Brain Injury in the Premature Infant

1. Brain Injury in the Premature Infant Nicole R. Dobson, MD MAJ, MC, USA Staff Neonatologist, National Naval Medical Center Assistant Professor of Pediatrics, Uniformed Services University of Health Sciences

2. Types of Brain Injury • Intraventricular hemorrhage • Periventricular leukomalacia • Periventricular hemorrhagic infarction • Cerebellar hemorrhage • Diffuse white matter injury

3. Outline • Intraventricular hemorrhage • Incidence • Pathogenesis and classification • Clinical presentation and diagnosis • Management • Complications • Periventricular leukomalacia • Post-hemorrhagic hydrocephalus • Outcome

4. Survival of VLBW Infants, 1997-2002 Adapted from Fanaroff et al., AJOG, Feb 2007

5. Survival of ELBW Infants Birth Weight 1990-1991: surfactant 1995-1996: antenatal steroids 1997-2002: current therapy (18,153 infants) Adapted from Fanaroff et al., AJOG, Feb 2007 Year of Birth

6. Morbidities of VLBW Infants Gr I Gr II Gr III Gr IV PVL Rate of IVH = 27% Rate of severe IVH = 12 % (no change from previous cohorts) Adapted from Fanaroff et al., AJOG, Feb 2007

7. Incidence of IVH • Major complication of premature birth • Frequency inversely related to birth weight and gestational age • 30-50% in infants <1000 grams • 10-20% in infants 1000-1500 grams • Rare in infants >1500 grams

8. Neuropathology • Subependymal germinal matrix • Prominent at 26-32 weeks gestation • Contains CNS precursor cells

9. Pathogenesis • Multifactorial • Intravascular factors • Changes in cerebral blood flow • Pressure-passive cerebral circulation • Fluctuations caused by mechanical ventilation • Increases/decreases in arterial pressure • Increases in cerebral venous pressure • Platelet and coagulation disturbances

10. Pathogenesis • Vascular factors • Immature, large vessels • Lack muscle and collagen • Presence of vascular border zone • Extravascular factors • No supportive stroma • Excessive amount of fibrinolytic activity

11. Classification • Papile classification (1978) • Determined by: • Site of hemorrhage • Presence or absence of ventricular dilation

12. Normal Head UltrasoundCoronal midline view

13. Normal Head UltrasoundCoronal midline view

14. Normal Head UltrasoundSagittal left view

15. Normal Head UltrasoundSagittal left view

16. Grade I IVHGerminal matrix (subependymal) hemorrhage

17. Grade II IVHHemorrhage in ventricles without dilation

18. Grade III IVHHemorrhage in ventricles with ventriculomegaly

19. Grade IV IVHIntraparenchymal hemorrhage

20. Clinical Presentation • Majority occur in first week of life • Three clinical presentations • Catastrophic • Subacute • Asymptomatic

21. Diagnosis • Head ultrasound primary means of diagnosis • Timing: Initial 3-5 days Follow-up 7-10 days Further studies as needed 4-6 weeks of life

22. Management • Prevention • Antenatal • Prevention of prematurity • Steroids • Delivery at tertiary care center • Intrapartum • Avoidance of prolonged labor • Avoidance of vaginal delivery???

23. Management • Prevention • Postnatal • Avoidance of hemodynamic disturbances • Appropriate treatment of RDS • Correct platelet and coagulation disturbances • No role for medications

24. Management • Supportive • Maintain adequate hematocrit • Maintain normal platelet count • Correct coagulation disturbances • Avoid abrupt hemodynamic changes

25. Complications • Germinal matrix and parenchymal destruction • Cyst formation

26. Complications • Periventricular hemorrhagic infarction

27. Periventricular Leukomalacia • White matter injury related to hypoxic-ischemic insults • Often bilateral • Associated with IVH • Can occur without IVH

28. PVL -Ultrasound Findings

29. Diffuse White Matter Injury Back, MRDD Research Reviews 2006; 12:129-140

30. Long-Term Consequences of White Matter Injury • Chronic disturbance of myelination • Permament motor impairment – cerebral palsy • Incidence ~25% (Hack et al., 2005; Miller et al., 2005) • Cognitive and learning disabilities • Incidence 25-50% (Litt et al., 2005)

