Abstract：Periventricular white matter damage is one of the characteristics of brain damage in preterm infants, and it is the most important type of encephalopathy. The pathological changes including the white matter of coagulation necrosis, oligodendrocyte damage, myelin damage, axonal injury and reactive gliosis and microglia infiltration in necrotic areas. All of these lesions are closely related to the nervous system sequelae in later-neonatal period. The pathogenesis of periventricular leukomalacia in premature infants are mainly cause by its immature brain vascular, and precursor oligodendrocytes of the attack of hypoxia, ischemia, infection, oxygen free radicals, inflammatory cytokines, increasing glutamate, and other high-risk factors. In this paper, an overview of progress in the study of the pathogenesis of periventricular white matter damage in premature infants through literature review to provide a theoretical support for clinical prevention, diagnosis and treatment.
［1］Paneth N. Classifying brain damage in preterm infants［J］. J Pediatr, 1999, 134(5): 527-529.
［2］Leviton A, Gilles F. Ventriculomegaly, delayed myelination, white matter hypoplasia, and “periventricular” leukomalacia: how are they related?［J］. Pediatr Neurol, 1996, 15(2): 127-136.
［5］Bauer M, Fast C, Haas J, Resch B, Lang U, Pertl B. Cystic periventricular leukomalacia in preterm infants: an analysis of obstetric risk factors［J］. Early Hum Dev, 2009, 85(3): 163-169.
［6］Kusters CD, Chen ML, Follett PL, Dammann O. “Intraventricular” hemorrhage and cystic periventricular leukomalaciain preterm infants: how are they related［J］. J Child Neurol, 2009, 24(9): 1158-1170.
［7］Aly H, Hammad TA, Essers J, Wung JT. Is mechanical ventilation associated with intraventricular hemorrhage in preterm infants?［J］. Brain Dev, 2012, 34(3): 201-205.
［8］Panigrahy A, Wisnowski JL, Furtado A, Lepore N, Paquette L, Bluml S. Neuroimaging biomarkers of preterm brain injury: toward developing the preterm connectome［J］. Pediatr Radiol, 2012, 42(1): 33-61.
［10］Cools F, Askie LM, Offringa M. Elective high-frequency oscillatory ventilation in preterm infants with respiratory distress syndrome: an individual patient data meta-analysis［J］. BMC Pediatr, 2009, 9: 33.
［11］Santesteban Otazu E, Rodríguez Serna A, Go-i Orayen C, Pérez Legorburu A, Echeverría Lecuona MJ, Martínez Ayucar MM, et al. Mortality and morbidity in very low birth weight infants in the Basque Country and Navarra (2001-2006): population-based study［J］. An Pediatr (Barc), 2012, 77(5): 317-322.
［12］Davis AS, Hintz SR, Van Meurs KP, Li L, Das A, Stoll BJ, et al. Seizures in extremely low birth weight infants are associated with adverse outcome［J］. J Pediatr, 2010, 157(5):720-725.
［13］Silveira RC, Procianoy RS, Dill JC, da Costa CS. Periventricular leukomalacia in very low birth weight preterm neonates with high risk for neonatal sepsis［J］. J Pediatr (Rio J), 2008, 84(3):211-216.
［14］Riddle A, Luo NL, Manese M, Beardsley DJ, Green L, Rorvik DA, et al. Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury［J］. J Neurosci, 2006, 26(11): 3045-3055.
［15］Nakanishi H, Yamanaka S, Koriyama T, Shishida N, Miyagi N, Kim TJ, et al. Clinical characterization and long-term prognosis of neurological development in preterm infants with late-onset circulatory collapse［J］. J Perinatol, 2010, 30 (11): 751-756.
［16］Roze E, Kerstjens JM, Maathuis CG. Risk factors for adverse outcome in preterm infants with periventricular hemorrhagic infarction［J］. Pediatrics, 2008, 122(1): 46-52.
［17］Volpe JJ. Electroencephalography may provide insight into timing of premature brain injury［J］. Pediatrics, 2009, 124(3): 542-544.
