You are here

Article Text

Article menu

Download PDFPDF

Review
Magnetic resonance imaging of preterm brain injury
  1. S J Counsell1,
  2. M A Rutherford1,
  3. F M Cowan2,
  4. A D Edwards2
  1. 1Robert Steiner Magnetic Resonance Unit, Imaging Sciences Department, MRC Clinical Sciences Centre
  2. 2Department of Paediatrics, Faculty of Medicine, Imperial College, Hammersmith Campus, DuCane Road, London, UK
  1. Correspondence to:
    Professor A D Edwards, Department of Paediatrics, Faculty of Medicine, Imperial College, Hammersmith Campus, DuCane Road, London W12 OHS, UK;
    david.edwards{at}ic.ac.uk

Abstract

Magnetic resonance imaging (MRI) has proved to be a valuable tool for monitoring development and pathology in the preterm brain. This imaging modality is useful for assessing numerous pathologies including periventricular leukomalacia, intraventricular haemorrhage/germinal layer haemorrhage, and periventricular haemorrhagic infarction, and can help to predict outcome in these infants. MRI has also allowed the detection of posterior fossa lesions, which are not easily seen with ultrasound. Additionally, and perhaps most relevant, quantitative MR studies have shown differences between the normal appearing preterm brain at term equivalent age and term born infants, confirming that the brain develops differently in the ex utero environment. Further studies using quantifiable MR techniques will improve our understanding of the effects of the ex utero environment, including aspects of neonatal intensive care on the developing brain.

  • magnetic resonance imaging
  • preterm brain injury
  • ADC, apparent diffusion coefficient
  • CSE, conventional spin echo
  • DEHSI, diffuse excessive high signal intensity
  • DWI, diffusion weighted imaging
  • FSE, fast spin echo
  • GA, gestational age
  • GLH, germinal layer haemorrhage
  • IVH, intraventricular haemorrhage
  • MR, magnetic resonance
  • MRI, magnetic resonance imaging
  • PHI, periventricular haemorrhagic infarction
  • PVL, periventricular leukomalacia
  • 3D, three dimensional

https://doi.org/10.1136/fn.88.4.F269

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    The developing brain is vulnerable to injury from many causes, resulting in significant mortality and morbidity despite recent improvements in neonatal intensive care, and at 30 months corrected age impairment can be identified in one half of all infants born at 25 weeks gestational age (GA) or less.1 However, even those with no identifiable disability at this age may experience learning difficulties when they enter mainstream school or have behavioural problems in adolescence.2–5

    The neuropathological correlates for neurodevelopmental impairments are incompletely defined. Most of our knowledge comes from ultrasound, which shows a relation between periventricular haemorrhagic infarction (PHI) and periventricular leucomalacia (PVL) and the development of cerebral palsy. There are, however, no pathological or imaging correlates for the spectrum of neurocognitive impairments seen in the child who was born preterm.

    Magnetic resonance imaging (MRI) provides an ideal and safe technique for imaging the developing brain. It is non-invasive and non-ionising and allows considerable differentiation of structures within the immature brain, showing the extensive maturation that occurs from 23 to 40 weeks gestation while these vulnerable infants are receiving intensive care. MRI shows the well recognised pathologies seen on ultrasound and in addition allows the detection of more subtle abnormalities.

    MRI OF THE NORMAL PRETERM BRAIN

    MRI provides excellent detail of the immature brain with good delineation of the cortex, white matter, and central grey matter structures.6,7 In the immature brain we have found that a T2 weighted fast spin echo (FSE) sequence gives the best contrast between different structures. The cortex is seen as high signal intensity on T1 weighted imaging and low signal on T2 weighted imaging, reflecting its high cellular density. Serial imaging allows the maturation of cortical folding to be assessed and scored.6,7 At 24 weeks GA the surface of the brain appears smooth apart from the parieto-occipital fissure, central sulci, cingulate sulci, calcarine sulci, and very wide Sylvian fissures (fig 1). Sulcation and gyration develop at different rates in different regions of the brain. At any given age prior to term, the folding of the central sulcus is the most advanced, followed by the medial occipital lobe. The parietal lobe is the next most advanced, followed by the frontal and posterior temporal lobes. The anterior temporal region is the least well developed. By term the cortex has extensive folding with the formation of tertiary sulci.

    Figure 1
    Figure 1

    Development of sulcation and gyration with increasing GA. Transverse T2 weighted FSE images at the level of the central sulcus at: (A) 25 weeks GA; (B) 28 weeks GA; (C) 30 weeks GA; (D) 33 weeks GA; (E) 39 weeks GA.

