Peripheral Nerves and Skeletal Muscles Robbins

Question 1

If one were to cut a peripheral nerve, how would regen happen?

Answer 1

Think Wallerian degeneration:

1. Within day of injury, distal axons begin to fragment and associated myelin sheaths unravel and disintegrate into spherical structures (myeline ovoids)
2. Macrophages recruited and participate in removal of axonal and myelin debris
3. Regen can start at site of transsection with growth cone formation and outgrowth of new branches
4. Scwhann cells and BM’s guid sprouting axons
5. Misguided branches are pruned
6. New myelin sheaths made but thinner and shorter
7. Could see degen and regen axons in a single biopsy!!
8. Reduction in signal strength owing to dropout of axons

Question 2

Mononeuropathies affect a _____ and result in deficits in a _____ distribution

Answer 2

single nerve; restricted; think trauma, entrapment, infections!!!!

Question 3

Polyneuropathies characterized by invovlement of ______, usually in _____ distribution; how is the pathology?

Answer 3

multiple nerves; symmetric;

deficits start in feet and ascend with disease progression

Question 4

Mononeuritis multiplex damages ______; example

Answer 4

several nerves; e.g. right wrist drop (R radial) and left foot drop (peroneal nerve), think VASCULITIS!!

Question 5

Polyradiculoneuropathies: affect

Answer 5

nerve roots as well as PERIPHERAL NERVES

Question 6

Guillain-Barre syndrome: cause, clinically, cell response, treat

Answer 6

Causes: can be Campylobacter, CMV, EBV, mycoplasma pneumoniae, or prior vaccination, but thought to be IMMUNE-MEDIATED DEMYELINATING NEUROPATHY
Clinically: ascending paralysis (weakness in distal limbs rapidly advancing to affect proximal muscle function); can get life-threatening respiratory paralysis; DTRs disappear early, can lose pain sensation, nerve condition velocity slowed, CSF protein can be elevated
Cell response: see T-cell mediated immune response with segmental demyelination induced by activated macrophages (latter can engulf myelin sheath)
Treat: plasmapheresis, IVIG, other system care

QandA: give ventilatory support for paralysis of the respiratory muscles

Question 7

Chronic inflammatory demyelinating poly(radiculo)neuropathy: causes, histo, treat

Answer 7

Causes: chronic acquired inflamm peripheral neuropathy, with symmetrical mixed sensorimotor polyneuropathy persisting for 2 MONTHS OR MORE!!
Histo: Think T cells, and complement-fixing IgG and IgM can be found on myelin sheath to help recruit macrophages; think ONION-BULBS with multiple layers of Schwann cells wrapping around axon

Question 8

Neuropathy associated with vasculitis: presents, histo

Answer 8

Presents: mononeuritis multiplex typically, with noninfectious inflamm of bv’s that can involve and damage peripheral nerves
Histo: Perivascular inflamm infiltrates; also pathcy axonal degen and loss

Question 9

Leprosy: forms, characteristics of each

Answer 9

Lepromatous leprosy: Schwann cells invaded by Mycobacterium leprae; symmetric polyneuropathy with most severe in relatively cool distal extremities and lower temperatures; think PAIN FIBERS being affected
Tuberculoid: cell-mediated immune response with dermal nodules containing granulomatous inflamm; more LOCALIZED NERVE INVOLVEMENT and fibrosis of perineurium and endoneurium

Question 10

HIV/AIDS can be associated with what early, and then later?

Answer 10

Early: mononeuritis multiplex akin to Guillain-Barre
Later: distal sensory neuropathy

Question 11

Diphtheria leads to

Answer 11

peripheral nerve dysfunction due to diphtheria exotoxin (bulbar and respiratory muscle dysfunction)

Question 12

VZV would show in the PNS

Answer 12

painful, vesicular skin eruption (shingles) in a distribution that follows sensory dermatomes; decreased cell-mediated immunity; mononuclear inflammatory cell infiltrates; focal destruction of the large motor neurons of ANTERIOR HORNS or cranial nerve motor nuclei!!

