1. Preterm Brain Injury and Neurodevelopmental Outcomes
Lilia C. De Jesus, MD

2. Brain Injury in Preterm Infants
Includes a variety of neuropathologic lesions
Periventricular leukomalacia (PVL), germinal matrix-intraventricular hemorrhage, posthemorrhagic hydrocephalus and other patterns of neuronal injury
Pathogenesis and preventive interventions

3. Periventricular Leukomalacia (PVL)
Characterized by multifocal areas of necrosis, forming cysts in the deep periventricular cerebral white matter, often symmetric and occur adjacent to the lateral ventricles
Correlates with development of cerebral palsy, cognitive & behavioral deficits

4. PVL - Pathogenesis Multifactorial
Prenatal, perinatal, postnatal factors
Hypoxia-ischemia, Infection & inflammation, excitotoxicity and oxidative stress
Combined insults
BP, CBF
J. Volpe, Ped Research 2001

5. PVL - Hypoxia-Ischemia
Vascular supply of cerebral WM
Distal end of the penetrating arteries not fully developed in preterm infants
Decrease CBF —> ischemia
2 types:
Focal - cystic necrosis, severe ischemia affecting deep WM
Diffuse - Border zone between long and short penetrators, peripheral
J. Volpe, Ped Research 2001

6. PVL - Risk Factors for Ischemia
Hypotension
Hypoxia
Marked hypocarbia
CHD - HLHS
PDA with retrograde cerebral diastolic flow
Infection or inflammation
IUGR/SGA

7. PVL - Ultrasound

8. PVL - Ultrasound
Grade 4

9. PVL - MRI

10. PVL -MRI
MRI - more sensitive in detecting WM abnormalities than cranial US
T1 weighted imaging - punctate areas of T1 signal hyper intensities
T1 hyperintense signal on the frontal horn of R lateral ventricle

11. T1 and T2 weighted images of a punctate lesion in the centrum ovale
WM Injury - MRI
T1 and T2 weighted images of a punctate lesion in the centrum ovale

12. PVL - Neuropathology PVL lesions with cystic changes
Diminution of WM volume
Thinning of corpus callosum
Ventriculomegaly
Deficiency of myelin

13. PVL - Neurodevelopmental Outcomes

14. Prevention Maintain cerebral perfusion
Avoid: hypotension, marked hypocarbia & hypercarbia, moderate hypoxemia
Prevent oligodendrocyte death related to free radical attack
Vitamin E, maternal abx or anticytokine agents, safe glutamate receptor antagonist
Magnesium, antenatal glucocorticoids

15. Intracranial Hemorrhage
Occurs primarily in preterm infants
Risk higher with decreasing gestation
Average incidence ~5% to 11%
Decrease in incidence due to antenatal corticosteroid use

16. Timing of IVH 90% occur within first 7 days
Majority within 72 hr of life
99% occur by 10 days of life

17. IVH - Neuropathology
GM - highly cellular & vascularized structure Most prominent between weeks GA
Neurons & glial cells migrate out during brain development, regressed by term
Abundant in the caudate nucleus and periventricular zone
Blood supply is from branch of anterior cerebral artery (Heubner artery)
Vessels in GM are primitive (immature vascular rete)

18. IVH - Neuropathology
Venous drainage from deep WM is through short & long medullary veins —> blood flows through GM —> terminal vein (positioned below the GM)
Parenchymal hemorrhage associated with GMH-IVH suggests VENOUS INFARCTION due to obstruction of this vein

20. Germinal Matrix Hemorrhage Grade 1

21. Germinal Matrix Hemorrhage Grade 2

22. Grade 3 GMH-IVH

23. Grade 4 - Intraparenchymal Hemorrhage
Most severe type
unlikely due to direct extension of pressure or blood in the ventricle
GMH leading to impaired venous drainage and venous infarction
mostly unilateral but can occur bilaterally
Can evolve into cystic lesions

24. GMH-IVH Prenatal Risk Factors
Chorioamnionitis (altered hemodynamic function)
Preeclampsia (enhanced maturation in utero)
ANS (direct maturational effect on fetal brain or reduction of severity of lung disease)

