Pathogenesis of Perinatal Brain Injury Flashcards
What are cystic lesions?
Large ‘holes’ in the brain.
Where do infants typically have brain injury?
In the deeper structures of the brain rather than the cortical structures.
What happens when white matter dies in the brain?
Ventricles compensate by increasing in size.
Where do focal lesions occur?
In the grey matter.
Which disease is likely to occur more than cancer?
Cerebral Palsy.
What are two main forms of acidosis?
Hypercapnia and metabolic acidosis. Both can be caused by umbilical cord occlusion.
What is hypercapnia?
High levels of carbon dioxide in the blood which makes H2CO3, lowering the pH of the blood.
“Respiratory Acidosis”.
What is metabolic acidosis?
An accumulation of lactic acid in the blood. Anaerobic metabolism occurs during hypoxia.
What is apoptosis?
Programmed cell death
What is asphyxia?
A condition arising when the body is deprived of oxygen, causing unconsciousness or death; suffocation.
After asphyxia occurs, what does the BP in the body do?
It increases to compensate for the decrease in BP. We require a certain BP for good perfusion for oxygen and glucose delivery.
How much ATP in our body is produced from ion channels/pumps?
About 1/3
What does adenosine do in the brain?
It is a neurotransmitter that shuts down brain function. It is a protective mechanism.
What do adenosine blockers do?
Inhibit adenosine so that there is an increase in brain function (speeding it up).
What are the 3 types of neural regeneration?
Peripheral Nerve Regeneration
Restoration of damaged central nerve cells
Wholesale genesis of new neurons.
In terms of oxygen, what is a stimulus for apoptosis to occur?
Hypoxia - HIF-1
What is prophylaxis and when is it applied?
It is treatment given or action taken to prevent disease. It is applied in the “pre-insult” phase.
What are the 4 main strategies of the evolution of injury treatment?
Pre-insult, insult, recovery and reorganisation.
What are the 3 phases in the recovery strategy?
- Reperfusion
- Latent
- Secondary
What is the time frame of the Reperfusion phase in recovery?
0 - 30 mins
What is the time frame of the Latent phase in recovery?
30 min - 6 hours
What is the time frame of the Secondary phase in recovery?
6 hrs - 2/3 days
What phase comes under the reorganisation strategy?
Tertiary phase (weeks, months, years)
When does neuroprotection occur?
During the recovery strategy
When does neurorepair and augmentation (increase in size) occur?
During the reorganisation strategy
What triggers necrosis to occur?
Factors that are external to the cell or tissue, such as infection, toxins, or trauma. Results in inflammation.
What is reperfusion injury?
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischaemia or lack of oxygen.
Free radicals are generated by the return of oxygen.
Blood pressure needs to be maintained.
What is hyperaemia?
The increase of blood flow to different tissues in the body.
How is the latent phase of recovery characterised?
By the absence of seizures (pre seizures) and
reduction in early cytotoxic edema. (Presence of this would be secondary phase).
What happens in the latent phase in hypoxic conditions?
The depletion of ATP and the reduction of resting membrane potentials in neurons and glia.
Potassium leaks out of cells and
depolarizes neurons leading to a massive release of glutamate (excitotoxicity). Act via
NMDA receptors, glutamate permits the intracellular influx of calcium, which triggers a number of potentially harmful enzymes.
What happens in the secondary phase of recovery following hypoxia?
The secondary phase of energy depletion coincides with the onset of cytotoxic edema and seizures.
An accumulation of excitotoxins, increased production of NO, and a fall in brain electrical
activity.
True/false: Most cells die after insult.
True.
True/False: Damage does not increase during recovery.
False, it does increase.
When is the best time to treat cerebral hypothermia with the cooling of the head?
1.5 - 5.5 hrs delay of cooling (latent phase).
NOT secondary phase as too many neurons have been lost. If there has been more than about 65% lost, no efficacy.
What is easy to monitor in a newborn?
