Acquired Injuries = Spinal Cord Injuries (SCI) and Traumatic Brain Injuries (TBI)

Lecture 4

Spinal Cord: What is it part of ? Where does it extend ? 2 functions ?

Part of the central nervous system

• Tightly packed column of nerve tissue that extends downwards from the brainstem through the central column of the spine.

Function:

• Relays motor (from spinal cord to muscles) and sensory (from periphery to brain) signals between the brain and periphery

• Provide separate neuronal circuits for our reflexes (e.g. knee-jerk reflex - you hit the patella and the knee will extend) Isolated circuit, does not need input from brain. IT just happens between muscles and spinal cord/

Describe the appearance of the spinal cord ?

Two major swellings or enlargements

• Cervical enlargement

occurs in the region associated with the origins of spinal nerves C5 to T1

» Innervate the upper limbs

• Lumbosacral enlargement

The region associated with the origins of spinal nerves L1 to S3

» INnervate the lower limbs - damage to this can mean patients cannot move lower limbs (damage to this can mean patients cannot move lower limbs)

Describe the internal structure of the spinal cord?

Grey matter ( contains cell bodies, appears dark in microscope) and white matter (contains axons whixh re surrounded by myelin sheath. Why it is known as white matter.

Grey matter (rich in cell bodies): shape of butterfly, with four “wings” called horns.

Grey matter is surrounded by a column of white matter (contains axons)

The external structure of the spinal cord ?

The external surface of the spinal cord is marked by a number of fissures / sulci.

• Anterior median fissure ( landmark to orientate yourself when you look dorsally (in the middle))

• Posterior median sulcus

• Posteriolateral sulcus (when you look laterally)

Spinal nerves: where does the spinal cord run from ? How much pairs ? Named ?

• Spinal cord runs from medulla oblongata to L1-L2

• 31 pairs of spinal nerves

• named according to their position with respect to associated vertebrae.

• There is 8 cervical nerves: C1 to C8, 12 Thoracic Nerves: T1 to T12

• 5 Lumbar nerves: L1-L5

• 5 sacarl nerves: S1-S5

• 1 coccygeal nerve

Spinal Cord Organisation ?

Sensory Information can enter spinal cord and motor information goes out of spinal cord. The motor information which leads to muscle contraction, they go out the anterior side of the spinal cord. On the posterior sesnory information goes in.

Spinal Cord Injury (SCI): what was the mortality rate in former times ? Why ?

In former times, there was a high mortality rate (80%)

Because they would stay in bed and not move leading to infection and not controlling bladder/ bowl. They often suffered from sepsis / infection

When did this change ? Names ? Rehabilitation ?

This changed after World War 1 because there was high amounts of patients who had SCI.

Donal Monroe (1930’s) Sir Ludwig Guttman (1940’s) - The first clinical people who treated SCI and they didnt just put them in a bed. They established rehabilitation centres. They recognised that when we do rehab this can help the outcomes of patients. Could decrease death rate to 30% due to establishment of rehab centres.

Rehabilitation:

• Physical

• Rehabilitation

• Bowel bladder management

• Physio & OT

Nomenclature of spinal nerves ?

Nerve C1: emerges between skull and C1 vertebrae

Nerve C2-C7: Emerge superior to pedicles

Nerve C8: emerges inferior to pedicle of CVIII vertebrae

Nerves T1 to Co: emerge inferior to pedicle of their respective vertebrae.

Quadriplegia vs Paraplegia ? Causes ?

1. Quadraplegia / Tetraplegia: complete paralysis that affects both arms and legs, trunk, pelvic organs (patients are incontinent and have troubles with bowel moveements).

Cause: spinal cord injury between C1-C8 (upper region of spinal cord)

• High quad (C1 to C4)

• Low quad (C5 to C8)

2. Paraplegia: complete paralysis affects all or parts of the trunk, legs and pelvic organs often still incontinent.

Cause: Injury either thoracic, lumbar or sacral. The higher the spinal cord injury the more severe it is

It is very important to provide sensory input there is still spasticity we can target and treat in the patients.

physio, ot and slt are the most important parts of treatment.

Complete vs Incomplete spinal cord Injury (SCI) ?

Complete: all feeling (sensory) and all ability to control movement (motor function) are lost below the spinal cord injury.

Incomplete: some motor or sesnory function below the affected area.

• Quadriparesis: Partial paralysis of arms and legs (weakness)

• Paraparesis: Partial paralysis of the lower limbs (weakness)

To understand why in quadraplegia the whole body is paralysed in contrast to paraplegia in contrast to paraplegia, we need to have a look at the spinal cord ?

So when patients have an injury in the cervical region, this leads to quadraplegia this is due to the fact that no sensory info can go up into the brain becuase this area is basically non-functional, however when you have an injury in your lower vertebrae, the sensory info from the upper parts can still go into the brain and also the motor in to muscles. Thats why patients who have an injury in lower parts of the spinal cord can still move legs and arms because the sensory info from this other part of spinal cord can still do its job whereas an injury high in spinal cord means no sensory info can go to brain.