    Unmyelinated cerebral white matter is shown as high signal intensity on T2 weighted imaging and low signal on T1 weighted imaging. On T2 weighted MRI, bands of low signal intensity are visible within the white matter, situated anterior, posterior, and lateral to the lateral ventricles.6 These represent relatively dense regions of glial cells migrating from the germinal matrix to the cerebral cortex8 (fig 2). At around 30 weeks GA, while the periventricular white matter remains high signal intensity, the low signal bands become difficult to visualise, presumably because the majority of the migrating cells have reached the cortex at this age.9 In addition to these areas of low signal intensity, areas of extremely high signal intensity on T2 weighted FSE images are visualised around the anterior horns of the lateral ventricles between 24 and 36 weeks GA. Similar high signal intensity areas in the shape of arrowheads are visualised in the posterior periventricular white matter at this GA.6 Histologically, these extremely high signal intensity areas are comprised of dense fibre bundles, which have a relatively low cellular density.8

    Figure 2
    Figure 2

    (A) Coronal T2 weighted FSE image of an infant at 25 weeks GA showing the unmyelinated white matter as high signal intensity and the cerebral cortex as low signal intensity. The germinal matrix is shown as low signal intensity around the head of the caudate nucleus (arrowhead), and low signal bands representing migrating glia are shown within the white matter (arrow). (B) TransverseT2 weighted FSE image at the mid-ventricular level of an infant at 25 weeks GA showing the germinal matrix as low signal intensity (arrows). (C) TransverseT1 weighted FSE image at the mid-ventricular level of an infant at 25 weeks GA showing the germinal matrix as high signal intensity (arrows).

    The germinal matrix is visible up to around 32 weeks GA as a prominent structure along the margins of the lateral ventricles (fig 2). After this age, small residual areas of germinal matrix are visualised at the anterolateral angles of the lateral ventricles and adjacent to the head of the caudate nucleus and in the roof of the temporal horn, a site not readily visualised with ultrasound. The germinal matrix is shown as high signal intensity on T1 weighted imaging and low signal intensity on T2 weighted FSE imaging.

    Myelin has been shown in numerous white matter tracts and grey matter nuclei in the preterm brain, corresponding to those sites that show myelination on histology at this age. These areas lie within the brain stem, cerebellar vermis, and the thalami. From 28 weeks GA, myelination is not visualised at any new site, until 36 weeks GA, when myelin is visualised in the corona radiata, the posterior limb of the internal capsule, the corticospinal tracts of the precentral and postcentral gyri, and the lateral geniculate bodies. We have found that T2 weighted FSE imaging is the best imaging pulse sequence to show myelin in grey matter nuclei; however, T1 weighted imaging shows myelin earlier in some white matter tracts in the preterm brain.10

    QUANTITATIVE MR TECHNIQUES

    Recently, quantitative MR techniques have been used to assess the preterm brain, the preterm brain at term equivalent age, and the preterm brain later in adolescence. These techniques produce objective and reproducible measurements that improve our understanding of brain development and provide a more accurate correlate for neurodevelopmental outcome.

    Techniques include three dimensional (3D) volumetric MR and measurements of cortical folding, which have been used to determine the increase in brain volume11 and cortical folding12 with increasing GA. Diffusion weighted imaging (DWI) is an MR technique which studies the Brownian motion of water in tissue and can be used to calculate apparent diffusion coefficients (ADCs), which quantify water molecular motion. Additionally anisotropy, which is a function of the directional dependence of water motion in a restricted environment, can be measured using DWI, and provides an insight into white matter structure. T1 and T2 relaxation values have also been studied in the preterm brain.13,14 These MR parameters are associated with cerebral water content, and are raised in pathology and in the immature brain.

    MRI ASSESSMENT OF CEREBRAL PATHOLOGY

    The developing brain is susceptible to injury from infective, ischaemic, and inflammatory insults. The majority of preterm infants show some evidence of brain injury on MRI in the early neonatal period.9

    WHITE MATTER ABNORMALITIES

    With the decline in the incidence of pathology such as PVL and IVH, diffuse white matter changes in the absence of more obvious focal lesions may now be the most common abnormality of the preterm brain.15 MRI has shown that there are a variety of white matter abnormalities that can be visualised in the preterm infant. It is not yet clear whether these represent a spectrum of one disorder or separate entities with different aetiological factors. These abnormalities may prove to be related to factors such as poor nutrition,16,17 steroids,18–20 and infection,21–23 which are known to affect development of the preterm brain.

