Abstract
Periventricular leucomalacia is a condition that causes lifelong disability and considerable economic burden. It occurs in premature infants of less than 32 weeks gestation due to their unique anatomical features. The white matter of these infants is poorly vascularised and contains oligodendrocyte progenitors (pre-oligodendrocytes), which are sensitive to the effects of ischaemia and infection. Only recently have newer imaging techniques identified both a diffuse and focal component of white matter damage. The most immature infants with diffuse injury develop white matter atrophy and ventriculomegaly; others with focal injury have cyst formation, resorption and gliosis. Since the original description by Virchow in 1867, much progress has been made in establishing the underlying cause of this condition. It is an ischaemia reperfusion injury of the white matter, free radicals being the final pathway to pre-oligodendrocyte destruction and impaired myelination. Contributory factors include hypotension, hypocarbia and infection. Conclusion:new imaging and EEG techniques are likely to improve our ability to predict disability in this vulnerable group of infants. Research is needed into blocking the pathway to pre-oligodendrocyte destruction and the safe use of free radical scavengers.
Similar content being viewed by others
Notes
An atom or group of atoms containing at least one unpaired electron and existing for a short period of time before reacting to produce a stable molecule.
Abbreviations
- DEHSI :
-
diffuse excesssive high signal intensity
- DTI :
-
diffusion tensor imaging
- DWI :
-
diffusion weighted imaging
References
Adcock LM, Moore PJ, Schlesinger AE, Armstrong DL (1998) Correlation of ultrasound with postmortem neuropathologic studies in neonates. Pediatr Neurol 19: 263–271
Ajayi-Obe M, Saeed N, Cowan FM, Rutherford MA, Edwards AD (2000) Reduced development of cerebral cortex in extremely premature infants. Lancet 356: 1162–1163
Arzoumanian Y, Mirmiran M, Barnes PD, Woolley K, Ariagno RL, Moseley ME, Fleisher BE, Atlas SW (2003) Diffusion tensor brain imaging findings at term-equivalent age may predict neurologic abnormalities in low birth weight preterm infants. AJNR 24: 1646–1653
Back SA (2001) Recent advances in human perinatal white matter injury. Prog Brain Res 132: 131–147
Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ (1998) Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 18: 6241–6253
Back SA, Luo NL, Borenstein NS Levine JM, Volpe JJ, Kinney HC (2001) Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 21: 1302–1312
Banker BQ, Larroche JC (1962) Periventricular leukomalacia of infancy. A form of neonatal anoxic encephalopathy. Arch Neurol 7: 386–410
Blackwell S, Romero R, Chaiworapongsa T, Kim YM, Bujold E, Espinoza J Camacho N, Hassan S, Yoon BH, Refuerzo JS (2003) Maternal and fetal inflammatory responses in unexplained fetal death. J Maternal Fetal Neonat Med 14: 151–157
Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK (1992) Activated microglia mediate neural cell injury via a nitric oxide mechanism. J Immunol 149: 2736–2741
Collins MP, Lorenz JM, Jetton JR, Paneth N (2001) Hypocapnia and other ventilation-related risk factors for cerebral palsy in low birth weight infants. Pediatr Res 50: 712–719
Colton CA, Gilbert DL (1993) Microglia, an in vitro source of reactive oxygen species in the brain. Adv Neurol 59: 321–326
Counsell SA, Rutherford MA (2002) Magnetic resonance imaging of the newborn brain. Curr Paediatr 12: 401–413
Counsell SJ, Allsop JM, Harrison MC, Larkman DJ, Kinnea NL, Kapellou O, Cowan FM, Hajnal JV, Edwards DA, Rutherford MA (2003) Diffusion-weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality. Pediatrics 112: 1–7
