66
Type 1 muscle has sustained force, aerobic exercise, low power, high resistance to fatigue, stains red due to high myoglobin and prottype is soleus (pigeon), type 2 fibers are for fast movement, anaerobic exercise, high power, low resistance to fatigue*, stains pale red tan (low myoglobin) and protype is what?
Pectroal (pigeon)
67
Curare is a muscle relaxant that blocks acetycholine receptors causing flaccid paralysis, what is a neurotoxin produced by clostridium botulinum which blocks release of ach from presynaptic neurons?
Botulism
68
Skeletal muscle atrophy is a common feature of many DOS, causes include loss of innervation, disuse, cachexia, old age and primary myopathies, severe atrophy may lead to loss* of muscle mass, neurogenic disease causes fiber type grouping and group atrophy, what is common and causes perifascicular atrophy?
Dermatomyositis
Note: prolonged corticosteroid tx and disuse leads to TYPE 2*** fiber atrophy and type 1 fibers are spared
69
SKM DOs may be via myopathic or neurogenic injury... segmental myofiber degeneration and regeneration causes release of creatine kinase CK** into blood which is a marker for muscle damage, regenerating fibers are rich in RNA so they stain how, with enlarged nuclei, with prominent nucleoli randomly distributed in the cytoplasm?
RNA stains Basophilic on HandE
70
Myofiber hypertrophy is due to adaptation to exercise or chronic myopathic conditions, cytoplasmic inclusions may be seen, including vacuoles, aggregates of proteins or clusters of?
organelles
71
There are 3 types of inflammatory myopathies, including infectious, noninfectious inflammatory and systemic inflammatory, noninfectious inflammatory myopathies include polymyositis, inclusion body myositis and what, which is the most common and see skin and muscle changes?
Dermatomyositis
*Biopsy shows deposition of complement MAC (C5b-9) in capillary beds of muscles and skin*
72
Dermatomyositis is seen in 4-6th decade, associated with a distinctive skin rash- lilac or heliotrope (purple) discoloration of upper eyelides assoc with periorbital edema, also see telangiestasias (dilated capillary loops) on nail folds, eyelids and gums, what lesions are seen which are scaling erythematous eruptionor dusky patches over knuckles, elbows and knees?
Grotton lesions
73
Dermatomyositis sx include *proximal muscles first (difficulty rising from chair or climbing stairs), 1/3 dev dysphagia (oropharyngeeal and esophageal m), 10% interstitial lung disease*, cardiac involvement is common but rarely causes cardiac failure, Auto antibodies associated with this disease includ anti-Jo1 (mechanics hand), anti-P155/P140 (paraneoplastic and juvenile) and what which is the most common?
Anti Mi2 (heliotrope rash and grotten papules)
74
Dermatomyositis increases risk of visceral cancer, 25% of adults with Dermatomyositis have an associated malignancy (paraneoplastic?), histo will show what, which is atrophic fibers grouped at the periphery of fascicles with mononuclear infiltrate in perimysial connective tissue?
Perifascicular Atrophy
Muscle bx- perimysial aggregates of mononuclear inflammatory cells and perifascicular atrophy
75
What type of dermatomyositis which has an avg age onset at 7 y/o, is the MC myopathy in children, inolves the GI tract (mucosal ulcers ,perforation), calcinosis and lipodystrophy (vs heart, lung or underlying malignancy in adults)?
Juvenile Dermatomyositis
76
What has an adult onset, with myalgia and weakness, with NO **cutaneous features and is a dx of exclusion, with *symmetrical proximal muscle involvement and may have inflamm involvement of heart and lungs and autoAbs, due to CD8 T cells in endomysium, necrotic and regerating fibers scattered through out fascicle with *endomysial* mononuclear infiltrate**, random distribution of affected fibers?
Polymyositis
77
What myositis which is a dz of late adulthood, greater than 50 yo, MC inflammatory myopathy in patients greater than 65*, slowly progressive muscle weakness, most severe in quadriceps and distal upper extremities*, starts with DISTAL muscles- esp extensors of knee and flexors of wrist and fingers *asymmetric, with dysphagia from esophageal and pharyngeal m involvement?
