Fetal Inflammation, White Matter Damage, and Cerebral Palsy

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Fetal Inflammation, White Matter Damage, and
Cerebral Palsy
Frances Glenn Mayson Symposium November 10,
2001 Michael OShea, MD, MPH Wake 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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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

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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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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

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Periventricular white matter damage (WMD)
Paneth N, Rudelli R, Kazam E, Monte W. Brain
Damage in the Preterm Infant, Cambridge Univ
Press
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Periventricular white matter damage
Paneth N, Rudelli R, Kazam E, Monte W. Brain
Damage in the Preterm Infant, Cambridge Univ
Press
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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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2 days of age
Volpe, JJ. Neurology of the Newborn, 1995 (3rd
edition)
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13 days of age
Volpe, JJ. Neurology of the Newborn, 1995 (3rd
edition)
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17 days of age
Volpe, JJ. Neurology of the Newborn, 1995 (3rd
edition)
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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
Percent with CP
Pinto-Martin et al. Pediatrics 1995 95249-54.
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White Matter Damage and Mental Retardation
Percent with MR
Whitaker et al. Pediatrics 1996 98719-29.
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White Matter Damage and Attention Deficit
Hyperactivity Disorder
Percent with ADHD
Whitaker et al. Arch Gen Psychiatry 1997
54847-56.
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White Matter Damage
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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
95249-54. Gilles and Murphy. J Neurol Neurosurg
Psych 1969 32404-413
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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
95249-54. Holling and Leviton. Devvelop Med
Child Neurol 1999 41136-139
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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
15127-136
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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

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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 1853-66.
Leviton A, Gilles F, et al. Am J Epidemiol
1976104621-6.
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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
1976104621-6
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White Matter Damage
Leviton A. Devel Med Child Neurol 1993
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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

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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 197627183-91
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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 197627183-91
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Debillon T et al. Pediatric Research 2000
47736-742
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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 20002841417-1424
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Chorioamnionitis and Cerebral Palsy
Wu YW and Colford JM. JAMA 20002841417-1424
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Initiators of Brain Damaging Processes Clinical
Events Associated with White Matter Damage and
Cerebral Palsy
Neonatal hypotension
Hypocarbia
Intrapartum acidosis
OShea TM and Dammann O. Clin Perinat 2000
27285-302
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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 199945500-509
• Benjelloun et al. Stroke 1999301916-24

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Initiators of Brain Damaging Processes Clinical
Events Associated with White Matter Damage and
Cerebral Palsy
Death of co-twin
OShea TM and Dammann O. Clin Perinat 2000
27285-302
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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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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

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White Matter Damage
Leviton A. Devel Med Child Neurol 1993
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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 1661576-87
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Lencki et al. AJOG 1994 1701345-51
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Yoon et al. AJOG 1995 172960-70.
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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 1999134324-332.
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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 182675-681
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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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Cytokines
Dammann and Leviton. Pediatr Res 1997421-8
Uterus
Fetal Circulation
?
?
Brain
Microglia
IVH
?
?
?
White Matter Damage
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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

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Modifiers of Brain Damaging Processes Factors
Associated with White Matter Damage and Cerebral
Palsy
Antenatal steroids
Hypothyroxinemia
OShea TM and Dammann O. Clin Perinat 2000
27285-302
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Transient Hypothyroxinemia and Cerebral Palsy
Risk
Percent with CP
Reuss ML et al. NEJM 1996 334821-827
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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 1999104541-50
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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 1999104541-50
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Potential protectors of white matter
Dammann and Leviton Pediatrics 1999104541-50
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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

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Damage Initiators Intrauterine infection Death of
co-twin Tissue ischemia
Damage Protectors Thyroxine Antenatal
steroids Growth factors
Damage Promoters Pro-inflammatory cytokines
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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 1999104541-50
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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?