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

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