Fetal brain injury

Revue

J. Neuroradiol., 2004, 31, 123-137 © Masson, Paris, 2004

FETAL BRAIN INJURY H. BRUNEL (2), N. GIRARD (1), S. CONFORT-GOUNY (3), A. VIOLA (1), K. CHAUMOITRE (1), C. D’ERCOLE (5), D. FIGARELLA-BRANGER (4), C. RAYBAUD (2), P. COZZONE (3), M. PANUEL (1) (1) Department of Radiology, Hopital Nord, Université de la Méditerranée. (2) Department of Neuroradiology, Hopital Timone. (3) CRMBM UMR CNRS 6612, Université de la Méditerranée. (4) Department of Pathology, Hopital Timone, Université de la Méditerranée. (5) Department of Obstetrics-Gynaecology, Hopital Nord, Université de la Méditerranée, Chemin des Bourrelly, 13915 Marseille cedex 20.

SUMMARY Improvements in MRI techniques widen the indications for fetal brain imaging and fetal brain injury represents the third indication of fetal brain magnetic resonance imaging (MRI) after the evaluation of suspected central nervous system (CNS) malformations and ventricular dilatation. Optimal MR imaging technique is necessary in order to collect as much data as possible about the fetal brain. Diffusion images can be used routinely in addition to the standard protocol of fetal brain MRI that consists of T1 and T2 weighted images of the fetal brain. Monovoxel proton magnetic resonance spectroscopy can also be performed in utero, but this technique is still more part of research protocol than of routine clinical protocol. Fetal brain injury includes hypoxia-ischemia, congenital infections (especially toxoplasmosis and cytomegalovirus infections), brain damage due to malformation such as vascular brain malformation and heart malformation, pregnancies at risk of fetal brain damage, and even inherited metabolic diseases, especially mitochondrial diseases. MRI findings in fetal brain injury consist of acute or chronic lesions that can be seen alone or in combination. Acute response of the fetal brain is less commonly seen than the chronic response compared to the brain response encountered in the postnatal period. Key words: human fetal brain, MRI, diffusion, MRS, brain injury, in utero.

RÉSUMÉ Lésions acquises du cerveau fœtal Grâce aux améliorations récentes des techniques d'IRM, les indications d'IRM cérébrale foetale sont aujourd'hui de plus en plus fréquentes. L'exploration des lésions acquises du cerveau foetal représente la troisième indication d'IRM cérébrale foetale, après l'évaluation morphologique des malformations cérébrales et des dilatations ventriculaires. Une technique optimale d'imagerie est nécessaire afin de permettre une analyse très précise du cerveau foetal. Le protocole standard comprend des séquences pondérées T1 et des séquences pondérées T2. L’ IRM en pondération de diffusion peut également être proposée en routine clinique. La spectroscopie monovoxel du proton peut être réalisée, mais n’est pas de pratique courante clinique. Les lésions cérébrales foetales acquises incluent l'hypoxo-ischémie, les infections congénitales (notamment la toxoplasmose et le cytomégalovirus), les lésions cérébrales consécutives à différentes malformations (malformations vasculaires cérébrales, malformations cardiaques par exemple), les grossesses à risque pour le cerveau foetal et les maladies métaboliques innées comme les maladies mitochondriales. La séméiologie IRM des lésions cérébrales foetales acquises comprend des lésions aiguës et des lésions chroniques, soit isolées, soit combinées. Les lésions aiguës du cerveau foetal sont moins fréquentes que les lésions chroniques, à l'inverse de ce que l'on constate dans la période post-natale. Mots-clés : Cerveau fœtale humain, IRM, diffusion, SRM, lésions acquises, in utero.

