Current Neurology and Neuroscience Reports

, Volume 8, Issue 2, pp 130–138 | Cite as

New concepts in perinatal hypoxia ischemia encephalopathy

Article

Abstract

This article summarizes recent insights into perinatal hypoxic-ischemic brain injury in the neonate. Before effective treatments can be offered, diagnosis, timing, and an understanding of the pathogenesis are imperative. The analysis of appropriate animal models is also summarized in this review. These models have provided interesting evidence that after hypoxia ischemia, progenitor cells in the postnatal brain are stimulated to generate new neurons and oligodendrocytes. The role of these newly generated cells is unclear, and mechanisms of migration and survival are currently being elucidated. A discussion of more recent imaging techniques, such as diffusion tensor imaging, is provided. This allows for improved understanding of the microstructural organization of white matter and how this is altered by hypoxic-ischemic injury. Neuroprotection with hypothermia is now occurring in full-term neonates that meet clinical criteria; however, specific therapies such as inhibition of non-N-methyl-D-aspartate receptors may offer improved outcomes by targeting specific pathways and populations of cells.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Volpe JJ: Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001, 7:56–64.PubMedCrossRefGoogle Scholar
  2. 2.
    du Plessis AJ, Volpe JJ: Perinatal brain injury in the preterm and term newborn. Curr Opin Neurol 2002, 15:151–157.PubMedCrossRefGoogle Scholar
  3. 3.
    Vannucci RC: Experimental biology of cerebral hypoxia-ischemia: relation to perinatal brain damage. Pediatr Res 1990, 27:317–326.PubMedCrossRefGoogle Scholar
  4. 4.
    Volpe JJ: Hypoxic-ischemic encephalopathy: clinical aspects. In Neurology of the Newborn, edn 4. Philadelphia: WB Saunders; 2001:331–394.Google Scholar
  5. 5.
    Badawi N, Kurinczuk JJ, Keogh JM, et al.: Antepartum risk factors for newborn encephalopathy: the Western Australia case-control study. BMJ 1998, 317:1549–1553.PubMedGoogle Scholar
  6. 6.
    Baskett TF, Allen VM, O’Connell CM, Allen AC: Predictors of respiratory depression in the term neonate. BJOG 2006, 113:769–774.PubMedCrossRefGoogle Scholar
  7. 7.
    Nelson KB: Is it HIE? And why that matters. Acta Paediatrica 2007, 96:1113–1114.PubMedGoogle Scholar
  8. 8.
    Badawi N, Felix JF, Kurinczuk JJ, et al.: Cerebral palsy following term newborn encephalopathy: a population-based study. Dev Med Child Neurol 2005, 47:293–298.PubMedCrossRefGoogle Scholar
  9. 9.
    Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976, 33:696–705.PubMedGoogle Scholar
  10. 10.
    Miller SP, Latal B, Clark H, et al.: Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy. Am J Obstet Gynecol 2004, 190:93–99.PubMedCrossRefGoogle Scholar
  11. 11.
    Inder TE, Volpe JJ: Mechanisms of perinatal brain injury. Sem Neonatol 2000, 5:3–16.CrossRefGoogle Scholar
  12. 12.
    Perlman JM: Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy. Pediatrics 2006, 117:S28–S33.PubMedCrossRefGoogle Scholar
  13. 13.
    Back SA, Luo NL, Borenstein NS, et al.: Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 2001, 21:1302–1312.PubMedGoogle Scholar
  14. 14.
    Back SA, Luo NL, Borenstein NS, et al.: Arrested oligodendrocyte lineage progression during human cerebral white matter development: dissociation between the timing of progenitor differentiation and myelinogenesis. J Neuropathol Exp Neurol 2002, 61:197–211.PubMedGoogle Scholar
  15. 15.
    Panigrahy A, Barnes PD, Robertson RL, et al.: Volumetric brain differences in children with periventricular T2-signal hyperintensities: a grouping by gestational age at birth. AJR Am J Roentgenol 2001, 177:695–702.PubMedGoogle Scholar
  16. 16.
