This document discusses hypoxic ischemic brain injury in newborns. It begins by defining terms like HIE, hypoxia, ischemia and asphyxia. It then notes the problem magnitude, with HIE affecting 1-5/1000 term newborns and being a major cause of neonatal death and cerebral palsy. The document reviews investigation techniques like EEG, ultrasound, CT and MRI and their findings. It discusses cell death mechanisms and neuroprotective strategies like hypothermia, magnesium sulfate, xenon, and antioxidants. Overall, the document provides an overview of hypoxic ischemic brain injury in newborns, including causes, effects, diagnostic tools, and potential treatment strategies.

1. Hypoxic ischemic brain insult in
newborn and infant
Diagnosis and Neuro-protection
Ayman El-sayed Ali Galhom
Ass. Pro. Neurosurgery
2013

2. Definition
• HIE – Acute brain injury that occurs before, during or
after birth (clinical and lab findings)
• Hypoxia – Reduced cerebral oxygenation
• Ischemia – Reduced perfusion
• Asphyxia _ refers to progressive hypoxia, hypercarbia
and acidosis. A cord pH < 7.00 is defined as pathologic
or severe fetal acid
• Necrosis – Cell death ( Traumatic, Acute cellular injury)
• Apoptosis – Programmed cell death

3. Problem magnitude
• HIE affects 1-5/1000 term newborns
– 25% of these mod – severe injury
• 0.7-1.2 million asphyxia-related neonatal deaths annually
• Significant burden of complications
– Cerebral Palsy
– Death
• 23% of neonatal deaths attributed to complications of
HIE
• 6-8% of CP is linked to HIE

4. Electron microscopic of dying neurons in
neocortex from an infant rat 48 hours after
HI
• Electron microscopic
images of dying
neurons in neocortex
from an infant rat 48
hours after HI
Apoptotic neuron with one
large apoptotic body including
condensed chromatin

5. Who is going apoptosis
• The developing brain, in normal
development, the neurons which have
made effective synaptic connections are
preserved, while cells that are not
electrically active undergo apoptosis.
• Cells in the developing brain are also at
increased risk to undergo apoptosis in
response to injurious stimuli.

6. Investigation
• Identification and characterization of the
severity, extent, location, and prognosis of
brain injury:
o Electro encephalogram (EEG)
o Ultrasonography(US)
o Computed tomography (CT)
o Magnetic resonance (MR) imaging
o Diffusion-weighted MRI
o MR spectroscopy

7. EEG
• EEG: Burst suppression pattern, low voltage or isoelectric EEG (poor outcome)
• Amplitude-integrated EEG: A Cerebral Function Monitor
via a single channel EEG (a-EEG), records activity from
two biparietal electrodes. It is performed within a few
hours of birth. The amplitude is integrated.
• Three distinct patterns of electrical activity are noted i.e.
normal, moderate and severe suppression ( abnormal
neurologic outcome) with a sensitivity of 100%, positive
predictive value of 85%.

8. UltraSonography
• Detection of hemorrhage, periventricular
leukomalacia (PVL), and hydrocephalus.
• Resistive index (RI) and cerebral perfusion
• Normally, the RI decreases with increasing
gestational age.
• Sustained asphyxia with intracranial
hemorrhage or diffuse cerebral edema
result in increased RI and poor outcome.

9. Sonography for Assessment
of HIE
Cranial sonography HI in 5day-old term girl.
A, Coronal sonogram shows
diffuse increase in echogenicity
of white matter consistent with
edema as well as increased
distinction of gray matter (arrows)
and white matter.
B, Color Doppler sonogram in
sagittal orientation shows
reversal of diastolic flow,
reflecting increased vascular
resistance secondary to edema

10. Computed tomography
• Less sensitive
• High water content in the neonatal brain
and high protein content of the CSF, result
in poor parenchymal contrast resolution.
• Radiation exposure.

11. Findings on CT
•Decrease in basal ganglia
density is finding of cytotoxic
edema
•Subtle loss of the normally sharp
transition from gray matter to
white matter at the
corticomedullary junction may be
the only discernible change
•Cerebral edema can best be
detected by the effacement of the
sylvian fissures and the
perimesencephalic fissures.
•The swelling is usually seen by 8
hours after the insult and usually
reaches a maximum between 72
and 96 hours
.

