fetal inflammation, white matter damage, and cerebral palsy frances glenn mayson symposium november...

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