Brain injury and its consequences in extremely premature babies

John Wyatt

Perinatal Brain Protection and Repair GroupUniversity College London

Survival of babies 23-25 weeks gestation UCLH 1981-2000

(as percentage of admissions to NICU)

Riley et al. Acta Paediatrica 2008; 97:159-65

Percentage of surviving extremely preterm infants with neurodevelopmental impairment

at 1 year of age, UCLH 1981-2000

Riley et al. Acta Paediatrica 2008; 97:159-65

Neurodevelopmental outcome at 8 years of age

< 28 weeks 28 – 32 weeks (n = 137) (n = 445)

Disability 23% 12%

Brain lesion detected 48% 22%by ultrasound

Vollmer et al, Pediatrics 2003, 112, 1108-1114

EPICURE nationwide study of all babies in UK and Ireland, born 22-25 weeks gestation in 1995.

Assessment at 6 years of age

Out of 241 survivors:• 15 were unable to walk due to cerebral palsy • 27 had severe learning difficulties• 4 blind and 7 severe hearing loss• Total of 32 had any severe disability

Marlow et al. NEJM 2005; 325: 9-19

Cognitive (IQ) scores for ex-premature infants at 6 years of age compared with class mates

White matter loss in the ex-preterm brain

Thinning of corpus callosum

Rate of cortical development is maximal between 22 weeks and term

25 wks GA 27 wks GA 32 wks GA

Rate of synaptic development

• ~ 1011 neurons in CNS• Each neuron develops ~ 103 synapses

• Therefore total of ~ 1014 synapses created – majority are formed between 22 and 40 weeks of gestation

= ~ 5 x 1011 synapses per day

= ~ 3 x 108 synapses per minute!

Cranial MRI scans at 14 years in a cohort of ex-preterm infants

MRI Ex-preterm Term controls

Normal 23% 71%

Equivocal 21% 24%

Abnormal 56% 5%

Stewart et al, Lancet 1999, 353: 1653-1657

MRI abnormalities in ex-preterm adolescents at 14 years

• MRI abnormalities correlated with abnormal behaviour scores.

• MRI abnormalities did not correlate with IQ, with

neurological signs or with need for extra educational help.

Grey matter changes in ex-preterm adolescentsNosarti et al, Brain 2002, 125, 1616-1623

White matter changes in ex-preterm adolescents

Nosarti et al, Brain 2002, 125, 1616-1623

Changed brain microstructure following developmental care programme

Als et al. Pediatrics 2004, 113, 846-857

Possible mechanisms of improved outcome following perinatal brain injury

• Cell differentiation and replacement from neuronal and glial precursor stem cells

• Refinement and selection of dendritic synaptic connections

• Rerouting of white matter connections• Development of alternative cortical

processing strategies

Conclusions• White matter injury in extremely premature infants is the

most important cause of long term neurodevelopmental disability.

• The developing central nervous system has remarkable potential for repair and compensation following perinatal injury

• New therapeutic approaches are required to translate experimental findings into practical therapies whilst babies are undergoing intensive care and following discharge from hospital

Acknowledgements

Ann StewartOsmund ReynoldsMatt AllinTopun AustinJenny BaudinAlan ConnollyDavid EdwardsMichelle de HaanAngela Huertas-CeballosDavid GadianRobin MurrayBrian Neville

UCL NHS TrustCentre for Perinatal Brain Protection &

RepairObstetrics & Gynaecology, Paediatrics & Child Health

Medical Physics & Bioengineering

Chiara NosartiFran O'BrienClaire PriceLarry RifkinKate RileyNikki RobertsonMaeve RooneySimon RothTeresa RusheAl SanthouseAlison SkinnerFaraneh Vargha-KhademBrigitte Vollmer