［18］Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA. The developing oligodendrocyte: key cellular target in brain injury in the premature infant［J］. Int J Dev Neurosci, 2011, 29(4): 423-440.
［19］Hatzidaki E, Giahnakis E, Maraka S, Korakaki E, Manoura A, Saitakis E, et al. Risk factors for periventricular leukomalacia［J］. Acta Obstet Gynecol Scand, 2009, 88(1): 110-115.
［21］Ten VS, Yao J, Ratner V, Sosunov S, Fraser DA, Botto M, et al. Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury［J］. J Neurosci, 2010, 30(6): 2077-2087.
［22］Ten VS, Starkov A. Hypoxic-ischemic injury in the developing brain: the role of reactive oxygen species originating in mitochondria［J］.Neurol Res Int, 2012, 2012: 542976.
［23］Vottier G, Pham H, Pansiot J, Biran V, Gressens P, Charriaut-Marlangue C, et al. Deleterious effect of hyperoxia at birth on white matter damage in the newborn rat［J］. Dev Neurosci, 2011, 33(3-4): 261-269.
［24］Fraser M, Bennet L, Van Zijl PL, Mocatta TJ, Williams CE, Gluckman PD, et al. Extracellular amino acids and lipid peroxidation products in periventricular white matter during and after cerebral ischemia in preterm fetal sheep［J］. J Neurochem, 2008, 105(6): 2214-2223.
［25］Inder T, Mocatta T, Darlow B, Spencer C, Volpe JJ, Winterbourn C. Elevated free radical products in the cerebrospinal fluid of VLBW infants with cerebral white matter injury［J］. Pediatr Res, 2002, 52: 213-218.
［26］Tekkok SB, Ye Z, Ransom BR. Excitotoxic mechanisms of ischemic injury in myelinated white matter［J］. J Cereb Blood Flow Metab, 2007, 27(9): 1540-1552.
［27］Gabryel B, Bielecka A, Stolecka A, Bernacki J, Langfort J. Cytosolic phospholipase A2 inhibition is involved in the protective effect of nortriptyline in primary astrocyte cultures exposed to combined oxygen-glucose deprivation［J］. Pharmacol Rep, 2010, 62(5): 814-826.
［28］Pallast S, Arai K, Pekcec A, Yigitkanli K, Yu Z, Wang X, et al. Increased nuclear apoptosis-inducing factor after transient focal ischemia: a 12/15-lipoxygenase-dependent organelle damage pathway［J］. J Cereb Blood Flow Metab, 2010, 30(6): 1157-1167.
［29］Gardoni F, Boraso M, Zianni E, Corsini E, Galli CL, Cattabeni F, et al. Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1βand NMDA stimulation［J］. J Neuroinflammation, 2011, 8(1): 14.
［30］Monier A, AdleBiassette H, Delezoide AL, Evrard P, Gressens P, Verney C. Entry and distribution of microglial cells in human embryonic and fetal cerebra cortex［J］. J Neuropathol Exp Neurol, 2007, 66(5): 372-382.
［31］Moon JB, Lee CH, Park CW, Cho JH, Hwang IK, Yoo KY, et al. Neuronal degeneration and microglial activation in the ischemic dentate gyrus of the gerbil［J］. J Vet Med Sci, 2009, 71: 1381-1386.
［32］Gharehbaghi MM, Peirovifar A, Gharehbaghi PM. Comparison of umbilical cord interleukin-6 in preterm infants with premature rupture of membranes and intact membranes［J］. Saudi Med J, 2008, 29(2):224-228.
［33］Neta GI, von Ehrenstein OS, Goldman LR, Lum K, Sundaram R, Andrews W, et al. Umbilical cord serum cytokine levels and risks of small-for-gestational-age and preterm birth［J］. Am J Epidemiol, 2010, 171(8): 859-867.
［34］Hassanein SM, El-Farrash RA, Hafez HM, Hassanin OM, Abd El Rahman NA. Cord blood interleukin-6 and neonatal morbidities among preterm infants with PCR-positive Ureaplasma urealyticum［J］. J Matern Fetal Neonatal Med, 2012, 25 (10): 2106-2110.
