Infection and white matter damage
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Infection and white matter damage
William Tarnow-Mordi
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Types of white matter injury
• Diffuse white matter damage*• Periventricular leukomalacia• Intraventricular haemorrhage
• Punctate haemorrhagic/ ischaemic lesions*• Periventricular haemorrhagic infarction*
* detection by ultrasound unreliable: MRI scanning is the gold standard
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Diffuse white matter abnormality
• Most preterm babies have diffuse white matter abnormality on MRI scan when they reach term equivalent
• This has been attributed to poor nutrition, infection, postnatal steroids
• Associated with ?vasogenic oedema, oligodendrocyte dysfunction or reduced axonal diameter
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Periventricular leukomalacia
• Histological diagnosis with “softening” of the white matter and focal cystic degeneration
• Occurs in 3 - 9% of all preterm babies < 30 weeks gestation
• Previously attributed to ischaemia, typically evolving 2 - 6 weeks after hypotensive insult
• Now also attributed to infection
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Periventricular leukomalacia
• On histology there is cytotoxic oedema, macrophage infiltration and
apoptosis (programmed cell death)
• Also associated with delayed myelination, probably because of glial necrosis and oligodendrocyte dysfunction
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Debillon et al
• Inoculated bacterial endotoxin (lipopolysaccharide) into uterus with 14 fetal rabbits at 80% of term pregnancy
• delivered the fetuses 12, 24 and 48 hr later
• after 48 hours, histology showed extensive programmed cell death (apoptosis), with periventricular leukomalacia and periventricular cyst formation
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• Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (corresponding to term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS
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Volpe: Pediatric Research 2003
• Three interacting, maturation-dependent factors predispose to PVL
• immature vascular supply to cerebral white matter
• impairment of cerebral blood flow autoregulation
• vulnerability of oligodendrocyte – to attack by free radicals– particularly after ischaemia-reperfusion injury
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Leviton and Gillies 1976
• Reviewed autopsies and notes of 40 infants with perinatal telencephalic leuco-encephalopathy (PTL)
• Compared with 76 infants who died without PTL
• PTL more common after– bacterial gram negative septicaemia
• ? Endotoxin damages developing white matter
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Brain damage
Infection / inflammation is an important proposed pathway in neonatal brain damage
Proposed pathogenesis of w hite m atter dam age
In f lam m a tionse con d a ry
toin fec tion
In flam m a tionse con d a ryto hypo x ia
a n d isch ae m ia
E n do ge no usd e ve lo pm en ta l
p ro tec tive fac to rs- o ligo trop h ins
D iso rde re d o lig od e n dro cytem ye lin a tion
a n d p re cu rsorm ig ra tion
Dammann & Leviton, Pediatrics 1999
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