12. MRI Findings in the Normal
Neonate
• On T1-weighted images, After 37 weeks of
gestational age. One third of the length of the
posterior limb of the internal capsule should be
hyperintense. corresponding to myelination.
• Hypointense signal intensity is normally seen in
T2-weighted images.
• Injury to white matter generally results in T1
hypointensity and T2 hyperintensity due to
ischemia-induced edema.

13. MRI examination in normal 4-day-old
fullterm boy.
A,
Axial T1-weighted image
shows normally increased
signal intensity of posterior
limb of internal capsule
(arrows)
B, Axial T2-weighted image
shows foci of normal
hypointense signal in
posterior limb of internal
capsule (arrows)
Relative to adjacent basal
ganglia and thalamus.

14. Pattern of brain injury
Mild to moderate hypoperfusion
The premature neonatal brain
(left) has a ventriculopetal
vascular pattern, and
hypoperfusion results in a
periventricular border zone of
white matter injury.
In the term infant (right), a
ventriculofugal vascular pattern
develops as the brain matures,
and the border zone during
hypoperfusion is more peripheral
with subcortical white matter and
parasagittal cortical injury

15. Grade of MRI injury
1- Increased signal intensity in the basal ganglia
on T1- weighted images
2- Increased signal intensity in the thalamus on
T1-weighted images.
3- Absent or decreased signal intensity in the
posterior limb of the internal capsule on T1weighted images (i.e., the “absent posterior limb
sign”)
4- Restricted water diffusion on diffusion-weighted
images.

16. 1-increased signal intensity on T1- weighted
images of the basal ganglia
• The basal ganglia and
thalamus) are the most
metabolically active in the
brain.
• The increased signal
intensity generally persists
for 2–4 months after the
insult.
• It is nonspecific because it
can be seen to a mild
degree in normal infants.

17. 2- Increased signal
intensity in the thalamus
on T1-weighted images.
The thalamus, like the
basal ganglia, is another
region that is more
susceptible to hypoxic
injury, making this
finding a relatively
sensitive and specific
sign

18. 3- Absent or decreased signal
intensity in the posterior limb of the
internal capsule on T1
This absent posterior limb sign is
due to loss of the normal increased
signal intensity that is associated
with myelination.
Noted on T1-weighted images,
Absence of the normal dark signal
intensity on T2-weighted images.

19. 4-Findings on DiffusionWeighted Imaging
Restricted diffusion in the basal ganglia,
the posterior limb of the internal capsule,
or the thalamus can be seen in the first
24 hours after birth, reach maximum
decrease in apparent diffusion coefficient
values at approximately 5 days.
Axial diffusion-weighted image DWI
shows hyperintense signal in basal
ganglia, thalami, and internal capsule.
Apparent diffusion coefficient map
shows hypointense signal in same
structures that are hyperintense in axial
DWI .

20. What is in the image ?
Axial CT scan obtained on day 1 of life shows
subtle bilateral hypo attenuation of the basal
ganglia and thalami, which are isoattenuated
compared with surrounding white matter.
Axial T1-weighted MR images (b, c) obtained
on day 5 of life show hyperintensity
Axial T2-weighted MR images (d, e) depict
corresponding hypointensity in the posterior
putamina, lateral thalami, and the sensorimotor
cortices bilaterally.
(f–h) Diffusion-weighted MR images reveal
hyperintensity in the basal ganglia (f),
hippocampi and occipital lobes (g), and the
sensorimotor cortices (h), findings
consistent with restricted diffusion and acute
ischemic injury

21. Normal MRI spectroscopy

22. MR spectroscopy
• Biochemical analysis of the “compromised
anaerobic” cerebral tissues.
• Elevated lactate and diminished Nacetylaspartate NAA concentrations.
• Elevation of choline relative to creatine,
• lactate-choline ratio of 1 indicates a
greater than 95% probability of adverse
neurodevelopmental outcome.

23. MR spectroscopy in a
term
(a) MR spectroscopy of a
single voxel in the
interarterial boundary zone
(b) At an echo time of 35
msec, demonstrates
nonspecific accumulation of
metabolite at 1.2–1.3 ppm
(*), with a characteristic
“doublet” configuration.
.
(c) Spectrum obtained at
an echo time of 144 msec
shows inversion of the same
metabolite, which is
characteristic for lactate.