INTRODUCTION Fetal brain injury represents the third indication for fetal brain magnetic resonance imaging (MRI) after the evaluation of suspected central nervous system (CNS) malformations and ventricular dilatation [5, 28-30, 33, 34]. Magnetic resonance imaging (MRI) is currently the method of choice to evaluate brain maturation [6, 11, 55, 58, 66] and development [2, 12, 25, 27, 38] as well as its anomalies [1, 13, 21, 23, 29, 30, 33, 34, 37, 40, 52, 62] and therefore constitutes a useful procedure in utero when ultrasonography is inconclusive. MRI allows also to illustrate the natural history of fetal brain injury with regards to the stage of development because MRI can be perReprint request: N. GIRARD, address above. e-mail: [email protected]

formed several times during the pregnancy in a given case. Fetal brain response to injury whatever its cause and origin is different from what we know from the neonatal and infantile periods [6, 22, 32, 43, 68]. Improvements in MRI techniques widen the indications for fetal brain imaging. The increasing use of prenatal MR scans may also be related to the safety of fetal MRI that has been highlighted since experimental studies did not show any side effects to the embryo. Optimal MR imaging technique is necessary in order to collect as much information as possible about the fetal brain condition. Diffusion images can also be used routinely [4]. Monovoxel proton spectroscopy can also be performed in utero. However this latter technique is not routinely developed and is still more part of research protocol than of routine clinical protocol.

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FIG. 1. – Séquence HASTE, matrice 512. Comparaison entre une image coronale obtenue à partir de 4 éléments antérieurs orientés horizontalement (a) et une image axiale obtenue à partir de 4 éléments antérieurs orientés verticalement (b). Notez l’asymétrie de signal des hémisphères cérébraux. La région temporale droite est plus claire que la gauche (b). Cette inhomogénéité n’est pas visible sur l’image a.

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FIG. 1. – HASTE images with a matrix of 512. Comparison between a coronal image obtained with 4 anterior elements oriented transversally (a) and an axial image obtained with 4 anterior elements placed vertically (b). Note the asymmetry in signal of the cerebral hemispheres; the right temporal area appears brighter than the contralateral side in b. This heterogeneity is not seen in a.

FIG. 2. – Comparaison entre des images coronales HASTE obtenues avec une matrice 512 (a) et une matrice 256 (b). Le contraste et la résolution spatiale sont meilleurs en a qu’en b. L’image est plus floue en b.

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FIG. 2. – Comparison of coronal HASTE images obtained with a matrix of 512 (a) and 256 (b). Contrast and resolution are better in a than in b. The image appears blurred in b compared to a.

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FIG. 3. – Comparaison entre une séquence turbo spin écho T1 (a, b) et une séquence écho de gradient T1 (c, d) chez un fœtus de 25 semaines présentant une agénésie partielle du corps calleux. L’hypersignal des noyaux gris centraux (a, c), du à une densité cellulaire élevée, et de la partie postérieure du tronc cérébral du aux processus de myélinisation (b, d) est plus facilement identifiable sur les séquences en écho de gradient (c, d). Il faut également souligner la meilleure différenciation entre le ruban cortical et la substance blanche sous-jacente sur les images en écho de gradient (image c comparée à l’image a).

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FIG. 3. – Comparison of TSE T1 WI (a, b) and GE T1 WI (c, d) in a fetal brain of 25 weeks presenting partial corpus callosal agenesis. The bright signal of the basal ganglia (related to high cellularity) (a, c) and posterior brainstem (caused by myelination gliosis and myelin) (b, d) is better identified on gradient echo images (c, d). Also note the clear differentiation of the cortical ribbon from the underlying white matter on gradient echo image (c) compared to the TSE image (a).

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a b c d e f FIG. 4. – Comparaison de séquences pondérées T1 en écho de gradient et saturation de graisse avec un TE à 11 ms (a, b, c) et à 5 ms (d, e, f). Sur la séquence à TE court la différenciation entre substance grise et substance blanche est plus évidente. Il faut également remarquer que le contraste dû à la myélinisation est amélioré, notamment au niveau de la scissure centrale (image d comparée à l’image a) ainsi qu’au niveau de la partie inférieure du tronc cérébral (image f comparée à l’image c). FIG. 4. – Comparison of GE T1 WI with fat saturation with a TE of 11 ms (a, b, c) and of 5 ms (d, e, f). On GE images with a short TE, the differentiation between the grey and white matter is better seen. Also note that the contrast related to the brain myelination is improved especially within the central sulcus (d compared to a), as well as within the lower brainstem (f compared to c).

