Traumatic Brain Injury Flashcards Preview

Neuro BSc Module 2 > Traumatic Brain Injury > Flashcards

Flashcards in Traumatic Brain Injury Deck (20):

What are some of the epidemiological features of TBI?

  • Account for 25% of all trauma deaths
  • High morbidity:
    • 19% vegetative or severely disabled
    • 31% good recovery 


What are the ways of clinically classifying TBI?

Head trauma can be called as Non-missile and missile

  • Missile - penetrating head trauma
  • Non-missile - no penetrating head trauma.
    • This tends to be road traffic accidents. 
    • The problem with non-missile trauma is due to acceleration/deceleration
    • Rotation (particularly damaging to midline structures)


Can also be classed as focal or diffuse

  • Focal: Pathology that can be seen, or quantified (i.e. extent of injury is known e.g. bruise to the brain)
  • Diffuse: Pathology that is difficult to see (i.e. diffuse damage across the brain), only generally noticeable post mortem (e.g. diffuse axonal injury) 


Identify the key neuropathological features of focal and diffuse traumatic brain injury (TBI)

Focal injury is caused by local contact effects of mechanical force. This leads to contusions and lacerations, which can lead to haemorrhages or a haematoma. The haemorrhage can be epidural (arterial) or subdural (venous), it can also be intracerebral or ventricular.


Diffuse injury is caused by acceleration/deceleration effects on the fiber tracts, vessels and ventricles. This force causes diffuse axonal injury in the white matter fibers, swelling and ischaemia.


Most cases of TBI have features of both in a mixed injury pattern.


Describe the pathophysiology of TBI

There is the primary damage (fracture, contusion, haemorrhage etc.) caused by the trauma, then also a delayed secondary damage. 

Types of primary damage depend on the mechanical force applied to the brain, and therefore whether it is a diffuse or focal injury:

  • Scalp laceration 
  • Skull fracture 
  • Cerebral contusion (bruise in the head) 
  • Cerebral laceration
  • Intercranial haemorrhage
  • Diffuse axonal injury (white matter tract)

Most TBIs show evidence of a mixed injury pattern. How you respond to this primary injury depends on a range of factors. The primary injury causes progressive damage mediated by calcium, receptor dysfunction, free radicals and inflammation.

This causes delayed secondary injuries, which include:

  • Ischaemia
  • Raised ICP
  • Seizures
  • Infection
  • Oedema

The result of these, balanced against treatments, lead to the functional outcome. 


What factors influence how you respond to the primary injury?

  • Age

  • Drugs

  • Nutrition

  • Pre-existing disease

  • Psychosocial status

  • Genetic make-up.


Describe the features of skull fractures

Fissure fractures often extend into base of skull. May pass through middle ear or anterior cranial fossa

Both these fractures can cause CSF leakage causing: otorrhoea or rhinorrhoea. This has a high Infection risk.

Basal skull fracture can produce a classic sign - battle’s sign & “racoon” eyes:


Describe the features of contusions

Contusions are produced when the brain in collision with skull. This produces surface “bruising”.

If pia mater is torn, it then becomes laceration.

Areas of the brain where contusions are more likely at the lateral surfaces of hemispheres, inferior surfaces of frontal and temporal lobes.

Acceleration/deceleration often causes a Coup and contrecoup injury. Coup and contrecoup as brain hits front of brain, rebounds, and hits back – so get contusions both at the from and the back.


Describe the features of DAI

DAI occurs at moment of injury caused by shear & tensile forces affecting axons. It is the most commonest cause of coma (when no bleed).


Midline structures particularly affected e.g. corpus callosum, rostral brainstem and septum pellucidum.


DAI grading:

Grade 1: Parasagittal frontal, internal capsule, cerebellum

Grade 2: As Grade 1 plus corpus callosum

Grade 3: As Grade 2 plus dorsal brainstem


What is the pathogenesis of DAI?

Primary Axotomy - Following damage to the axon (physical tear in the membrane), influx of calcium (and many calcium activated proteases e.g. calpain), leads to axonal sealing and cytoskeletal disruption. In cases where there is immediate disconnection, this is called primary axotomy.


Secondary axotomy - Following damage to the axon, there is an influx of calcium (and many calcium activated proteases e.g. calpain), leads to axonal sealing and cytoskeletal disruption. There can be a degree of repair and stabilisation of the damaged axon allowing it to carry on functioning as normal (however, it remains weaker than a healthy axon). A secondary insult can cause a late disconnection.


What causes brain swelling (oedema)?

Causes raised ICP


There are two potential reasons why the brain may swell. It may be vasogenic or cytotoxic.

  • Vasodilatation and increased CBV (congestive)
  • Blood vessel damage (vasogenic oedema)
  • Increase water content of cells (cytotoxic cerebral oedema)

It is probably due to the combination of both these effects.


What are the types of herniation and what do they lead to?

There are three areas where raised ICP may cause tissue to herniate. Due to the rigidity of the dura.

  • Subfalcine herniation – cingulate cortex herniates under falx cerebri (causes midline shift and ventricular compression)
  • Tentorial herniation (also called uncal herniation) – herniation of medial temporal lobe into posterior cranial fossa around the tentorial notch/tentorium cerebelli
  • Tonsillar herniation – cerebellar tonsils herniates through foramen magnum - leads to coning


List the molecular and cellular pathways that have been implicated in TBI

Similar to in stroke. Cellular damage is mediated by Ca2+ influx, the generation of free radicals and inflammation. This leads to enzyme and gene modulation, which either leads the cell down an apoptotic pathway, necrosis, or repair and recovery.