Dammann O, Allred EN, Kuban K, Van Marter LJ, Stewart JE, Pagano M, Leviton A (2001) Hypocarbia during the first 24 postnatal hours and white matter echolucencies in newborns ≤28 weeks gestation. Pediatr Res 49: 388–393
Dammann O, Phillips TM, Allred EN, O’Shea TM, Paneth N, Van Marter LJ, Bose C, Ehrenkranz RA, Bednarek FJ, Naples M Leviton A (2001) Mediators of fetal inflammation in extremely low gestational age newborns. Cytokine 13: 234–239
Dammann O, Allred EN, Kuban K,Van Marter LJ, Pagano M,Sanocka U, Leviton A (2002) Systemic hypotension and white-matter damage in preterm infants. Dev Med Child Neurol 44: 82–90
Debillon T, N’Guyen S, Muet A, Quere MP, Moussaly F, Roze JC (2003) Limitations of ultrasonography for diagnosing white matter damage in preterm infants. Arch Dis Child Fetal Neonatal Ed 88: F275–F279
De Felice C, Toti P, Laurini RN, Stumpo M, Picciolini E, Todros T, Tanganelli P, Buonocore G, Bracci R (2001) Early neonatal brain injury in histologic chorioamnionitis. J Pediatr 138: 101–104
De Reuck J, Chattha AS, Richardson EPJ (1972) Pathogenesis and evolution of periventricular leukomalacia in infancy. Arch Neurol 27: 229–236
De Vries L, Rennie JM (1999) Preterm brain injury. In: Rennie JM, Roberton NRC (eds) Textbook of neonatology. Churchill Livingstone, Edinburgh, pp 1252–1271
Duggan PJ, Maalouf EF, Watts TL, Sullivan MHF, Counsell SJ, Allsop J, Al-Nakib L, Rutherford MA, Battin M, RobertsI, Edwards AD (2001) Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet 358: 1699–1700
Garcia-Cazorla A, Sans A, Baquero M, Garcia-Borgo M, Arellano M, Poo P, Gean E (2004) White matter alterations associated with chromosomal disorders. Dev Med Child Neurol 46: 148–153
Gilles FH (2001) Telencephalic angiogenesis: a review. Dev Med Child Neurol Suppl 86: 3–5
Goldenberg RL, Hauth JC, Andrews WW (2000) Intrauterine infection and preterm delivery. N Engl J Med 342: 1500–1507
Grether JK, Nelson KB, Walsh E, Willoughby RE, Redline RW (2003) Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med 157: 26–32
Hack M, Wilson-Costello D, Friedman H, Taylor GH, Schluchter M, Fanaroff AA (2000) Neurodevelopment and predictors of outcomes of children with birth weights of less than 1000 g. Arch Pediatr Adolesc Med 154: 725–731
Hack M, Flannery D, Schluchter M, Cartar L, Borawski E, Klein N (2002) Outcomes in young adulthood for very low-birth-weight infants. N Engl J Med 346: 149–157
Hannah M (2001) Antibiotics for preterm prelabour rupture of membranes and preterm labour? Lancet 357: 973–974
Haynes RL, Folkerth RD, Keefe RJ, Sung I, Swzeda LI, Rosenberg PA, Volpe JJ, Kinney HC (2003) Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J Neuropath Exp Neurol 62: 441–450
Hill A, Melson GL, Clark HB, Volpe JJ (1982) Hemorrhagic periventricular leukomalacia: diagnosis by realtime ultrasound and correlation with autopsy findings. Pediatrics 69: 282–284
Hoekstra RE, Ferrara B, Couser RJ, Payne NR, Connett JE (2004) Survival and long-term neurodevelopmental outcome of extremely premature infants born at 23–26 weeks’ gestational age at a tertiary center. Pediatrics 113: e1–e6
Holling EE, Leviton A (1999) Characteristics of cranial ultrasound white-matter echolucencies that predict disability: a review. Dev Med Child Neurol 41: 136–139
Hüppi PS, Murphy B, Maier SE, Zientara GP, Inder TE, Barnes PD, Kikinis R, Jolesz FA, Volpe JJ (2001) Microstructural brain development after perinatal cerebral white matter injury assessed by diffusion tensor magnetic resonance imaging. Pediatrics 107: 455–460
Inder TE, Hüppi PS, Warfield S, Kikinis R, Zientara GP, Barnes PD, Jolesz F, Volpe JJ (1999) Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol 46: 755–760
Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ (2003) White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR 24: 805–809
Inder TE, Buckland L, Williams CE, Spencer C, Gunning MI, Darlow BA, Volpe JJ, Gluckman PD (2003) Lowered electroencephalographic spectral edge frequency predicts the presence of cerebral white matter injury in premature infants. Pediatrics 111: 27–33
Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ (2003) Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr 143: 171–179
Ito T, Kadowaki K, Takahashi H, Nagata N, Makio A, Terakawa N (1997) Clinical features of and cardiotocographic findings for premature infants with antenatal periventricular leukomalacia. Early Hum Dev 47: 195–201
Kadhim H, Tabarki B, Verellen G, De Prez C, Rona AM, Sébire G (2001) Inflammatory cytokines in the pathogenesis of periventricular leucomalacia. Neurology 56: 1278–1284
Kehrer M, Goetz R, Krägeloh-Mann I, Schöning M (2002) Measurement of volume of cerebral blood flow in healthy preterm and term neonates with ultrasound; Lancet 360: 1749–1750
Kinney HC, Armstrong D (2002) Perinatal neuropathology In: Graham D, Lantos P (eds) Greenfield’s Neuropathology. Arnold, London, pp 557–559
Krägeloh-Mann I, Toft P, Lunding J, Andresen J, Pryds O, Lou HC (1999) Brain lesions in preterms: origin, consequences and compensation. Acta Paediatr 88: 897–908
Kubota T, Okumura A, Hayakawa F, Kato T, Itomi K, Kuno K, Watanabe K (2001) Relation between the date of cyst formation observable on ultrasonography and the timing of injury determined by serial electroencephalography in preterm infants with periventricular leukomalacia. Brain Dev 23: 390–394
Kumazaki K, Nakayama M, Sumida Y, Ozono K, Mushiake S, Suehara N, Wada Y, Fujimura M (2002) Placental features in preterm infants with periventricular leukomalacia. Pediatrics 109: 650–655
Lahra MM, Jeffery HE (2004) A fetal response to chorioamnionitis is associated with early survival after preterm birth. Am J Obstet Gynecol 190: 147–151
Lamont RF, Duncan SL, Mandal D, Bassett P (2003) Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 101: 516–522
Larroque B, Marret S, Ancel P, Arnaud C, Marpeau L, Supernant K, Pierrat V, Rozé JC, Matis J, Cambonie G, Burguet A, Andre M, Kaminski M, Bréart G (2003) White matter damage and intraventricular hemorrhage in very preterm infants: the Epipage Study. J. Pediatr 143: 477–483
Lehnardt S, Lachance C, Patrizi S, Lefebre S, Follet PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22: 2478–2486
Little WJ (1853) Lectures on the nature and treatment of the deformities of the human frame. Longmans, Green, London, pp 1–402
Maalouf EF, Duggan PJ, Rutherford MA, Counsell SJ, Fletcher AM, Battin M, Cowan F, Edwards AD (1999) Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr 135: 351–357
Mallard C, Welin AK, Peebles D, Hagberg H, Kjellmer I (2003) White matter injury following systemic endotoxemia or asphyxia in the fetal sheep. Neurochem Res 2: 215–223
Miller SP, Shevell MI, Patenaude Y, O’Gorman AM (2000) Neuromotor spectrum of periventricular leukomalacia in children born at term. Pediatr Neurol 23: 155–159
Nelson KB, Grether JK, Dambrosia JM, Walsh E, Kohler S, Satyayarana G, Nelson PG, Dickens BF, Phillips TM (2003) Neonatal cytokines and cerebral palsy in very preterm infants. Pediatr Res 53: 600–607
Okumura A, Hayakawa F, Kato T, Maruyama K, Kubota T, Suzuki M, Kidokoro H, Kuno K, Watanabe K (2003) Abnormal sharp transients on electroencephalograms in preterm infants with periventricular leukomalacia. J Pediatr 143: 26–30
Pal BR, Preston PR, Morgan MEI, Rushton DI, Durbin GM (2001) Frontal horn thin walled cysts in preterm neonates are benign. Arch Dis Child Fetal Neonatal Ed 85: F187–F193