［35］Tsukimori K, Komatsu H, Yoshimura T, Hikino S, Hara T, Wake N, et al. Increased inflammatory markers are associated with early periventricular leukomalacia［J］. Dev Med Child Neurol, 2007, 49(8): 587-590.
［37］Kumral A, Baskin H, Yesilirmak DC, Ergur BU, Aykan S, Genc S, et al. Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain［J］. Neonatology, 2007, 92(4): 269-278.
［38］Moore CS, Abdullah SL, Brown A, Arulpragasam A, Crocker SJ. How factors secreted from astrocytes impact myelin repair［J］.J Neurosci Res, 2011, 89(1): 13-21.
［39］Burd I, Balakrishnan B, Kannan S. Models of fetal brain injury, intrauterine inflammation, and preterm birth［J］. Am J Reprod Immunol, 2012, 67(4): 287-294.
［40］Bass WT, Buescher ES, Hair PS, White LE, Welch JC, Burke BL. Proinflammatory cytokine-receptor interaction model improves the predictability of cerebral white matter injury in preterm infants［J］. Am J Perinatol, 2008, 25(4): 211-218.
［41］Shen Y, Yu HM, Yuan TM, Gu WZ, Wu YD. Erythropoietin attenuates white matter damage, proinflammatory cytokine and chemokine induction in developing rat brain after intrauterine E. coli infection［J］. Neuropathology, 2009, 29(5): 528-535.
［42］Amaral AI, Teixeira AP, Martens S, Bernal V, Sousa MF, Alves PM. Metabolic alterations induced by ischemia in primary cultures of astrocytes: merging 13C NMR spectroscopy and metabolic flux analysis［J］. J Neurochem, 2010, 113(3): 735-748.
［43］Yin Z, Jiang H, Lee ES, Ni M, Erikson KM, Milatovic D, et al. Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation［J］. J Neurochem, 2010, 112(5): 1190-1198.
［44］Billiards SS, Haynes RL, Folkerth RD, Borenstein NS, Trachtenberg FL, Rowitch DH, et al. Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia［J］. Brain Pathol, 2008, 18(2): 153-163.
［45］Weiss J, Takizawa B, McGee A, Stewart WB, Zhang H, Ment L, et al. Neonatal hypoxia suppresses oligodendrocyte Nogo-A and increases axonal sprouting in a rodent model for human prematurity［J］. Exp Neurol, 2004, 189(1): 141-149.
［46］Borrie SC, Baeumer BE, Bandtlow CE. The Nogo-66 receptor family in the intact and diseased CNS［J］. Cell Tissue Res, 2012, 349(1): 105-117.
［47］Volpe JJ. Systemic inflammation, Oligodendroglial maturation, and the encephalopathy of prematurity［J］. Ann Neurol, 2011, 70(4): 525-529.
［48］Tyler CP, Paneth N, Allred EN, Hirtz D, Kuban K, McElrath T, et al. Brain damage in preterm newborns and maternal medication: the ELGAN Study［J］. Am J Obstet Gynecol, 2012, 207(3): 191-192.
［49］Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat［J］. Pediatrics, 1995, 95(6): 868-874.
［50］Leviton A, Kuban K, O′Shea TM, Paneth N, Fichorova R, Allred EN, et al. The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: the ELGAN study［J］. J Pediatr, 2011, 158(6): 897-903.
［51］Amin SB, Prinzing D, Myers G. Hyperbilirubinemia and language delay in premature infants［J］. Pediatrics, 2009, 123(1): 327-331.
［52］Resch B, Resch E, Freidl T, Maurer U, Haas J, Müller W. Preterm twin and triplet pregnancies are at increased risk for the development of cystic periventricular leukomalacia［J］. Eur J Paediatr Neurol, 2013, 17(2): 148-152.
［53］Kakita H, Hussein MH, Yamada Y, Henmi H, Kato S, Kobayashi S, et al. High postnatal oxidative stress in neonatal cystic periventricular leukomalacia［J］. Brain Dev, 2009, 31(9): 641-648.
