LM 3.4: Pathology of Nerve and Muscle

Question 1

what is axonal disease?

Answer 1

chronic injury to a motor neuron results in atrophy of the axon, starting at the most distal extent = “dying back pattern”

if you damage the motor neuron, the most distal regions are what’s effected first; aka the nerves that go out to your arms and legs! then the axon dies back towards the middle of the body

the clinical consequence is a “stocking and glove” distribution of sensory loss, and/or a distal pattern of muscle weakness

in contrast, primary muscle diseases usually present with a proximal pattern of muscle weakness.

Question 2

how thick is the myelin in comparison to the axon diameter?

Answer 2

2:1

Question 3

what is the dying back phenomenon of axons?

Answer 3

the distal branches of the nerves die and then it moves proximally

you can see this on a picture where the myelin sheath is degrading as you get more distal

in a cross section, you can see a collapsed Schwann cell! there’s no axon or myelin and you just see a squished up Schwann cell because the axon has disappeared and the Schwann cell is no longer making myelin

Question 4

what is Wallerian degeneration?

Answer 4

the degeneration process that happens following trauma

if you cut a nerve, the distal part will die because it’s no longer connected to the cell body!

first the distal axon shrivels up and degenerates and then the Schwann cell turns into a macrophage and starts digesting its own myelin and then finally, the axon and myelin disappear and you just end up with endoneurium filled with useless Schwann cells

however, if the cell body is still healthy, it’ll try to regenerate if the endoneurium is still in tact! and then the Schwann cells will reactivate and start making myelin if the cell body successfully regenerates an axon!

Question 5

what is a regenerative cluster?

Answer 5

multiple nerve fibers inside a single original nerve fiber

this is a clue that there was damage to the axon previously and it’s trying to regenerate

Question 6

what is myelin disease?

Answer 6

primary injury to peripheral nerve myelin results in a more random pattern of nerve fiber degeneration

chronic, repeated attempts at remyelination lead to formation of “onion bulb” structures from multiple dividing Schwann cells from each episode of remyelination –> this is usually seen with hereditary demyelinating diseases

Question 7

what is macrophage-mediated demyelination?

Answer 7

a macrophage surrounds a myelinated axon and is stripping away the myelin

Question 8

what are the immune mediated peripheral nerve diseases?

Answer 8

1. guillain-barre syndrome (acute)

2. chronic inflammatory demyelinating polyradiculopathy (chronic)

Question 9

what are the infectious mediated peripheral nerve diseases?

Answer 9

1. leprosy
2. diptheria
3. varicella zoster

Question 10

what is guillain-barre syndrome?

Answer 10

an acute, life threatening disease that’s an autoimmune attack on the myelin often following flu-like illness

there is lymphocytic infiltration and macrophage stripping of the myelin of axons which leads to rapidly ascending paralysis

COD is usually respiratory failure so respiratory support reduces mortality until the disease passes and the nerves remyelinate

Question 11

what ia chronic inflammatory demyelinating polyradiculopathy?

Answer 11

it’s a chronic relapsing disease that is due to chronic demyelination/remyalination so you see the onion bulbs!!

since it’s autoimmune and long term, you try to treat it with corticosteroids or plasmapheresis to try and tone down the immune response

Question 12

how does lepromatous leprosy cause neuron damage?

Answer 12

a bacteria that can lead to Schwann cell infection and that causes demyelination and if it’s bad enough, it could even cause axonal loss (but the main attack is on Schwann cells)

the bacteria has preferential involvement with the pain fibers first so patients usually present with unnoticed limb trauma

Question 13

how does tuberculoid leprosy cause neuron damage?

Answer 13

lead to Schwann cell infection and that causes demyelination and if it’s bad enough, it could even cause axonal loss (but the main attack is on Schwann cells)

you’ll see granulomas in
small dermal nerves!!

involvement is more focal

Question 14

what is charcot-Marie-Tooth diseases?

Answer 14

it’s a large group of different disorders that’s classified into 3 main groups

generally mild disease and people will have a normal life span

type I = demyelinating with onion bulbs

type II = neuronal disease

type III = genetically and morphologically diverse; so they don’t fit into either

Question 15

what is diabetic neuropathy

Answer 15

very common…50% of diabetics have neuropathy after 25 years of diabetes!!

it starts out as sclerosis of intrafascicular arterioles = diabetic small vessel disease –> but eventually the nerves get starved from oxygen and you get nerve damage

the nerves will be surrounded by collagen instead of myelin

there’s a preferential involvement of small fibers, with loss of pain sensation with consequent distal limb ulcerations –> diabetics will get infections from untreated injuries that can lead to amputation

Question 16

other than diabetes, what other things can cause neuropathy?

Answer 16

1. uremic –> kidney problems with high nitrogen can damage nerves
2. alcoholic
3. amyloid neuropathy –> amyloid is a variety of proteins that can precipitate into an insoluble lump in the nerves
4. various vitamin deficiencies
5. neurotoxic environmental toxins; especially lead and arsenic

Question 17

what is a traumatic neuroma?

