Review of Nerve & Muscle Structure & Basic Pathology of Neuromuscular Diseases

Question 1

What are the three layers of connective tissue which group skeletal muscle? What do they group specifically?

Answer 1

Epimysium - encircles the muscle

Perimysium - encircles the fascicles of muscle via collagenous septae

Endomysium - encircles the the individual muscle cells via a matrix of Type I / III collagen

Question 2

What is a triad vs a dyad and where do they exist in muscle?

Answer 2

Triad - T-tubule + 2 terminal cisternae (extensions of sarcoplasmic reticulum), exist at A/I junction in SKELETAL muscle, 2 per sarcomere

Dyad - T-tubule + 1 terminal cisternae, exist at Z line in CARDIAC muscle, 1 per sarcomere

Question 3

What is a normal pattern of muscle fibers in a muscle?

Answer 3

Random admixture of the two types of muscle fibers: Type 1 and Type 2 with not one taking major predominance

Type 1: Dark

Type 2: Light

-> mixture = checkerboard appearance

Question 4

What is the difference between a Type 1 / 2 muscle fiber and how do you account for their appearance?

Answer 4

Type 1: Think “1 slow red ox”
Slow-twitch fibers for sustained contraction, appear red due to high myoglobin and mitochondria for oxidative metabolism

Type 2: Opposite, fast-twitch fibers which fatigue easily and appear white due to lack of mitochondria and increased glycogen levels

Question 5

What stain can be used to differentiate between Type 1 / 2 muscle fiber?

Answer 5

Myosin ATPase stain. At pH 9.4, the staining patterns are flipped and Type 2 fibers will stain dark while type 1 stains white

Question 6

What are the H band and M line?

Answer 6

M line - myomesin line, where the thick filaments are attached in the center of the A band

H band - center area of the A band which gets smaller as the muscle contracts. I band also gets smaller, A band is Always the same length.

Question 7

What is a motor neuron, what does it control, and what dictates its size?

Answer 7

It is a single neuron which controls fibers of a specific type (Type I/II) within a muscle, arranged in a motor unit.

Muscles with fine control (i.e. extraocular muscles) will have smaller motor neurons which innervate fewer muscle fibers per unit (tight control)

Question 8

What reflex are intrafusal fibers involved in?

Answer 8

These are the muscle spindle fibers

• > involved in primary myotatic reflex arc “stretch reflex”
• > maintenance of muscle tone by alpha/gamma coactivation

Question 9

What muscle fiber types will hypertrophy in aerobic vs strength training and what fiber type atrophies first?

Answer 9

Strength training - Type 2 hypertrophy

Aerobic training - increased Type 1 fiber oxidative capacity

Disuse leads to relative atrophy of Type 2 fibers

Question 10

What is the sequence of events in upper motor neuron injury?

Answer 10

Damage -> paralysis of voluntary movement

Initial flaccid paralysis -> later spastic paralysis due to imbalance of central inhibition

Eventual muscle atrophy due to disuse (vs muscle atrophy due to denervation in LMN injury)

Question 11

What is neurogenic atrophy and does it include NMJ disease?

Answer 11

Skeletal muscle dysfunction and ultimately atrophy due to abnormalities in its innervation

Does not include NMJ diseases

Question 12

What histopathologic phenomenon is common in neurogenic atrophy? What will occur as the denervating process ultimately finishes?

Answer 12

Fiber type grouping - ability of adjacent nerve terminals to sprout and renervate denervated myocytes leads to homogeneity of fiber types in an area (all innervated by collaterals from one motor unit) -> loss of checker board appearance due to all muscle fibers becoming the same type.

Group atrophy - denervation leads to massive atrophy of muscle fascicles or muscles (loss of key motor units)

Question 13

What are common drugs / toxins which can cause myopathies?

Answer 13

Statins, steroids, alcohol, cocaine

Question 14

What are the clinical features of myopathies, including type of weakness and lab values?