Inclusion Body Myositis
78
Inclusion Body Myositis on histo shows rimmed vacuoles (inclusion with reddish granular rimming- purpleish) highlight by basophilic granules around the periphery, endomysial fibrosis, what kind of stain shows this?
Gomori Trichrome
79
Treatment of inflammatory myopathies- prior to corticosteroids, prognosis for dermatomyositis and polymyositis was poor (mortality of 50%). Immunosupressive drugs are used if what (which is first line tx)? (third line tx is IViG, cyclophosphamide, cyclosporine, rituximab, inclusion body myositis usually responds POORLY to steroids....
CORTICOSTEROIDS ARE FIRST LINE
80
Toxic myopathies can be caused by prescription or recreation drugs and hormonal imbalances. What such as atrorvastatin, simvastatin, and pravastatin can cause myopathy, 1.5% of users feel this?
Statin drugs
81
Chloroquine and hydroxychloroquine are antimalarial drugs can cause toxic myopathies, now used as long term tx for systemic autoimmune dzs, drug induced lysosomal storage myopathy, causes slowly progressive muscle weakness, type 1 fibers are affected**, ICU myopathy is AKA myosin deficit myopathy associated with critical illness with corticosteroid tx- profound weakness. What causes acute or chronic proximal muscle weakness associated with exophthalamic opthalmoplegia -swelling of eyelids edema conjuctiva and diplopia?
Thyrotoxic Myopathy
82
NOTE: alcohol may produce rhabdomyolysis, myoglobinuria, and renal failure with acute myalgia
NOTE: x linked dominant - 100% daughters are affected from father
X linked recessive- 100% sons affected via positive mom
WOOF
83
Congenital myopathies may present in infancy with muscle defects that tend to be static or to improve over time. What inherited diseases of SKM cause progressive muscle damage with sx occuring after infancy*, congenital dystrophies tend to present in infancy, often assoc with developmental abnormalities of the CNS as well as progressive muscle damage?
Muscular Dystrophies
84
Xlinked Muscular Dystrophies include ducenne DMD which is more common and more severe, and becker BMD is same genetic locus, other MDs include limb girdle muscular dystrophy LGMDs which are autosomal dominant or recessive and due to what complex of proteins?
Sarcoglyan complex of proteins
85
What muscular dystrophy is due to mutation in DMD gene, Xp21, the dystrophin gene, 2/3 are familial, female carries are asymptomatic, increased creatine kinase CK is seen, risk for developing cardiomyopathy (along with affected males), most common, sx before 5y/o and wheelchair by 10-12?
Duchenne Muscular Dystrophy
LOF mutation- frameshift mutation
Tx: supportive
86
What MD starts in late childhood adolescene and has a nearly normal lifespan with more prominent cardiac dz*, assoc with a decreased amount of dystrophin (not complete loss)?
Becker Muscular dystrophy
87
DMD has NO dystrophin gene so effects are more widespread. Dystrophin and dystrophin associated protein complex form an interface between the intracellular contractile apparatus and extracellular connective tissue matrix (concentrated at the plasma membrane over Z bands)- has a role of transferring force of contraction to CT proposed to be basis for myocyte degeneration in absence of dystrophin. What is seen in both and is enlargement of muscles of lower leg assoc with weakness- increase bulk due to increased size of muscle fibers initially, and later due to increased fat and CT?
Pseudohypertrophy
88
Histology of both BMD and MMD include variation in fiber size, increased number of internalized nuclei, degeneration, necrosis, and phagocytosis of muscle fibers, regen of muscle fibers, proliferation of endomysial CT, in DMD- enlarged rounded hyaline fibers that have lost their cross striations*, later stages show muscle almost totally replaced by fat and CT, so it is important to do what early?