Question 13

In diabetes, what is causing the peripheral neuropathy? What can happen to peripheral nerves? What is the actual neuropathy? What can happen with ANS?

Answer 13

Hyperglycemia causes nonenzymatic glycosylation of proteins, lipids, and nucleic acids, and AGE products could activate inflamm signaling and interfere with normal protein function, with foot and ankle fractures and chronic skin ulcers possible!;
injury potentially by ROS;
DISTAL symmetric diabetic SENSORIMOTOR polyneuropathy!!;
Postural hypotension, incomplete emptying of the bladder, and sexual dysfunction

Question 14

List some toxic causes of peripheral neuropathies:

Answer 14

Alcohol, heavy metals, organic solvents, chemo agents

Question 15

List examples of neuropathies associated with malignancy:

Answer 15

1. Direct infiltration or compression of peripheral nerves (brachial plexopathy from neoplasms of apex of lung, obturator palsy from pelvic malignant neoplasm, cranial nerve palsies, polyradiculopathy involving lower extremity)
2. Chemo, radiation, poor nutrtion, infection
3. Paraneoplastic neuropathies (think sensorimotor neuronopathy associated with small cell lung cancer; CD8 cytotoxic T-cell attack on DRG; sensory symptoms start distally typically)
4. Neuropathy associated with monoclonal gammopathies (IgM secreted might be associated with demyelinating peripheral neuropathy, IgA or IgG also associated with peripheral neuropathy, amyloid, POEMS, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes)

Question 16

Peripheral nerve subjected to increased pressure is what? What is the most common example? Clinical features?
Other examples?

Answer 16

Compression neuropathy (entrapment neuropathy); carpal tunnel with compression of median nerve at level of wrist within compartment delimited by trasnverse carpal ligament (think women!!);
numbness and paresthesias of tips of thumb and first two digits;
ulnar nerve, peroneal nerve, radial nerve (Saturday night palsy)

Question 17

First example of inherited peripheral neuropathy? Molecular

Answer 17

Charcot-Marie-Tooth disease: distal muscle atrophy, sensory loss, foot deformities; demyelination and remyelination including Schwann cell hyperplasia and onion bulb formation;
CMT1 (autosomal dom; most common subtype of hereditary motor and sensory neuropathy; duplication of region on chromosom 17 including PMP22 gene)
CMTX: X-linked forms of CMT disease (think GJB1 gene, which encodes connexin32)
CMT2: autosomal dominant neuropathies caused by mutations in MFN2 gene with axonal rather than demyelinating injury

Question 18

One-liners about the other four peripheral neuropathies listed

Answer 18

Hereditary sensory neuropathies with/without autonomic neuropathy: loss of pain and temp sensation
Hereditary neuropathy with pressure palsy: deletion of PMP22 gene, with compression of individual nerves
Familial amyloid polyneuropathies: germ line mutations of the transthyretin gene and deposition of amyloid fibrils in number of tissues

Question 19

Congenital Myasthenic Syndrome:

Answer 19

Autosomal recessive mode of inheritance with mutations in presyn, syn, or postsyn proteins (e.g. loss of function mutations in gene encoding a subunit of ACh receptor)

Question 20

Inclusion body myositis: age, presentation, labs, specific features, treat

Answer 20

Age: Think older than 50; most common inflamm myopathy in patients older than 65
Presentation: slowly progressive muscle weakness in quads and distal upper extremity muscles, dysphagia not uncommon
Labs: elevated CK; antibody to cN1A described
Specific: endomysial fibrosis and fatty replacement, beta amyloid, TDP-43, ubiquitin, RIMMED VACUOLES (just thnk some sort of inclusions in either myofibers or cytoplasm!!)
Treat: Still corticosteroids for front-line!!

