Injury and Repair of the Nervous System

Question 1

Who was Clint Hallam and why is he important?

Answer 1

Cut off arm in 1984

Received first ever forearm transplant in 1998 in Lyon, France

Question 2

How does a limb transplant work (in terms of revascularisation and nerve regrowth)?

Answer 2

• After revascularization, a composite tissue allograft is viable… but not functional!
• The axons of the recipient have to regrow and replace the axons of the donor to reinnervate the muscles and the sensory end organs within the graft
• The donor nerves only serve as temporary scaffold for the axons to grow into

Question 3

What happens to nerve axons after nerve damage?

Answer 3

• Comparison between nerve axon and train track

- In a train track damage is localised, whereas in axons damage is not simply localised to the site of injury

Question 4

What are the main challenges of nerve repair?

Answer 4

• Nerve damage may spread:
  o Through anterograde degeneration (=Wallerian degeneration)
  o Through retrograde degeneration (axonal “die-back”)
  o To the cell body (spinal cord, ganglia)
  o Through transneuronal degeneration
• Nerve repair is not always successful: repairs may happen but the attempts may not always be successful!

Question 5

What does the success of nerve repair depend on?

Answer 5

• The success of nerve repair will depend on:
  o The severity of the initial injury (primary damage)
   What has been damaged; how much has been damaged
  o The extent of the secondary damage

Question 6

What is neurapraxia?

Answer 6

• Temporary loss of motor and sensory function due to blockage of nerve conduction (see diagram/table in lecture notes)

Question 7

What is axonotmesis?

Answer 7

• A disruption of axons, resulting from severe crush or contusion (see diagram/table in lecture notes)

Question 8

What is neurotmesis?

Answer 8

• Both the axons and the nerve sheath are disrupted (see diagram/table in lecture notes)

Question 9

Summarise the challenges of nerve repair.

Answer 9

• Nerve damage may spread
• Nerve repair may happen but is NOT always successful
• The success of repair depends on the severity of the injury (primary and secondary)

Question 10

What must the nerve cell body do after damage has been done?

Answer 10

Know an injury has happened

Respond to the injury

Question 11

What happens in cells in the dorsal root ganglion after damage occurs?

Answer 11

• After damage there is a burst of action potentials that let the dorsal root ganglion know that there is a problem
• Disruption of retrograde flow
• Altered Phenotype (cells change their function)
  o NEURONS SWITCH FROM A TRANSMISSION STATE TO A GROWTH STATE
  o  ion channels and proteins involved in neurotransmission
  o proteins involved in axonal growth
• Neurotrophic factors
  o released by innervated cells
  o taken up by the nerve terminals
  o transported retrogradely to the neuronal cell body to promote neuronal growth and survival
• Examples of neurotrophic factors:
  o NGF: Nerve Growth Factor
  o BDNF: Brain-Derived Neurotrophic Factor
  o GDNF: Glial cell-Derived Neurotrophic Factor
  (see diagrams in the lecture notes)

Question 12

How are Schwann cells involved in the process of nerve regeneration?

Answer 12

• Schwann cells divide, secrete trophic factors to attract axon, then remyelinate new axon
• Growth rate: 1mm / day (can vary from 0.5 - 9mm / day)
• After complete nerve transection, only a low percentage of adult patients will regain normal function

See diagram in lecture notes

Question 13

Why is early repair associated with a better outcome?

Answer 13

1. Prolonged axotomy significantly reduces the number of motoneurons and their axons that can regenerate
2. After 1 month, Schwann cells down-regulate regeneration-associated factors
3. Prolonged muscle denervation:
   o Muscle atrophy and fibrosis
   o Profound decrease in numbers of regenerating axons through the deteriorating intra-muscular sheath

See diagram in lecture notes

Question 14

Can nerves regenerate in the PNS?

Answer 14

• In the PNS, nerve can regenerate, but this is always imperfect

Question 15

How quickly did the nerves regenerate in Clint Hallam’s new arm?

Answer 15

• What happened to Clint Hallam?
  o Growth rate: 2 mm / day
  o Sensory recovery:
   By 100 days: at the wrist (= 200 mm for the ulnar nerve)
   By 1 year: at all fingertips (= 360 mm)
   By 2 years: discriminates pain, hot/cold, sharp blunt in hand & fingers
  o Motor recovery:
   At 3 months: grip & pinch movement
   At 12 months: intrinsic hand muscle activity appeared into the abductor digiti minimi muscle
   At 16 months: very weak muscle activity in the other intrinsic hand muscles

Question 16

How does CNS nerve regeneration occur after a spinal cord injury?

Answer 16

• Spinal cord trauma produces a site of primary cell death (the “epicentre”), which rapidly spreads into a zone of secondary cell death
• Macrophages and microglia engulf debris and the injury site becomes walled off by a glial scar
  o A physical and chemical barrier for neuroregeneration!
   ENGULFS DEBRIS
   SEALS THE LESION SITE
   REPAIRS THE Blood-Spinal Cord Barrier
   EXPRESSES CHEMICALS THAT INHIBIT AXON GROWTH (CHONDROITIN SULPHATE PROTEOGLYCANS –CSPGs)
• At the glial scar, axons show an abortive sprouting response; distal tracts undergo Wallerian degeneration

See diagrams in lecture notes

Question 17

What are the two main barriers to CNS repair?

Answer 17

• Two main barriers to CNS repair:
  1. Hostile Environment
  o Scar tissue (physical; chemical barrier –CSPGs)
   Myelin-associated inhibitory proteins:
   Nogo proteins;
   Omgp (Oligodendrocyte myelin glycoprotein)
  2. Poor regenerative response

Question 18

Are there many possibilities for CNS repair?

Answer 18

• In the CNS, the possibilities for regeneration are limited –but research is ongoing…

Question 19

What are the steps in assisting CNS regeneration?

Answer 19

1. Neuroprotection
   o To contain the effects of early trauma, inflammation, and scar formation
   o Injected with Omega-3 polyunsaturated fatty acids – docosahexaenoic acid (DHA) (with Prof. Adina Michael-Titus) in these pictures
2. Promotion of axonal regeneration
   o Positive trophic support (e.g. adding growth factors)
   o Counteracting inhibitory influences
3. 3. Guiding axonal regrowth
      o to re-establish appropriate connectivities
4. Activity based rehabilitation
   - 5 hours of physiotherapy, 5 days a week (in Derek Fidyka’s case)
   - Stabilises new synapses and reverses muscle atrophy

A combinatorial approach offers the greatest hope for treatment in the CNS

See diagrams in lecture notes

Question 20

What is chromatolysis?

Answer 20

• Chromatolysis = precursor to apoptosis - nucleus moves towards cell edge