Insults to the Developing Brain & Effect on Neurodevelopmental Outcomes

Transcription

1 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

2 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

3 Brain Injury in the Preterm Infant Recent 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

4 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

5 Development of the Preterm Brain

6 Development of the Preterm Brain Serial MRI Images

7 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

8 Development of Preterm Brain Growth of Cerebellum

9 Brain Injury in the Preterm Infant Predictors 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

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

11 Intraventricular Hemorrhage Papile 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

12 Intraventricular Hemorrhage Relative risk inversely related to gestational age and birth weight Multifactorial

13 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

14 Neurodevelopmental Outcome Trends Over Time Wilson-Costello, et al Pediatrics 2005 Compared survival and rates of ND impairment between period I ( ) and period II ( ) N=496 infants < 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

15 Changes In Outcome Over Time Wilson-Costello, et al Pediatrics 2005 Period I ( ) Period II ( ) Survival 49% 67%* Severe IVH 22% 22% PVL 2% 7%* CP 16% 25% NDI 26% 36%*

16 Changes In Outcome Over Time Hintz, et al Pediatrics 2005 Compared various outcomes of 839 ELBW infants in the NICHD Neonatal Research Network in Epoch I ( ) vs Epoch II ( ) 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 <70 but similar PDI, NDI and CP

17 Intraventricular Hemorrhage Adams-Chapman, et al Pediatrics 2008 NICHD 2004* (N=7693) Grade 1 13% Grade 2 7% Grade 3 7% Grade 4 6% Cohort of infants born between

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

19 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

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

21 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 <70 Highlights the baseline risk for abnormal outcome in the ELBW population

22 ND Outcome and CUS Findings O shea, et al Am J Epidemiol 1998 Major CUS abnormality and diagnosis of CP: 32% diplegia 52% quadriplegia 70% hemiplegia

23 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!

24 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

25 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

26 ND Outcome Associated with Grade I-II IVH Normal CUS (N=258) Grade I-II IVH (N=104) Mean MDI * MDI < (25%) 47 (45%)* Mean PDI * PDI < (28%) 36 (35%) * Neuro 14 (5%) 13 (13%) * Abnml NDI 72 (28%) 49 (47%)*

27 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, visualmotor and tactile perceptual skills

28 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)

29 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

30 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

31 Brain Injury in the Preterm Infant Dyet, et al Pediatrics 2007 Serial MRI imaging on 119 infants wks gestation and correlated with outcome WMI was common and correlated with adverse outcome

32 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

33 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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35 ND Outcome of ELBW with PHH and Shunts Adams-Chapman et al Pediatrics 2008 Infants born January 1, 1993-December 31, 2002 weighing < 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

36 Results 15,454 <1000gm 726 Major Malformations 14, deaths <18 months 9,486 eligible No IVH No Shunt 5,163 Grade 1-2 No shunt 1,532 7,776 82% F/U rate Grade 3-4 No Shunt 770 Grade 3-4 Shunt missing data

37 PHH and ND Outcome Bayley Scales Infant Development-IIR Group No IVH/ No Shunt IVH 3-4/ No Shunt IVH 3-4/ Shunt *p 0.05 Mean MDI Score s.e. 80.6* * * 1.2 Median MDI Mean PDI Score s.e * * * 1.1 Median PDI

38 PHH and ND Outcomes Months AA Group MDI < 70 PDI <70 CP NDI IVH 3-4/shunt vs IVH 3-4 No Shunt 1.4 *** ( ) 1.80 *** ( ) 1.96 *** ( ) 1.37 *** ( ) IVH 3-4/shunt vs No IVH/No Shunt 1.57 *** ( ) 2.72*** ( ) 3.69 *** ( ) 1.68 *** ( ) *p 0.05, **p 0.01, ***p by Wald chi-square test

39 PHH and ND Outcome Interesting clinical finding - 14% (32/228) of infants with PHH and shunts had normal functioning at 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

40 Understanding the Complexity and Beauty of the Human Brain

41 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

42 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

43 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

44 Cerebellum and Brain Injury Limperopolous, et al Pediatrics 2007 Volumetric MRI at term equivalent in 74 infants < 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

45 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

46 Cerebellum and Brain Injury Trophic effect between development of cerebral and cerebellar tissues

47 Neurodevelopmental Outcome Damage to caudate nucleus associated with impaired spatial memory tasks Variables will affect school performance

48 PHH and ND Outcome Bayley Scales Infant Development-IIR Group Mean MDI Score s.e. Median MDI Mean PDI Score s.e. Median PDI No IVH/ No Shunt 80.6* * IVH 3-4/ No Shunt 73.0* * IVH 3-4/ Shunt 63.0* * * - P<0.05

49 Brain Injury in the Preterm Infant Abernethy volume in caudate and hippocampus Reduced IQ Reiss Isaacs Peterson White matter in males; Grey matter in males and females Hippocampal volumes Sensorimotor and midtemporal cortex Quantitative measures correlates with IQ in females Impairment of memory tasks Reduced IQ

50 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

51 Thank You!