Answer 14

Symmetrical weakness, affecting proximal > distal muscles
Fatiguability

Features of myonecrosis: myoglobinuria, elevated CK, hyperkalemia

Question 15

How does myofiber regeneration occur and what does it look like under the microscope?

Answer 15

Satellite cells are the stem cells of muscle -> regeneration will follow necrosis in myopathies

Looks like basophilic fiberes in areas of necrosis

Question 16

What pathology is characteristic of Duchenne / Becker muscular dystrophies in early and late stage?

Answer 16

Early - Myonecrosis due to loss of structural entegrity, leads to inflammation and fibrosis of endomysium

Late - Regeneration by satellite cells cannot keep up, leads to fibrofatty replacement of muscle

Question 17

What are the mechanisms of polymyositis vs dermatomyositis?

Answer 17

Polymyositis - autoinvasive CD8+ T cells with endomysial inflammation due to direct attack of muscles

Dermatomyositis - Antibody or immune-complex mediated microangiopathy (affects blood vessels) with secondary muscle damage

Question 18

What are some causes of steroid myopathy and how does it occur?

Answer 18

1. Iatrogenic steroid
2. Endocrinopathies i.e. Cushing’s disease

Steroids impair muscle protein / carbohydrate metabolism due to insulin resistance and protein catabolism -> selective atrophy of Type 2 fibers

Question 19

What dermatomes innervate the following?

1. Posterior half of skull
2. Nipple
3. Xiphoid process
4. Umbilicus

Answer 19

1. Posterior half of skull (S2) - anterior half is trigeminal nerve
2. Nipple - T4 = Teat pore
3. Xiphoid process - T7
4. Umbilicus = Belly ButTen = T10

Question 20

What dermatomes innervate the following?

1. Inguinal ligament
2. Knee
3. Penis / anus

Answer 20

Inguinal Ligament: IL = L1

Knee: Down on all 4’s = L4

Penis: S2,3,4 keep your penis off the floor

Question 21

How does regeneration typically occur following Wallerian degeneration?

Answer 21

Denervated Schwann cells proliferate, forming cords of residual Schwann cells called Bands of Bungner
-> help guide re-growth of axon in unison with the endoneurial tube formed via the basal lamina

Question 22

What can happen if regeneration following Wallerian degeneration goes wrong?

Answer 22

Formation of traumatic neuroma -> abberent regeneration forms a tumor-like mass of nerve fibers, Schwann cells, and scar tissue

Question 23

Other than Wallerian degeneration, what are two other neuronal pathologies which can occur to peripheral nerves?

Answer 23

1. Axonal dystrophy -> distal axonal degeneration, also called dying back neuropathy
2. Segmental demyelination -> damage or loss of myelin internodes along length of axon, also called hypertrophic neuropathy (see later)

Question 24

What neurons are particularly affected in distal axon degeneration and how do they appear?

Answer 24

Particularly the longest axons

• > distal ed will appear swollen
• > will lead to a progressive loss of axons overtime

Question 25

What are the consequences of segmental demyelination?

Answer 25

1. Remyelinated segments may not conduct as efficiently as normal segments (shorter internodal segments)
2. Onion bulb formations -> concentric proliferation of Schwann cells and collagen around nerve fiber leads to enlargement of nerve fascicle called “hypertrophic neuropathy”

Question 26

How are peripheral neuropathies classified?

Answer 26

1. Type of nerve involved - sensory/motor/autonomic
2. Anatomic pattern of involvement
3. Clinical time course
4. Primary involvement of axon or myelin sheath

Question 27

What is polyneuropathy vs mononeuropathy multiplex?

Answer 27

Polyneuropathy - symmetric involvement of multiple nerves -> i.e. “stocking and glove” distal neuropathy

Mononeuropathy multiplex - asymmetric involvement of multiple nerves, usually involving different areas of the body