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Fetal Inflammation, White Matter Damage, and Cerebral Palsy. Frances Glenn Mayson Symposium November 10, 2001 Michael O’Shea, MD, MPH Wake Forest University School of Medicine. Acknowledgements. Alan Leviton, MD - Harvard University Nigel Paneth, MD - Michigan State Univ

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fetal inflammation white matter damage and cerebral palsy

Fetal Inflammation, White Matter Damage, and Cerebral Palsy

Frances Glenn Mayson Symposium

November 10, 2001

Michael O’Shea, MD, MPH

Wake Forest University School of Medicine

acknowledgements
Acknowledgements
  • Alan Leviton, MD - Harvard University
  • Nigel Paneth, MD - Michigan State Univ
  • Olaf Damman, MD - Harvard University
slide3

Prenatal

Infection

Neurologic Disabilities

slide4

Topics for Discussion

  • 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
definition of cerebral palsy
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
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
Cerebral Palsy: Associated Problems
  • Mental retardation
  • Visual impairment
  • Speech difficulty
  • Feeding and growth problems
  • Orthopedic problems
slide11

Topics for Discussion

  • 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
slide12

Periventricular white matter damage (WMD)

Paneth N, Rudelli R, Kazam E, Monte W.

Brain Damage in the Preterm Infant, Cambridge Univ Press

slide13

Periventricular white matter damage

Paneth N, Rudelli R, Kazam E, Monte W.

Brain Damage in the Preterm Infant, Cambridge Univ Press

slide16

2 days of age

Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)

slide17

13 days of age

Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)

slide18

17 days of age

Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)

expressions of white matter damage on cranial ultrasound
Expressions of White Matter Damage on Cranial Ultrasound
  • Periventricular echodensity
  • Periventricular echolucency
  • Ventriculomegaly
white matter damage and cerebral palsy
White Matter Damage and Cerebral Palsy

Percent with CP

Pinto-Martin et al. Pediatrics 1995; 95:249-54.

white matter damage and mental retardation
White Matter Damage and Mental Retardation

Percent with MR

Whitaker et al. Pediatrics 1996; 98:719-29.

white matter damage and attention deficit hyperactivity disorder
White Matter Damage and Attention Deficit Hyperactivity Disorder

Percent with ADHD

Whitaker et al. Arch Gen Psychiatry 1997; 54:847-56.

slide23

40%

Mental

Retardation

30%

Behavioral

Problems

Cerebral

Palsy

Learning

Disabilities

60%

?

White Matter Damage

white matter damage not evident on ultrasound
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 ultrasound1
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 ultrasound2
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

slide27

Topics for Discussion

  • 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
perinatal infection and cerebral white matter damage
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
“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

slide30

White Matter Damage

Leviton A. Devel Med Child Neurol 1993

slide31

Topics for Discussion

  • 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
initiators of brain damaging processes perinatal infection
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 infection1
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

slide35

Initiators of Brain Damaging

Processes: Perinatal Infection

“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

chorioamnionitis and cystic periventricular leukomalacia
Chorioamnionitis and Cystic Periventricular Leukomalacia

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

slide38

Chorioamnionitis and Cerebral Palsy

Wu YW and Colford JM. JAMA 2000;284:1417-1424

slide39

Initiators of Brain Damaging Processes:

Clinical Events Associated with

White Matter Damage and Cerebral Palsy

Neonatal hypotension

Hypocarbia

Intrapartum acidosis

O’Shea TM and Dammann O. Clin Perinat 2000; 27:285-302

hypoxia ischemia and brain damage role of inflammation
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

slide41

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
Death of a Co-twin and Cerebral Palsy
  • In the surviving twin:
    • disseminated intravascular coagulation
    • stimulated cytokine production?
slide43

Topics for Discussion

  • 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
slide44

White Matter Damage

Leviton A. Devel Med Child Neurol 1993

tumor necrosis factor and 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
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
slide47

Romero et al.

AJOG 1992;

166:1576-87

perinatal infection and brain damage in preterm infants1
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
neonatal cytokine levels and subsequent cerebral palsy
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 infants2
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
slide54

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
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
slide56

Cytokines

Dammann and Leviton. Pediatr Res 1997;42:1-8

Uterus

FetalCirculation

?

?

Brain

Microglia

IVH

?

?

?

White Matter Damage

slide57

Topics for Discussion

  • 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
slide59

Modifiers of Brain Damaging Processes:

Factors Associated with

White Matter Damage and Cerebral Palsy

Antenatal steroids

Hypothyroxinemia

O’Shea TM and Dammann O. Clin Perinat 2000; 27:285-302

transient hypothyroxinemia and cerebral palsy risk
Transient Hypothyroxinemia and Cerebral Palsy Risk

Percent with CP

Reuss ML et al. NEJM 1996; 334:821-827

antenatal steroids and white matter damage cerebral palsy
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
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

slide63

Potential protectors of white matter

Dammann and Leviton Pediatrics 1999;104:541-50

slide64

Topics for Discussion

  • 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
slide65

Damage Initiators

Intrauterine infection

Death of co-twin

Tissue ischemia

Damage Protectors

Thyroxine

Antenatal steroids

Growth factors

Damage Promoters

Pro-inflammatory

cytokines

slide66

PROTECTORS

DAMAGEPROMOTERS

Postconception Age

slide67

A. Insult(s) component

B. Developmental component

Exposure related ...

Developmentally-regulated ...

a. vascular / ependymal factors

b. oligodendroglia development

c. endogenous protectors

(trophic factors)

Hypoxia -

Ischemia -

Reperfusion

?

?

Infection

Increased vulnerability

Inflammation

White Matter Damage

Damman and Leviton Pediatrics 1999;104:541-50

slide68

SystemicInflammation

Prenatal

Infection

Chemokines

?

Cytokines

Adhesion

Molecules

Growth Factors

and Hormones

White Matter Damage

Cell Death

Pre-OL OL

Neurologic Disabilities

slide69

Potential Strategies for Prevention

of White Matter Damage in Preterms

  • Prevention / treatment of perinatal infections?
  • Block activity of damaging cytokines?
  • Enhance endogenous protectors against cytokine-induced damage?