24. Keep your eye on
•
•
•
•
•
•
•
Ventilation
Fluid Status
Oliguria
Hypotension
Glucose status
Seizures
Cerebral edema

25. Neuro-protective strategies Clinical issues
1) Who to treat? - infant at highest risk.
2) When to treat? - early therapeutic
window is short.
3) How long to treat? - unclear.
4) What is the treatment?
(The difficulty in achieving neuro-protection during the secondary
injury phase has been assumed to be due to amplification of
inflammatory signals or cascades extending past a point of no return
for mitochondrial adaptation and caspase activation)

26. Potential Mechanisms of Injury Following Hypoxia-Ischemia
HYPOXIA-ISCHEMIA
ANAEROBIC GLYCOGLYSIS
ATP
ADENOSINE
GLUTAMATE
LACTATE
NMDA RECEPTOR
hypothermia
HYPOXANTHINE
INTRACELLULAR Ca+
ALLOPURINOLA
XANTHINE
OXIDASE
MgSO4
Xenon
ACTIVATES LIPASES
ACTIVATES
NOS
XANTHINE
O2
FREE RADICALS
FREE FATTY ACIDS
O2
NITRIC OXIDE
FREE RADICAL
SCAVENGERS
FREE RADICALS
FREE RADICALS

27. Strategies
Cerebral metabolic rate
Block NMDA receptor channel
Glutamate release
Interventions
Hypothermia
Magnesium sulphate (MgSO4)
Xenon (risk ventilation, expensive)
Adenosine , agonist
Adenosine uptake inhibitor
Inhibit voltage sesnsitive ca++
channels
Calcium channel blockers
(flunarizine, nimodipine)
Blockage of inflammatory
mediators
Phospholipase A2, Indomethcin
Prevent free radical generation
Indomethacin
Iron chelators
Allopurinol , oxypurinol
NOS inhibitor
Free radical reactions
Attenuate apoptosis
Free radical scavengers
Allupurinol (very early)
Vitamine C, E
Caspase inhibitor

28. Potential Mechanisms of Action
of Hypothermia
•
•
•
•
•
•
•
•
Reduces cerebral metabolism
Preserves ATP levels
Decreases energy utilization
Suppresses Excitotoxic AA accumulation
Reduces NO synthase activity
Suppresses free radical activity
Inhibits apoptosis
Prolongs therapeutic window?

29. Hypothermia
• Depth of cooling (mild (>32C), moderate (28– 32C),
deep (20–28C), profound (5–20 C), and ultra-profound
(<5C).
• Duration of cooling brief durations of hypothermia (0.5–
5 h), whereas others used longer periods (12–48 h).
• Durations of 1–3 h appeared effective, Longer
durations is needed when the initiation of cooling is
delayed.
• Timing of cooling better within first 1 hour after insult,
however, even delayed post ischemic hypothermia can
reduce the extent of ischemic injury due to focal cerebral
ischemia.

30. Hypothermia
• Hypothermia with a delay of up to 6 h is
still effective provided cooling maintained
for 1–2 days.
• Long-term protection has been observed
up to 2 months with 2-h intra ischemic
cooling, in global ischemia up to 6 months
protection provided cooling is maintained
for 24 h.

31. Candidates for
Therapeutic Hypothermia
neonates
Neonates > 36
weeks gestation
at birth
Neonates >
1800 grams
(3lbs, 15.5oz) at
birth
Ability to start
treatment within
6 hours from
birth time*
Abnormal
neurologic exam

32. Continued Inclusion Criteria
Cord Blood Gas
• pH < 7.0 or Base Deficit >16 (-16)
Baby’s 1st Blood Gas at <1hr of life
• pH 7.01 to 7.15 or Base Deficit 10-15.9
Apgar Scores
• ≤ 5 at 10 minutes
Resuscitation efforts
• Continued need for PPV or Intubation at 10 minutes

33. Who should NOT be cooled?
Babies <36
Weeks
<1800gm
Congenital CNS
problems
Hemorrhagic or
traumatic Brain
Injury
Known poor
prognosis
(Trisomy 13, 18)
“in extremis”

34. Total body cooling
• Cooling Blanket
• Cooling Wrap
• Monitoring Goals
– Core Temperature goal = 33-34C*
– 48 hours of cooling
– Slow Re-warming
• Over 6 to 12 Hours