    DIFFUSE WHITE MATTER ABNORMALITY

    The majority of preterm infants at term equivalent age appear to have areas of diffuse excessive high signal intensity (DEHSI) within the cerebral white matter (fig 3).9 These changes are most marked in the periventricular white matter, but may be evident throughout the white matter. Assessment of these changes is difficult with visual analysis as the appearances are markedly influenced by the windowing used prior to image processing. This has lead to strategies that allow a more objective measurment. DWI has shown raised ADC values in the cerebral white matter in infants with DEHSI compared to preterm infants with normal white matter, suggesting that DEHSI represents diffuse white matter disease.24 ADC values were comparable with those obtained from infants with obvoius white matter pathology such as PVL and PHI. It is unclear what causes the increase of ADCs in DEHSI, but it may be due to vasogenic oedema, oligodendrocyte damage, or a reduced axonal diameter. DEHSI represents one of the many differences between the preterm brain at term equivalent age and the brain of the term born infant. Quantitative MR techniques may be used to further delineate these differences.

    Figure 3
    Figure 3

    Transverse T2 weighted FSE image of an infant at 40 weeks GA, who was born at 30 weeks GA, showing DEHSI within the cerebral white matter (arrows).

    PERIVENTRICULAR LEUKOMALACIA

    PVL is a histological diagnosis with “softening” of the white matter and focal cystic degeneration.25 Its incidence is 3–9% in preterm infants.26 Traditionally, PVL was thought to be due to ischaemia, but recent studies have suggested an infective cause.27–29 PVL is shown as periventricular regions that are hypointense on T1 weighted imaging30 and high signal intensity on T2 weighted imaging in the early neonatal period. These areas may become cystic and lead to dilatation of the lateral ventricles, particularly in the region of the posterior parietal white matter adjacent to the occipital horn. Additionally, areas of short T1, presumably a haemorrhagic component, have been identified in the acute/subcacute stage.31 DWI has identified PVL as areas of high signal intensity, representing restricted diffusion, before cysts were evident on ultrasound.32 Additionally, Roelants-van Rijn and colleagues33 reported high signal intensity on DWI adjacent to cystic areas, which we have also seen in an infant at 32 weeks GA with PVL (fig 4A–C). On histology, these areas were found to be undergoing active degeneration with cytotoxic oedema, apoptosis, and macrophage infiltration.33 We have noted increased T1 and T2 relaxation values in the white matter adjacent to cystic areas, probably representing more diffuse white matter damage.34 Chronically, DWI shows low signal areas in the affected white matter. At this time ADCs are elevated, representing frank cystic lesions and areas of vasogenic oedema. By term equivalent age, the cystic lesions are often incorporated into the lateral ventricles, resulting in the characteristic squared off appearance of the posterior horns (fig 4D). Frequent associated findings are thalamic atrophy35 and abnormal signal intensity within the PLIC.36 The latter may help predict neuromotor outcome.

    Figure 4
    Figure 4

    PVL in an infant at 28 weeks GA. (A) Transverse T1 weighted image at the mid-ventricular level showing cystic PVL as areas of low signal within the cerebral white matter posterior and anterior to the lateral ventricles (arrows). (B) Transverse T2 weighted FSE image at the mid-ventricular level showing the cystic lesions as high signal intensity (arrows). (C) DWI image showing areas of restricted diffusion around the lateral ventricles as high signal intensity (arrows). (D) T2 weighted FSE image of the same infant at 40 weeks GA showing squared off posterior horns of the lateral ventricles (arrows) and diminished white matter posteriorly. Cystic lesions are shown anterior to the anterior horns of the lateral ventricles (arrowheads).

    PVL is associated with delayed myelination, which is probably caused by extensive glial necrosis and oligodendrocyte dysfunction as a consequence of white matter injury.37 3D volumetric MRI has shown that preterm infants with PVL have a reduced cortical grey matter volume at term compared to both preterm infants with no evidence of PVL and normal term control infants.38 These findings suggest that PVL has an impact on cerebral cortical development, which may help to explain the cognitive deficits associated with this condition.

    PUNCTATE HAEMORRHAGIC/ISCHAEMIC LESIONS

    Non-specific focal lesions have been identified in the cerebral white matter on MRI studies of the preterm brain.39 These lesions are high signal intensity on T1 weighted imaging and frequently, but not always, low signal on T2 weighted imaging (fig 5), suggesting that they may be haemorrhagic/ischaemic rather than purely haemorrhagic. The distribution of lesions varies and is not restricted to the immediate periventricular white matter. These punctate lesions may develop into areas of long T2 consistent with gliosis on later MRI.40 Neurodevelopmental outcome appears to be inversely related to the number of lesions present on early MRI.40

    Figure 5
    Figure 5

    (A) Transverse T1 weighted image of an infant at 29 weeks GA showing a high signal lesion adjacent to the optic radiation on the left (arrow). (B) Transverse T2 weighted FSE image showing the lesion as low signal (arrow).