EARLY biopsy - end point morphology of BMD and DMD are very similar
89
Regenerating muscle fibers stain blue with large nuclei, and on histo there is complete absence of endomysial coverage, myofibers vary in size but fascicular muscle architecture is maintained, advanced disease is associated with what on bx?
fatty replacement and endomysial fibrosis
*IHC- absence of normal sarcolemmal staining pattern DMD and reduced in BMD
90
What dystrophy is characterized by stiffness difficulty releasing grip due to sustained involuntary contraction of a group of muscles, can be elicited by percussion on thenar eminence, sx include skeletal m weakness, cataracts, endocrinopathy, and cardiomyopathy-- AD mutation in CTG trinucleotide for DMPK, anticipation occurs and there are ring fibers and sarcoplasmic masses?
Myotonic Dystrophy- triple repeat expansion disorder
SX: weakness, contractions, SOB and edema with cardiomyopathy
CK signifcantly elevated
91
Myotonic Dystrophy presents with abnl gait, then atrophy of the facial muscles causing ptosis, and hatchet face with frontal balding, cataracts and cardiomyopathy, on histo you see what which are parasite like?
Ring fibers
92
What dystrophy is less common*, mutations in genes that encode nuclear lamina proteins, traid sx - slowly progressive humeroperoneal weakness, cardiomyopathy* with conduction defects and early contractures of the achilles tendon, spine and elbows, Xlinked form EMD1 and AD form is EMD2?
Emery Dreifuss Muscular Dystrophy
93
What less common dystrophy causes muscle weakness that preferentially involves proximal muscle groups, multiple AD and AR entities, age of onset and severity of dz vary greatly?
Limb-Girdle Muscular Dystrophy
94
Many inborn errors of lipid or glycogen metabolism affect SKM- two general patterns of muscle dystrophy include sx with exercise or fasting (severe m cramping and pain/ rhabdomyolysis), and 2) slowly progressive muscle damage. What deficiency is the MC, episodic muscle damage with exerciing and fasting due to impaired transport of free fatty acids to mitochondria?
Carnitine Palmitoyltransferase II Def
95
McArdle Dz (myophosphorylase def.) is a glycogen storage disease with episodic muscle damage with exercise, what deficiency is has 3 types, mild is adult form, causing myopathy of respiratory and truncal muscles, and severe is generalized glycogenesis of infancy due to impaired conversion of glycogen to glucose causing accumulation of glycogen in lysosomes?
Acid Maltase Deficiency = POMPE dz (severe infantile form)
96
mT myopathies (oxidative phosphorylation diseases) are mutations in both nucelar and mT genes, causing LACK of ATP = SKM and other tissues rich in ATP requirements are affected, sx include weakness, increase CK or rhabdomyolysis, chronic progressive external opthalmoplegia is common, and what muscle is most commonly affected due to exceptoinally atp requirement?
Extraocular Muscles*
97
mT myopathies (oxidative phosphorylation diseases) are mutations in both nucelar and mT genes, causing LACK of ATP = SKM and other tissues rich in ATP requirements are affected, sx include weakness, increase CK or rhabdomyolysis, chronic progressive external opthalmoplegia is common, and what muscle is most commonly affected due to exceptoinally atp requirement?
Extraocular Muscles*
98
What are aggregates of abnormal mitochondria under the sarcolemma (red on trichrome stain) causing distortion of myofibrils, and on EM shows morphologically abnormal mT with concentric membranous rings = phonograph records with rhomboid paracrystalline-parking lot*** inclusions (alterations in cristae of mT)?
Ragged Red Fibers = mT myopathies
99
What atrophy is an AR neuropathic disorder, loss of motor neurons leading to muscle weakness and atrophy, infants with THIS neurologic or neuromuscular disease may present with generalized hypotonia which = floppy infant?
Spinal Muscular Atrophy SMA
100
DDx for floppy infant or infantile hypotonia includes primary disease of SKM (MG), congenital myotonia, congenital myopathies, congenital muscular dystrophies, abnormalities of the brain (encephalopathy) and neuronopathies like spinal muscular atrophy which is the *prototypic example*, SMA is AR and seen in 1/6000 births, and destroys what part of the spinal cord?
Anterior horn cells
101
Spinal Muscular Atrophy SMA begins in childhood or adolescence and loss of fibers begin in utero, survival motor neuron 1 SMN1**** is the mutated gene (homozygous disruption), see large zones of atrophic myofibers mixed with scattered NL or hypertrophied myofiber- retain innervation. What is the MC SMA (type 1)- onset at birth with floppy baby and death at less than 3, muscle weakness of truncal extremity muscles intially, followed by chewing, swallowing and breathing difficulties?
