Insults to the Developing Brain

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Insults to the Developing Brain Effect on
Neurodevelopmental Outcomes

• Ira Adams-Chapman, MD
• Assistant Professor of Pediatrics
• Director, Developmental Progress Clinic
• Emory University School of Medicine
• Atlanta, GA

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Brain Injury in the Preterm Infant

• ELBW infants continue to have a significant rate
  of neurodevelopmental (ND) impairment
• Concerning data regarding rates of disability
  among ELBW survivors
• Importance of identifying specific risk factors
  associated with adverse ND outcome

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Brain Injury in the Preterm InfantRecent Advances

• IVH and PVL are the major pathologic indicators
  of brain injury and are known predictors of
  adverse ND outcome
• Increased awareness of other causes of neonatal
  brain injury that affect long term ND outcome
• Improved understanding of the developing preterm
  brain and the unique risk for injury during this
  critical period in human brain development

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Development of the Preterm Brain

• Dynamic process that continues until the end of
  gestation
• Subcortical neurons detectable at 10 wks
• Neuronal proliferation continues through mid
  gestation
• Maturation not complete until late gestation

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Development of the Preterm Brain
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Development of the Preterm Brain Serial MRI Images
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Development of the Preterm Brain

• Germinal matrix is the source of neuronal
  precursor cells
• Germinal matrix is the source for glial precursor
  cells which give rise to the oligodendrocyte
  which is critical for white matter development
  and cortical networking
• Explains why even mild degrees of IVH may result
  in disruption of important developmental pathways
  resulting in severe brain injury

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Development of Preterm BrainGrowth of Cerebellum
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Brain Injury in the Preterm InfantPredictors of
Adverse Outcome

• Severe IVH /PVL
• Male Gender
• Postnatal steroids and Chronic Lung Disease
• Necrotizing Enterocolitis
• Infection
• Growth impairment
• Unrecognized aspects of care that have adverse
  impact on long term outcome

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Intraventricular Hemorrhage

• Majority occur within first 3 days (90)
• Many are clinically silent events
• Need for screening in high risk population

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Intraventricular HemorrhagePapile Criteria

• Grade 1- Subependymal
• Grade 2 - Blood in the ventricle but no
  dilatation
• Grade 3 Blood in the ventricle w/dilatation
• Grade 4 Parenchyma
• Limitations of nomenclature reflects in
  variability in reported outcomes

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Intraventricular Hemorrhage

• Relative risk inversely related to gestational
  age and birth weight
• Multifactorial

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Intraventricular Hemorrhage

• Overall, rates of severe IVH have decreased over
  the past decade
• Improved maternal and neonatal care
• Increased use of antenatal steroids since NIH
  Concensus Statement in 1994

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Neurodevelopmental OutcomeTrends Over Time

• Wilson-Costello, et al Pediatrics 2005
• Compared survival and rates of ND impairment
  between period I (1982-1989) and period II
  (1990-1998)
• N496 infants lt 1000 grams
• Increased overall survival rate and rate of
  survival with impairment
• For every 100 infants in period II, 18 additional
  infants survived, of whom 11 were impaired

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Changes In Outcome Over TimeWilson-Costello, et
al Pediatrics 2005
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Changes In Outcome Over TimeHintz, et al
Pediatrics 2005

• Compared various outcomes of 839 ELBW infants in
  the NICHD Neonatal Research Network in Epoch I
  (1993-1996) vs Epoch II (1996-1999)
• Infants born in Epoch I were more likely to have
  Severe IVH (35 vs 24) and PVL (8 vs 5) p,
  0.05
• Infants in Epoch I were more likely to have MDI
  lt70 but similar PDI, NDI and CP

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Intraventricular HemorrhageAdams-Chapman, et al
Pediatrics 2008
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Periventricular Leukomalacia

• Cystic necrosis of the periventricular white
  matter
• Motor tract travel through this area
• Highly correlated with adverse motor outcome and
  CP

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Periventricular Leukomalacia

• Important role in cortical organization and
  neuronal networking
• Disruption of these WM pathways may result in
  difficulty with processing and cognitive skills
• Discrete focal injury results in disruption of
  remote pathways

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• How Well Do MRI and Cranial Ultrasound
  Abnormalities Correlate with ND Outcome?