Cardioresp function, other organs, etc.
What is not so common to monitor in a newborn?
Brain activity and blood flow
Brain oxygenation
(EEG, NIRS)
With reperfusion and restoration of blood flow/oxygen after insult, what happens?
Recovery of oxidative metabolism (latent phase)
In hypoxic conditions, how is energy produced to maintain oxidative phosphorylation?
PCr donates it’s phosphate group to ADP, producing ATP so that oxidative phosphorylation may occur.
What does focal cystic necrosis involve?
All cellular elements.
Brain injury in the preterm infant predominantly involves damage to what?
White matter.
Which structures are relatively spared in preterm infant brain injury?
Cerebral cortex and grey matter structures.
What four things can MRI imaging of white matter show?
Cavitary white matter lesions
Diffuse white matter lesions
Ventriculomegaly
Decreased volume of white matter tracts (white matter atrophy)
What is ventriculomegaly?
The dilation of the lateral ventricles.
Do preterm babies have smaller brains?
Yes.
In a term infant, what time of lesions would predominantly occur?
Widespread grey matter lesions.
This is selective neuronal death (smaller insults - hippocampus, cortex and striatum) and Laminar cell death (more severe espec. in striatum and cortex).
Also focal grey matter lesions.
What is the main difference between brain injury in preterm and term infants?
Preterm: white matter lesions
Term: grey matter lesions
True/false. Neurons in the preterm brain are mores susceptible to injury.
FALSE. Neurons in the term brain are more susceptible to injury.
What is pseudolaminar necrosis?
Superficial layers of cortex are almost separated from the deeper layers.
How likely is Cerebral Palsy to occur?
10 times more likely than cancer.
How often is a child born with Cerebral Palsy?
Every 20 minutes.
What are common symptoms of Cerebral Palsy?
- arm and leg weakness
- if they walk, it’s abnormal
- curvature of spine
- swallowing/eating problems
- learning disabilities
- social alienation
When do babies typically get brain injury?
With new imaging technologies, have determined that injuries occur well BEFORE birth.
What are 4 causes of Perinatal brain injury?
- Hypoxia-ischemia
- Infection
- Accident/trauma
- Teratogens (drug use, alcohol, smoking…)
What are causes of fetal hypoxia-ischemia?
- placental abruption
- tight umbilical cord knot (severe)
- twisted umbilical cord knot and meconium staining (moderate)
- prolonged birth
- CV instability or heart disease (cerebral hypoperfusion)
- cardiorespiratory arrest
- preterm lung development
What is hypoxemia?
Low oxygen in arterial blood.
What is the driving force for oxygenation in the body?
Partial pressure of oxygen.
What pressure does hypercapnia look at?
PCO2
If there is impaired waste removal, what happens to cause brain injury?
Accumulation of CO2 -> Respiratory acidosis -> hypoxia and acidosis = impaired CV system -> reduced brain blood flow and O2 = hypoxia-ishemia -> brain injury.
If there is fetal hypoxia, what happens to cause brain injury?
Anaerobic metabolism and lactate production -> metabolic acidosis -> hypoxia + acidosis = impaired CV system -> reduced brain blood flow and O2 = hypoxia-ischemia -> brain injury.
Define cellular homeostasis.
Ability of cell to maintain its normal function over a range of different conditions. The loss of this causes cell damage.
What are 4 key homeostatic mechanisms?
– i. Maintenance of intra/extracellular ionic gradients by ion pumps
– ii. Production of ATP (energy) under aerobic and anaerobic conditions
– iii. Delivery of oxygen/energy to brain cells (blood perfusion to brain)
– iv. Matching of cellular metabolic activity (demand) to energy supply
Ion pumps require how much energy in order to maintain homeostasis?
1/3 of all ATP produced.
What is the equation for oxidative phosphorylation?
Glucose + 6O2 -> 38 ATP +6CO2 + 6H2O
True/False. The brain has a limited store of ATP.
