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Fetal Inflammation, White Matter Damage,
and Cerebral Palsy
Frances Glenn Mayson SymposiumNovember 10, 2001
Michael O’Shea, MD, MPHWake Forest University School of Medicine
Acknowledgements
* Alan Leviton, MD - Harvard University
* Nigel Paneth, MD - Michigan State Univ
* Olaf Damman, MD - Harvard University
Neurologic Disabilities
PrenatalInfection
* Cerebral palsy * White matter damage in preterm infants* Historical perspective * Initiators of brain damaging processes* Molecules that promote brain damage* Molecules that modify or prevent brain
damage processes* Preventing brain damage
Topics for Discussion
INITIATIONDAMAGE
PROMOTION DAMAGE OUTCOME
IntrauterineInfection
Fetal InflammatoryResponse
FetalVasculitis
Pro-inflammatory
Cytokines
WhiteMatter
DamageLow anti-
inflammatoryCytokines
Low T4 andother growth
factors
Cerebra l Palsy
MentalRetardation
AttentionDeficit
LearningProblems
TIMELate second trimester Neonatal period 2+ years
Non-infectious
factors
Immaturity
SEQUELAE
UltrasoundAbnormality
INSUFFICIENTPROTECTION
Other inflammation-rela teddamage promoters
ExtrauterineInfection
A
B
D
E
C
Definition of Cerebral Palsy
“a group of non-progressive, but often changing, motor impairment syndromes secondary to lesions or anomalies of the brain arising in the early stages of its development.”
Mutch L et al Dev Med Child Neurol 1992
Descriptors of Cerebral Palsy
* Spastic (84%) hemiplegia diplegia quadriplegia
* Dyskinesia (8%) athetoid dystonic
* Ataxic (7%)
Blair E., Stanley F. MRDD Res Rev 1997.
Cerebral Palsy: Associated Problems
* Mental retardation
* Visual impairment
* Speech difficulty
* Feeding and growth problems
* Orthopedic problems
* Cerebral palsy * White matter damage in preterm infants* Historical perspective * Initiators of brain damaging processes* Molecules that promote brain damage* Molecules that modify or prevent brain
damage processes* Preventing brain damage
Topics for Discussion
Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
Periventricular white matter damage (WMD)
Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
Periventricular white matter damage
Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
2 days of age
Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
13 days of age
Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
17 days of age
Expressions of White Matter Damage on Cranial Ultrasound
* Periventricular echodensity
* Periventricular echolucency
* Ventriculomegaly
White Matter Damage and Cerebral Palsy
0
10
20
30
40
50
60
No WMD WMD
Per
cent
wit
h C
P
Pinto-Martin et al. Pediatrics 1995; 95:249-54.
White Matter Damage and Mental Retardation
0
5
10
15
20
25
30
35
40
45
No WMD WMD
Per
cent
wit
h M
R
Whitaker et al. Pediatrics 1996; 98:719-29.
White Matter Damage and Attention Deficit Hyperactivity
Disorder
0
5
10
15
20
25
30
35
No WMD WMD
Per
cent
wit
h A
DH
D
Whitaker et al. Arch Gen Psychiatry 1997; 54:847-56.
Mental Retardation
40%
White Matter Damage
Cerebral Palsy
60%LearningDisabilities
?
BehavioralProblems
30%
White Matter Damage not Evident on Ultrasound
* 1/2 of preterm children who later have cerebral palsy do not have white matter abnormality on their neonatal ultrasound
* 2/3 of infants with foci of periventricular leukomalacia also histologic evidence of diffuse white matter damage
Pinto-Martin et al. Pediatrics 1995; 95:249-54.Gilles and Murphy. J Neurol Neurosurg Psych 1969; 32:404-413
White Matter Damage not Evident on Ultrasound
* 1/3 of infants with unilateral sonographically defined white matter damage have bilateral spasticity
* ventriculomegaly, without focal white matter abnormality, is predictive of subsequent cerebral palsy
Pinto-Martin et al. Pediatrics 1995; 95:249-54.Holling and Leviton. Devvelop Med Child Neurol 1999; 41:136-139
White Matter Damage not Evident on Ultrasound
* Periventricular echodensity and echolucency have been described as the “tip of the iceberg” of glial cell injury
Leviton and Gilles. Pediatr Neurol 1996; 15:127-136
* Cerebral palsy * White matter damage in preterm infants* Historical perspective * Initiators of brain damaging processes* Molecules that promote brain damage* Molecules that modify or prevent brain
damage processes* Preventing brain damage
Topics for Discussion
Perinatal Infection and Cerebral White Matter Damage
* 41 babies with white damage identified at autopsy (80 controls)
* white matter damage associated with bacteremia (odds ratio = 5)
* no association with markers of hypoxia
Leviton A, Gilles F. J Neurol Sci 1973; 18:53-66. Leviton A, Gilles F, et al. Am J Epidemiol 1976;104:621-6.
“We hypothesize that endotoxin from bacteremia adversely affects developing white matter ….”
