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

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

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

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

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

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

PVL - Ultrasound

PVL - Ultrasound Grade 4

PVL - MRI

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

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

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

PVL - Neurodevelopmental Outcomes

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

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

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

IVH - Neuropathology GM - highly cellular & vascularized structure Most prominent between 24-34 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)

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

Germinal Matrix Hemorrhage Grade 1

Germinal Matrix Hemorrhage Grade 2

Grade 3 GMH-IVH

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

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)

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

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

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

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

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

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 36-40 weeks PMA

GMH - IVH Diagnosis Post hemorrhagic hydrocephalus - 30% of infants with any degree of hemorrhage; develops 10-20 days after onset of bleed PVL (venous infarction due to impaired venous drainage) Porencephalic cyst (2-3 weeks)

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

GMH - IVH Prevention Pharmacologic: ANS - Risk for IVH - OR 0.54 CI 0.43-0.69 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 0.53-0.82; long term follow-up unable to show survival without impairment at 18 months

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

High Risk Infant Follow-up Clinic Improvement in survival of extremely preterm infants Survival rates: VON 87.5% (501g-1500g, 2009) NICHD 72% (GA 22-28 wk, 2003-2007) Long term complication of extreme prematurity Neurodevelopmental impairment (NDI) Referral to educational programs or subspecialty care to provide the BEST possible outcome

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

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

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 - 42 months of age Cognitive, Motor (fine & gross), Language (receptive and expressive)

Vermont Oxford Network

VON - Morbidity Rates

VON - Morbidity Rates 2000 vs. 2009

Neuroimaging should not be used in isolation to predict outcomes

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