True.
At what partial pressure will no more ATP be produced?
Below PO2 of 1mmHg. (thus very low oxygen available)
What is the limiting factor to maintaining cellular energy?
The amount of oxygen. NOT glucose.
During hypoxia, metabolism becomes…?
Anaerobic.
What is the equation for anaerobic metabolism?
Glucose -> 2ATP + lactate
less effective and ACIDOSIS
What happens when there is ATP exhaustion?
Failure ATP ion exchangers -> DEPOLARISATION -> repeated/uncontrolled -> injury processes begin.
With decreasing BP, what happens to the rate of cell death?
It increases. Cell survival requires good perfusion.
What is asphyxia?
A condition when the body is deprived of oxygen.
Why does the fetal HR initially decrease in asphyxia?
To preserve energy.
What 4 main responses occur in a fetus during asphyxia?
- Dec. HR
- Early inc. BP
- Peripheral vasoconstriction
- Reduced brain blood flow
What protective response does the brain undergo during a reduced energy supply?
The brain tries to reduce its activity. Partly adenosine mediated.
Cell lysis is caused by what?
Excessive osmosis or hyperhydration (oedema). The cell membrane can’t handle the osmotic pressure of the water inside so lyses.
In apoptosis, what can you see in the early apoptotic and late apoptotic cell?
Early: membrane blebs
Late: apoptotic bodies and nuclear fragments
Is there an inflammatory response with apoptosis?
No.
Is apoptosis energy dependent?
Yes.
Is apoptosis upregulated with injury?
Yes.
Is injury an evolutionary process?
Yes. Cell loss is not only during insult, but afterwards as well.
Is post-asphyxial hypoperfusion to the brain a common response? What happens to the EEG amplitude?
Yes.There is a decrease in the EEG amplitude.
What does reduced cerebral blood flow (CBF) reflect?
Reduced brain metabolism - not damaging.
Hypoperfusion is controlled by which nervous system?
The sympathetic nervous system.
How does Phentolamine effect the SNS?
It blocks the SNS receptors thus preventing hypoperfusion.
How does phentolamine effect brain injury?
It blocks EEG suppression in the latent phase and increases EEG spiking, increasing brain injury. SO EEG is partially neuroprotective.
How can NMDA receptor inhibitors effect brain injury?
NMDA receptor inhibitors can block EEG spiking activity, reducing brain injury. SO EEG transients are mediated by glutamate and trigger cell injury.
How do glutamate receptors trigger cell death?
Over-activation of glutamate receptors can trigger intracellular Ca2+ levels and trigger cell death.
Explain glutamate excitotoxicity.
During insult and after insult
During: Energy low -> glutamate transporters fail. Accumulation of extracellular glutamate and excessive glutamate receptor activation.
After: cerebral energy normal, thus glutamate levels normal. BUT:
- glutamate receptors hypersensitive to normal glutamate.
- SO during latent phase, excessive glutamate receptor activity triggers lots of intracellular Ca2+ and apoptosis.
What signal in the apoptosis pathway is the final executor of cell death?
Caspase-3
Pathways leading to caspase-3 activation require what?
Time.
True/False. Dead cells in the latent phase can come back.
FALSE.
Is hypoperfusion related to BP?
No.
True/False: Secondary phase of energy failure is NOT driven by deficits in brain oxygenation or nutrient supply.
True.
Secondary oxidative metabolism failure will cause what in the mitochondria?
Mitochondrial failure.
Does the EEG recover in the secondary phase?
Yes.
Does blocking seizures improve brain injury?
No.
When does edema recover?
In the latent phase. It increases again during the secondary phase of cell death.
What are the 4 main characteristics of secondary phase of injury?
- secondary failure of oxidative metabolism
- Stereotypic evolving seizures (big seizures)
- Hyperaemia (increased CBF and volume)
- Secondary edema – necrosis/lysis ongoing
