Lecture 25: Pathogenesis Of Perinatal Brain Injury

Question 1

What results from perinatal brain injury

Answer 1

Death

Motor dysfunction

Impaired cognition

Question 2

When do babies get brain injury

Answer 2

Before, during or after birth

Question 3

Causes of perinatal brain injury
HIAT

Answer 3

Hypoxia - ischaemia (reduced oxygen & blood flow to brain)

Infection (common in preterm babies) [maternal, fetal/postnatal, cytokine production]

Accident/trauma

Teratogens (drug use, smoking alcohol) -> directly affect brain(poison, injury) & 2° actions on oxygenation, nutrient provision & blood flow to brain

Question 4

Causes of fetal hypoxia - ischemia

Answer 4

Placental abruption

Prolonged labour

Preterm lung development

Severe tight umbilical cord knot (baby moving in placenta)

Twisted umbilical cord and moderate meconium staining

Cardiovascular instability / congenital heart disease (cerebral hypoperfusion)

Cardio respiratory arrest

Question 5

Define asphyxia

• adults & fetus

What does severe asphyxia result in

Answer 5

Impaired respiratory gasses exchange: O2 lack, CO2 excess

Adults: breathing interruption/ inadequate oxygen supply

Fetus: insufficient oxygen supply & CO2 removal (placental/umbilical cord compromise)

Severe -> Hypoxia-ischemia

Question 6

What is hypoxia

What causes high altitude hypoxia (altitude sickness)

What is hypoxemia

Answer 6

Low oxygen (insufficient to tissue to maintain bodily function)

Altitude sickness : Partial pressure O2 decreases due to high altitude (low atmospheric pressure)

Oxygen reduction in arterial blood

Question 7

Define ischemia

What is partial pressure

What is the driving force for oxygenation in the body?

What is PO2 in the body?

Answer 7

Blood supply reduction

Pressure enforced by a gas in a mixture of other gases

Partial pressure of oxygen in the body.

Measure of O2 dissolved in body

Question 8

What contributes to blood oxygenation

Answer 8

PO2 dissolved in blood, O2 bound to haemoglobin, haemoglobin concentration

Question 9

What is hypercapnia?

What does it lead to

Answer 9

High CO2 dissolved in blood

Metabolic and respiratory acidosis

Question 10

What is respiratory acidosis?

What is metabolic acidosis?

Answer 10

Too much carbon dioxide - Water + CO2 -> H2CO3 (carbonic acid)

Anaerobic metabolism (hypoxia) produce lactate -> Lactic acid accumulation in blood from too much lactic acid

Question 11

What is the importance of the umbilical cord/ placenta?

Answer 11

Remove waste products
Mother provide nutrients and oxygen

Question 12

draw mindmap

Describe how fetal asphyxia & impaired blood supply leads to brain injury

Answer 12

1. Fetal asphyxia/ impaired blood circulation -> fetal hypoxia(O2 less) -> anaerobic metabolism & lactate production -> metabolic acidosis
2. Fetal asphyxia/impaired blood circulation -> impaired waste removal (CO2 more) -> CO2 accumulate -> respiratory acidosis

Hypoxia & (R & M) acidosis -> impaired cardiovascular system -> reduced brain blood flow & oxygen -> brain injury

Question 13

Brain injury - term infant

1. Basal ganglia/ thalamic pattern
2. Watershed pattern

Answer 13

1. • Neuronal loss
     
     • Associated with : severe disability & acute sentinel events (very severe umbilical cord occlusion)
2. • Vascular watershed zones affected (further away from blood supply, injured first)
     - white matter & overlying cortex - injured
     - deficits : cognitive, less sever motor
     - associate : events like prolonged labour

Oligodendrocyte loss

Question 14

Brain injury - preterm infant

1. Grey matter & cerebral cortex
2. White matter

Brain of preterm babies are..

Answer 14

1. Widely spread
2. Most vulnerable, focal cystic necrosis (white matter holes), non cystic oligodendrocyte cell death, diffuse myelination failure, cystic & diffuse white matter lesions, ventriculomegaly (ventricles -> too large) , white matter tract atrophy

Smaller

Question 15

Cerebral palsy

• challenges

Answer 15

Results from asphyxia / preterm birth

• learning disabilities
• limb contractures
• abnormal walking
• arm & leg weakness
• swallowing/feeding problems
• spine curvature

Question 16

How does asphyxia affect fetal brain perfusion

Answer 16

Low BP -> increase cell death, low brain blood flow, low blood perfusion to brain -> low O2 & glucose delivery -> cell death pathway activate

Question 17

How can umbilical cord occlusion cause brain injury

Answer 17

Reduced fetal O2 & glucose delivery -> impaired cardiovascular function -> reduced blood pressure & flow to brain -> brain injury

Question 18

What are some fetal response to maintain brain perfusion during asphyxia?

Why can they be dangerous

Answer 18

• Low heart rate -> protective mechanism to preserve energy
• Early BP increase, peripheral blood flow reduction (vasoconstriction) to non essential organs
• reduced energy supply -> reduce brain activity (try)

When hypotension occurs, brain damage occurs.
Ischaemia & reduced blood oxygenation -> energy failure -> brain cell death

Question 19

What happens to brain metabolic activity during asphyxia

Answer 19

Reduced to match reduced energy supply.

Adenosine mediated (in part)

Question 20

Normal cellular homeostatic functions that would be affected by hypoxia - ischaemia

homeostatic

Answer 20

1. Intra/extracellular ion gradient (membrane potential) maintenance by ion pumps -> ATP dependent.
   - no ATP -> cell damage (membrane potentials loss)
2. Aerobic/anaerobic respiration -> ATP Production
3. Oxygen/energy delivery to brain cells (blood perfusion to brain)
4. Matching cellular metabolic activity to energy supply

Question 21

Cellular homeostasis

Explain oxidative phosphorylation in aerobic metabolism and when anaerobic metabolism is employed.

What happens when there is insufficient ATP?

Answer 21

Oxidative phosphorylation (aerobic metabolism):
- mitochondria
- produce 38 ATP (lots)

Anaerobic metabolism (glycolysis):
- brain -> very high ATP demand but limited stores
- relied on during hypoxia -> limiting factor: oxygen
- produced 2 ATP (less)
- less effective & acidosis

Insufficient ATP: ATP-dependent membrane pump failure, Na+, Ca2+, Cl- build up in cells and K+ out of cells, electrochemical gradient & extrude Ca2+ & Na+ ability loss, anoxic depolarisation

Question 22

How does
- anoxic depolarisation
- cell swelling
- excitotoxicity
caused by lack of ATP lead to brain cell death?

Answer 22

Hypoxia -> neurons depolarise-> glutamate release in synaptic cleft -> neighboring neurons trigger to depolarise -> cells hyperpolarise -> cells: transient electrically silent - no activate -> spreading depression waves (cannot fire)

Ions into cell -> water move in too by osmosis -> reversible or necrosis

Excessive glutamate -> toxic -> glutamate receptors overactivation -> increase [Ca2+] -> trigger injury & cell death pathways

Question 23

How does brain cells die by
- necrosis
- apoptosis

Answer 23

1. Cell swells and lyses due to excessive osmosis and hyperhydration -> cell death product release into extracellular space -> inflammatory response
2. Selective cell death upregulated with injury. No inflammatory response and energy dependent signaling pathway. Tightly regulated physiological process