Inflammation also causes the breakdown of the BBB, allowing immune cell infiltration and macrophage/microglia activation. Through subsequent ROS, complement activation, oedema and cytokine release, this causes apoptosis and necrosis. Anti-inflammatory cytokines and phagocytosis leads to repair and regeneration.


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What is dementia pugilistica?

A form of dementia that occurs in patients following repeated traumatic axonal injury. E.g. boxers, American football players, rugby players. Also for IED (improvised explosive device) blast injuries

It mimics Alzheimer’s disease, and appears to be caused by (or related to) Amyloid-Beta plaque formation

This beta amyloid deposition in the brain also seems to occur after acute head injury, (30% of 152 patients show Aβ pathology


What is CTE, it's definition, and features?

A doctor in Boston found that NFL players had a similar pathology, as after repetitive traumatic injuries, they often had severe psychological problems. She called this Chronic Traumatic Encephalopathy (CTE), but we're unsure if this is a separate entity to dementia pugilistica.


Definition of CTE pathology -Presence of:

  • (i) Foci of perivascular NFT and astrocytic tangles (unlike diffuse in AD)
  • (ii) Irregular cortical distribution of NFT and astrocytic tangles with a predilection for the depths of sulci
  • (iii) Clusters of subpial and periventricular astrocytic tangles in the cerebral cortex, diencephalon, basal ganglia and brainstem
  • (iv) Neurofibrillary tangles in the cerebral cortex located preferentially in the superficial layers.


There is also evidence of Tau-pathologies in these patients, which is very odd, as usually found in 65-year old patients with Alzheimer's dementia!


2 major clinical presentations:

  • Behavior/mood variants (generally younger onset)
  • Cognitive impairment (generally older onset) 


What is the pathophysiology of the primary injury?

The primary injury is mechanical damage, and can be:

  • Contact effects/impact
  • Inertial effects/non-impact
  • Coup/Contre coup



This mechanical damage causes tissue deformation → Immediate focal injury in close proximity to the energy loading. The focal injury is manifested as:

  • Contusions (a bruise due to ruptured blood vessels).
  • Lacerations (when brain is cut or torn, with a tear in the pia-arachnoid layer over the injury)
  • Haemorrhages


Shearing/tearing forces are non-impact effects, which cause injury after a few seconds → Diffuse injury anywhere in the brain, but white matter structures are particularly susceptible:

  • (Diffuse) axonal injury
  • Swelling


These manifestations of the primary injury are exclusively sensitive to preventive but not therapeutic measures.


What is the pathophysiology of the secondary injury?

Primary injury causes damage via excitotoxicity and calcium influx. This causes inflammation through cytokines and chemokines, free radical formation and mitochondrial damage

There are many secondary injury cascades. Taking the example of inflammation:

  • Long-term process after TBI
  • The double edge sword: pro- inflammatory and anti-inflammatory mechanisms which are necessary in healing, but also pathological.
  • Inflammation is proportional to severity. The proportionality is similar in animals, but in humans is more longer-lasting than In animals.

Early on, DAMPs, cytokines and chemokines are released at the site of injury, to tell the immune system there is damage. This is followed by invasion of neutrophils and monocytes from the blood into the brain. As you can see, it takes a while for the brain's immune system to kick in; microglia and to some extent astrocytes take time to become activated.

The sum of these effects will cause ischaemia, hypoxia, oedema and infection. 


Why do clinical trials for TBI fail?

  1.  Drug selection → rush to trials
    • CRASH study (People in treatment group died a lot more than control group)
      • Global suppression of inflammation after TBI.
      • Based on insufficient animal data
  2. Trial design: Low number of participants show good results, where as this is not carried to larger multicentre trials.
  3. Patient selections
    • Mild, moderate or severe TBI?
    • Confounding factors (substance use, comorbidities etc.)
    • Sex? Sex hormones have a neuroprotective effect.
  4. Endpoints
    • Glasgow outcome scale?
    • Motor or cognitive impairments?
    • Survival? 


What can be done about failing clinical trails in the TBI space?

  • Prevention, identify risk-groups, improve safety → reduce incidence
  • Come away from looking for a magic pill. Multifunctional drugs targeting multiple secondary pathways.
  • Stimulate neurorestorative processes
  • Target identification → proper drug selection for clinical trial
  • Disease monitoring → long-term effects
  • Outcome evaluation → choice of appropriate endpoints

This requires experimental (animal) models of TBI! 


What is the Catch 22 in TBI modelling?

Catch 22: Models of TBI need to reduce the complexity of human TBI in-order to model it, and prevent the same issues as seen in clinical trials. BUT there needs to be enough complexity to retain enough overall validity for translation!


What is the rationale and pros and cons of in-vitro TBI modelling?

The point of using these is to reduce complexity and heterogeneity of in vivo TBI. I.e. Need to remove confounding factors such as inflammation, bleeding and ischaemia. In order to study on single isolated factors, such as biomechanics, excitotoxicity, apoptosis.



  • Repeatable
  • Controlled biomechanics
  • Environment and pathophysiological isolation
  • High throughput and screening approaches



  • It is just a snap-shot
  • Does not show clinical improvement
  • Does not show functional outcome or network effects
  • Does not show extra-CNS effects