LM 3.4: Pathology of Nerve and Muscle Flashcards
what is axonal disease?
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.
how thick is the myelin in comparison to the axon diameter?
2:1
what is the dying back phenomenon of axons?
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
what is Wallerian degeneration?
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!
what is a regenerative cluster?
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
what is myelin disease?
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
what is macrophage-mediated demyelination?
a macrophage surrounds a myelinated axon and is stripping away the myelin
what are the immune mediated peripheral nerve diseases?
- guillain-barre syndrome (acute)
2. chronic inflammatory demyelinating polyradiculopathy (chronic)
what are the infectious mediated peripheral nerve diseases?
- leprosy
- diptheria
- varicella zoster
what is guillain-barre syndrome?
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
what ia chronic inflammatory demyelinating polyradiculopathy?
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
how does lepromatous leprosy cause neuron damage?
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
how does tuberculoid leprosy cause neuron damage?
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
what is charcot-Marie-Tooth diseases?
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
what is diabetic neuropathy
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
other than diabetes, what other things can cause neuropathy?
- uremic –> kidney problems with high nitrogen can damage nerves
- alcoholic
- amyloid neuropathy –> amyloid is a variety of proteins that can precipitate into an insoluble lump in the nerves
- various vitamin deficiencies
- neurotoxic environmental toxins; especially lead and arsenic
what is a traumatic neuroma?
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!
what is a compression neuropathy?
when there’s not enough space for the nerves and you damage them
like carpal tunnel syndrome!!!
what is amyotrophic lateral sclerosis?
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
how do you test for ALS?
there’s a lot of brown staining which indicates neuronal death and axonal loss
what happens to the muscle during ALS?
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
what is infantile spinal muscular atrophy?
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
what genetic mutation causes infantile spinal muscular atrophy
SMN1 gene mutation
causes neuron death but the mechanism is unknown
what is type 1 muscle fibers?
red, slow myosin, endurance
rich in mitochondria and myoglobin so they’re very aerobic
marathon runners will have more of these muscle fibers
what is type 2 muscle fibers?
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
what does a normal muscle fiber look like?
- fibers are all the same size
- tightly packed fibers
- polygonal shaped; not circular, straight edges
- multiple peripheral nuclei
which diseases are atrophic muscle diseases?
- neurogenic atrophy
motor neuron disease or peripheral neuropathies
- selective atrophy of type 2 muscle fibers
which diseases are autoimmune muscle diseases?
- myasthenia gravis
- polymyositis
- dermatomyositis
which diseases are hereditary muscle diseases?
- muscular dystrophy
- congenital myopathy
- metabolic myopathies
what is the progression of chronic denervation?
- 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!
- if a neuron dies, there will be motor unit loss which causes small group atrophy
- 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
- then if this new neuron gets damaged, you’ll get further motor unit loss with large group atrophy
what could cause selective atrophy of type 2 muscle fibers?
- disuse
- chronic disease
- cachexia
- 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
what is myasthenia gravis?
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
what is eaton-lambert syndrome?
a clinically similar disease to myasthenia gravis that is a paraneoplastic syndrome with a presynaptic block; anticholinesterase agents do not help
what is polymyositis?
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
what is dermatomyositis?
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
what is inclusion body myopathy?
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
what is duchenne muscular dystrophy?
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
what is becker muscular dystrophy?
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
what is myotonic muscular dystrophy?
it’s a trinucleotide repeat disease – the gene has extra trinucleotide repeats that cause problems
what do you see in an H&E stain of duchenne MD?
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:
- myofiber degeneration = altered staining properties of fibers, vacuolization, macrophage invasion, etc
- myofiber regeneration = centralal, enlarged nuclei and basophilia due to increased RNA content
what are some of the causes of neonatal hypotonia?
poor prognosis:
1. infantile spinal muscular atrophy
- acid maltase deficiency (Pompe disease)
better prognosis:
1. congenital myopathies!
what are congenital myopathies?
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
what are some examples of metabolic myopathies?
- glycogen storage diseases
- lipid storage diseases
- mitochondrial defects
what is phosphorylase deficiency?
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
what is acid maltase deficiency?
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
which diseases are lipid storage diseases of muscle?
- muscle carnitine deficiency
- carnitine palmityltransferase deficiency
- systemic carnitine deficiency
what is muscle carnitine deficiency?
a mild disease with generalized weakness
what is carnitine palmityltransferase deficiency?
a mild disease resembling muscle phosphorylase deficiency
what is systemic carnitine deficiency ?
a more severe disease with episodes of hepatic insufficiency and encephalopathy
what are mitochondrial diseases involving muscle?
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
what is acute quadriplegic myopathy?
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