FIG. 5. – Comparaison entre une coupe coronale HASTE (a) et une coupe TRUE FISP 2D (b) obtenues en matrice 512. Le contraste et la pondération T2 sont meilleurs sur l'image HASTE. Remarquez que l'organisation en couches du parenchyme cérébral est mieux analysable sur l’image a que sur l’image b.

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FIG. 5. – Comparison of coronal HASTE (a) and TRUE FISP 2D (b) images obtained with an identical matrix of 512. The contrast and T2 weighting are improved on HASTE image. Note that the layering of the cerebral mantle is better identified in a than in b.

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FIG. 6. – Image sagittale reconstruite à partir d'une séquence TRUE FISP 3D, permettant l'obtention de coupes de 1,6 mm d'épaisseur, chez un foetus de 34 semaines présentant une hydrocéphalie. L'hypersignal correspondant à l'aqueduc de Sylvius n'est pas identifiable, suggérant une sténose de celui-ci. FIG. 6. – Reconstructed sagittal image of a TRUE FISP 3D sequence allowing 1,6 mm thick section, in a fetus of 34 weeks with hydrocephalus. Note that the bright signal of the aqueduct of Sylvius is not identified suggestive of aqueductal stenosis.

MR IMAGING AND PROTON MR SPECTROSCOPY TECHNIQUES Classical MR protocol includes single shot T2 weighted images (WI) following the 3 planes of the fetal head. Additional T1 WI are also performed in our experience in the sagittal, coronal and axial planes of the fetal head.

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Sedation of the mother is not always necessary along with the improvement of T2-weighted sequences that can be obtained in 30 seconds. However T1 WI of good quality require longer sequences (from 1 to 2 min), so that sedating the mother is often necessary in order to achieve a complete evaluation of the fetal brain including T1 and T2 WI as it is performed in the neonatal period. However, in breech presentation or transverse lie position, the fetal head moves along with the mother’s breathing. Fetal sedation is obtained by maternal premedication with flunitrazepam administered orally 15 min to 1 h before the MR examination. A combination of anterior body phased array coil of 4 elements is used together with the posterior spinal coils. The 4 anterior elements of the body phased array coil are placed transversally joining the posterior coils in order to achieve good signal homogeneity (figure 1). Parallel acquisition technique currently permits to obtain HASTE images with a matrix of 512 that gives an excellent identification of the cerebral parenchyma layering and low chemical shift artifacts compared to haste images with a matrix of 256 (figure 2). Regarding T1 WI, spin echo (SE), turbo spin echo (TSE), and gradient echo (GE) images can be obtained. Gradient echo images (FLASH sequence i.e. Fast Low Angle Shot) are used in our experience because of excellent differentiation between the cortical ribbon, white matter, and ventricular walls

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FIG. 7. – IRM de diffusion chez un foetus de 27 semaines (a, b), et de 23-24 semaines (c, d). Images TRACE avec une valeur b = 1000 (a, c) et images d'ADC (b, d). La couche intermédiaire de la substance blanche frontale est bien visible (flèche courbe sur les images a et c), de même que les fibres du corps calleux qui traversent la ligne médiane (2 flèches rectilignes sur l’image a) et que les fibres de la commissure antérieure (flèche blanche sur l’image c). La matrice germinale est également bien identifiable (flèche noire sur l’image c). Ces structures apparaissent en hypersignal sur les images TRACE et en hyposignal sur les images ADC.

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FIG. 7. – Diffusion images obtained in a fetus of 27 weeks (a, b) and of 23-24 weeks (c, d). TRACE images with a b value of 1000 (a, c) and ADC images (b, d). Are well identified the intermediate layer of the frontal white matter (curved arrow in a, c), the fibers crossing the midline at the level of the corpus callosum (arrows in a) and of the anterior commissure (white arrow in c), the thick germinal matrix (black arrow in c). These structures display a bright signal on TRACE images and a low signal on ADC images.

