fetal inflammation, white matter damage, and cerebral palsy frances glenn mayson symposium november...
TRANSCRIPT
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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
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Acknowledgements
* Alan Leviton, MD - Harvard University
* Nigel Paneth, MD - Michigan State Univ
* Olaf Damman, MD - Harvard University
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Neurologic Disabilities
PrenatalInfection
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* 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
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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
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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
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Descriptors of Cerebral Palsy
* Spastic (84%) hemiplegia diplegia quadriplegia
* Dyskinesia (8%) athetoid dystonic
* Ataxic (7%)
Blair E., Stanley F. MRDD Res Rev 1997.
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Cerebral Palsy: Associated Problems
* Mental retardation
* Visual impairment
* Speech difficulty
* Feeding and growth problems
* Orthopedic problems
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* 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
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Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
Periventricular white matter damage (WMD)
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Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
Periventricular white matter damage
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Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
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Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
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Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
2 days of age
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Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
13 days of age
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Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)
17 days of age
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Expressions of White Matter Damage on Cranial Ultrasound
* Periventricular echodensity
* Periventricular echolucency
* Ventriculomegaly
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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.
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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.
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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.
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Mental Retardation
40%
White Matter Damage
Cerebral Palsy
60%LearningDisabilities
?
BehavioralProblems
30%
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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
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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
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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
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* 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
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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.
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“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
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Leviton A. Devel Med Child Neurol 1993
White Matter Damage
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* 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
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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
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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
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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
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“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
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Debillon T et al. Pediatric Research 2000; 47:736-742
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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)
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Wu YW and Colford JM. JAMA 2000;284:1417-1424
Chorioamnionitis and Cerebral Palsy
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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
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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
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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
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Death of a Co-twin and Cerebral Palsy
* In the surviving twin: disseminated intravascular
coagulation stimulated cytokine production?
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* 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
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Leviton A. Devel Med Child Neurol 1993
White Matter Damage
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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
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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
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Romero et al.AJOG 1992; 166:1576-87
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Lencki et al. AJOG 1994; 170:1345-51
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Yoon et al. AJOG 1995; 172:960-70.
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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
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Grether JK et al. J Pediatr 1999;134:324-332.
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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
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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
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Hypothetical Model of Neonatal White Matter Damage
Dammann O, Durum S, Leviton A. Trends in Neurosciences June 2001
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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
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Fetal Circulation
Brain
IVH
White Matter Damage
Microglia
CytokinesUterus
?
? ?
?
?
Dammann and Leviton. Pediatr Res 1997;42:1-8
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* 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
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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
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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
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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
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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
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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
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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
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* 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
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Damage Initiators
Intrauterine infectionDeath of co-twinTissue ischemia
Damage Protectors
ThyroxineAntenatal steroidsGrowth factorsDamage Promoters
Pro-inflammatory cytokines
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PROTECTORS
DAMAGE PROMOTERS
Postconception Age
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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
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Growth Factorsand Hormones
Neurologic Disabilities
ChemokinesCytokines
AdhesionMolecules
Cell Death
?
PrenatalInfection
Systemic Inflammation
White Matter Damage
Pre-OL OL
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* 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