Factors That Contribute to Cognitive and Neurobehavioral

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Factors That Contribute to Cognitive and
Neurobehavioral Deficits in Premature
Graduates of Intensive Care
Jeffrey Perlman MB
Professor of Pediatrics
Weill Medical College
Cornell Medical Center
New York
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Background

• The survival rates of VLBW infants including
  those born at the cutting edge of viability
  continues to increase. In addition there has been
  a concomitant reduction in the occurrence of
  known neurosonographic correlates of adverse
  outcome i.e severe IVH
• However as follow-up has extended into school age
  and adolescence it has become apparent that a
  large number of graduates are exhibiting
  neurobehavioral problems in the absence of
  cerebral palsy.

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Summary of Long Term Cognitive/Behavioral
Deficits in in VLBW infants at Longer Term (6-14
years) Follow up

• The academic achievement of approximately 30-50
  of VLBW infants is in the subnormal range.
• VLBW infants have IQ scores approximately 1 SD
  lower than full term controls. This has been
  documented worldwide and independent of social
  environment particularly in those countries with
  homogeneous populations.
• The attention deficit hyperactivity disorder
  affects approximately 20-30 of VLBW infants as
  compared to 6-8 of full term controls.
• Psychiatric disorders at adolescence affect from
  25-30 of VLBW infants as compared 5-10 of full
  term controls.

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Survival () of Very Low Birth Weight Infants
Admitted to the NICU at Parkland Hospital for
years 1980-2000.
1980- 1985
1986- 1990
1991- 1995
1996- 2000
Survival
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18 month Outcome of VLBW infants lt 1000g Birth
weight in the NICHD for the period 1996-1998

• 55/220 (25) with an abnormal CNS examination
  e.g. cerebral palsy
• 103/220 (47) with a MDI lt 70

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Birth Rates in the US - 2000
Births
Number Total Births
4064948 lt 2500g (7.6)
308936 lt1500g (1.42)
56909 lt1000g (
0.65) 26422
From Hoyert et al Annual Summary of Vital
Statistics 2000 Pediatrics 20011081241
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Outline

• Describe vulnerable regions in developing brain
  that increase risk for cognitive injury
• Review some medical complications and
  interventions association with prematurity that
  increase risk for cognitive injury
• Review potential environmental factors that may
  contribute to the genesis of cognitive injury.

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Factors/Events Increasing the Propensity for
Brain Injury

• Hemorrhagic-ischemic white matter injury
• Disruption of one or more organizational events
  in brain development
• Transient overexpression of glutamatergic
  receptors within basal ganglia
• Hippocampal vulnerability to hypoxia/ischemia and
  /or stress

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Severe IVH (Grade 4 IVH)
Cystic PVL
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Ultrasound Status and Global Cognitive Functioning
Global Cognitive Total Normal IVH
PL/VD Outcomes (n597)
(n468) (N83) (N46)
Normal Intelligence 529 (89)
436 (93) 73 (88) 20 (43.5) Borderline
Intelligence 38 (6.0) 26 (5.6) 5
(6.0) 7 (15.2) Mental Retardation 30
(5.0) 6 (1.3) 5 (6.0) 19 (41.0)
Normal Intelligence Stanford Binet composite gt
84, Borderline lt 84, Mental Retardation lt 68
IVH germinal and intraventricular hemorrhage PL
Parenchymal lesion, VD Ventricular Dilation
From Whitaker et al. Pediatrics 199698719
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Factors/Events Increasing the Propensity for
Brain Injury

• Hemorrhagic-ischemic white matter injury
• Disruption of one or more organizational events
  in brain development
• Transient overexpression of glutaminergic
  receptors within basal ganglia
• Hippocampal vulnerability to hypoxia/ischemia and
  /or stress

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Coronal Section of Brain Illustrating Potentially
Vulnerable Areas of a Developing Brain
Lateral Ventricle
Caudate Nucleus
Periventricular White Matter
Thalamus
Lentiform Nucleus
Claustrum
Hippocampus
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The Potential Importance of the Basal Ganglia to
Cognitive Injury

• The Basal ganglia (BG) and more specifically the
  corpus striatum play a central role in the
  feedback loop that modulates cortical function.
  Disruption of cortico-striatal function seem to
  be of particular importance with regard to
  neurobehavioral abnormalities.
• The BG are vulnerable to injury during a
  restricted period
• during brain development. One important
  reason is that the neurons are enormously rich in
  glutaminergic synapses which emanate from the
  cerebral cortex
• Several lines of evidence point to the
  importance of excitatory amino acids and in
  particular glutamate in the genesis of
  neuronal death with hypoxia and or ischemia.