35. Total body cooling

36. Cool Cap
• Neuor-protection while
minimizing side-effects
of hypothermia
• Cooling cap with
circulating water placed
on head for 72 hours
• Reduced brain
temperature
• Body maintained at
defined temp

37. Neuroprotectants
• Multiple therapies are instituted at once.
• Hypothermia is less likely to be effective
(e.g., delayed cooling) and combine it with
another neuroprotective.
• Combination of magnesium MgCl2,
tirilazad, and hypothermia (MTH)
significantly reduced the infarct by 77%.
• Hypothermia and caffeinol reduced infarct
size to similar extents (50%).

38. Combined therapy
• NMDA antagonist MK-801 on postischemic days 3,
5, and 7, animals showed long-lasting
neurobehavioral protection out to 6–8 W.
• Hypothermia 4 h combined with cytokine IL-10,
immediately and 3 days later, histologic protection
in hippocampal CA1 up to 2 months.
• Anti-inflammatory treatment with dipyrone
prevented the long-term loss of protection by
hypothermia possibly by preventing post ischemic
hyperthermia

39. Allupurinol
• Reduce the formation of free-radicals.
• Maintain the blood-brain barrier.
• Oxypurinol are inhibitors of xanthine oxidase.
(oxypurinol crosses BBB more easily than
allopurinol).
• Direct scavenging of free radical.
• Inhibition of neutrophil accumulation.
• Chelation of metal ions such as ferric iron.
• Allopurinol has no positive effect when started
too late and at low doses

40. Xenon
• A non-competitive antagonist of NMDA.
• Inhibition of the calcium/calmodulin
dependent protein kinase II.
• Activation of anti-apoptotic effectors (BclXL and Bcl-2 and induced expression of
hypoxia inducible factor 1α).
• Very expensive and its administration is
rather complicated, since it requires
intubation and ventilation of the patient,

41. Magnesium sulfate (MgSO4)
•
•
•
•
•
•
NMDA receptor antagonist.
Reduces calcium entry into the cell.
Direct actions on mitochondrial activity.
Anticonvulsant properties.
Increasing cerebral blood flow.
An antiapoptotic role and prevent neuronal
cell loss.

42. Melatonin
• Melatonin is an endogenously produced
indoleamine (primarily formed by the pineal gland).
• It is distributed widely in tissues, cells and
subcellular compartments including the brain.
• A potent endogenous antioxidant by scavenging
free radicals and upregulating Antioxidant
pathways.
• Antiapoptotic and anti-inflammatory effects
(reduces the up-regulation of pro-inflammatory
cytokines).

43. Vitamin E, Deferoxamine
• An antioxidant and free-radical scavenger
• Deferoxamine prevents the formation of
free radicals from iron since it is a free
metal-ion chelator.
• Improves cerebral metabolism in animal
models of HI.

44. N-acetylcysteine (NAC)
• NAC is a free radical scavenger and restores
intracellular glutathione levels, attenuating
reperfusion injury,
• Decreasing inflammation and NO production in
models of stroke.
• Low toxicity, Cross the placenta and BBB.
• When combined with hypothermia, NAC
decreased infarct volume, improved myelin
expression and functional outcomes after focal
HI injury in rate.

45. Erythropoietin (Epo)
• A primary endogenous cytokine that
promotes red blood cell maturation.
• Endogenous Epo is a 30.4 kD glycoprotein
that regulates red blood cell differentiation
by inhibiting apoptosis of erythroid
progenitors in marrow.
• Neuroprotective actions have been known
for 20 years in anemic patients exhibited
neuromuscular function improvement after
EPO.

46. Epo Trials in Term Infants
• The first trial of Epo therapy for neuroprotection
in term infants born > 37 weeks with moderate to
severe hypoxic-ischemic encephalopathy (HIE)
has now been completed 2009.
• Zhu et al. randomized eligible babies to either
Epo (n=83) or conventional (n=84) treatment.
Epo group received 500 U/kg every other day for
2 weeks, with the first dose administered by 48
hours of life.