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ND Outcome and Normal CUS

• Laptook, et al for NICHD 2005
• Evaluated ND outcome of 1473 ELBW infants with
  normal CUS
• 9.4 of infants with normal CUS were diagnosed
  with CP
• 29 of infants with normal CUS had MDI lt70
• Highlights the baseline risk for abnormal outcome
  in the ELBW population

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ND Outcome and CUS Findings

• Oshea, et al Am J Epidemiol 1998
• Major CUS abnormality and diagnosis of CP
• 32 diplegia
• 52 quadriplegia
• 70 hemiplegia

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ND Outcome and CUS Findings

• Ultrasound has limited ability to detect white
  matter lesions
• MRI more sensitive
• Disruption in cerebral maturation, more diffuse
  CNS injury or subtle changes not visible by
  ultrasound
• Bottom Line A normal CUS does not equate to
  normal ND outcome !

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ND Outcome Associated with Grade I-II IVH

• Most common form of IVH in the ELBW population
  but limited information on outcome
• Historically, these infants felt to be at low
  risk
• Growing concern that hemorrhage may be associated
  with destruction of glial precursors and brain
  development

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ND Outcome Associated with Grade I-II IVH

• Patra, Wilson-Costello, et al J Ped 2006
• Compared ND outcome of 706 ELBW infants with
  Grade I-II IVH to those with normal CUS from
  single center
• Higher rate of impairment and lower MDI scores in
  those with Grade I-II IVH

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ND Outcome Associated with Grade I-II IVH
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ND Outcome Associated with Grade I-II IVH

• Lowe and Papile Am J Dis Child 1990
• Evaluated infants with Grade I-II IVH who were
  normal at 2 yrs and reevaluated at 5 years of age
• Infants with Grade I-II IVH had more difficulty
  with neuropsych testing including,
  visual-perceptual, visual-motor and tactile
  perceptual skills

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ND Outcome Associated with Grade I-II IVH

• Frisk and Whythe Dev Neuropsychol 1994
• Evaluated impact of mild IVH on language
  development
• Infants with mild IVH had problems with skills
  requiring short term and working memory
• Other authors have found no differences in those
  with Grade I-II IVH (?where to mention)

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Brain Injury Associated with Mild IVH- MRI
Findings

• Vasileiadis, et al Pediatrics 2004
• MRI at adjusted term gestation in cohort of VLBW
  population from a single center
• Excluded infants with risk that could confound
  outcome (sepsis, IVH, PVL, NEC)
• Compared those with No IVH to Uncomplicated IVH
• MRI showed reduction of cortical gray matter
  volume in infants with uncomplicated IVH
• No difference in subcortical gray matter, white
  matter or CSF volumes.
• Important to understanding the broader spectrum
  of brain injury in the LBW infant

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ND Outcome and CUS Findings

• Prognostic value of a normal cranial ultrasound
  limited, particularly in ELBW population
• MRI data is more sensitive
• Use caution when counseling parents about outcome
  
• Healthy respect for the possibility of brain
  injury in the extremely immature infant

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Brain Injury in the Preterm Infant

• Dyet, et al Pediatrics 2007
• Serial MRI imaging on 119 infants 23-30 wks
  gestation and correlated with outcome
• WMI was common and correlated with adverse
  outcome

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Brain Injury in the Preterm Infant

• Miller, et al J Pediatr 2005
• Evaluated serial MRI in 89 preterm infants and
  performed ND studies
• WMI more common than predicted by US data- up to
  35
• Extent of WMI correlated with adverse outcome
• CBL hemorrhage in 10
• Severe IVH correlated with adverse outcome

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Brain Injury in the Preterm Infant