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Cranial Ultrasound Scan From an Infant with
Linear Hyperechogenicity Supplying the Basal
Ganglia
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Linear Hyperechogenicity (LHE)within Basal
Ganglia and Thalamus

• LHE was observed in 10/193 (5) infants lt 1250g
  birth weight
• The postnatal age to initial sonographic
  diagnosis was 4 weeks (range 1-11weeks)
• Infants with LHE versus matched controls were
  more likely to have received
  Antenatal Steroids 90 vs
  45, p 0.02 Test positive for CMV
  44 vs 0, p 0.02 Treated for
  hypothyroidism 30 vs 0, p 0.03

Chamnanvanakij et al Pediatr Neurol 200023129
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Bayley Scales of Infant Development assessment at
18 months adjusted age
Data are presented as mean ? S.D. BSID Bayley
Scale of Infant Development BRS Behavioral
Rating Scale
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Coronal Section of Brain Illustrating Potentially
Vulnerable Areas of a Developing Brain
Lateral Ventricle
Caudate Nucleus
Periventricular White Matter
Thalamus
Lentiform Nucleus
Claustrum
Hippocampus
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Hippocampal Vulnerability

• The hippocampus is important to learning and
  memory
• acquisition.
• It is especially vulnerable to hypoxia and is a
  target of
• stress hormones.
• Vulnerability may be increased in developing
  brain in
• VLBW infants in part as a result of
• a) Increased glutamate recognition sites
• b) High dependency on thyroid hormone
• c) Excessive glucocorticoid (GC)exposure
  secondary
• to medications/stress

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Hippocampal Volume and Everyday Memory in Very
Low Birth Weight Children
Test/Variable Preterms
Full-Term
N11 n8
p values Verbal IQ
90 (79-111) 108.5 (89-133)
0.02 Freedom from distraction 94 (66-106)
106.5 (84-140) 0.006 Mathematics reasoning
93 (79-110) 107.5 (93-124)
0.02 Numerical operations 81 (71-103)
107.5 (94-119) 0.001 Volumetric
measurements Intracranial Volume 1436
(1284-1603) 1466 (1324-1650) NS Lt
Hippocampus 3390 (3147-3812)
4080(3559-4291) 0.002 Rt Hippocampus
3379 (2949-3888) 4012 (3637-4297) 0.002
Values are median (range) Isaacs et al Pediatric
Res 200047713
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• Factors/Events Predisposing to Cognitive Injury
  in Developing Brain of VLBW Infants
• Vulnerable Brain Regions Primary
  Medical Problems ? Germinal Matrix ??
  ? Chronic Lung Disease
• ?? ? Periventricular White Matter ??
  ? Apnea and Bradycardia
• ?? ? Subplate Neurons ?? ?
  Nutrition
• ? ? Thalamus/Basal Ganglia ? ?
  Hypothyroidism
• ? Hippocampus
  ? Infections
• ? ? Medications e.g. Steroids
• 
  ?
  Hyperbilirubinemia
• Environment
• ? Parent-Child Interaction ? Excessive
  Sound ? Constant Light

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Chronic Lung Disease (CLD) and Adverse
Neurodevelopmental Outcome

• Approximately 40 Of VLBW lt 1000g develop CLD
• CNS findings attributed to CLD include -
• - Progressive neurologic disease
  i.e seizures,
• neurologic deterioration and
  death
• - Non progressive neurologic
  disease - often with
• associated IVH
• - Movement disorder
• Neuropathology often demonstrates diffuse hypoxic
  and/or ischemic changes involving gray and white
  matter
• CLD is an independent risk factor for abnormal
  neurologic outcome (OR1.84CI 1.28-2.61)
• Most of these descriptions of CNS abnormalities
  preceded the use of postnatal steroids

Campbell Clin Ped 1988277, Perlman Pediatrics
1989 Vohr Pediatrics 20001051216.
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Potential Mechanisms of Injury in Infants who
develop Chronic Lung Disease