47. Epo Trials in Term Infants
• Epo treatment improved neurologic signs
at 7, 14, and 28 days as assessed by
Thompson Neurologic Assessment,
reduced disability for moderate HIE, and
reduced the incidence of cerebral palsy at
18 months of age.
• Death or disability at 18 months was
present in 43.8% of controls compared to
24.6% of Epo-treated subjects (p < 0.02)

48. Mechanisms of Epo Neuroprotection
• Epo receptor (EpoR) activation can trigger
different signaling pathways. Epo prevents
neuronal apoptosis via Janus
kinase/Stat5 activation and NFκB
phosphorylation.
• Epo is reported to stimulate vascular
endothelial growth factor secretion and
angiogenesis.

49. Mechanisms of Epo
Neuroprotection
• Epo stimulation of brain derived neurotrophic
factor (BDNF).
• Neurons specifically express hemoglobin in
response to either hypoxia or Epo, and that
neuronal hemoglobin is neuroprotective.
• Enhanced erythropoiesis which increases iron
utilization, thereby decreasing free iron and
reducing oxidative brain injury.
• Stabilizing oxygen availability, and reducing
inflammation, complement.

50. Mechanism of action

51. Epo and ADHD
• Hyperactivity Disorder (ADHD)
dopaminergic neurotransmission from the
mesencephalon to the forebrain is critical
for proper motor and cognitive processing.
• Epo has trophic effects on dopaminergic
neurons. In vitro evidence established that
rEpo promotes the growth, differentiation,
and function of cultured dopaminergic
cells.

52. Risk of epo
• Adults (e.g. hypertension, clotting,
seizures, polycythemia, and death)
• Preterm infants have a long history of Epo
treatment, with few reported side effects.

53. Selenium
• Selenium is an essential component of the
rare amino acid selenocysteine (Sec) and
is incorporated at the catalytic site of
various selenium dependant enzymes
such as glutathione peroxidase (GPx),
thioredoxin reductases, and one
methionine-sulfoxidereductase.

54. Selenium
• Seleno-enzymes play important roles in:
1. Immune function, antioxidant defense and
intracellular redox regulation and modulation.
2. Selenium prevents glutamate and hypoxia-induced
cell death.
3. Selenium preserves mitochondrial respiration
biogenesis, and complex activities
4. Genetic inactivation of all selenoproteins in
neurons leads to progressive neuro-degeneration

55. Neuroprotective effect of selenium pretreatment against
glutamate toxicity and hypoxia
Selenium pretreatment
significantly improved
cell survival from
glutamate toxicity (4
mM) and hypoxia /
reoxygenation (10/12
h).

56. Selenium pretreatment
reduces ischemic brain
damage
Microphotographs of NeuN
immunostaining shows the
neuronal population in control
and ischemic brain area of
selenium and saline pretreated
mouse. Cerebral ischemia
caused neuronal degeneration
at 24 h of ecirculation in
striatum and some part of
overlying cortex in saline
treated mice. Selenium
pretreatment, in contrast,
restricted the neuronal damage
to only striatal area of the brain
after 24 h of recirculation

57. Stem cell
• During HI brain injury, neurons, glia and endothelial cells
are damaged. Endogenous regeneration mechanisms
have been shown to exist in the brain with ischemic
injury, stimulating neural stem cell proliferation and
differentiation in cerebral neurogenic areas.
• However, the capacity of the neonatal brain to respond
to enhanced endogenous neurogenesis following
neonatal HI may depend on timing and severity of
event.
• Recent advances suggest that stem cell
transplantation may improve repair of the damaged
brain. Neural stem cells can renew and differentiate
themselves between cells of all glial and neuronal
lineages.

58. Stem cell
• HI induced brain damage can also be treated with
mesenchymal stem cells. MSCs may also secrete
several trophic factors including colony stimulating
factor-1, VEGF, basic fibroblast growth factor, nerve
growth factor and brain derived neurotrophic factor.
• In these sense, the intracranial administration of MSCs
several days after HI event has shown a decreased
histological damage and an improved outcome in rat HI
model.
• Stem cell transplantation has the potential to become a
future neuroprotective and regenerative therapy for
ischemic brain damage.

59. Gene Therapy
• Bcl-2 gene (anti-apoptotic gene, protects
ischemic neurons) transfer from 1.5 to 5 h
if hypothermia (33C) was initiated
immediately after reperfusion and
maintained for 3 h.
• Therapeutic window for FK506 treatment
in brain ischemia if combined with
hypothermia expanded to 2 h is under
research.

60. Thank you