Peripheral Nerve and Skeletal Muscle

Question 1

Motor unit

Answer 1

Functional unit of neuromuscular system. Composed of lower motor
neuron (anterior horn of spinal cord) or cranial nerve motor nucleus (brain stem), axon
of that neuron and muscle fibers it innervates

Question 2

Nerve fiber

Answer 2

Principal structural component of peripheral nerve. Composed of the
axon, Schwann cells and myelin sheath

Question 3

Axons

Answer 3

Contain organelles and cytoskeletal structures (microfilaments,
neurofilaments, microtubules, mitochondria, vesicles, smooth ER, and lysosomes). No
protein synthesis in the axon. Axoplasmic flow delivers proteins and other substances
synthesized in the perikaryon down the axon.

Question 4

Myelination

Answer 4

PNS axons are myelinated in segments (internodes) separated by
nodes of Ranvier. A single Schwann cell supplies the myelin sheath for each internode.
Myelin protein zero (MPZ) makes up >50% of PNS myelin protein, peripheral myelin
protein 22 is found in compacted myelin

Question 5

Nerve

Answer 5

Numerous nerve fibers grouped into fascicles by connective tissue sheaths.
Myelinated and unmyelinated fibers are intermingled in the fascicle

Question 6

Connective tissue components: Epineurium

Answer 6

encloses entire nerve;

Question 7

Connective tissue components: perineurium

Answer 7

encloses each fascicle

Question 8

Connective tissue components: endoneurium –

Answer 8

surrounds individual nerve fibers.

Question 9

Segmental Demyelination

Answer 9

occurs when there is dysfunction of the
Schwann cell or damage to myelin sheath (no primary abnormality of the axon).
Disintegrating myelin is engulfed first by Schwann cells then by macrophages.

Question 10

Segmental Demyelination: Repair:

Answer 10

The denuded axon stimulates remyelination. Certain cells in the endoneurium
can replace injured Schwann cells. These cells proliferate and encircle eventually
remyelinating the denuded area. Newly formed myelinated internodes are shorter than
normal requiring several to bridge the demyelinated region. The new myelin sheath is
also thin in proportion to the diameter of the axon.

Question 11

Segmental Demyelination: Sequential demyelination and remyelination

Answer 11

Tiers of Schwann cells accumulate that on
cross-section appear as layers of Schwann cell cytoplasm and basement membrane
around a thinly myelinated axon (onion bulb)

Question 12

Axonal degeneration and muscle fiber atrophy

Answer 12

the result of primary
destruction of the axon with secondary disintegration of its myelin sheath. Damage to
axon occurs due to focal event (trauma, ischemia) or more generalized abnormality
affecting the neuron cell body or its axon.
When axonal injury occurs due to a focal lesion the portion of the fiber distal to the
lesion undergoes wallerian degeneration:
1) Axon begins to breakdown within ~24 hrs,
2) Affected Schwann cells begin to catabolize myelin then engulf axon fragments,
3) Recruited macrophages phagocytose axonal and myelin-derived debris.
In slowly evolving neuronopathies or axonopathies, evidence of axonal degeneration is
scant because only a few fibers are actively degenerating at any given time.
The muscle fibers within the affected motor unit lose their neural input and undergo
denervation atrophy.
The stump of the proximal portion shows degenerative changes involving only the most
distal two or three internodes and then undergoes regenerative activity.

Question 13

Nerve regeneration

Answer 13

proximal stumps of degenerated axons sprout and elongate and
may develop new growth cones. Growth cones are guided by vacated Schwann cells.
The evidence of regeneration is called the regenerating cluster: Multiple closely
aggregated, thinly myelinated small-caliber axons.
Regeneration is a slow process limited by the movement of tubulin, actin, and
intermediate filaments, ~1mm/day.