• Recurrent hypoxia
• Hypercarbia ? Acidosis
• Recurrent infections
• Medications - steroids
  
  
  
  
  
• - diuretics
• Nutritional compromise

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Head Growth in an Infant with Bronchopulmonary
Dysplasia
Moore et al Pediatrics 1986
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Glucocorticoids (GC) and the Risk for Brain Injury

• Recent data suggest that GC are associated with ?
  incidence of adverse neurodevelopmental outcome.
• Sustained elevations of GC can modify the
  structure and function of the developing brain
  including
• - ? CBF to hippocampus
• - ? white matter proteins,
• - delayed myelination of optic axons,
• - ? activity of hypothalamic-pituitary-adre
  nal axis
• CLD is associated with neurodevelopmental deficits

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Recurrent Apnea and Bradycardia and the Potential
for Cognitive Deficits

• Apnea with associated bradycardia is a common
  problem and affects up to 90 of VLBW infants.
• With prolonged bradycardia there is progressive
  hypotension with an ? risk for a reduction in
  CBF.
• Data linking apnea and bradycardia to abnormal
  outcome is conflicting.
• Medications used to treat apnea e.g. theophylline
  may ? risk for brain injury
• A recent study reported an association of mental
  retardation ( MDI lt 70) with the duration as well
  as the dose of doxapram

Sreenan et al J Pediatr 200139832
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• Factors/Events Predisposing to Cognitive Injury
  in Developing Brain of VLBW Infants
• Vulnerable Brain Regions Primary
  Medical Problems ? Germinal Matrix ??
  ? Chronic Lung Disease
• ?? ? Periventricular White Matter ??
  ? Apnea and Bradycardia
• ?? ? Subplate Neurons ?? ?
  Nutrition
• ? ? Thalamus/Basal Ganglia ? ?
  Hypothyroidism
• ? Hippocampus
  ? Infections
• ? ? Medications e.g. Steroids
• 
  ?
  Hyperbilirubinemia
• Environment
• ? Parent-Child Interaction ? Excessive
  Sound ? Constant Light

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Foundation Fact
Infants in a busy NICU are frequently exposed to
stressful environmental conditions on a daily
basis. Examples include attachment to multiple
monitoring devices and intravenous lines that
invariably limit positive caregiver or
parental interactions, high noise levels, and
variable bright light. Sustained stress in the
NICU may have adverse effects on brain
development.
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Is stress bad for the brain?

• Sustained exposure to stress with release of
  glucocorticoids can result in hippocampal
  degeneration.
• Monkeys who died suddenly with gastric ulcers
  had marked hippocampal degeneration versus
  controls without ulcers.
• Depressed patients with ? GC secretion had
  bilateral reduced hippocampal volumes compared to
  age matched controls
• Vietnam vets with posttraumatic stress disorder
  had smaller hippocampal volumes and had deficits
  in short term verbal when compared to controls
• Premature infants lt 30 wks GA examined at
  adolescence with MRI and neuropsychologic testing
  had comparable head circumferences and normal
  neurologic examinations but ? hippocampal volumes
  and specific deficits in everyday memory and
  mathematics when compared to term controls

Uno J Neurosci 93,1996.1989, Sapolsky Science
273,1996,Seline Proc. Natl.Acad Sci Brenner Am J
Psychiatry 152,1995, Isaacs Pediatr Res 2000
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Postnatal handling Increases Glucocorticoid
Receptor expression and alters Corticotrophin
Releasing Hormone response to stress
Handling
? Pituitary-Thyroid
Activation Propylthiouracil
? Triodothyronine
? Hippocampus
Ketanserin ?
Serotonin ?
? Cyclic AMP ? Protein
Kinase A ? Nerve Growth Factor
? Inducible Factor A ?
Activator Protein 2 (AP2) ?
? GC receptor
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Positive Impact of Handling in Newborn Rats

• Rats handled daily from birth until weaning (DOL
  22) had ? basal GC levels and secreted less GC
  in response to stress at all ages tested when
  compared to non handled rats.
• Non handled rats exhibited hippocampal cell loss
  and spatial memory deficits , findings that were
  almost absent in the handled rats
• Handling had no effect on NGF1-A or AP2
  expression in amygdala, hypothalamus or
  somatosensory cortex. Moreover handling had no
  effect on mineralocorticoid receptor expression
  in hippocampal neurons

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Potential Mechanisms of Glucocorticoid Induced
Hippocampal Injury

• ? Extracellular glutamate activity
• Blockade of glucose entry into neurons thereby
  altering intracellular metabolism and increasing
  vulnerability during stress i.e. with hypoxia
• ? toxicity to oxygen free radicals

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Environmental Enrichment Induces Experience
Induced Neuroplasticity

• Mice reared in an enriched environment
  demonstrate an increase in hippocampal granular
  cell layer and dentate gyral volume.
• When subjected to spatial learning tasks
  enriched mice performed better with fewer
  errors than non-enriched mice
• ? GC and NGFI receptor expression was noted in
  enriched mice.