    INTRAVENTRICULAR/GERMINAL LAYER HAEMORRHAGE

    The appearance of haemorrhage on MRI depends on the age and site of the haemorrhage, and the pulse sequence used (table 1).41 IVH usually arises from a GLH in preterm infants, and is the most common form of intracranial neonatal haemorrhage.42 The incidence of IVH in preterm infants increases with decreasing birth weight.42–44 An association between thrombophilic disorders, such as factor V Leiden heterozygosity, and IVH has recently been established.45 GLH is shown as low signal on T2 weighted imaging (fig 6) and high signal intensity on T1 weighted imaging. GLH may occur at any site along the immature ventricle wall, but most commonly arises from the germinal matrix over the caudate head and in the roof of the temporal horn. It can be differentiated from the normal germinal layer by its irregular appearance, and it is slightly more hypointense on T2 weighted imaging. The low signal intensity on T2 weighted imaging may persist for several months because of the presence of haemosiderin. GLHs were shown in one third of preterm infants on MRI in the early neonatal period.9 It is thought that this lesion may damage oligodendroglial progenitors and disrupt their migration, potentially resulting in impaired myelination. A further consequence of GLH may be damage to astrocytic precursors bound for the upper layers of the cerebral cortex, and thereby impairment of cortical neuronal development.46 Neurological outcome in infants with IVH depends largely on the severity of the haemorrhage and the site of any parenchymal infarction.47–50

    View this table:
    Table 1

    Evolution of signal intensity in parenchymal haemorrhage41

    Figure 6
    Figure 6

    Transverse T2 weighted FSE image of an infant at 27 weeks GA showing bilateral germinal layer haemorrhages (arrows).

    PERIVENTRICULAR HAEMORRHAGIC INFARCTION

    Blood in the cerebral white matter is drained by the medullary veins, into the veins of the germinal matrix, and finally into the terminal veins. Periventricular haemorrhagic infarction (PHI) probably occurs as a consequence of obstruction of venous drainage and subsequent infarction of the white matter.51 Diminished cerebral blood flow in the periventricular white matter has been shown by positron emission tomography,52 and Doppler ultrasound has shown reduced blood flow velocity in the terminal vein on the affected side,53 suggesting impaired venous drainage. The periventricular haemorrhage is shown as a fan shaped structure, due to obstructed medullary veins, of low signal intensity on T2 weighted FSE imaging (fig 7).54,55 Parenchymal haemorrhagic infarction results in interruption of projection and association fibres and oligodendroglial damage, which disrupts myelination. PHI and large GLHs may also affect the subplate neurones, which are concerned with cortical neuronal organisation and in the connection of association and projection fibres with the cerebral cortex.46 It is possible that injury to the subplate neuronal layer may result in cognitive delays and attention deficits in this group of infants.56

    Figure 7
    Figure 7

    (A) Sagittal and (B) coronal T2 weighted FSE image of an infant at 27 weeks GA, showing bilateral intraventricular/germinal layer haemorrhages with parenchymal involvement on the right in a fan shaped distribution (arrows).

    Large PHI is associated with a high incidence of mortality57,58 which is related to the extent of the lesion.59–61 In surviving infants, a porencephalic cyst usually develops at the site of the lesion. Infants with a unilateral lesion and asymmetry in the myelination of the posterior limb of the internal capsule on term MRI have a high incidence of hemiplegia. This may not be due to primary involvement of the posterior limb of the internal capsule, but may occur secondarily as a result of Wallerian degeneration.62

    CEREBELLAR HAEMORRHAGE

    Cerebellar haemorrhage has been observed in 10–25% of very low birth weight preterm infants at postmortem examination63 and is associated with traumatic birth,64 injury from tightly bound ventilator masks,65,66 and supratentorial haemorrhage.63,65,67 Using the posterior fontanelle, ultrasound has shown cerebellar haemorrhage in just under 3% of preterm infants weighing less than 1500 g, most of whom did not have extensive supratentorial haemorrhage.68 We have seen haemorrhagic lesions within the cerebellum on MRI in 8% of preterm infants born at less than 32 weeks gestation, and the incidence increased with decreasing GA69 (fig 8). Morbidity is high for infants with large supratentorial and cerebellar haemorrhages.64,70 In those that survive, specific neurological signs related to cerebellar damage are difficult to show,71 and the neurological signs that occur may be due to co-occurring lesions. In the light of evidence that the cerebellum plays an important role in cognitive functioning,72 further studies are required to assess the impact of isolated cerebellar haemorrhages on neurodevelopmental outcome.68

    Figure 8
    Figure 8

    (A) Transverse and (B) coronal T2 weighted FSE images of an infant at 25 weeks GA showing a haemorrhage within the cerebellum on the right (arrow).

