Peripheral Nerve Degeneration Flashcards
Identify & define the indicated components of the provided image:
- Enodneurium: surrounds individual axons
- Perineurium: bundles groups of axons into fascicles
-
Epineurium: surrounds groups of fascicles & also forms the protective sheath on the nerve
- find blood supply
Fill out the blacked out sections on this table:
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Which Sunderland degree classifications of nerve injury do not require physician intervention?
1, 2, & 3
What tests can be performed in order to classify the degree of nerve injury?
sensory & motor testing
nerve conduction studies
surgery
MRI - Diffusion Tensor Imaging
What defines the proximal end of a nerve injury? Distal end?
Proximal: where all the axons are still attached to the soma
Distal: only has axons (that will degrade)
What is the human response to nerve injury? How does it work?
Wallerian Degeneration (Controlled inflammatory response)
getting rid of distal end → clearing everything up, then regrow the axon to innervate the target tissue
- Degeneration (distal axon)
- Regeneration (of proximal axon)
- Re-innervation (target tissue)
Where in the body does Wallerian degeration occur? Why?
ONLY in PNS
degeneration in CNS is too slow (b/c oligodendrocytes do not help the same way the schwan cells do),
regeneration is not supported b/c it is not a permissive environment (d/t development of glial scars- that helps make sure structure is still intact, but inhibits growth)
Describe what happens within the first 24 hrs of Wallerian Degeneration
-
Calcium influx from extracellular space (both in proximal & distal end) → induces a sealing of the ends
- proximal part usually degenerates up to first node of ranvier
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Degeneration
- proximal part usually degenerates up to first node of ranvier
- all of distal nerve degenerates
- Myelin breakdown begins
- resident macrophages begin clean up (induced by intact schwann cells)
Describe what happens by 48hrs of Wallerian Degeneration
- Axon & myelin breakdown continues distally
- myelin debris inhibits outgrowth from proximal stump
What variable is important in determining timeline of Wallerian Degeneration?
Where the injury occurred & the length of distal nerve that needs to be degenerated & how much needs to be regenerated
(ie. if injury in proximal arm, a lot of nerve needs to be degenerated, much less if injury is in finger)
What substance inhibits the outgrowth of the axon from the proximal stump?
myelin debris
Describe what happens by 72hrs of Wallerian Degeneration
- more macrophages called in from circulation that build up along whole distal nerve
- reactive Schwann cells proliferate & line up → begin to form tube : Bands of Bungner
What is the purpose of the Bands of Bungner?
the regrowing axon will use a guidance to find the target tissue
Describe what is happening about 1 week into Wallerian Degeneration?
- macrophages subside (when debris of myelin is mostly cleared up)
- substances are gone that inhibit the growth cone
- anti-inflammatory agents are present
- reactive Schwann cells continue to form Bands of Bungner → basically ready to be used as a cue for regrowth
Describe what is happening weeks-years into Wallerian Degeneration?
- once the regrown axon has found the target tissue (to increase conduction speed)
- Schwann cells are regenerating myeline
- axon fiber matures & thickens
- hopefully → regain of function
24-36 hrs post injury, Schwann cells release what substances? This has what effect?
- Proinflammatory agents → signal to resident macrophages to start clearing debris
- TNFa
- IL-1B
36-48 hrs post injury, what is happening at the molecular level in Wallerian Degeneration? This has what effect?
- Proinflammatory agents → stimulate fibroblasts
- TNFa
- IL-1B → recruits monocytes from the circulation (differentiate into macrophages & help with clean up)
- MCP-1
- Fibroblast → tells schwann cells to proliferate & phagocytosis
- GM-CSF
48-72 hrs post injury, what is happening at the molecular level in Wallerian Degeneration? This has what effect?
- Schwann Cell
- MCP-1 → peak macrophage concentration helping to clear debris
- Macrophages (after most of debris has been cleared)
- IL-10 (anti inflammatory)
- stops the controlled inflammatory response “Walllerian Degeneration” by preventing Schwann cells from releasing TNFa & IL-1B
- IL-10 (anti inflammatory)
- Schwann cells start forming Bands of Bungner
What is occurring at the molecular level 3-7 days post injury in Wallerian Degeneration?
- Schwann cells →tell proximal stump that it is time to regrow the axon
- NGF
- BDNF
- Fibroblasts → potentiate axon growth
- NGF
- Macrophage → numbers will decrease
- IL10
At what time point in Wallerian Deneration does the new axon start to grow?
7-10 days post injury
What is the rate of axon growth during regeneration?
1-4 mm/day
What variables impact the prognosis for a functional recovery?
- site of injury
- proximal (long) vs distal (short)
- axon diameter/length
- small regenerates better (C > A)
- patient’s age
- better in younger patients
- delay before intervention
- observation for spontaneous recovery
Functional recovery is highly dependent on what variable?