Leviton A, Gilles F, Neff R, Yaney P. Multivariate analysis of risk of perinatal telencephalic leucoencephalopathy. Am J Epidemiol 1976;104:621-6
Leviton A. Devel Med Child Neurol 1993
White Matter Damage
* Cerebral palsy * White matter damage in preterm infants* Historical perspective * Initiators of brain damaging processes* Molecules that promote brain damage* Molecules that modify or prevent brain
damage processes* Preventing brain damage
Topics for Discussion
INITIATIONDAMAGE
PROMOTION DAMAGE OUTCOME
IntrauterineInfection
Fetal InflammatoryResponse
FetalVasculitis
Pro-inflammatory
Cytokines
WhiteMatter
DamageLow anti-
inflammatoryCytokines
Low T4 andother growth
factors
Cerebra l Palsy
MentalRetardation
AttentionDeficit
LearningProblems
TIMELate second trimester Neonatal period 2+ years
Non-infectious
factors
Immaturity
SEQUELAE
UltrasoundAbnormality
INSUFFICIENTPROTECTION
Other inflammation-rela teddamage promoters
ExtrauterineInfection
A
B
D
E
C
Initiators of Brain Damaging Processes: Perinatal Infection
* Animals models: cerebral white matter damage produced by perinatal infection
* In epidemiologic studies perinatal infection is associated with: white matter damage cerebral palsy
Initiators of Brain Damaging Processes: Perinatal Infection
* Kittens injected with endotoxin intra- peritoneally develop cerebral white matter damage
Gilles FH, Leviton A, Kerr CS. Endotoxin leucoencephalopathy in the telencephalon of the newborn kitten. J Neurol Sci 1976;27:183-91
“Prolonged exposure of the newborn kitten to a lipopolysaccharide results in a telencephalic leucoencephalopathy characterized by astrogliosis and necrosis.”
Gilles FH, Leviton A, Kerr CS. Endotoxin leucoencephalopathy in the telencephalon of the newborn kitten. J Neurol Sci 1976;27:183-91
Initiators of Brain Damaging Processes: Perinatal Infection
Debillon T et al. Pediatric Research 2000; 47:736-742
Chorioamnionitis and Cystic Periventricular Leukomalacia
Wu YW and Colford JM. JAMA 2000;284:1417-1424
Authors Odds ratio (95% CI)
Baud et al 2.5 (1.4-4.1)Spinillo et al 1.4 (0.2-11.7)Wiswell et al 2.0 (0.6 - 7.0)Zupan et al 3.9 (2.3-6.5)Perlman et al 7.3 (1.9-28.2)Roland et al 2.4 (1.1-5.2)SUMMARY 3.0 (2.2-4.0)
Wu YW and Colford JM. JAMA 2000;284:1417-1424
Chorioamnionitis and Cerebral Palsy
Neonatal hypotension
Intrapartum acidosis
Hypocarbia
Initiators of Brain Damaging Processes: Clinical Events Associated with
White Matter Damage and Cerebral Palsy
O’Shea TM and Dammann O. Clin Perinat 2000; 27:285-302
Hypoxia-ischemia and Brain Damage: Role of Inflammation?
* Experimental ischemia produces: increases in brain cytokines neutrophil infiltration sustained activation of microglia and
astroglia
Bona et al Pediatr Res 1999;45:500-509
Benjelloun et al. Stroke 1999;30:1916-24
Initiators of Brain Damaging Processes: Clinical Events Associated with
White Matter Damage and Cerebral Palsy
Death of co-twin
O’Shea TM and Dammann O. Clin Perinat 2000; 27:285-302
Death of a Co-twin and Cerebral Palsy
* In the surviving twin: disseminated intravascular
coagulation stimulated cytokine production?
* Cerebral palsy * White matter damage in preterm infants* Historical perspective * Initiators of brain damaging processes* Molecules that promote brain damage* Molecules that modify or prevent brain
damage processes* Preventing brain damage
Topics for Discussion
Leviton A. Devel Med Child Neurol 1993
White Matter Damage
Tumor Necrosis Factor and White Matter Damage
* production of platelet activating factor
* hypotension
* production of interleukin-1
* oligodendrocyte damage
Leviton A. Devel Med Child Neurol 1993
Perinatal Infection and Brain Damage in Preterm Infants
* Preterm labor associated with intrauterine infection and rise in cytokines
* Increased levels of cytokines are associated with cerebral palsy
* Cytokines can damage white matter
Romero et al.AJOG 1992; 166:1576-87
Lencki et al. AJOG 1994; 170:1345-51
Yoon et al. AJOG 1995; 172:960-70.
Perinatal Infection and Brain Damage in Preterm Infants
* Preterm labor associated with intrauterine infection and rise in cytokines
* Increased levels of cytokines are associated with cerebral palsy
* Cytokines can damage white matter
Grether JK et al. J Pediatr 1999;134:324-332.
