1. Overall message
    • Perinatal brain injury is a continuum--over time and space
    • Pathogenesis is a complex and multifactorial process--vascular, molecular, inflammatory, genetic etc
  2. What is perinatal brain injury?
    Perinatal--period occurring around the time of birth, from the period when the baby is about a 7th of its birthweight (about 500 grams) --about 5 months before and 1 month after

    WHO--when birth weight is normally 500g and ends 7 days after birth
  3. Perinatal asphyxia continuum
    • lots of development during the perinatal period
    • @24 weeks, the brain is still not formed into differentiated areas, still immature with less folding
    • 1/2 of brain grows in last trimester, exponential growth that is very vulnerable to injury
  4. Etiology of stroke/hypoxia
    Strokes and hypoxia accepted as diseases of the elderly, 3rd leading cause of death, 12.3% of all strokes occur in individuals <45 years

    None of the stats look at strokes or hypoxic ischemic events in new borns--happens in 1% of all term babies, 20-30% of premies (6% of babies born premature)

    When babies experience hypoxia/ischemia it is usually a global event because blockage of oxygen is usually at the placenta, so whole brain is cut off from nutrients

    • stroke--interruption of blood flow in specific vasular territory
    • hypoxia--lack of oxygen in blood (can have without ischemia)
    • ischemia--lack of blood flow to tissue area (with hypoxia)
  5. Scope of the problem
    • Developmental disabilities like CP, Epilepsy, vision/hearing loss, learning disabilities --27% of diability in kids
    • --no impact on what is currently being done for CP, rates still increase
    • --increases in survival for premies but also increased chances of brain damage

    Among kids diagnosed for DD, 25% have hypoxic ischemic insults
  6. Perinatal brain injury continuum
    Fetus-->genetic vulnerabilties-->toxic vulnerabilities-->infections--->vascular---> newborn

    used to think that the main cause of injury was intrapartum hypoxia

    • bt 24-34 weeks --periventricular leukomalacia--around ventricles of the brain, specific cell types, as they go through gestation, different parts become more suceptible--older=deeper grey matter structures, then cortical structures
    • 24-26 weeks----selective neuronal necrosis
  7. Mechanisms of brain injury during perinatal time frame
    More blood vessels in term babies, vessels unite in older babies (anastamose)

    blood vessels run perpindic to cortex, grow down from the cortex and up from the ventricles, but they don't meet and unite, there is a lack of blood flow around the middle. When blood flow is reduced during placental issues etc, middle areas more sensitive because there is less blood flow to these areas to begin with.
  8. Mechanisms of brain injury during perinatal time frame
    sensory/motor areas spread over the surface of the cortex, near the surface the axons are more spread out, damage between these areas mostly likely causes upper limb damage, damage lower down where the axons are closer causes more damage, possibly quadriplegia

    parasaggital infarct--causes MR and seizures
  9. White matter damage
    white matter and oligodendroglia are intrinsically sensitive to lack of blood flow

    • undifferentiated oligodendroglia present early, most sensitive to toxins in brain like glutamate
    • --have highest concentration of stored iron, which contributes to damage from free radicals
  10. ATP effects
    • 1. after hypoxia-ischemia, ATP diminishes to 30% of what it was. 60% of ATP is needed to keep cell walls strong, once it is diminished, cell walls can't stay up and will explode/implode
    • --if blood can be restored to an area, and enough energy can be created to keep the walls up, the cell will live

    3. Glutamate--normally used in differentiation, guides things, but accumulation of glutamate is toxic and releases calcium which causes an inflamatory response, and breaks down organelles in cells

    -newborn brain might be damaged more by the same insult that an adult would have, but have a better chance of survival because plates of brain are not fused
  11. mechanism pathway
    Necrosis path: Hypoxia-ischemia/asphyxia -->cellular energy failure--> glutamate release--> intracellular calcium release--> inflamatory response, cytoskeleton disruption, membrane injury, and freeradical production

    Apoptotic path:reperfusion--damage that happens when you get blood flow going back to the deprived area --> inflammatory response and free radical formation

    during the inflammatory response, the white cells stick around for a long time which gives lots of time for treatment

    if mothers get an infection, can cause chorioamniotisis--inflammed chorion) which can also cause injury
  12. Pattern of injury
    • Premmies--white matter injuries
    • Full term babies--grey matter injuries

    injury in infants is quite complex, its a moving target of very rapid development, and trying to intervene in this rapidly changing target is very difficult
  13. Conclusions
    • Perinatal hypoxia ischemia is a complex disorder--duration, timing and evolution of the injury matters
    • --complex pattern of brain injury
    • --treatment is complicated

    • perinatal brain injruy occurs--throughout the last trimester and first month of life
    • perinatal injury occurs most often during antepartum
    • most common injury --white matter
    • at the basis of perinatal injury--depeletion of energy resources
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