25. GMH-IVH Intrapartum Factors Mode of delivery
Neonatal transport for infants born outside of tertiary center
Delayed cord clamping

26. GMH-IVH Neonatal Factors
RDS - associated complications on MV (hypercarbia, pneumothorax, acidosis)
Hypercarbia (potent cerebral vasodilator) and severe acidosis

27. GMH - IVH Cardiovascular Factors
ANS - associated with reduction of need for BP support & severity of RDS
fluctuations in blood pressure
limitations in autoregulation of cerebral blood flow

28. GMH-IVH
Diagnosis
Catastrophic deterioration - sudden deterioration in infant’s clinical state; increase in oxygen or vent support; fall in BP and acidosis; sudden drop in HCT
Saltatory - gradual in onset; change in the spontaneous movements
Asymptomatic - no obvious clinical signs; 25%- 50% of infants with GMH-IVH

29. GMH - IVH Diagnosis Ultrasound Method of choice
Non-invasive bedside technique
good correlation of US findings with autopsy findings
small bleeds in other areas of brain not always identified
immediate access, can be repeated as often as indicated

30. GMH - IVH Diagnosis AAP - Screen <30 weeks
Canadian Pediatric Society - Screen < 32 weeks
Timing - screening by first week of life shows 90% of all hemorrhages
scan at 7-14 days of age and at weeks PMA

31. GMH - IVH
Diagnosis
Post hemorrhagic hydrocephalus - 30% of infants with any degree of hemorrhage; develops days after onset of bleed
PVL (venous infarction due to impaired venous drainage)
Porencephalic cyst (2-3 weeks)

32. GMH - IVH Management minimal handling
prevent fluctuations in BP or CO2 levels
gentle ventilation
treat any coagulopathy to prevent extension of bleed
blood transfusion
EEG to detect subclinical seizures
Monitor development of hydrocephalus, CSF drainage, VPS

33. GMH - IVH Prevention Pharmacologic:
ANS - Risk for IVH - OR 0.54 CI
Antenatal Magnesium - no reduction in IVH rates but long term follow-up showed improvement in gross motor function
Antenatal/postnatal Phenobarbital - unable to show reduction in risk for GMH-IVH
Postnatal Indomethacin - OR 0.66 CI ; long term follow-up unable to show survival without impairment at 18 months

34. Cerebellar Hemorrhage
Can occur in ~2.5% of high risk preterm infants
Increase in detection with MRI, US - mastoid views
Associated with neuromotor, behavioral, and cognitive delays

38. High Risk Infant Follow-up Clinic
Improvement in survival of extremely preterm infants
Survival rates: VON 87.5% (501g-1500g, 2009)
NICHD 72% (GA wk, )
Long term complication of extreme prematurity
Neurodevelopmental impairment (NDI)
Referral to educational programs or subspecialty care to provide the BEST possible outcome

39. High Risk Infant Follow-up
Impaired cognitive skills
Motor deficits including fine or gross motor delay, CP
Sensory impairment (vision & hearing losses)
Behavioral and psychological problems

40. High Risk Infant Follow-up
All ELBW and VLBW infants with a prolonged NICU course or conditions associated with poor neurodevelopmental outcomes
Individual with Disabilities Education Act (IDEA), a federal law, mandates early intervention for eligible patients between birth and 3 years of age
Most NICU patients will meet eligibility criteria for diagnostic evaluation (medical, nutritional, speech, hearing, vision, development and family)
Eligibility for Early Intervention Program vary from state to state

41. High Risk Infant Follow-up
Medical evaluation including neurologic examination and developmental screeners
24 months corrected age - Psychometric testing
assesses developmental functioning in infants & young children between 1 month months of age
Cognitive, Motor (fine & gross), Language (receptive and expressive)

42. Vermont Oxford Network

43. VON - Morbidity Rates

44. VON - Morbidity Rates 2000 vs. 2009

50. Neuroimaging should not be used in isolation to predict outcomes

51. Thank You!