    QUANTITATIVE MR IN PRETERM BRAIN INJURY

    Quantitative MR techniques have identified anomalies which are not visualised on conventional MRI. Preterm infants at term have higher ADC values in the central white matter and lower relative anisotropy than infants born at term.73 Additionally, ADC values are raised in the posterior limb of the internal capsule, and regional anisotropy in the thalamus and cortical grey matter is altered in preterm infants with intrauterine growth retardation compared to appropriately grown preterm infants at term equivalent age, suggesting altered development of these regions.74

    Although brain volume in preterm infants at term was similar to that of infants born at term, the surface area of the cortex and cortical folding was reduced in preterm infants.12 Additionally, Peterson et al showed reduced volumes of the basal ganglia, corpus callosum, amygdala, hippocampus, and cerebellum in preterm infants at 8 years of age compared with term born controls.75 These findings provide objective evidence that brain development differs in preterm infants compared to infants born at term.

    Quantitative MR techniques are also providing an insight into the effects of drugs; for example, 3D volumetric MRI has shown a reduction in cortical grey matter volume in preterm infants treated with dexamethasone when compared to untreated preterm infants, implying that dexamethasone impairs cortical grey matter development.76 Similar findings have been reported in term infants exposed to multiple doses of antenatal steroids.77

    REFERENCES

    1. ↵
      Wood NS, Marlow N, Costeloe K, et al. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med2000;343:378–84.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      Briscoe J, Gathercole SE, Marlow N. Short-term memory and language outcomes after extreme prematurity at birth. J Speech Lang Hear Res1998;41:654–66.
      OpenUrlPubMedWeb of Science
    3. Marlow N, Roberts L, Cooke R. Outcome at 8 years for children with birth weights of 1250 g or less. Arch Dis Child1993;68:286–90.
      OpenUrlAbstract/FREE Full Text
    4. Briscoe J, Gathercole SE, Marlow N. Everyday memory and cognitive ability in children born very prematurely. J Child Psychol Psychiatry2001;42:749–54.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      Botting N, Powls A, Cooke RW, et al. Attention deficit hyperactivity disorders and other psychiatric outcomes in very low birthweight children at 12 years. J Child Psychol Psychiatry1997;38:931–41.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      Battin MR, Maalouf EF, Counsell SJ, et al. Magnetic resonance imaging of the brain in very preterm infants: visualization of the germinal matrix, early myelination, and cortical folding. Pediatrics1998;101:957–62.
      OpenUrlAbstract/FREE Full Text
    7. ↵
      Childs AM, Ramenghi LA, Cornette L, et al. Cerebral maturation in premature infants: quantitative assessment using MR imaging. Am J Neuroradiol2001;22:1577–82.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      Felderhoff-Mueser U, Rutherford MA, Squier WV, et al. Relationship between MR imaging and histopathologic findings of the brain in extremely sick preterm infants. Am J Neuroradiol1999;20:1349–57.
      OpenUrlAbstract/FREE Full Text
    9. ↵
      Maalouf EF, Duggan PJ, Rutherford MA, et al. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr1999;135:351–7.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      Counsell SJ, Maalouf EF, Fletcher AM, et al. Magnetic resonance imaging assessment of myelination in the very preterm brain. Am J Neuroradiol2002;23:872–81.
      OpenUrlAbstract/FREE Full Text
    11. ↵
      Huppi PS, Warfield S, Kikinis R, et al. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann Neurol1998;43:224–35.
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      Ajayi-Obe M, Saeed N, Cowan FM, et al. Reduced development of cerebral cortex in extremely preterm infants. Lancet2000;356:1162–3.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      Counsell SJ, Kennea NL, Herlihy AH, et al. T2 relaxation values in the developing preterm brain. International Society of Magnetic Resonance in Medicine 2001:410.
    14. ↵