QandA: think single-fiber necrosis and regeneration with predominantly endomysial cytotoxic T cells; inclusions are stained by Congo red and represent a form of intracellular amyloid

Question 21

Causes of toxic myopathies can include:

Answer 21

1. STATINS!!!
2. Chloroquine and hydroxychloroquine (drug-incuded lysosomal storage myopathy presenting with slowly progressive muscle weakness)
3. ICU myopathy or myosin deficient myopathy (during course of treatment for critical illness)
4. Thyroid dysfunction (think thyrotoxic myopathy with exophthalmic ophthalmoplegia ; also hypothyroidism causing cramping or aching of muscles and decreased movement, slowed reflexes, issues with skeletal muscle)
5. Alcohol (rhabdo, myoglobinuria, renal failure)

Question 22

Congenital muscular dystrophies have two important groups:

Answer 22

1. Conditions with defects in EC matrix surrounding myofibers (think Ullrich congenital muscular dystrophy, or UCMD, and merosin deficiency; UCMD with hypotonia, proximal contractures, and distal hyperextensibility)
2. Conditions with abnormalities in receptors for ECM matrix (post-translational mod of alpha-dystroglycan by O-linked glycosylation disrupted, which can lead to defects of CNS and eyes causing seizures, mental retardation and blindness)

Question 23

Myotonic dystrophy: cause, presentation, pathogenesis at molecular level

Answer 23

Cause: Autosomal dominant multisystem disorder
Presentation: skeletal muscle weakness, cataracts, endocrinopathy, cardiomyopathy; MYOTONIA (involuntary contraction of muscles)
Pathogenesis: expansions of CTG triplet repeats in myotonic dystrophy protein kinase (DMPK) gene; think of a defective CLC1 as being responsible for MYOTONIA!!

QandA: adult onset and congenital; slow muscle relaxation (myotonia) and progressive muscle weakness and wasting; think atrophy of type I fibers and hypertrophy of type II fibers; internally situated nuclei

Question 24

Emery-Dreifuss Muscular Dystrophy: cause, presentation, mutations in molecular level

Answer 24

Cause: mutations in genes that encode nuclear lamina proteins
Presentation: slowly progresive humeroperoneal weakness, cardiomyopathy associated with conduction defects, and early contractures of Achilles tendon, spine, and elbows
Forms: X-linked (EMD1) and autosomal form (EMD2) with mutations in genes encoding emerin and lamin A/C, respective (normally maintain shape and mechanical stability of nucleus during muscle contraction)

Question 25

Fascioscapulohumeral dystrophy: cause, molecular pahtogenesis

Answer 25

Cause: prominent weakness of facial muscles and muscles of the shoulder girdle (autosomal dominant)
Pathogenesis: overexpression of DUX4, which encodes TFs

Question 26

Limb-Girdle Muscular Dystrophy: characterized by

Answer 26

muscle weakness that preferentially involves proximal muscle groups

Question 27

Many inborn errors of lipid or glycogen metabolism affect _____; some examples are

Answer 27

skeletal muscle;
Carnitine palmitoyltransferase II deficiency: lipid metabolism disorder causing episodic muscle damage with exercise or fasting, with impaired transport of FFAs into mito (QandA)
Myophosphorylase deficiency (McArdle): glycogen storage disease that affects skeletal muscle and results in episodic muscle damage with exercise
Acid maltase deficiency: can't convert glycogen to glucose so can lead to Pompe disease in infants (QandA: autosomal recessive, inherited, metabolic disorders with inability to degrade glycogen; think neonatal/early infantile with severe hypotonia and areflexia, enlarged tongue, cardiomegaly; skeletal muscle, cardiac muscle, CNS, liver involvement; use enzyme replacement therapy

Question 28

Mito Myopathies: what do they tend to impair? Examples?

Histo, clinical

Answer 28

Impair ability of mito to generate ATP and can involve skeletal muscle to manifest as weakness, elevations in serum CK levels, or rhabdomyolysis; chronic progressive external ophthalmoplegia (high requirements for ATP);
histo: ragged red fibers, histochemical staining for cytochrome oxidase
Clinical: could get mito encephalomyopathy with lactic acidosis and strokelike episodes; Kearns-Sayre syndrome (ophtalmoplegia, pigmentary degeneration of the retina, complete heart block); myoclonic epilepsy with RAGGED RED FIBERS and Leber hereditary optic neuropathy!!