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FIG. 8. – Images HASTE en coupe coronale (a) et axiale (c) ; images de diffusion en coupes axiales (b, d), chez un foetus de 26 semaines qui présente des critères échographiques d'hypoxie foetale (a, b) et à titre de comparaison chez un foetus normal au même âge gestationnel (c, d). Il n’y a pas d’anomalie significative du cerveau anormal sur les images HASTE (image a comparée à l’image c). En revanche, l’aspect en multicouche du manteau cérébral n’est pas identifiable sur le cerveau anormal (image b comparée à l’image d). Cet aspect est évocateur d’une atteinte de la substance blanche.

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FIG. 8. – Coronal (a) and axial (c) HASTE images, and axial diffusion images (b, d) obtained in a 26 weeks fetus presenting US criteria of fetal hypoxia (a, b) compared to the normal aspect expected at the same age (c, d). The abnormal brain does not show evidence of signal changes on T2 WI (a compared to c). On the other hand the normal layering of the cerebral hemisphere is not identified in the abnormal brain (b compared to d) suggestive of white matter damage.

as opposed to TSE images (figure 3). Fetal head contrast can be improved on the 1.5 Tesla magnet by adding two bands of saturation that are positioned on the maternal subcutaneous fat of the abdominal wall and of the lower back, by using gradient echo images with fat saturation in order to suppress the signal from peritoneal fat, and by using a GE sequence with short TE (figure 4). Regarding T2 WI, TSE, HASTE images can be obtained [61, 64, 69]. Acquisition time of HASTE (Half-Fourier Single Shot Turbo Spin -Echo) images is short: about 2 sec for each slice, that is 30 sec for

FIG. 9. – Illustration de la localisation du volume d'intérêt en spectroscopie monovoxel du cerveau foetal sur une coupe pondérée T1 parasagittale. FIG. 9. – Illustration of the location of the volume of interest on a parasagittal T1 WI.

15 slices. Images obtained from HASTE sequence are true T2-weighted images with low susceptibility weighting and sequential slice capability. This last advantage improves the management of fetal movement. The low susceptibility is in one way an advantage giving a very high contrast of the layering of the developing brain and in an other way a disadvantage because of the difficulty in depicting old hemorrhage. TRUE FISP images can also be obtained. However the contrast given by these images is not as clear as with HASTE images in our experience (figure 5). 3D T2 weighted sequence (TRUE FISP sequence) is available in utero allowing 1,6 mm thick contiguous sections, which are extremely helpful in evaluating the midline, cortical sulcation and skull base abnormalities. Figure 6 shows ventricular dilatation with an undetectable aqueduct of sylvius. Other types of sequences can be used under special conditions: Angiographic images are obtained at our institution by a sequential 2D FLASH sequence which gives a good compromise between vascular and tissular contrast; inversion recovery images allow a very good delineation of the cortical ribbon, extra-axial CSF spaces and consequently of lesions developed from the subarachnoid space [33, 34]. Diffusion images (echo planar images) can also be performed [4, 65] such as in the neonatal period to detect cytotoxic and/or vasogenic edema [16, 17, 51]. However the acute response of the fetal brain is not as common as the neonatal brain response. On the other hand, T2 diffusion images are extremely useful

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FIG. 10. – Aspect typique d'une spectroscopie monovoxel du cerveau foetal normal, obtenue en séquence PRESS avec un TE à 30 ms (a, c, e) puis avec un TE à 135 ms (b, d, f), à 22 (a, b), 27 (c, d) et 34 (e, f) semaines de gestation. FIG. 10. – Typical proton MR spectra of healthy fetal brain from subjects obtained with a PRESS sequence at TE=30 ms (a,b,c); and with a PRESS sequence at TE=135 ms (d,e,f), respectively at 22, 27, and 34 weeks of gestation.