    Thompson DK, Warfield SK, Carlin JB, et al.: Perinatal risk factors altering regional brain structure in the preterm infant. Brain 2007, 130:667–677.PubMedCrossRefGoogle Scholar
  17. 17.
    Kukley M, Capetillo-Zarate E, Dietrich D: Vesicular glutamate release from axons in the white matter. Nat Neurosci 2007, 10:311–320.PubMedCrossRefGoogle Scholar
  18. 18.
    Ziskin JL, Nishiyama A, Rubio M, et al.: Vesicular release of glutamate from unmyelinated axons in white matter. Nat Neurosci 2007, 10:321–330.PubMedCrossRefGoogle Scholar
  19. 19.
    Inder TE, Huppi PS, Warfield S, et al.: Periventricular white matter injury in the premature infant is associated with a reduction in cerebral cortical gray matter volume at term. Ann Neurol 1999, 46:755–760.PubMedCrossRefGoogle Scholar
  20. 20.
    Kesler SR, Ment LR, Vohr B, et al.: Volumetric analysis of regional cerebral development in preterm children. Pediatr Neurol 2004, 31:318–325.PubMedCrossRefGoogle Scholar
  21. 21.
    Inder TE, Warfield SK, Wang H, et al.: Abnormal cerebral structure is present at term in premature infants. Pediatrics 2005, 115:286–294.PubMedCrossRefGoogle Scholar
  22. 22.
    Roohey T, Raju TN, Moustogiannis AN: Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical analysis. Early Hum Dev 1997, 47:115–146.PubMedCrossRefGoogle Scholar
  23. 23.
    Yager JY: Animal models of hypoxic-ischemic brain damage in the newborn. Sem Pediatr Neurol 2004, 11:31–46.CrossRefGoogle Scholar
  24. 24.
    Northington FJ: Brief update on animal models of hypoxic-ischemic encephalopathy and neonatal stroke. ILAR J 2006, 47:32–38.PubMedGoogle Scholar
  25. 25.
    Hagberg H, Bona E, Gilland E, Puka-Sundvall M: Hypoxiaischaemia model in the 7 day old rat: possibilities and shortcomings. Acta Paediatr Suppl 1997, 422:85–88.PubMedGoogle Scholar
  26. 26.
    Vannucci RC: Experimental biology of cerebral hypoxia-ischemia: relation to perinatal brain damage. Pediatr Res 1990, 27:317–326.PubMedCrossRefGoogle Scholar
  27. 27.
    Ment LR, Schwartz M, Makuch RW, Stewart WB: Association of chronic sublethal hypoxia with ventriculomegaly in the developing rat brain. Brain Res Dev 1998, 111:197–203.CrossRefGoogle Scholar
  28. 28.
    Fagel DM, Ganat Y, Silbereis J, et al.: Cortical neurogenesis enhanced by chronic perinatal hypoxia. Exp Neurol 2006, 199:77–91.PubMedCrossRefGoogle Scholar
  29. 29.
    Weiss J, Takizawa B, McGee A, et al.: Neonatal hypoxia suppresses oligodendrocyte Nogo-A and increases axonal sprouting in a rodent model for human prematurity. Exp Neurol 2004, 189:141–149.PubMedCrossRefGoogle Scholar
  30. 30.
    Back SA, Riddle A, Hohimer AR: Role of instrumented fetal sheep preparations in defining the pathogenesis of human periventricular white-matter injury. J Child Neurol 2006, 21:582–589.PubMedCrossRefGoogle Scholar
  31. 31.
    Sheldon RA, Sedik C, Ferriero DM: Strain-related brain injury in neonatal mice subjected to hypoxia-ischemia. Brain Res 1998, 810:114–122.PubMedCrossRefGoogle Scholar
  32. 32.
    Levison SW, Goldman JE: Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Neuron 1993, 10:201–212.PubMedCrossRefGoogle Scholar
  33. 33.
    Doetsch F, Caille I, Lim DA, et al.: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999, 97:703–716.PubMedCrossRefGoogle Scholar
  34. 34.
    Romanko MJ, Rola R, Fike JR, et al.: Roles of the mammalian subventricular zone in cell replacement after brain injury. Progress Neurobiol 2004, 74:77–99.CrossRefGoogle Scholar
  35. 35.