      Ferrie JC, Barantin L, Saliba E, et al. MR assessment of the brain maturation during the perinatal period: quantitative T2 MR study in premature newborns. Magn Reson Imaging1999;17:1275–88.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      Kuban KC, Leviton A. Cerebral palsy. N Engl J Med1994;330:188–95.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      Lucas A, Morley R, Cole TJ. Randomised trial of early diet in preterm babies and later intelligence quotient. BMJ1998;317:1481–7.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      Morley R. The influence of early diet on later development. J Biosoc Sci1996;28:481–7.
      OpenUrlPubMedWeb of Science
    18. ↵
      Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed2000;83:F177–81.
      OpenUrlAbstract/FREE Full Text
    19. Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med2001;344:95–101.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics1998;101:E7.
      OpenUrlPubMed
    21. ↵
      Dammann O, Kuban KC, Leviton A. Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev2002;8:46–50.
      OpenUrlCrossRefPubMedWeb of Science
    22. Duggan PJ, Maalouf EF, Watts TL, et al. Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet2001;358:1699–700.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      Hitti J, Tarczy-Hornoch P, Murphy J, et al. Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks’ gestation or less. Obstet Gynecol2001;98:1080–8.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      Counsell SJ, Allsop JM, Harrison MC, et al. Quantitative analysis of the cerebral white matter in preterm infants using diffusion weighted imaging. Pediatr Res2002;51(suppl S):2552.
      OpenUrl
    25. ↵
      Volpe JJ. Neurology of the newborn. Philadelphia: WB Saunders, 2001.
    26. ↵
      Perlman JM. White matter injury in the preterm infant: an important determination of abnormal neurodevelopment outcome. Early Hum Dev1998;53:99–120.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      Debillon T, Gras-Leguen C, Verielle V, et al. Intrauterine infection induces programmed cell death in rabbit periventricular white matter. Pediatr Res2000;47:736–42.
      OpenUrlCrossRefPubMedWeb of Science
    28. Perlman JM, Risser R, Broyles RS. Bilateral cystic periventricular leukomalacia in the premature infant: associated risk factors. Pediatrics1996;97(6 pt 1):822–7.
      OpenUrlAbstract/FREE Full Text
    29. ↵
      Zupan V, Gonzalez P, Lacaze-Masmonteil T, et al. Periventricular leukomalacia: risk factors revisited. Dev Med Child Neurol1996;38:1061–7.
      OpenUrlPubMedWeb of Science
    30. ↵
      van de Bor M., Guit GL, Schreuder AM, et al. Early detection of delayed myelination in preterm infants. Pediatrics1989;84:407–11.
      OpenUrlAbstract/FREE Full Text
    31. ↵
      Sie LT, van der Knapp MS, Wezel-Meijler G, et al. Early MR features of hypoxic-ischemic brain injury in neonates with periventricular densities on sonograms. Am J Neuroradiol2000;21:852–61.
      OpenUrlAbstract/FREE Full Text
    32. ↵
      Inder T, Huppi PS, Zientara GP, et al. Early detection of periventricular leukomalacia by diffusion-weighted magnetic resonance imaging techniques. J Pediatr1999;134:631–4.
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      Roelants-van Rijn AM, Nikkels PG, Groenendaal F, et al. Neonatal diffusion-weighted MR imaging: relation with histopathology or follow-up MR examination. Neuropediatrics2001;32:286–94.
      OpenUrlPubMedWeb of Science
    34. ↵
      Counsell SJ, Herlihy AH, Robertson NJ, et al. Elevation of T1 and T2 values in the cerebral white matter in periventricular leukomalacia. Proceedings of the International Society of Magnetic Resonance in Medicine2000;3:1933.
      OpenUrl
    35. ↵
      Lin Y, Okumura A, Hayakawa F, et al. Quantitative evaluation of thalami and basal ganglia in infants with periventricular leukomalacia. Dev Med Child Neurol2001;43:481–5.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      Roelants-van Rijn AM, Groenendaal F, Beek FJ, et al. Parenchymal brain injury in the preterm infant: comparison of cranial ultrasound, MRI and neurodevelopmental outcome. Neuropediatrics2001;32:80–9.
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      Takashima S, Iida K, Deguchi K. Periventricular leukomalacia, glial development and myelination. Early Hum Dev1995;43:177–84.