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Hippocampal Volume and Everyday Memory in Very
Low Birth Weight Children
Volumetric Preterms
Full-Term Measurements
N11 n8 p
values Intracranial Volume 1436
(1284-1603) 1466 (1324-1650) NS Lt
Hippocampus 3390 (3147-3812)
4080(3559-4291) 0.002 Rt Hippocampus
3379 (2949-3888 4012 (3637-4297) 0.002
Values are median (range) Isaacs et al Pediatric
Res 200047713
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Stress
Glucocorticoid Release
Hippocampal Injury
Hippocampal Volume Loss
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Environmental Stress and The Potential Impact on
Cognitive Development

• Parent-Child Interaction-
• Positive intervention - kangaroo care
• Excessive Sound
• Constant Light

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Noise and Infant Development

• Constant loud noise may impact upon
  neurodevelopment.
• For example chicks that have a structural and
  auditory development similar to humans, stop
  peeping in response to a novel auditory stimulus.
  However when stimuli are repeated several times,
  the chicks habituate and no longer pause
  following a stimulus.
• In the NICU loud noise ( 80dB) is associated
  with ? O2 and altered behavioral and
  physiological responses.
• A recent survey of adult hospital employees
  indicated that noise levels gt 55dB were high
  enough to interfere with work and appeared to
  affect comfort and anxiety.

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Noise levels in Room 306
Isolette 50-60 Talking 70-80 on
rounds Cleaning 60-80 Baby crying
60-100
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Environmental Stress and The Potential Impact on
Cognitive Development

• Parent-Child Interaction
• Excessive Sound
• - Positive Intervention- Music
• Constant Light

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Bright Light

• The ability to modify light is critical to the
  development of circadian rhythms (CR).
• CR are endogenously generated with a periodicity
  of approximately 24 hours and affect behavior and
  physiology e.g. sleep wake cycles. It is
  necessary to reset the clock each day, otherwise
  endogenous clock oscillations run free or out of
  phase with the external light dark cycle.
• Although the fetal biological clock is capable of
  generating CR and responding to maternal signals,
  cyclical lighting does not appear to induce an
  earlier onset of postnatal circadian development.

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Parkland NICU -Old Style
NICU-State of the Art
Cyclical Recessed Lighting
Individualized Music
Relaxed Atmosphere Average Noise Level
50-55dB
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Complex Issues Related to Environmental
Stimulation

• The potential developmental impact of
  environmental enrichment or stimulation is
  complex, and influenced in part by factors such
  as the timing or mode of stimulation.
• Thus premature visual stimulation of quail
  embryos before hatching is associated with
  earlier postnatal development of social
  preferences. However chicks with accelerated
  visual patterning, fail to demonstrate typical
  auditory responsiveness to maternal cues.
• Furthermore it appears that a combination rather
  than a single stimulation is necessary for early
  intersensory functioning.

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Medical and Environmental Factors Potentially
Influencing Glucocorticoid Release and
Hippocampal Injury
CLD AB Hypothyroidism Bilirubin Steroids Stress
Environmental Stimulation Music Kangaroo care
Hippocampal GC Receptor
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Conclusions

• A substantial number of VLBW graduates of
  intensive care develop cognitive and behavioral
  problems, even in the absence of neuro-imaging
  abnormalities.
• Both medical complications of prematurity and
  therapeutic interventions coupled with a
  stressful environment greatly increase the risk
  for basal ganglia and hippocampal injury.
• This talk is not all encompassing and there are
  additional prenatal (i.e. in utero stress, drug
  exposure), neonatal (i.e.infectious) and post
  discharge social and environmental contributing
  factors.
• The design of any intervention strategy has to
  account for these multiple variables.