Answer 17

if the peripheral nerve sheath is still in tact, the regenerative axon will try to find it and reestablish a connection

but if the damage was so bad, the axon still tries to regenerate but it just makes a huge ball of lost axons that are trying to figure out something to do and you get a nodule

a common way that this happens is after an amputation!

these things usually aren’t bad but if they get big you can get a lot of pain from these nerve lumps!

Question 18

what is a compression neuropathy?

Answer 18

when there’s not enough space for the nerves and you damage them

like carpal tunnel syndrome!!!

Question 19

what is amyotrophic lateral sclerosis?

Answer 19

ALS is a disease of the neurons that innervate muscles aka degeneration of corticospinal tract

there’s death of the anterior horn motor neurons and atrophy of the ventral nerve roots!! so literally everything nerve related degenerates from the spinal cord down to the muscle

there is myelination fiber loss in both lateral and anterior corticospinal tract

patients preset with slowly progressive, ascending paralysis but there is preservation of sensory modalities because it’s just the motor neurons that are effected

the brain is also totally intact so the patients have total cortical function too

presents in middle aged people

Question 20

how do you test for ALS?

Answer 20

there’s a lot of brown staining which indicates neuronal death and axonal loss

Question 21

what happens to the muscle during ALS?

Answer 21

muscle atrophy

the fascicles contain tiny muscle fibers with what looks like tons of nuclei but it’s really just because the muscle fibers have shrunk since there’s no longer a nerve going to them

Question 22

what is infantile spinal muscular atrophy?

Answer 22

aka Werdnig-Hoffman disease so sort of like ALS but in babies and it’s genetic

the motor system, anterior horn and muscles deteriorate so patients present with neonatal hypotonia = floppy baby syndrome

there is death within the first 1-2 years of life

Question 23

what genetic mutation causes infantile spinal muscular atrophy

Answer 23

SMN1 gene mutation

causes neuron death but the mechanism is unknown

Question 24

what is type 1 muscle fibers?

Answer 24

red, slow myosin, endurance

rich in mitochondria and myoglobin so they’re very aerobic

marathon runners will have more of these muscle fibers

Question 25

what is type 2 muscle fibers?

Answer 25

white muscle fibers, fast myosin, strength and speed

can generate more force

rich in glycolytic enzymes and glycogen

great for if you want to be a sprinter or muscle builder

Question 26

what does a normal muscle fiber look like?

Answer 26

1. fibers are all the same size
2. tightly packed fibers
3. polygonal shaped; not circular, straight edges
4. multiple peripheral nuclei

Question 27

which diseases are atrophic muscle diseases?

Answer 27

1. neurogenic atrophy

motor neuron disease or peripheral neuropathies

2. selective atrophy of type 2 muscle fibers

Question 28

which diseases are autoimmune muscle diseases?

Answer 28

1. myasthenia gravis
2. polymyositis
3. dermatomyositis

Question 29

which diseases are hereditary muscle diseases?

Answer 29

1. muscular dystrophy
2. congenital myopathy
3. metabolic myopathies

Question 30

what is the progression of chronic denervation?

Answer 30

1. normal muscle

a neuron innervates multiple muscle fibers = motor unit; but all of the same muscle fiber type; so there’s type 1 and type 2 neurons!

2. if a neuron dies, there will be motor unit loss which causes small group atrophy
3. collateral axonal sprouting, rein nervation and fiber type grouping with giant motor units

fiber types will change to match the new neuron that’s innervating them post-regeneration

4. then if this new neuron gets damaged, you’ll get further motor unit loss with large group atrophy

Question 31

what could cause selective atrophy of type 2 muscle fibers?

Answer 31

1. disuse
2. chronic disease
3. cachexia
4. corticosteroids

type 2 = strength fibers –> these get larger when you work on them so if you don’t exercise, type 2 fibers shrink in size while the type 1 fibers are fine! you can tell the difference because with an innervation problem both fiber types will decrease in type but if it’s selective atrophy of type 2 fibers then it’ll only be type 2 fibers that are smaller

Question 32

what is myasthenia gravis?

Answer 32

a disease where there are autoantibodies against acetylcholine receptor so there’s immunological destruction of the neuromuscular junction –> there’s destruction of the neuromuscular synaptic folds in the motor end plate

sometimes there’s compensatory overproduction of neurosecretory granules in the pre-synaptic membrane so you have higher ACh levels to try and compensate which works for a while

patients strength will decrease with use but will increase with rest; this happens because they are running out of acetylcholine!

can be associated with thymic hyperplasia or thymoma or other autoimmune diseases

Question 33

what is eaton-lambert syndrome?

Answer 33

a clinically similar disease to myasthenia gravis that is a paraneoplastic syndrome with a presynaptic block; anticholinesterase agents do not help

Question 34

what is polymyositis?

Answer 34

inflamed muscles due to cytotoxic T cells which are sensitized against the muscle and attack the muscle

H&E stain you’ll see a lot of neutrophils and other PMNs in the muscle tissue attacking it

patients present with a lot of pain

can treat with corticosteroids to suppress the immune system

Question 35

what is dermatomyositis?

