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1、Acknowledgements,Alan Leviton,MD-Harvard UniversityNigel Paneth,MD-Michigan State UnivOlaf Damman,MD-Harvard University,Cerebral palsy White matter damage in preterm infantsHistorical perspective Initiators of brain damaging processesMolecules that promote brain damageMolecules that modify or preven
2、t brain damage processesPreventing brain damage,Topics for Discussion,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 Neu
3、rol 1992,Descriptors of Cerebral Palsy,Spastic(84%)hemiplegiadiplegiaquadriplegiaDyskinesia(8%)athetoiddystonicAtaxic(7%),Blair E.,Stanley F.MRDD Res Rev 1997.,Cerebral Palsy:Associated Problems,Mental retardationVisual impairmentSpeech difficultyFeeding and growth problemsOrthopedic problems,Cerebr
4、al palsy White matter damage in preterm infantsHistorical perspective Initiators of brain damaging processesMolecules that promote brain damageMolecules that modify or prevent brain damage processesPreventing brain damage,Topics for Discussion,Paneth N,Rudelli R,Kazam E,Monte W.Brain Damage in the P
5、reterm 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 ed
6、ition),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 echodensityPeriventr
7、icular echolucencyVentriculomegaly,White Matter Damage and Cerebral Palsy,Percent with CP,Pinto-Martin et al.Pediatrics 1995;95:249-54.,White Matter Damage and Mental Retardation,Percent with MR,Whitaker et al.Pediatrics 1996;98:719-29.,White Matter Damage and Attention Deficit Hyperactivity Disorde
8、r,Percent with ADHD,Whitaker et al.Arch Gen Psychiatry 1997;54:847-56.,White Matter Damage,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 ultrasound2/3 of infants with foci of periventricular
9、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 b
10、ilateral spasticityventriculomegaly,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 a
11、nd 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 infantsHistorical perspective Initiators of brain damaging processesMolecules that promote brain damageMolecules that modi
12、fy or prevent brain damage processesPreventing 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,Levi
13、ton 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.
14、Am J Epidemiol 1976;104:621-6,Leviton A.Devel Med Child Neurol 1993,White Matter Damage,Cerebral palsy White matter damage in preterm infantsHistorical perspective Initiators of brain damaging processesMolecules that promote brain damageMolecules that modify or prevent brain damage processesPreventi
15、ng brain damage,Topics for Discussion,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
16、 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 lipop
17、olysaccharide 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,Debill
18、on T et al.Pediatric Research 2000;47:736-742,Chorioamnionitis and Cystic Periventricular Leukomalacia,Wu YW and Colford JM.JAMA 2000;284:1417-1424,AuthorsOdds ratio(95%CI)Baud et al2.5(1.4-4.1)Spinillo et al1.4(0.2-11.7)Wiswell et al2.0(0.6-7.0)Zupan et al3.9(2.3-6.5)Perlman et al7.3(1.9-28.2)Rolan
19、d et al2.4(1.1-5.2)SUMMARY3.0(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,OShea TM and Damm
20、ann O.Clin Perinat 2000;27:285-302,Hypoxia-ischemia and Brain Damage:Role of Inflammation?,Experimental ischemia produces:increases in brain cytokinesneutrophil infiltrationsustained activation of microglia and astroglia Bona et al Pediatr Res 1999;45:500-509Benjelloun et al.Stroke 1999;30:1916-24,I
21、nitiators 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;27:285-302,Death of a Co-twin and Cerebral Palsy,In the surviving twin:disseminated intravascular coagulationstimulated cytokine prod
22、uction?,Cerebral palsy White matter damage in preterm infantsHistorical perspective Initiators of brain damaging processesMolecules that promote brain damageMolecules that modify or prevent brain damage processesPreventing brain damage,Topics for Discussion,Leviton A.Devel Med Child Neurol 1993,Whit
23、e Matter Damage,Tumor Necrosis Factor and White Matter Damage,production of platelet activating factorhypotensionproduction of interleukin-1oligodendrocyte damage,Leviton A.Devel Med Child Neurol 1993,Perinatal Infection and Brain Damage in Preterm Infants,Preterm labor associated with intrauterine
24、infection and rise in cytokinesIncreased 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 lab
25、or associated with intrauterine infection and rise in cytokinesIncreased 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 FactorOdds ratio(95%CI)Funisitis5
26、.5(1.2-24.5)Histologic chorioamnionitis3.3(0.6-18.0)AF IL-6 2.95 ng/ml6.4(1.3-33.0)AF IL-8 3.0 ng/ml5.9(1.1-30.7)AF WBC 19 cells/mm35.3(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
27、in cytokinesIncreased 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 ca
28、scade Stimulate neutrophil-induced oxidative brain cell damageStimulate macrophage-induced brain cell damageStimulate or inhibit glial cell apoptosisAlter glial cell differentiation,Fetal Circulation,Brain,IVH,White Matter Damage,Microglia,Cytokines,Uterus,?,?,?,?,?,Dammann and Leviton.Pediatr Res 1
29、997;42:1-8,Cerebral palsy White matter damage in preterm infantsHistorical perspective Initiators of brain damaging processesMolecules that promote brain damageMolecules that modify or prevent brain damage processesPreventing brain damage,Topics for Discussion,Antenatal steroids,Modifiers of Brain D
30、amaging Processes:Factors Associated with White Matter Damage and Cerebral Palsy,Hypothyroxinemia,OShea TM and Dammann O.Clin Perinat 2000;27:285-302,Transient Hypothyroxinemia and Cerebral Palsy Risk,Percent with CP,Reuss ML et al.NEJM 1996;334:821-827,Antenatal Steroids and White Matter Damage/Cer
31、ebral Palsy,Increase neonatal blood pressureAnti-oxidant activityEnhanced oligodendrocyte developmentInhibition pro-inflammatory cascade,Dammann and Leviton Pediatrics 1999;104:541-50,Thyroxine and Neonatal Brain,Thyroid oligodendrocyte differentiation(more differentiated oligodendroglial cells=more
32、 resistant to cytokine-induced damage),Dammann and Leviton Pediatrics 1999;104:541-50,Dammann and Leviton Pediatrics 1999;104:541-50,Potential protectors of white matter,Cerebral palsy White matter damage in preterm infantsHistorical perspective Initiators of brain damaging processesMolecules that p
33、romote brain damageMolecules that modify or prevent brain damage processesPreventing brain damage,Topics for Discussion,Damage InitiatorsIntrauterine infectionDeath of co-twinTissue ischemia,Damage ProtectorsThyroxineAntenatal steroidsGrowth factors,Damage PromotersPro-inflammatory cytokines,A.Insul
34、t(s)component,Exposure related.,Infection,Hypoxia-Ischemia-Reperfusion,?,Inflammation,?,White Matter Damage,B.Developmental component,Developmentally-regulated.,a.vascular/ependymal factorsb.oligodendroglia developmentc.endogenous protectors(trophic factors),Increased vulnerability,Damman and Leviton Pediatrics 1999;104:541-50,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,