      OpenUrlCrossRefPubMedWeb of Science
    38. ↵
      Inder TE, Huppi PS, Warfield S, et al. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol1999;46:755–60.
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      Franco P, David P, Verheulpen D, et al. Neurological follow-up of preterms with nonspecific focal MRI white matter signal abnormalities. Childs Nerv Syst2002;18:103.
      OpenUrl
    40. ↵
      Sie LT, van der Knaap MS, Hart AA, et al. Predictive value of neonatal MRI with respect to late MRI findings and clinical outcome. A study in infants with periventricular densities on neonatal ultrasound. In: Sie LTL, ed. Early MRI and outcome in perinatal hypoxic-ischaemic white matter injury. Amsterdam, 2001:93–119.
    41. ↵
      Rutherford MA. Hemorrhagic lesions of the newborn brain. In: Rutherford MA, ed. MRI of the neonatal brain. London: WB Saunders, 2002:171–200.
    42. ↵
      Volpe JJ. Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis. Semin Pediatr Neurol1998;5:135–51.
      OpenUrlCrossRefPubMed
    43. Sheth RD. Trends in incidence and severity of intraventricular hemorrhage. J Child Neurol1998;13:261–4.
      OpenUrlAbstract/FREE Full Text
    44. ↵
      Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994. Pediatrics2000;105:1216–26.
      OpenUrlAbstract/FREE Full Text
    45. ↵
      Petaja J, Hiltunen L, Fellman V. Increased risk of intraventricular hemorrhage in preterm infants with thrombophilia. Pediatr Res2001;49:643–6.
      OpenUrlPubMedWeb of Science
    46. ↵
      Evrard P, Gressens P, Volpe JJ. New concepts to understand the neurological consequences of subcortical lesions in the premature brain. Biol Neonate1992;61:1–3.
      OpenUrlCrossRefPubMedWeb of Science
    47. ↵
      Papile LA, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr1983;103:273–7.
      OpenUrlCrossRefPubMedWeb of Science
    48. Resch B, Gedermann A, Maurer U, et al. Neurodevelopmental outcome of hydrocephalus following intra-/periventricular hemorrhage in preterm infants: short- and long-term results. Childs Nerv Syst1996;12:27–33.
      OpenUrlCrossRefPubMedWeb of Science
    49. Levy ML, Masri LS, McComb JG. Outcome for preterm infants with germinal matrix hemorrhage and progressive hydrocephalus. Neurosurgery1997;41:1111–17.
      OpenUrlPubMedWeb of Science
    50. ↵
      Vohr B, Garcia CC, Flanagan P, et al. Effects of intraventricular hemorrhage and socioeconomic status on perceptual, cognitive, and neurologic status of low birth weight infants at 5 years of age. J Pediatr1992;121:280–5.
      OpenUrlCrossRefPubMedWeb of Science
    51. ↵
      Takashima S, Mito T, Ando Y. Pathogenesis of periventricular white matter hemorrhages in preterm infants. Brain Dev1986;8:25–30.
      OpenUrlPubMedWeb of Science
    52. ↵
      Volpe JJ, Herscovitch P, Perlman JM, et al. Positron emission tomography in the newborn: extensive impairment of regional cerebral blood flow with intraventricular hemorrhage and hemorrhagic intracerebral involvement. Pediatrics1983;72:589–601.
      OpenUrlAbstract/FREE Full Text
    53. ↵
      Taylor GA. Effect of germinal matrix hemorrhage on terminal vein position and patency. Pediatr Radiol1995;25(suppl 1):S37–40.
      OpenUrlPubMed
    54. ↵
      Counsell SJ, Maalouf EF, Rutherford MA, et al. Periventricular haemorrhagic infarct in a preterm neonate. Eur J Paediatr Neurol1999;3:25–7.
      OpenUrlCrossRefPubMed
    55. ↵
      Haddad J, Messer J, Aranda J. Periventricular haemorrhagic infarction associated with subependymal germinal matrix haemorrhage in the premature newborn. Report of two cases. Eur J Pediatr1992;151:63–5.
      OpenUrlCrossRefPubMedWeb of Science
    56. ↵
      Volpe JJ. Subplate neurons-missing link in brain injury of the premature infant? Pediatrics1996;97:112–13.
      OpenUrlAbstract/FREE Full Text
    57. ↵
      de Vries LS, Roelants-van Rijn AM, Rademaker KJ, et al. Unilateral parenchymal haemorrhagic infarction in the preterm infant. Eur J Paediatr Neurol2001;5:139–49.
      OpenUrlCrossRefPubMed
    58. ↵
      Perlman JM, Rollins N, Burns D, et al. Relationship between periventricular intraparenchymal echodensities and germinal matrix-intraventricular hemorrhage in the very low birth weight neonate. Pediatrics1993;91:474–80.
      OpenUrlAbstract/FREE Full Text
    59. ↵