Functional consequences high quadriplegic (C1-C4) ?

Injury C1-C4:

• Severe motor + sensory loss to head and extremities (arms + legs)

• Continuous ventilation (can’t breath themself)

Injury C3:

• Better control of head, cannot move arms + legs

• May require ventilation

Injury C4:

• Enhanced ability to breath (still completely paralysed)

Functional consequences low quadriplegic (C5 to C7) ?

Injury to C5:

• Require assistive device. They can flex wrist, flex elbow, grasp something, can abduct shoulder.

C6

• Able to extend and flex wrist

• Pronate forearm

• Abduct or pull on the shoulder

Injury to C7:

• More normal arm and hand function

• Able to extend fingers

• Flex wrist, extend elbows + shoulders

• Abduct shoulders

Spinal Shock: What is it ? Cause ? Features ?

Period of hypoactivity of the spinal cord below the level of injury lasting for hours to weeks.

Cause: Severe spinal cord Injury

Features:

• Loss of reflexes

• Flaccid paralysis of striated muscles (cannot move / contract muscles)

• Flaccid paralysis of bladder (incontinent)

• Paralytic ileus (life-threatening when bowels arents moving, complete loss of bowels. Treated in hospital.

Outcomes after spinal cord Injury (SCI) ? Age group affected ? Main cause ? Extent of Injury ?

Age groups affected (16-30yrs)

Main cause: Vehicle Accident

Extend of Injury

• Incomplete quadriplegia (30%)

• Complete quadriplegia (22%)

• Incomplete paraplegia (19%)

• Complete paraplegia (25%)

• Complete neurological recovery (0.9%) - once neurons are dead, they can not be generated again in our human body.

Functional levels after SCI ? How to test ?

Can they move arms, or legs. Can help see what part of spinal cord. For eg. T1 might be affected if region of lower forearm is sensitive.

Motor scale:

0: no movement

1: muscle flicker

2: Full range of motion, no gravity

3: Full range of motion, gravity

4; full range of motion, resistance

5: normal

Sensory: Light touch, pin prick, anaI sensation.

Life expectancy following a spinal cord Injury ? Age ? Yrs left to live ? The older you get ?

20 yrs: 37.9 years left to live

40 yrs: 21.6 years left to live

60 yrs: 8.8 years left to live

The older the patient the more severe the outcomes, because they often have other conditions or diseases of CNS. Muscles are weaker when we age.

Spinal Cord Injury: What does it mean ? Side effect ?

The vertebrae compresses spinal cord and doesn’t allow sensory info to pass from periphery into the brain

We often have a massive bleed after a SCI and it affect neighbouring neurons. That is why its important that we treat bleed as soon as possible when they come into the clinic.

Pathophysiology of SCI ? primary injury ? secondary injury ?

Primary injury: mechanical shearing of axons + blood vessels. Immediate damage to neurons

Secondary INjury: Often fatal, microvascular and neuronal injury due to cascades. Cause more harm over time.

What happens the myelin sheath ? Determinants of recovery ?

The myelin sheath gets damaged over time will further degenerate if you wait longer.

Determinants of recovery

• Preservation of axons

• Preservation of myelin thickness

After a SCI, Is there just primary effects ? What happens when you damage neurons ? What does this lead to ?

When there is a SCI, there is not just primary effects there is secondary effects.

When you damage neurones, they massively release ions (potassium, sodium, calcium), they also release neurotransmitter like glutamate (which is excitatory), the ions + neurotransmitters cause a massive imbalanve in the neighbouiring nerve tiossue This leads to mitochondrial dysfunction (oxidative stress) and calpain activation. This damages neighbouring neurones. When we have a lot of oxidative stress, this leads to energy failure leading to death of neurones. When we have a lot of calcium release it leads to oxidative damage. This damages the blood vessels which surrounds the neurones. This leads to less blood supply and further damage to myelin sheath and further damage ti myelin sheath and further loss of neurones

Inflammation ion SCI ?

When a patient has a SCI and you want longer the primary insult often extends into the neighbouring regions of the spinal cord and causes them more damage to the neighbouring neurones.

Inflammation in SCI - cells and cytokines ?

So when a patient has a spinal cord injury theres a massive release of inflammatory cells. There is a release of monocytes, lymphocytes, microglia and nuetraphils.

Sp all of them furthermore damage neuronal tissue of the spinal cord and lead to chronic inflammation.

Therapeutic Avenues: What happens neurons when they are dead ?

Neurones when they are dead and we cannot replace them.

However, we can suppress the inflammatory response of the spinal cord. We do these by prescribing patients cortisones.

Methylprednisolone: is a cortisone. ITs a glucacorticoid. It reduces basically all of these cytokines and inflammatory cells.

Patients who receive a glucacorticoid ?

