Brain Damage in the Preterm Infant Postnatal Preventive ：在早产儿出生后预防性脑损伤
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* 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.
Disabilities
?
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 ultrasound
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 2019.
Cerebral Palsy: Associated Problems
* Mental retardation * Visual impairment * Speech difficulty * Feeding and growth problems * Orthopedic problems
Fet al Vasculitis
Proinfla mmat ory
Cytokines
Other inflammation-rela ted damage promoters
Immat urit y
Low antiinflammato ry
Cytokines
Low T4 and other growth
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
* Periventricular echodensity and echolucency have been described as the “tip of the iceberg” of glial cell injury
Leviton and Gilles. Pediatr Neurol 2019; 15:127-136
* 2/3 of infants with foci of periventricular leukomalacia also histologic evidence of diffuse white matter damage
Pinto-Martin et al. Pediatrics 2019; 95:249-54. Gilles and Murphy. J Neurol Neurosurg Psych 1969; 32:404-413
damage processes * Preventing brain damage
Perinatal Infection and Cerebral White Matter Damage
* 41 babies with white damage identified at autopsy (80 controls)
Fetal Inflammation, White Matter Damage,
and Cerebral Palsy
Frances Glenn Mayson Symposium November 10, 2019
Michael O’Shea, MD, MPH Wake Forest University School of Medicine
Disorder
35
30
25
20
15
10
5
0
No WMD
WMD
Whitaker et al. Arch Gen Psychiatry 2019; 54:847-56.
30%
40% Mental
Retardation
Behavioral
Problems Cerebral Palsy
Learning
60%
factors
DAMAGE OUTCOME SEQUELAE
C D
White Matter Damage
E
Ultrasound Abnorm ality
Cerebra l P alsy
Me ntal Retardation
Atte ntio n Deficit
Lea rning Pro blems
INSUFFICIENT PROTECTION
Neurologic Disabilities
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
Pinto-Martin et al. Pediatrics 2019; 95:249-54. Holling and Leviton. Devvelop Med Child Neurol 2019; 41:136-139
White Matter Damage not Evident on Ultrasound
Periventricular white matter damage
Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
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
White Matter Damage
Percent with CP
White Matter Damage and Cerebral Palsy
60 50 40 30 20 10
0
No WMD
WMD
Pinto-Martin et al. Pediatrics 2019; 95:249-54.
Percent with MR
White Matter Damage and Mental Retardation
damage processes * Preventing brain damage
Periventricular white matter damage (WMD)
Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
damage processes * Preventing brain damage
INITIATION
A Intrauterine
Infe ction
B Extrauterine
Infe ction
Noninfectio us
factors
DAMAGE PR OMOT IO N
Fetal Inflam matory Response
“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
TIME
Late second trimester Neonatal period 2+ years
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.”
Acknowledgements
* Alan Leviton, MD - Harvard University * Nigel Paneth, MD - Michigan State Univ * Olaf Damman, MD - Harvard University
Prenatal Infection
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
17 days of age Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
Expressions of White Matter Damage on Cranial Ultrasound
* Periventricular echodensity * Periventricular echolucency * Ventriculomegaly
45 40 35 30 25 20 15 10
5 0
No WMD
WMD
Whitaker et al. Pediatrics 2019; 98:719-29.
Percent பைடு நூலகம்ith ADHD
White Matter Damage and
Attention Deficit Hyperactivity
Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
2 days of age Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
13 days of age Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
* 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.
Disabilities
?
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 ultrasound
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 2019.
Cerebral Palsy: Associated Problems
* Mental retardation * Visual impairment * Speech difficulty * Feeding and growth problems * Orthopedic problems
Fet al Vasculitis
Proinfla mmat ory
Cytokines
Other inflammation-rela ted damage promoters
Immat urit y
Low antiinflammato ry
Cytokines
Low T4 and other growth
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
* Periventricular echodensity and echolucency have been described as the “tip of the iceberg” of glial cell injury
Leviton and Gilles. Pediatr Neurol 2019; 15:127-136
* 2/3 of infants with foci of periventricular leukomalacia also histologic evidence of diffuse white matter damage
Pinto-Martin et al. Pediatrics 2019; 95:249-54. Gilles and Murphy. J Neurol Neurosurg Psych 1969; 32:404-413
damage processes * Preventing brain damage
Perinatal Infection and Cerebral White Matter Damage
* 41 babies with white damage identified at autopsy (80 controls)
Fetal Inflammation, White Matter Damage,
and Cerebral Palsy
Frances Glenn Mayson Symposium November 10, 2019
Michael O’Shea, MD, MPH Wake Forest University School of Medicine
Disorder
35
30
25
20
15
10
5
0
No WMD
WMD
Whitaker et al. Arch Gen Psychiatry 2019; 54:847-56.
30%
40% Mental
Retardation
Behavioral
Problems Cerebral Palsy
Learning
60%
factors
DAMAGE OUTCOME SEQUELAE
C D
White Matter Damage
E
Ultrasound Abnorm ality
Cerebra l P alsy
Me ntal Retardation
Atte ntio n Deficit
Lea rning Pro blems
INSUFFICIENT PROTECTION
Neurologic Disabilities
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
Pinto-Martin et al. Pediatrics 2019; 95:249-54. Holling and Leviton. Devvelop Med Child Neurol 2019; 41:136-139
White Matter Damage not Evident on Ultrasound
Periventricular white matter damage
Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
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
White Matter Damage
Percent with CP
White Matter Damage and Cerebral Palsy
60 50 40 30 20 10
0
No WMD
WMD
Pinto-Martin et al. Pediatrics 2019; 95:249-54.
Percent with MR
White Matter Damage and Mental Retardation
damage processes * Preventing brain damage
Periventricular white matter damage (WMD)
Paneth N, Rudelli R, Kazam E, Monte W. Brain Damage in the Preterm Infant, Cambridge Univ Press
damage processes * Preventing brain damage
INITIATION
A Intrauterine
Infe ction
B Extrauterine
Infe ction
Noninfectio us
factors
DAMAGE PR OMOT IO N
Fetal Inflam matory Response
“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
TIME
Late second trimester Neonatal period 2+ years
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.”
Acknowledgements
* Alan Leviton, MD - Harvard University * Nigel Paneth, MD - Michigan State Univ * Olaf Damman, MD - Harvard University
Prenatal Infection
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
17 days of age Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
Expressions of White Matter Damage on Cranial Ultrasound
* Periventricular echodensity * Periventricular echolucency * Ventriculomegaly
45 40 35 30 25 20 15 10
5 0
No WMD
WMD
Whitaker et al. Pediatrics 2019; 98:719-29.
Percent பைடு நூலகம்ith ADHD
White Matter Damage and
Attention Deficit Hyperactivity
Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
2 days of age Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)
13 days of age Volpe, JJ. Neurology of the Newborn, 2019 (3rd edition)