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FIG. 11. – Images HASTE dans le plan axial (a) et coronal (b). Spectroscopie cérébrale foetale en séquence PRESS avec un TE à 30 ms (c) puis avec un TE à 135 ms (d), chez un foetus de 33 semaines. Les lésions cérébrales sont représentées par une dilatation ventriculaire unilatérale modérée avec une hémorragie ancienne de la matrice germinale. Le spectre obtenu dans la substance blanche homolatérale à la ventriculomégalie est caractérisé par une augmentation majeure de la créatine, fortement évocatrice d'une gliose (c), un taux élevé de glutamine-glutamate et un élargissement du pic de N-acétylaspartate, suggérant la présence d'un métabolite supplémentaire dont le pic de résonance se superpose à celui du N-acétylaspartate. Cette hypothèse est soutenue par le faible niveau de N-acétylaspartate sur le spectre correspondant à un TE long (d). Par ailleurs, le pic correspondant à la résonance de la choline semble diminué sur la séquence à TE long (par comparaison avec les spectres obtenus chez les foetus normaux du même âge), ce qui suggère que le pic de résonance de la choline observé sur la séquence à TE court correspond en fait à plusieurs métabolites. FIG. 11. – Proton MR spectra of fetal brain obtained with PRESS sequence at TE=30 ms (a); and at TE=135 ms (b), from an abnormal fetal brain at 33 weeks of gestation. Brain damage consists of unilateral mild ventricular dilatation with old hemorrhage of the germinal matrix (not shown). The spectrum obtained in the white matter ipsilateral to the ventriculomegaly is characterized by a marked increase in creatine highly suggestive of gliosis (a), a high content of glutamine and glutamate and a broad resonance peak of N-acetylasparte suggesting the presence of an additional compound whose resonance peaks are superimposed with N-acetylasparte resonances. This hypothesis seems corroborated by the low level of N-acetylasparte at long echo time (b). Interestingly, the resonance of choline is apparently decreased at long echo time when compared to age-matched controls which suggests that the resonance peak observed at short echo time reflects the presence of several metabolites.

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FIG. 12. – Grossesse triple dont deux jumeaux sont monochoriaux. L’un des jumeaux est décédé à 16 semaines de gestation. L’IRM a été effectuée sur le survivant à 28 semaines (a, b), puis à 34 semaines (c, d), en séquence HASTE dans le plan axial (a, c) et dans le plan coronal (b, d). À 28 semaines, il existe une perte de substance blanche temporale associée à une nécrose responsable d’un hypersignal. L’organisation cérébrale en couches n’est plus visible à ce niveau et les espaces sous-arachnoïdiens sont élargis en regard. A 34 semaines la nécrose est toujours visible. Des anomalies corticales y sont associées, suggérant une schizencéphalie (flèche sur la figure c) avec une micropolygyrie sur les berges.

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FIG. 12. – Multiple pregnancy. Triplet with monochorionic twins and death of one twin at 16 weeks. The survivor twin is imaged at 28 (a, b) and 34 weeks (c, d). Axial (a, c) and coronal (b, d) HASTE images. Loss of white matter is seen in the right temporal area as well as necrosis that displays bright signal (b) at week 28. The normal layering is not identified in the same area with prominent subarachnoid spaces overlying the brain necrosis. At week 34 the white matter necrosis is still seen. Additional cortical lesion is currently identified suggestive of schizencephaly (arrow in c) with adjacent micropolygyria bordering the schizis.

in detecting old and small hemorrhagic foci. Diffusion images also can show the intermediate layer of the white matter prior 30 weeks of gestation (figure 7) and the premyelinating tracts through anisotropic images that can show anisotropy in tracts in which myelin is not detected with conventional T1 and T2 sequences [57]. The possibility to illustrate normal maturation can be highly useful to detect minor anomalies of the corpus callosum in utero, as well as white matter anomalies (figure 8). Anisotro-

pic, trace and ADC images are routinely obtained at our institution with b values of 500 and 1000. A potential role of proton magnetic resonance spectroscopy (MRS) exists in utero. Although the feasibility of fetal brain spectroscopy has been already demonstrated [42, 45, 46], metabolic mapping of the fetal brain at different gestational ages from 18 to 40 weeks is still needed. Proton MRS has become a noninvasive tool for examining cerebral metabolism in the neonate and infant in vivo [18, 67]. Spectra of the normal brain obtained at short

FIG. 13. – Hémorragie chez un fœtus de 33 semaines, exploré en séquence pondérée T1 dans le plan coronal (a) et en HASTE axial (b). Il existe un hématome sous dural apparaissant en hypersignal T1 et de signal mixte en pondération T2 (hyper et hyposignaux). On note également la présence d’une hydrocéphalie ainsi que d’une hémorragie intra-ventriculaire au sein du ventricule latéral droit apparaissant en hyposignal T2.