Question 14

Inflammatory Neuropathies

Answer 14

haracterized by inflammatory infiltrates in peripheral

nerves, roots, ganglia

Question 15

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating

Polyradiculoneuropathy)

Answer 15

Life-threatening
1-3 cases/100,000 in US
4
Characterized by weakness beginning with distal muscles which rapidly
progresses to proximal muscles (ascending paralysis)

Question 16

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating

Polyradiculoneuropathy): Pathogenesis:

Answer 16

2/3 of cases are preceded by an acute, influenza-like illness from
which the patient has recovered by the time the neuropathy becomes
symptomatic (Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus,
and Mycoplasma pneumoniae infections and prior vaccination have a
significant epidemiologic association with G-B syndrome)

Question 17

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating

Polyradiculoneuropathy): Morphology

Answer 17

Dominant histopathologic finding is inflammation of peripheral nerve
(perivenular and endoneurial infiltration by lymphocytes, macrophages,
and a few plasma cells).

Question 18

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating

Polyradiculoneuropathy): Segmental demyelination

Answer 18

he primary lesion but damage to axons is
also characteristic esp. in severe disease. Cytoplasmic processes from
macrophages penetrate the basement membrane of Schwann cells,
stripping away the myelin sheath from the axon. Remnants of the myelin
sheath are engulfed by macrophages.

Question 19

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating

Polyradiculoneuropathy): Remyelination

Answer 19

follows the demyelination

Question 20

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating

Polyradiculoneuropathy): Clinical Course:

Answer 20

Ascending paralysis
Loss of deep tendon reflexes
Sensory involvement may be detected
Nerve velocity is slowed
Elevation of protein in CSF from inflammation and altered
permeability of the microcirculation within the spinal roots
Many patients spend weeks in ICU before recovering normal
function
Mortality 2-5% (down from 25%) from respiratory paralysis,
autonomic instability, cardiac arrest, and complications of
treatmen

Question 21

Leprosy: Lepromatous leprosy:

Answer 21

Schwann cells are invaded by Mycobacterium leprae,
proliferating and eventually infecting other cells

Segmental demyelination and remyelination
Loss of both myelinated and unmyelinated axons
As infection advances: Endoneurial fibrosis and multilayered thickening of the
perineurial sheaths occur
Patients develop a symmetric polyneuropathy predominantly involving pain
fibers and resulting in loss of sensation. Patient is unaware of injurious stimuli
and damaged tissues. Result is large traumatic ulcers may develop in extremities

Question 22

Leprosy: Tuberculoid leprosy

Answer 22

Cell-mediated immune response to M. leprae, manifested
by nodular granulomatous inflammation in the dermis.
Cutaneous nerves in the vicinity of the inflammation are injured; axons, Schwann
cells and myelin are lost.
Fibrosis of the perineurium and endoneurium occurs.
Patients have a much more localized nerve involvement

Question 23

Varicella-Zoster Virus

Answer 23

Latent infection of neurons in the sensory ganglia of the spinal cord and brain
stem following chickenpox.
Reactivation leads to a painful, vesicular skin eruption in the distribution of
sensory dermatomes (thoracic or trigeminal most common)
Affected ganglion show neuronal destruction and loss, accompanied by
abundant mononuclear inflammatory infiltrates, regional necrosis with
hemorrhage may be found. Peripheral nerve shows axonal degeneration after
the death of the sensory neurons.

Question 24

Peripheral Neuropathy in Adult-Onset Diabetes Mellitus

Answer 24

50% of diabetics have peripheral neuropathy clinically after 25 years
6
• Nearly 100% have conduction abnormalities
• Categorized as distal symmetric sensory or sensorimotor neuropathy,
autonomic neuropathy, and focal or multifocal asymmetric neuropathy.
Morphology:
• Axonal neuropathy seen in patients with a distal symmetric sensorimotor
neuropathy.
• Segmental demyelination seen in chronic axonal neuropathies
• Relative loss of small myelinated fibers and of unmyelinated fibers, but
large fibers are also affected.
• Whether lesions are due to ischemia or metabolic derangements is unclear

Question 25

Peripheral Neuropathy in Adult-Onset Diabetes Mellitus: Clinical course:

Answer 25

• Symmetric neuropathy is most common peripheral neuropathy • Patients develop decreased sensation in distal extremities with less evident motor abnormalities. • Loss of pain sensation results in development of ulcers that heal poorly because of diffuse vascular injury • Dysfunction of the autonomic nervous system affects 20-40% of diabetics, nearly always associated with a distal sensorimotor neuropathy. • Some patients esp. elderly with a long history of diabetes develop a peripheral neuropathy manifested as a disorder of single individual peripheral or cranial (oculomotor) nerves (mononeuropathy) or of several individual nerves in an asymmetric distribution. Pathogenesis of mononeuropathies in adult-onset diabetes is thought to involve vascular insufficiency, creating ischemic injury of the peripheral nerve

Question 26

Transection

Answer 26

Regeneration can still occur, slowly ▪ Regrowth may be complicated by discontinuity between the proximal and distal portions of the nerve sheath as well as by the misalignment of individual fascicles ▪ Axons may continue to grow resulting in a mass of tangled axonal processes known as a traumatic neuroma. Within this mass small bundles of axons appear randomly oriented each however is surrounded by organized layers containing Schwann cell, fibroblasts and perineurial cells.

Question 27

Compression neuropathy (entrapment neuropathy): Carpal tunnel syndrome:

Answer 27

Most common entrapment neuropathy • Results from compression of the median nerve at the level of the wrist within the compartment delimited by the transverse carpal ligament • Women > men • Bilateral frequently • Sx: numbness and paresthesias of the tips of the thumb and first two digits Other compression neuropathies: Ulnar nerve at elbow Peroneal nerve at knee Radial nerve in upper arm

Question 28

Hereditary motor and sensory neuropathies

Answer 28

Most common form of hereditary neuropathies Affect both strength and sensation Present as a spectrum of disorders, all caused by mutations in genes whose products are involved in the formation and maintenance of myelin

Question 29

HMSN I – Charcot-Marie-Tooth Disease, hypertrophic form

Answer 29

Most common hereditary peripheral neuropathy Presents in childhood or early adulthood Patients may be asymptomatic or show symptoms of distal muscle weakness, atrophy of the calf muscle, orthopedic problems of the foot

Question 30

HMSN I – Charcot-Marie-Tooth Disease: Genetics

Answer 30

Genetically heterogeneous, duplication of large region of chromosome 17p11.2 – p12 results in segmental trisomy of the duplicated region. The gene for peripheral myelin protein 22 is in the duplicated region. Chromosome 1 has genetic locus with myelin protein zero which produces an identical clinical phenotype (HMSN 1B). Disease in other patients shows linkage to chromosome 16p.

Question 31

HMSN I – Charcot-Marie-Tooth Disease: Morphology:

Answer 31

Demyelinating neuropathy. Histology shows consequences of repetitive demyelination and remyelination with multiple onion bulbs – more pronounced in distal nerves. Redundant layers of Schwann cell hyperplasia surrounding individual axons are associated with enlargement of individual peripheral nerves that may be individually palpable, which has led to the term hypertrophic neuropathy

Question 32

HMSN I – Charcot-Marie-Tooth Disease:Clinical course:

Answer 32

AD Slowly progressive Disability of sensorimotor deficits and associated orthopedic problems are usually limited in severity and normal life span is typical

Question 33

HMSN II

Answer 33

AD Signs and symptoms similar to HMSN I Nerve enlargement not seen Disease presents at slightly later age Less common than HMSN I Histology: Loss of myelinated axons predominant finding. Segmental demyelination of internodes is infrequent suggesting that the site of primary cellular dysfunction is the axon or neuron

Question 34

HMSN III – Dejerine-Sottas Disease

Answer 34

AR ▪ Slowly progressive ▪ Presents in early childhood with delay in reaching developmental milestones (such as acquisition of motor skills). ▪ Trunk and limb muscles are involved, enlarged peripheral nerves can be detected by inspection and palpation. ▪ DTRs depressed or absent ▪ Nerve conduction velocity is slowed ▪ Genetically heterogeneous: Genes include peripheral myelin protein 22, myelin protein zero, periaxin, early growth response 2

Question 35

HMSN III – Dejerine-Sottas Disease: Morphology:

Answer 35

Size of individual peripheral nerve fascicles is increased, abundant onion bulb formation, segmental demyelination, evidence of axonal loss, remaining axons are smaller caliber