Infection and white matter damage William Tarnow-Mordi

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

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

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

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

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

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

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

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

Brain damage Infection / inflammation is an important proposed pathway in neonatal brain damage Dammann & Leviton, Pediatrics 1999