• Woodward, et al NEJM 2006
• Evaluated 167 infants with both MRI and ND
  followup at 2 years of age
• 21 of infants had mod-severe WMI and were
  predictive of CP and adverse cognitive outcome
• 49 of infants had gray matter abnormalities
  which were predictive of adverse outcome and CP

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ND Outcome of ELBW with PHH and Shunts

• Adams-Chapman et al Pediatrics 2008
• Infants born January 1, 1993-December 31, 2002
  weighing lt 1000 grams who participated in the GDB
  and F/U studies for the NICHD Network
• 19 participating network centers
• Excluded infants with major congenital
  malformations and syndromes

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Results
15,454 lt1000gm
726 Major Malformations
14,728
5242 deaths lt18 months
9,486 eligible
82 F/U rate
No IVH No Shunt 5,163
Grade 1-2 No shunt 1,532
Grade 3-4 No Shunt 770
Grade 3-4 Shunt 228
7,776
83 missing data
7,693
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PHH and ND Outcome Bayley Scales Infant
Development-IIR

• p0.05

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PHH and ND Outcomes 18-22 Months AA

• p 0.05, p 0.01, p0.001 by Wald
  chi-square test

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PHH and ND Outcome

• Interesting clinical finding -
• 14 (32/228) of infants with PHH and shunts had
  normal functioning at 18-22 months
• ? Why the variability in outcome
• ?How would they compare at an older age
• Variables associated with improved outcome
  included
• Female gender
• No PVL
• Normal growth parameters at 18 months

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Understanding the Complexity and Beauty of the
Human Brain
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Brain Injury in the Preterm Infant

• IVH and PVL are important predictors of brain
  injury in the preterm infant
• Long term follow up studies indicate that other
  variables are involved in the cascade of brain
  injury
• Subtle injury to cortical and subcortical region
  are difficult to identify in the neonate but are
  important to understanding brain function and ND
  outcome

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Complexity of Brain Development

• Prefrontal lobe higher cognitive function and
  behavior
• Frontal language and motor cortex
• Parietal lobe sensory integration
• Temporal lobe auditory processing, visual
  coordination and behavior
• Motor cortex motor function and sensation
• Basal ganglia coordination
• Occipital lobe vision and visual integration
• Hippocampus - memory
• Cerebellum balance and fine motor
• Periventricular white matter motor tracts

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Cerebellum and Brain Injury

• Cerebellar injury increasingly recognized in
  preterm infants
• May be associated with difficulty with cognitive
  function, fine motor skills, coordination, ataxia
  and motor sequencing
• Direct cerebellar injury or secondary injury
  secondary to damage in another part of the brain

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Cerebellum and Brain Injury

• Limperopolous, et al Pediatrics 2007
• Volumetric MRI at term equivalent in 74 infants lt
  32 wks gestation
• Cerebellar volumes reduced in all infants with
  abnormal MRI findings
• Infants with PVHI had reduced volume of
  contralateral cerebellar hemisphere
• Infants with unilateral CBH had smaller
  contralateral cerebral hemisphere volumes

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Cerebellum and Brain Injury

• Infants with PVHI had marked reduction in
  cerebellar cortical gray matter volumes in
  absence of direct CBL injury
• Infants with CBL hemorrhage had the greatest
  reduction in CBL volumes
• All preterm infants had smaller cerebellar
  volumes compared to term infants

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Cerebellum and Brain Injury

• Trophic effect between development of cerebral
  and cerebellar tissues

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Neurodevelopmental Outcome

• Damage to caudate nucleus associated with
  impaired spatial memory tasks
• Variables will affect school performance

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PHH and ND Outcome Bayley Scales Infant
Development-IIR
- Plt0.05
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Brain Injury in the Preterm Infant
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Brain Injury in the Preterm Infant

• Human brain development is a dynamic process
• ELBW infants are at significant risk for brain
  injury due to potential for injury during a
  critical phase in brain development
• Intraventricular hemorrhage is a serious
  complication of prematurity associated with
  adverse outcome especially when severe
• Injury to various areas of the developing brain
  are associated with adverse outcome

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Thank You!