31. Post-Hemorrhagic Ventricular Dilatation • Progressive enlargement until width at intraventricular foramen exceeds 4 mm over 97%ile for gestational age • Precedes hydrocephalus (progressive enlargement of head and ventricular system) • Develops in 15-25% of VLBW infants with IVH

32. Post-Hemorrhagic Ventricular Dilatation • Results from obstruction of CSF flow • Impaired resorption • Inefficient fibrinolysis • Enhanced synthesis • of collagen • Increased concentration • of TGF-β

33. Post-Hemorrhagic Ventricular Dilatation

34. Post-Hemorrhagic Ventricular Dilatation • May cause secondary injury to peri-ventricular white matter • Pathogenesis • Ischemia from raised intracranial pressure and parenchymal compression • Oxidative stress from free radical generation • Actions of inflammatory cytokines

35. Management of Post-Hemorrhagic Ventricular Dilatation • Objectives • Prevent damage secondary to increased ICP • Avoid need for permanent shunt • Interventions • Repeated LPs or ventricular taps • Diuretic therapy • Intraventricular fibrinolytic therapy • Surgical – external drainage, reservoir placement, VP shunt

36. Management Adapted from Murphy et al., Arch Dis Child Fetal Neonatal Ed, 2002

37. Repeated LPs or Ventricular Taps • Evaluated in 4 randomized trials • 280 infants enrolled • Intervention made no difference to numbers of shunt operations, deaths, or disabled infants • Trend towards increased CSF infection in infants who had multiple taps Whitelaw A. Repeated LPs or ventricular taps for preventing morbidity and shunt dependence in newborn infants with IVH. The Cochrane Library, 2001.

38. Diuretic Therapy • Decrease CSF production • Two controlled trials • 193 infants enrolled • No effect on mortality or VP shunt rate • Increased risk of impairment at 1 year Whitelaw A, Kennedy C, Brion LP. Diuretic therapy for newborn infants with PHVD. The Cochrane Library, 2001.

39. Intraventricular Fibrinolysis • Small number of uncontrolled pilot studies • One randomized trial – 50% of infants required shunt in each group • Significant risk for infection and secondary bleeding • Fibrinolytic agents may increase TGF-β concentrations in CSF

40. Surgical Treatments • External ventricular drainage • Pro: Immediate control of raised ICP, removes blood and protein • Con: High risk of infection, catheter blockage • Ventricular reservoir • Pro: Easy drainage of CSF • Con: Infection risk, skin ulceration • VP shunt • Pro: Definitive treatment • Con: Risk of blockage, infection, skin ulceration

41. Experimental Surgical Treatments • Endoscopic coagulation of choroid plexus • Third ventriculostomy • Ventriculosubgaleal shunt • Drainage, irrigation, and fibrinolytic therapy (DRIFT)

42. Outcome • Difficult to predict • PHVD predictive of poor outcome • 15-20% mortality • 50% become shunt dependent • 60% disabled • Cystic PVL associated with worse outcome

43. Outcome Spastic diplegia - classic form of cerebral palsy associated with premature birth

44. Outcome • Futagi et al., Pediatric Neurology, 2005 • 335 children w/ IVH born between 1981-1999 • Mean GA 28 weeks, weight 1162 grams • Outcomes: • Normal 56.1% • Cerebral palsy 22.4% • Mental retardation 10.2% • Borderline intelligence 11.3% • Gr I – 70% normal; Gr IV – 15% normal • Minimal improvement in outcome between 1980s and 1990s

45. Outcome • Patra et al., The Journal of Pediatrics, 2006 • 362 infants born between 1992-2000 • Normal head US – 258 • Isolated Gr I-II IVH – 104 • Mean GA 26 weeks, weight 805 grams • Outcome at 20 mos corrected age: Gr I-II IVH associated with poorer neurodevelopmental outcomes

46. Outcome • Grade III/IV IVH associated with worse outcomes • Presence of cystic PVL and PHVD predictive of worse outcome • Absence of IVH does not guarantee good outcome • Low-grade IVH may be marker for under-lying white matter injury not detectable on US

47. Questions?