TIME!
Chronically axotomized neurons leads to:
- schwann cell atrophy
- target tissue atrophy
- muscle & end-plate only good for 1 yr
What situations can lead to proximal degeneration?
direct trauma to cell body → necrosis
axotomy → controlled apoptosis (not well understood)
Are spinal motor neurons or sensory neurons more likely to experience retrograde cell death?
- sensory (exogenous neutrophins help survival)
- motor:
- 20-30% apoptosis in proximal lesion
- most peripheral lesion regenerate
What is the intervention if a nerve gap is present? If it is <5mm? If it is >5mm?
- < 5mm → suture ends together
- >5 mm → another approach
- just suturing will lead to excessive tension that impairs regeneration
What is the biggest problem in suturing the two end of a nerve gap?
scar formation
if a scar develops between proximal & distal nerve ends, this physically blocks axonal sprouts from finding distal nerve
What is the most critical step in all nerve repairs?
nerve debridement - getting rid of the scars
What are the 3 different methods to suture the ends of nerves back together?
-
Epineural neurrhaphy
- use topography of vasculature to align proximal & distal ends
- faster & less traumatizing to the tissue
- Groups fascicular neurorrhaphy
- strip away epineurium & suture groups of fascicles together
- individual fascicular neurorrhaphy
What are the benefits & risks of choosing epineural neurorraphy?
- benefit
- good alignment using blood vessels
- fast
- risk
- no guarantee of good fascicular alignment
What are the benefits & risks of choosing fascicular neurorraphy?
- benefit
- better change good fascicular alignment
- risk
- slower
- may not produce better clinical outcomes
What are the benefits & risks of choosing individual fascicular neurorraphy?
- benefit
- best chance for good fascicular alignment
- risk
- very slow
- increased number of sutures may cause too much scar formation
What structures are used to bridge the gap between nerve ends when the gap is > 5 mm?
nerves
blood vessels
synthetic conduits
What is an “autograft” & what are the benefits and risks to this approach to bridging nerves?
nerve from the patient is sacrificed to repair the damaged nerve
- benefit
- “gold standard”
- sural nerve is commonly used (don’t need it really)
- risk
- additional surgical trauma is required
- undergo normal Wallerian degeneration to provide natural pathways for outgrowth → double suture site increases scar formation to impair regeneration
What is an “allograft” & what are the benefits and risks to this approach to bridging nerves?
a nerve is taken from cadaver & is used to repair the damaged nerve
- benefit
- no additional patient surgical procedures required
- risk
- rejection is a large problem
- not a permanent problem b/c axon regrows through graft & graft degenerates
- patients on immunosuppressant drugs
- rejection is a large problem
What is a “conduit” & what are the benefits and risks to this approach to bridging nerves?
a way to trap important matrix proteins, growth factors, & schwann cells at the place where it is needed
What are the 3 types of conduits & important features of each?
- Biological conduit
- graft taken from patient (ie. venous)
- biodegradable
- synthetic collagen
- FDA approved
- degeneration with time
- maximum gap length 3mm
- graft taken from patient (ie. venous)
- Nonbiological material
- silicone
- experimental
- does not degenerate - additional surgery
- silicone
What are the phases of regeneration through a conduit?
-
fluid phase
- accumulation neutrophilic factors & ECM molecules
-
Matrix phase
- fibrin cable formation
-
Cellular phase
- Schwann cell migration, proliferation & alignment, and tissue cable formation
- formation fo Bands of Bungner
-
Axonal phase
- growth of daughter axons (proximal to distal) across de novo tissue cable
-
Myelination phase
- myelination of regenerated immature axons forming mature axonal fibers
What is a major problem with conduit repair?
Axons are all over the place in the distal nerve b/c you cannot really create alignment
What is something that patient can do to enhance regeneration?
exercise
What are the problems that occur with poor regeneration?
- loss of sensory & motor function
- neuroma - intense, chronic pain
- axonal sprouts fail to locate distal nerve
- axonal sprouts continue to grow but form un-inervated mass
What is the process behind neuroma formation?
scar formation blocks neurite access to distal nerve → but they continue to grow
the can lead to the formation of a neuroma; particularly in areas that are exposed to repeated trauma
What can be done if a neuroma is formed?
- surgery is often required to remove the neuroma
- nerve regeneration can be attempted (nerve graft / conduit)
- the resected nerve can be buried in muscle to protect it & prevent regeneration of the neuroma
What drugs can be given to patients suffering from a neuroma? Mechanism?
Gabapentin & Pregabalin
inhibit Cava2d & reduce pain
What ion channels are increased that lead to chronic neuropathic pain often seen with neuromas?
Nav1.3
Nav1.8
Nav1.9
Cava2d