    Parent JM: Injury induced neurogenesis in the adult mammalian brain. Neuroscientist 2003, 9:261–272.PubMedCrossRefGoogle Scholar
  36. 36.
    Laywell ED, Rakic P, Kukekov VG, et al.: Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci U S A 2000, 97:13883–13888.PubMedCrossRefGoogle Scholar
  37. 37.
    Suzuki SO, Goldman JE: Multiple cell populations in the early postnatal subventricular zone take distinct migratory pathways: a dynamic study of glial and neuronal progenitor migration. J Neurosci 2003, 23:4240–4250.PubMedGoogle Scholar
  38. 38.
    Merkle FT, Tramontin AD, Garcia-Verdugo JM, et al.: Radial glia give rise to adult neural stem cells in the subventricular zone. Proc Natl Acad Sci U S A 2004, 101:17528–17532.PubMedCrossRefGoogle Scholar
  39. 39.
    Yang Z, Levison SW: Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone. Neuroscience 2006, 139:555–564.PubMedCrossRefGoogle Scholar
  40. 40.
    Ong J, Plane JM, Parent JM, Silverstein FS: Hypoxic-ischemic injury stimulates subventricular zone proliferation and neurogenesis in the neonatal rat. Peds Res 2005, 58:600–606.CrossRefGoogle Scholar
  41. 41.
    Yang Z, Levison SW: Perinatal hypoxic/ischemic brain injury induces persistent production of striatal neurons from subventricular zone progenitors. Dev Neurosci 2007, 29:331–340.PubMedCrossRefGoogle Scholar
  42. 42.
    Plane JM, Liu R, Wang TW, et al.: Neonatal hypoxic-ischemic injury increases the forebrain subventricular zone neurogenesis in the mouse. Neurobiol Dis 2004, 16:585–595.PubMedCrossRefGoogle Scholar
  43. 43.
    Felling RJ, Snyder MJ, Romanko MJ, et al.: Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia. J Neurosci 2006, 26:4359–4369.PubMedCrossRefGoogle Scholar
  44. 44.
    Ganat YM, Silbereis J, Cave C, et al.: Early postnatal astroglial cells produce multilineage precursors and neural stem cells in vivo. J Neurosci 2006, 26:8609–8621.PubMedCrossRefGoogle Scholar
  45. 45.
    Kuhn HG, Winkler J, Kempermann G, et al.: Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult brain. J Neurosci 1997, 17:5820–5829.PubMedGoogle Scholar
  46. 46.
    Tureyen K, Vemuganti R, Bowen KK, et al.: EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain. Neurosurgery 2005, 57:1254–1263.PubMedCrossRefGoogle Scholar
  47. 47.
    Bongarzone ER, Byravan S, Givogri MI, et al.: Plateletderived growth factor and basic fibroblast growth factor regulate cell proliferation and the expression of notch-1 receptor in a new oligodendrocyte cell line. J Neurosci Res 2000, 62:319–328.PubMedCrossRefGoogle Scholar
  48. 48.
    Aguirre A, Dupree JL, Mangin JM, Gallo V: A functional role for EGFR signaling in myelination and remyelination. Nat Neurosci 2007, 10:990–1002.PubMedCrossRefGoogle Scholar
  49. 49.
    Barkovich AJ: MR imaging of the neonatal brain. Neuroimaging Clin North Am 2006, 16:117–135.CrossRefGoogle Scholar
  50. 50.
    Rutherford MA, Pennock JM, Counsell SJ, et al.: Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics 1998, 102:323–328.PubMedCrossRefGoogle Scholar
  51. 51.
    Mercuri E, Rutherford M, Barnett A, et al.: MRI lesions and infants with neonatal encephalopathy. Is the APGAR score predictive? Neuropediatrics 2002, 33:150–156.PubMedCrossRefGoogle Scholar
  52. 52.
    Jyoti R, O’Neil R, Hurrion E: Predicting outcome in term neonates with hypoxic-ischaemic encephalopathy using simplified MR criteria. Pediatr Radiol 2006, 36:38–42.PubMedCrossRefGoogle Scholar
  53. 53.