Parrot J (1877) Clinique de nouveau-nés, L’Arthrepsie. Masson G (ed). Masson & Cie, Paris, pp 281–345
Paul DA, Coleman MM, Leef KH, Tuttle D, Stefano JL (2003) Maternal antibiotics and decreased periventricular leukomalacia in very low-birth-weight infants. Arch Pediatr Adolesc Med 157: 145–149
Pierrat V, Duquennoy C, van Haastert IC, Ernst M. Guilley N, De Vries LS (2001) Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed 84: F151–F156
Redline RW, Wilson-Costello D, Borawski E, Fanarof AA, Hack M (1998) Placental lesions associated with neurological impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab Med 122: 1091–1098
Resch B, Vollaard E, Maurer U, Haas J, Rosegger H, Müller W (2000) Risk factors and determinants of neurodevelopmental outcome in cystic periventricular leucomalacia. Eur J Pediatr 159: 663–670
Rezaie P, Dean A (2002) Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system. Neuropathology 22: 106–132
Schwindt J, Brugger PC, Mittermayer C, Chalubinski K, Prayer D (2003) Fetal magnetic resonance imaging can visualize evolving periventricular leukomalacia. Ultrasound Obstet Gynecol 22[Suppl 1]: 31
Shevell MI, Majnemer A Morin I (2003) Etiologic yield of cerebral palsy: a contemporary case series. Pediatr Neurol 28: 352–359
Sie L, van der Knaap M, Oosting J, de Vries L, Lafeber H, Valk JMR (2000) Patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia. Neuropediatrics 31: 128–136
Sofue A, Okumura A, Hayakawa F, Watanabe K (2003) Sharp waves in preterm infants with periventricular leukomalacia. Pediatr Neurol 29: 214–217
Staudt M, Niemann G, Grodd W, Krägeloh-Mann I (2000) The pyramidal tract in congenital hemiparesis: relationship between morphology and function in periventricular lesions. Neuropediatrics 31: 257–264
Staudt M, Pavlova M, Böhm S, Grodd W, Krägeloh-Mann I (2003) Pyramidal tract damage correlates with motor dysfunction in bilateral periventricular leukomalacia. Neuropediatrics 34: 182–188
Takashima S, Tanaka S (1978) Development of cerebrovascular architecture and its relationship to periventricular leukomalacia. Arch Neurol 35: 11–16
Tsuji M, Saul JP, du Plessis A, Eichenwald E, Sobh J, Crocker R, Volpe JJ (2000) Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 106: 625–632
Van Gelder-Hasker MR, Van Wezel-Meijler G, De Groot L, Van Geijn HP, De Vries JIP (2003) Peri-and intraventricular sonography in second- and third-trimester high-risk fetuses: a comparison with neonatal ultrasound and relation to neurological development. Ultrasound Obstet Gynecol 22: 110–120
Vermeulen RJ, Sie LT, Jonkman EJ, Strijers RLM, Lafeber HN, Uitdehaag BMJ, van der Knaap MS (2003) Predictive value of EEG in neonates with periventricular leukomalacia. Dev Med Child Neurol 45: 586–590
Virchow R (1867) Zur pathologischen Anatomie des Gehirns: 1 Congenitale encephalitis und Myelitis. Virchow Arch Path Anat 38: 129–142
Volpe JJ (2001) Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res 50: 553–562
Volpe JJ (2003) Cerebral white matter injury of the premature infant—more common than you think. Pediatrics 112: 176–180
Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR (2000) Neurologic and developmental disability after extremely preterm birth. N Engl J Med 343: 378–384
Wu YW (2002) Systematic review of chorioamnionitis and cerebral palsy. MRDD Res Rev 8: 25–29
Yoon BH, Park CW, Chaiworapongsa T (2003) Intrauterine infection and the development of cerebral palsy. Br J Obstet Gynaecol 110: 124–127
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Blumenthal, I. Periventricular leucomalacia: a review. Eur J Pediatr 163, 435–442 (2004). https://doi.org/10.1007/s00431-004-1477-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-004-1477-y