Fetal Inflammation, White Matter Damage, and Cerebral Palsy

1. 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

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

3. Prenatal Infection Neurologic Disabilities

4. 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

6. 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

7. Descriptors of Cerebral Palsy • Spastic (84%) • hemiplegia • diplegia • quadriplegia • Dyskinesia (8%) • athetoid • dystonic • Ataxic (7%) Blair E., Stanley F. MRDD Res Rev 1997.

10. Cerebral Palsy: Associated Problems • Mental retardation • Visual impairment • Speech difficulty • Feeding and growth problems • Orthopedic problems

11. 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

12. Periventricular white matter damage (WMD) Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press

13. Periventricular white matter damage Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press

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

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

16. 2 days of age Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)

17. 13 days of age Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)

18. 17 days of age Volpe, JJ. Neurology of the Newborn, 1995 (3rd edition)

19. Expressions of White Matter Damage on Cranial Ultrasound • Periventricular echodensity • Periventricular echolucency • Ventriculomegaly

20. White Matter Damage and Cerebral Palsy Percent with CP Pinto-Martin et al. Pediatrics 1995; 95:249-54.

21. White Matter Damage and Mental Retardation Percent with MR Whitaker et al. Pediatrics 1996; 98:719-29.

22. White Matter Damage and Attention Deficit Hyperactivity Disorder Percent with ADHD Whitaker et al. Arch Gen Psychiatry 1997; 54:847-56.

23. 40% Mental Retardation 30% Behavioral Problems Cerebral Palsy Learning Disabilities 60% ? White Matter Damage

24. 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

25. 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

26. 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

27. 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

28. 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.

29. “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

30. White Matter Damage Leviton A. Devel Med Child Neurol 1993

31. 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

33. 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

34. 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

35. 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

36. Debillon T et al. Pediatric Research 2000; 47:736-742

37. 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

38. Chorioamnionitis and Cerebral Palsy Wu YW and Colford JM. JAMA 2000;284:1417-1424

39. 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

40. 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

41. 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

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

43. 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

44. White Matter Damage Leviton A. Devel Med Child Neurol 1993

45. 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

46. 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

47. Romero et al. AJOG 1992; 166:1576-87

48. Lencki et al. AJOG 1994; 170:1345-51

49. Yoon et al. AJOG 1995; 172:960-70.

50. 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