Answer 35

extrafasciular inflammation

due to antibodies attacking the blood vessels around the muscle

H&E stain you’ll see neutrophils outside the muscle because they’re attacking the blood vessels, not the muscle; there’s also small muscle fibers around the edge of the fasicle because of decreased blood flow

patients present with pain and a rash

can treat with corticosteroids to suppress the immune system

Question 36

what is inclusion body myopathy?

Answer 36

muscle is degenerating and there’s inflammatory cells

the inflammatory cells are NOT causing the damage, they’re reacting to the damage/degenerartion so it’s not due to an overactive immune system —> so you can’t treat it with steroids!!!!!

this is a disease of elderly patients

H&E stain looks a lot like polymyositis

Question 37

what is duchenne muscular dystrophy?

Answer 37

deficiency of dystrophin gene

dystrophin anchors the cytoskeleton to the extracellular matrix through several dystrophin-associated glycoproteins (DAGs) –> DAGs protect the lipid bilayer of muscle and separate the outside of the muscle from the muscle so they keep certain ions out of the muscle and the muscle from breaking down

x-linked; high mutation rate and the dystrophin gene is totally non-function

onset at ages 5-6 with death in the late teens of early 20s due to increasing weakness

patients are usually boys because it’s x-linked, and they end up in a wheelchair by the time they’re 5-6 and dead by their 20s

Question 38

what is becker muscular dystrophy?

Answer 38

milder form of duchenne MD; kids get sick at an older age like 10 years old

it’s due to a truncated dystrophin molecule due to a multiple of 3 base deletion

Question 39

what is myotonic muscular dystrophy?

Answer 39

it’s a trinucleotide repeat disease – the gene has extra trinucleotide repeats that cause problems

Question 40

what do you see in an H&E stain of duchenne MD?

Answer 40

degenerating muscle –> the muscle fibers are not all next to each other, there’s collagen pushing them apart which also makes the fibers round instead of polygonal

in muscles, we don’t really have cell death; muscle fibers are long myotubes so you can kill a segment but the segment next to it is fine and the nuclei can move over and regenerate so you can see this in the stain too

all of this is called myopathic changes in muscles:

1. myofiber degeneration = altered staining properties of fibers, vacuolization, macrophage invasion, etc
2. myofiber regeneration = centralal, enlarged nuclei and basophilia due to increased RNA content

Question 41

what are some of the causes of neonatal hypotonia?

Answer 41

poor prognosis:
1. infantile spinal muscular atrophy

2. acid maltase deficiency (Pompe disease)

better prognosis:
1. congenital myopathies!

Question 42

what are congenital myopathies?

Answer 42

there’s a fixed structural defect that causes the muscle to be weak but the muscles don’t get worse over time like with neuron problems! so these people will grow up and be fine even if that means they won’t be a track star

the most common is centronuclear myopathy so this means that the nuclei are in the middle of the cell instead of in the periphery

Question 43

what are some examples of metabolic myopathies?

Answer 43

1. glycogen storage diseases
2. lipid storage diseases
3. mitochondrial defects

Question 44

what is phosphorylase deficiency?

Answer 44

aka McArdles

patients are phosphorylase deficient which means they can’t breakdown glycogen

glycogen storage disease that’s mild with onset in adulthood

patients have exercise intolerance with later weakness

Question 45

what is acid maltase deficiency?

Answer 45

aka Pompe disease

it’s a glycogen storage disease of muscle that is a severe neonatal disease and leads to floppy baby syndrome

death within 1-2 years

Question 46

which diseases are lipid storage diseases of muscle?

Answer 46

1. muscle carnitine deficiency
2. carnitine palmityltransferase deficiency
3. systemic carnitine deficiency

Question 47

what is muscle carnitine deficiency?

Answer 47

a mild disease with generalized weakness

Question 48

what is carnitine palmityltransferase deficiency?

Answer 48

a mild disease resembling muscle phosphorylase deficiency

Question 49

what is systemic carnitine deficiency ?

Answer 49

a more severe disease with episodes of hepatic insufficiency and encephalopathy

Question 50

what are mitochondrial diseases involving muscle?

Answer 50

you’re going to have problems with tissues that need lots of aerobic ATP production which may involve muscle, nerve, heart, retina, and/or brain; producing various syndromes

when this involves muscle you get muscle weakness due to mitochondrial dysfunction

in an EM, the mitochondria look weird

mitochondria have DNA and are capable of proliferating so a certain stain will show you “ragged red fiber” which indicates that mitochondria are over proliferating to try and compensate

Question 51

what is acute quadriplegic myopathy?

Answer 51

it’s an acute loss of myosin thick filaments; they literally don’t have any thick filaments

it often occurs in patients who are critically ill and respirator-dependent, especially following treatment with corticosteroids and with neuromuscular blocking agents

it’s due to the drugs that were given to treat the acute disease!

patients recover with time, assuming that their critical illness resolves and you take them off the drugs