They have better neurological recovery

Future therapuetic possibilities ? (6)

• Anti-oxidants - microvasculature and parenchyma protection

• Mitochondrial protectants

• Calpain inhibitors (inhibit calcium release)

• COX2 inhibitors (anti inflammatory drugs which dampen the inflammatory response after SCI)

• Remyleination: pharmacological or transplantation of oligodendroglia precursors or Schwann cells: not in the moment in clinical trial of human patients, shown in mouse models

• Neural stem cell transplatation

TRaumatic Brain INjury: What is it ? Causes ? Symptoms ? Types ?

It is an injury to the brain caused by an external force.

Causes:

• Falls (28%) older patients with limited balance + coordination

• Motor vehicle crashes (20%)

• Struck by / against events (19%)

• Assaults (11%)

Symptoms (moderate to severe TBI) can include:

• slurred speech

• profound confusion

• Seizures if severe

• Persistant headache

• coma very severe

Types:

Direct impact, acceleration - decelleration injury, blast injury.

Heterogeneity of TBI ?

Damage:

Focal: injury is confined to one area of the brain

Diffuse: more than one area of the brain

Penetrating : an object eneters but does not exit, projectile breaches the cranium but does not exist

Closed: non-penetrating injury to the brain with no break in the skull.

Outcome influenced ?

• pre-morbitities and co-morbitities

• Gender / age - more severe in older patients

• Genetic

Phineas gage: recovery ? What happened ? What did this do ?

iron rod was driven completely through his head, in forehead and out of eye

» destruction of his brains left frontal lobe

» personality change, became aggressive. 1st demo of personbality in the frontal lobe.

• Phineas Gage influenced 19th century discussion about the mind and brain.

• Brain’s role in detremining personality

• Damage to specific parts of the brain might induce speciific mental changes.

Concussion: What is it ? Causes ?

Mild traumatic brain injury (mTBI)

Is a head injury that temporailiy affects brain functioning

Causes: external forces acting on the head are transferred to the brain (e.g. motor vehicle collisions, sport injuries)

Symptoms of concussion ? When does this happen ?

• Loss of consciousness

• Memory LOss

• Headache

• Difficulty with thinking / concentrating / balance

• Blurred viison

• Mood changes / Sleep Disturbances

» May begin immediately or 1-2 days after injury

Pathophysiology: when you get older ?

When you get older leads to neurodegenerative diseases.

• neuropathological changes

• Impaired neuotransmission, loss of synapses

• changes in metabolic processes

• may alter brain physiology for hours to years

• may lead to long term neuropathological consequences (axonal degeneration, neuroinflammation). Most of the symptoms become visible as you age.

Treatment ??

• Physical and Cognitive Rest (24-48hrs)

• Analgesics (Paracetomol)

Post concussion symptoms:

Cognitive symptoms:

• Attention problems

• Memory dysfunction

• Fogginess

• Fatigue

• Cognitive Slowing

Sleep disturbance:

• Difficulty falling asleep

• Sleeping less than usual

Emotional:

• Lability

• Depression

• Nervousness

• Irritability

Somatic symptoms:

• Visual problems

• Dizziness

• Balance difficulties

• Headaches

• LIght / Sound sensitivity

• Nausea

Chronic Neurodegeneration and TBI ?

Not just primary insult, the effects can be seen months or years later

There is more severe volume loss in the brain as time goes on.

Mechanisms or chronic neurodegeneration in TBI: primary vs secondary ?

Primary injury: direct mechanical damage (Acute phase (sec-minutes)

• Rapid neuronal cell death (bioenergetic failure/ necrosis)

Secondary injury (first phase) - delayed phase hrs - days

• Excitotoxcity (release of ions in the brain

• Ischaemia (vascular damage (blood vessels)

• Mitochondrial dysfunction

• Inflammation

• Delayed cell death (apoptosis)

Secondary injury ( second phase) Chronic phase (Months to years)

• Late neuronal cell death

• Inflammation (microglial - mediated neurotoxicity)

• Continuing and expanding tissue damage

Why in a brain injury, do we have more damage occuring over time ?

We have specialised cells in our brain, called microgllial cells. They look like stars when we have an insult in our brain, these inflammatory cells are released to that area, they release a lot of neurotransmitters and cytokines to repair this area, but they also lead to chronic inflammation, leads to further damage which expands over time.

Secondary Injury pathways in TBI ? (6)

Cause further damage to brain

1. Oxidative stress

• Free radicals

• Lipid peroxidation

• Both of these lead to further damage to neurones

2. Excitotoxcity

• Gltatmate (neurotransmitter)

• NMDA receptor activation

• Ca 2+ influx (damages neurones)

3. Mitochondrial dysfunction

• increase in PARP-1 activation

• decrease in NAD + / ATP levels

• Increase in Calpain activation

• Permeabilization of MPTP

• (leads to oxidative stress)

4. Inflammation

• Pro-inflammatory cytokines

• Nitric oxide

• Prostaglandins

5. BBB (blood brain barrier) disruption

• Cerebral edema

• HYpoxia

• Ischaemia (disruption in blood suppply + oxygen supply of the brain leads to cell death)

6. Cell death

• Necrosis

• Caspase - dependent (caspase 3)

• Caspase-independent (AIF)

After a TBI, you have massive inflammation in brain + spinal cord which further damages neurones.