Question 29

Spinal muscular atrophy: causes, who, molecular

Answer 29

Causes: neuropathic disorder in which loss of motor neurons leads to muscle weakness and atrophy
Who: think infants with generalized hypotonia (“floppy infant”)
Molecular: autosomal recessive with loss-of-function mutations in SMN1 (issues with motor neuron survival)

QandA: loss of motor neurons in infancy, and biopsy specimen shows group atrophy of myofibers

Question 30

Ion channel myopathies: cause, examples

Answer 30

Causes: autosomal dominant;
Examples: KCNJ2 (affect K channel and lead to Andersen-Twail syndrome, autosomal disorder)
SCN4A (mutations affecting sodium channel)
CACNA1S (missense mutations in muscle calcium channel; hypokalemic paralysis)
CLC1: can cause myotonia congenita
RYR1: can lead to MALIGNANT HYPERTHERMIA (QandA: consider this when the patient’s temperature increases rapidly in the context of a surgical procedure done under anesthesia)!!

Question 31

Schwannomas: causes, histo, where are they, treat

Answer 31

Causes: Benign tumors that exhibit Schwann cell differentiation and arise from peripheral nerves; lose NF2 gene product MERLIN!!
Histo: Antoni A (spindle cells) and Antoni B (hypocellular); Verocay bodies; Scwhann cell origin of the tumors borne out by immunoreactivity for S-100
Where are they: most schwannomas occur at cerebellopontine angle, attached to vestibular branch of eighth nerve (think tinnitus and hearing loss!!!)
Treat: surgical removal is CURATIVE!!

Question 32

Localized cutaneous neurofibroma: cause, histo

Answer 32

Causes: loss of NF1 gene product (would normally inhibit RAS activity by stimulating activity of GTPase)
Histo: bland Schwann cells, with mast cells, perineurial cells, CD34+ spindle cells, and fibroblasts

Question 33

Diffuse neurofibroma: histo

Answer 33

pseudo-Meissner corpuscles or tactile-like bodies; tumor infiltrates dermis and subcutaneous CT, entraps fat and appendage structures and producing a plaque-like appearance

Question 34

Plexiform neurofibroma: histo

Answer 34

bag of worms appearance; collagen seen in bundles likened to “shredded carrot”

Question 35

NF I: causes, clinical features

Answer 35

Causes: autosomal dominant and loss-of-function mutations in NF1 gene (17q11.2)
Clinical: mental retardation or seizures, skeletal defects pigmented nodules of the iris (Lisch nodules), and cuttanoues hyperpigmented macules (cafe au lait spots)

Question 36

NF II: causes, clinical features

Answer 36

Causes: autosomal dominant with loss of 22q12
Clinical: think bilateral eighth-nerve schwannomas and multiple meningiomas

Question 37

Hurler syndrome:

Answer 37

inherited defect in mucopolysaccharid metabolism

Question 38

In denervation of a muscle fiber,

Answer 38

you would see adipose tissue replace muscle fibers since there is atrophy proceeding to complete loss of myofibrils

Question 39

Stimulation of type II fibers elicit

Answer 39

a faster, shorter, and more powerful contraction than occurs in type I fibers; suitable for rapid contractions of brief duration and react to strength training with HYPERTROPHY!!

Question 40

Morton neuroma is a

Answer 40

form of compressive neuropathy in which a plantar nerve is trapped between metatarsal heads; chronic injury leads to growth of tangled mass of axons, fibroblasts, and perineurial cells!!

Question 41

Mitochondrial encephalopathy with lactic acidosis and strokelike episodes can

Answer 41

lead to mitochrondrial myopathies, encephalopathies, and deafness; also maternal pattern of inheritance

Question 42

Congenital Myopathy

Answer 42

Muscular weakness not worsening, no muscle pain on palpation, subsarcolemmal aggregates of rod-shaped intracytoplasmic influsions and normal serum CK