Wernig Hoffman
lack motor neurons = SKM atrophy
102
on histo with Spinal Muscular Atrophy SMA, there is spinal muscular atrophy with groups of round atrohpic muscle fibers or panfascicular atrophy*, resulting from denervation, what are rarely seen compared to atrophic rounded myofibrils, which are larger than those innervated and have undergone compensatory hypertrophy?
innervated hypertrophied myofibers
103
Ion channel myopathies (channelopathies) are mutations affecting function of ion channels proteins, most are AD- symptoms include epilepsy, migraine, movement DOs with cerebellar dysfunction, peripheral N dzs, and muscle dz, inc or dec excitability causing hypo/hypertonia- hypotonia is associated with both increased, decreased or normal what?
serum potassium
hyperkalemic/hypokalemic/normokalemix periodic paralysis
MCC of hypokalemic paralysis is CACNA1S mutation = caclium channel mut
104
What central core disease is due to a AD RYR1 (ryanodine receptor) mutation, associated with a hypermetabolic state with tachycardia, tachypnea, muscle spasms, and hyperpyrexia, can be triggered by anesthetics, usually halogenated inhalational agents, anesthetic triggers efflux of Ca from sarcoplasmic reticulum which causes tetany and excessive heat production?
Malignant Hyperthermia**
severe painful tetanic muscle spasms, difficulty reducing temperature
tx with dantrolene
105
What disease is AD mut of chr3, tumor supressor, involved in regulating expression of erythropoietin (via VEGF) causing polycythemia, also see hemangioblastomas of cerebellum and retina, cysts of pancreas, liver and kidneys, *renal cell carcinoma* and pheochromocytoma?
VHL mutation- Von Hippel-Lindau Disease
106
What disease is AD, causing seizures, autism, mental retardation, two kinds type 1 chr 9 hamartin and type 2 chr 16 tuberin, causes cortical tubers, renal angiomyolipomas, pulmonary lymphagioleiomyomatosis, cardiac rhabdomyomas, and cutaneuous lesions* = angiofibromas, subungal fibromas*, shagreen pathches of thickening and ash leaf patches of hypopigmented areas?
tuberous sclerosis complex (candle guttering- drop like masses bulge into the ventricles of the brain)
107
NF1 type one is common AD, causing neurofibromas of peripheral nerves, optic nerve gliomas, lisch nodules of iris and cafe au lait spots = hyperpig cutaneous nodules, NF type 2 is less common AD, see increase in meningiomas* and ependymomas, and what which is very improtant?**
Bilateral Scwannomas - CN VIII 8 at cerebellopontine angle
108
Schwannoma is a peripheral nerve sheath benign tumor that shows schwann cell differentiation, test S100+, located a the cerebellar pontine angle, acoustic neuroma is at CNVIII and causes tinnitus and hearing loss, what are comprised of dense spindle cells that contain *verocay bodies* which are palisading nuclei around nuclear free zones?
Antoni A
Antoni B is loose cells/hypocellular with myxoid extracellular matrix
(both types mixed together in schwannomas +hyalinized BVs)
109
NFs are benign nerve sheath tumors that are more *heterogeneous* - the neoplastic schwann cells are ADMIXED with perineruical like cells, fibroblast, mast cells and CD34+ spindle cells, unlike schwannomas... NF is either sporadic or NF1 associated, associated with superficial cutaneous NFs, diffuse NFs, or plexiform neurofibroma which can malignantly transform to MPNST and feels/looks like?
a bag of worms (plexiform neurofribroma)
110
MPNST or malignant peripheral nerve sheath tumor is an uncommon HIGH GRADE tumor, 1/2 of the HG tumors arise in NF1 patients, associated with divergent differentiation in terms of the presence of focal areas that exhibit glandular, cartilaginous, osseous, and rhabdomyoblastic morphology, this is known as?
Triton tumor = Rhabdomyoblastic differentiation