Neonatal Cytokine Levels and Subsequent Cerebral Palsy
Risk Factor Odds ratio (95% CI)
Funisitis 5.5 (1.2-24.5)Histologic chorioamnionitis 3.3 (0.6-18.0)AF IL-6 > 2.95 ng/ml 6.4 (1.3-33.0)AF IL-8 > 3.0 ng/ml 5.9 (1.1-30.7)AF WBC > 19 cells/mm3 5.3 (1.0-27.8)
Yoon BH et al. AJOG 2000; 182:675-681
Perinatal Infection and Brain Damage in Preterm Infants
* Preterm labor associated with intrauterine infection and rise in cytokines
* Increased levels of cytokines are associated with cerebral palsy
* Cytokines can damage white matter
Hypothetical Model of Neonatal White Matter Damage
Dammann O, Durum S, Leviton A. Trends in Neurosciences June 2001
Possible Mechanisms for
Cytokine-induced Brain Damage * Trigger coagulation cascade
* Stimulate neutrophil-induced oxidative brain cell damage
* Stimulate macrophage-induced brain cell damage
* Stimulate or inhibit glial cell apoptosis
* Alter glial cell differentiation
Fetal Circulation
Brain
IVH
White Matter Damage
Microglia
CytokinesUterus
?
? ?
?
?
Dammann and Leviton. Pediatr Res 1997;42:1-8
* Cerebral palsy * White matter damage in preterm infants* Historical perspective * Initiators of brain damaging processes* Molecules that promote brain damage* Molecules that modify or prevent brain
damage processes* Preventing brain damage
Topics for Discussion
INITIATIONDAMAGE
PROMOTION DAMAGE OUTCOME
IntrauterineInfection
Fetal InflammatoryResponse
FetalVasculitis
Pro-inflammatory
Cytokines
WhiteMatter
DamageLow anti-
inflammatoryCytokines
Low T4 andother growth
factors
Cerebra l Palsy
MentalRetardation
AttentionDeficit
LearningProblems
TIMELate second trimester Neonatal period 2+ years
Non-infectious
factors
Immaturity
SEQUELAE
UltrasoundAbnormality
INSUFFICIENTPROTECTION
Other inflammation-rela teddamage promoters
ExtrauterineInfection
A
B
D
E
C
Antenatal steroids
Modifiers of Brain Damaging Processes: Factors Associated with
White Matter Damage and Cerebral Palsy
Hypothyroxinemia
O’Shea TM and Dammann O. Clin Perinat 2000; 27:285-302
Transient Hypothyroxinemia and Cerebral Palsy Risk
0
5
10
15
20
25
30
35
22-27 28-29 30-31 32-33
Gestational age in weeks
Low T4
Nl T4
Per
cent
with
CP
Reuss ML et al. NEJM 1996; 334:821-827
Antenatal Steroids and White Matter Damage / Cerebral Palsy
* Increase neonatal blood pressure
* Anti-oxidant activity
* Enhanced oligodendrocyte development
* Inhibition pro-inflammatory cascade
Dammann and Leviton Pediatrics 1999;104:541-50
Thyroxine and Neonatal Brain
* Thyroid oligodendrocyte differentiation (more differentiated oligodendroglial cells = more resistant to cytokine-induced damage)
Dammann and Leviton Pediatrics 1999;104:541-50
OligodendrocyteDifferentiation Survival Prot / Remyel
Steroids, Thyroid BDNF, NGF, NT-3 IL-6, LIF, CNTF astrogenic VEGF exp in hypoxiabFGF EGF IGFs PDGF
TGF
Neuregulin IL-2
Dammann and Leviton Pediatrics 1999;104:541-50
Potential protectors of white matter
* Cerebral palsy * White matter damage in preterm infants* Historical perspective * Initiators of brain damaging processes* Molecules that promote brain damage* Molecules that modify or prevent brain
damage processes* Preventing brain damage
Topics for Discussion
Damage Initiators
Intrauterine infectionDeath of co-twinTissue ischemia
Damage Protectors
ThyroxineAntenatal steroidsGrowth factorsDamage Promoters
Pro-inflammatory cytokines
PROTECTORS
DAMAGE PROMOTERS
Postconception Age
A. Insult(s) component
Exposure related ...
Infection
Hypoxia -
Ischemia -
Reperfusion?
Inflammation
?
White Matter Damage
B. Developmental component
Developmentally-regulated ...
a. vascular / ependymal factors
b. oligodendroglia development
c. endogenous protectors
(trophic factors)
Increased vulnerability
Damman and Leviton Pediatrics 1999;104:541-50
Growth Factorsand Hormones
Neurologic Disabilities
ChemokinesCytokines
AdhesionMolecules
Cell Death
?
PrenatalInfection
Systemic Inflammation
White Matter Damage
Pre-OL OL
* Prevention / treatment of perinatal infections?
* Block activity of damaging cytokines?
* Enhance endogenous protectors against cytokine-induced damage?
Potential Strategies for Prevention of White Matter Damage in Preterms