    Woodward LJ, Anderson PJ, Austin NC, et al.: Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006, 355:685–694.PubMedCrossRefGoogle Scholar
  54. 54.
    Ward P, Counsell S, Allsop J, et al.: Reduced fractional anisotropy on diffusion tensor magnetic resonance imaging after hypoxic ischemic encephalopathy. Pediatrics 2006, 117:e619–e630.PubMedCrossRefGoogle Scholar
  55. 55.
    Cascio CJ, Gerig G, Piven J: Diffusion tensor imaging: application to the study of the developing brain. J Am Acad Child Adolesc Psychiatry 2007, 46:213–223.PubMedCrossRefGoogle Scholar
  56. 56.
    Rutherford M, Counsell S, Allsop J, et al.: Diffusion-weighted magnetic resonance imaging in term perinatal brain injury: a comparison with site of lesion and time from birth. Pediatrics 2004, 114:1004–1014.PubMedCrossRefGoogle Scholar
  57. 57.
    Miller SP, Vigneron DB, Henry RG, et al.: Serial quantitative diffusion tensor imaging of the premature brain: development in newborns with and without injury. J Magn Resonance Imaging 2002, 16:621–632.CrossRefGoogle Scholar
  58. 58.
    Bartha AI, Yap KR, Miller SP, et al.: The normal neonatal brain: MR imaging, diffusion tensor imaging, and 3D MR spectroscopy in healthy term neonates. Am J Neuroradiol 2007, 28:1015–1021.PubMedCrossRefGoogle Scholar
  59. 59.
    Huppi PS, Inder TE: Magnetic resonance techniques in the evaluation of the perinatal brain: recent advances and future directions. Sem Neonatol 2001, 6:195–210.CrossRefGoogle Scholar
  60. 60.
    Nagy Z, Lindstrom K, Westerberg H, et al.: Diffusion tensor imaging on teenagers, born at term with moderate hypoxic-ischemic encephalopathy. Pediatr Res 2005, 58:936–940.PubMedCrossRefGoogle Scholar
  61. 61.
    van Pul C, Buijs J, Vilanova A, et al.: Infants with perinatal hypoxic ischemia: feasibility of fiber tracking at birth and 3 months. Radiology 2006, 240:203–214.PubMedCrossRefGoogle Scholar
  62. 62.
    Pajevic S, Pierpaoli C: Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: application to white matter fiber tract mapping in the human brain. Magn Reson Med 1999, 42:526–540.PubMedCrossRefGoogle Scholar
  63. 63.
    Enhorning G, Westin B: Experimental studies of the human fetus in prolonged asphyxia. Acta Physiol Scand 1954, 31:359–375.PubMedCrossRefGoogle Scholar
  64. 64.
    Gluckman PD, Wyatt JS, Azzopardi D, et al.: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial. Lancet 2005, 365:663–670.PubMedGoogle Scholar
  65. 65.
    Shankaran S, Laptook AR, Ehrenkranz RA, et al.: Wholebody hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005, 353:1574–1584.PubMedCrossRefGoogle Scholar
  66. 66.
    Gallo V, Patneau DK, Mayer ML, Vaccarino FM: Excitatory amino acids receptors in glial progenitor cells: molecular and functional properties. Glia 1994, 11:94–101.PubMedCrossRefGoogle Scholar
  67. 67.
    Talos DM, Fishman RE, Park H, et al.: Developmental regulation of alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex. J Comp Neurol 2006, 497:42–60.PubMedCrossRefGoogle Scholar
  68. 68.
    Talos DM, Follett PL, Folkerth RD, et al.: Developmental regulation of alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. II: Human cerebral white matter and cortex. J Comp Neurol 2006, 497:61–77.PubMedCrossRefGoogle Scholar
  69. 69.
    Follett PL, Deng W, Dai W, et al.: Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J Neurosci 2004, 24:4412–4420.PubMedCrossRefGoogle Scholar
  70. 70.
    Perlman JM: Intervention strategies for neonatal hypoxic-ischemic cerebral injury. Clin Ther 2006, 28:1353–1365.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Department of NeurologyChildren’s National Medical CenterWashington, DCUSA

Personalised recommendations