      van de Bor M, Verloove-Vanhorick SP, Baerts W, et al. Outcome of periventricular-intraventricular hemorrhage at 2 years of age in 484 very preterm infants admitted to 6 neonatal intensive care units in the Netherlands. Neuropediatrics1988;19:183–5.
      OpenUrlPubMedWeb of Science
    60. McMenamin JB, Shackelford GD, Volpe JJ. Outcome of neonatal intraventricular hemorrhage with periventricular echodense lesions. Ann Neurol1984;15:285–90.
      OpenUrlCrossRefPubMedWeb of Science
    61. ↵
      Guzzetta F, Shackelford GD, Volpe S, et al. Periventricular intraparenchymal echodensities in the premature newborn: critical determinant of neurologic outcome. Pediatrics1986;78:995–1006.
      OpenUrlAbstract/FREE Full Text
    62. ↵
      de Vries LS, Groenendaal F, van Haastert IC, et al. Asymmetrical myelination of the posterior limb of the internal capsule in infants with periventricular haemorrhagic infarction: an early predictor of hemiplegia. Neuropediatrics1999;30:314–19.
      OpenUrlCrossRefPubMedWeb of Science
    63. ↵
      Grunnet ML, Shields WD. Cerebellar hemorrhage in the premature infant. J Pediatr1976;88(4 pt 1):605–8.
      OpenUrlCrossRefPubMedWeb of Science
    64. ↵
      Martin R, Roessmann U, Fanaroff A. Massive intracerebellar hemorrhage in low-birth-weight infants. J Pediatr1976;89:290–3.
      OpenUrlCrossRefPubMedWeb of Science
    65. ↵
      Pape KE, Armstrong DL, Fitzhardinge PM. Central nervous system pathology associated with mask ventilation in the very low birthweight infant: a new etiology for intracerebellar hemorrhages. Pediatrics1976;58:473–83.
      OpenUrlAbstract
    66. ↵
      Tuck S, Ment LR. A follow-up study of very low-birthweight infants receiving ventilatory support by face mask. Dev Med Child Neurol1980;22:633–41.
      OpenUrlPubMedWeb of Science
    67. ↵
      Donat JF, Okazaki H, Kleinberg F. Cerebellar hemorrhages in newborn infants. Am J Dis Child1979;133:441.
      OpenUrlCrossRefPubMed
    68. ↵
      Merrill JD, Piecuch RE, Fell SC, et al. A new pattern of cerebellar hemorrhages in preterm infants. Pediatrics1998;102:E62.
      OpenUrlCrossRefPubMed
    69. ↵
      Kennea NL, Rutherford MA, Counsell SJ, et al. Brain injury in extremely preterm infants at birth and at term corrected age using magnetic resonance imaging. Pediatr Res2002;51(suppl S):2559.
      OpenUrl
    70. ↵
      Perlman JM, Nelson JS, McAlister WH, et al. Intracerebellar hemorrhage in a premature newborn: diagnosis by real-time ultrasound and correlation with autopsy findings. Pediatrics1983;71:159–62.
      OpenUrlAbstract/FREE Full Text
    71. ↵
      Mercuri E, He J, Curati WL, et al. Cerebellar infarction and atrophy in infants and children with a history of premature birth. Pediatr Radiol1997;27:139–43.
      OpenUrlCrossRefPubMedWeb of Science
    72. ↵
      Scott RB, Stoodley CJ, Anslow P, et al. Lateralized cognitive deficits in children following cerebellar lesions. Dev Med Child Neurol2001;43:685–91.
      OpenUrlCrossRefPubMedWeb of Science
    73. ↵
      Huppi PS, Maier SE, Peled S, et al. Microstructural development of human newborn cerebral white matter assessed in vivo by diffusion tensor magnetic resonance imaging. Pediatr Res1998;44:584–90.
      OpenUrlCrossRefPubMedWeb of Science
    74. ↵
      Zimine S, Lazeyras F, Henry F, et al. Diffusion tensor imaging of human newborns. Evidence of altered brain development in newborn babies with intruterine growth restriction. Proceedings of ISMRM Workshop on Diffusion Weighted MRI: Biophysical Issues—What Can We Measure? ISMRM, 2002:323.
    75. ↵
      Peterson BS, Vohr B, Staib LH, et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA2000;284:1939–47.
      OpenUrlCrossRefPubMedWeb of Science
    76. ↵
      Murphy BP, Inder TE, Huppi PS, et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics2001;107:217–21.
      OpenUrlAbstract/FREE Full Text
    77. ↵
      Modi N, Lewis H, Al Naqeeb N, et al. The effects of repeated antenatal glucocorticoid therapy on the developing brain. Pediatr Res2001;50:581–5.
      OpenUrlPubMedWeb of Science

    Linked Articles

    • Fantoms
      Fantoms
      Martin Ward Platt
      Archives of Disease in Childhood - Fetal and Neonatal Edition 2003; 88 F260-F260 Published Online First: 01 Jul 2003. doi: 10.1136/fn.88.4.F260-a