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FIG. 13. – Hemorrhage. Coronal T1 WI (a) and axial HASTE (b) in a fetus of 33 weeks. Subdural hemorrhage showing bright signal on T1 WI. The lesion displays low and bright signal on T2 WI. Also note the associated hydrocephalus and intraventricular hemorrhage of the right lateral ventricle that shows a low signal intensity on T2 WI.

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FIG. 14. – T1 coronal (a), HASTE coronal (b) et sagittal (c), chez un fœtus de 32 semaines. Examen histologique (d). Il existe des anomalies de la substance blanche apparaissant en hyposignal T1 et en hypersignal T2 (flèches sur les figures b et c) des régions sous corticales frontales, notamment à gauche, suggérant une leucomalacie confirmée à l’analyse histologique.

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FIG. 14. – Axial T1 WI (a), and coronal (b) HASTE images and sagittal (c) in a fetus of 32 weeks. Histology (d). White matter abnormality is seen as low signal intensity on T1 WI and bright signal intensity on T2 (arrow in b and c) in the subcortical white matter of the frontal areas predominantly of the left cerebral hemisphere suggestive of leukomalacia that was confirmed at histology.

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FIG. 15. – Ventriculomégalie unilatérale chez un fœtus de 33 semaines exploré pour une séroconversion toxoplasmique. Séquences HASTE en coupes sagittale (a) et axiales (b,c,d). Il faut noter une irrégularité de la paroi ventriculaire du ventricule latéral gauche (flèche sur la figure b). Remarquez encore l’épaississement de l’épendyme et de la zone germinale au niveau de l’atrium du ventricule latéral (flèche sur la figure d).

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FIG. 15. – Unilateral ventriculomegaly in a fetus of 33 weeks that has been imaged for toxoplasmosis seroconversion. Sagittal (a) and axial (b, c, d) HASTE images. Note the irregular ventricular wall of the right lateral ventricle (arrow in b). Also note the thickened ependymal/germinal zone at the atria level (arrow in d).

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FIG. 16. – Atrophie. Séquence HASTE, coupes axiale (a) et sagittale (b), chez un fœtus de 27 semaines présentant un oligoamnios et un immobilisme fœtal. Il existe une ventriculomégalie modérée bilatérale avec élargissement des espaces sousarachnoïdiens dans les régions pariétales. La substance blanche a pratiquement disparu dans les régions pariéto-temporooccipitales, notamment à droite. Notez l’irrégularité du ruban cortical suggérant une micropolygyrie (flèche sur la figure a).

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FIG. 16. – Atrophy. Axial (a) and sagittal (b) HASTE images of a 27 weeks old fetus presenting with oligohydramnios and decreased fetal movements. Mild bilateral ventriculomegaly with enlarged subarachnoid spaces in the parietal areas. The white matter is almost absent in the parieto-temporo-occipital areas predominantly on the right side. Also note the irregular cortical ribbon suggestive of micropolygyria (arrow in a).

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TE are dominated by the peaks of four metabolites: N-acetyl-aspartate (NAA) at 2 ppm, creatine (Cr) at 3 ppm, choline (Cho) at 3.20 ppm and inositol (Ino) compounds at 3.56 ppm. 1H MRS studies have shown that NAA is specific of neurons while myoinositol is a glial marker. Creatine (and phosphocreatine) has been identified in both cell populations and is considered as an index of cell density. Choline is a constituent of membranes and an intermediary of the phosphatidylcholine pathway involved in catabolic and anabolic processes. This feature has great implications in the assessment of brain maturation or detection of various diseases. Increased choline in an adult brain generally discloses a degenerative or

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tumoral disease whereas in neonates it is expressing a physiological process (myelination). From a technical point of view, proton spectroscopy is more difficult to perform in utero compared to the postnatal period because the coils used are not dedicated to brain imaging. Body phased array coils (4 coils) are used in combination with spinal coils (2 coils). Using images of fetal brain obtained in transverse, coronal and sagittal orientations, the proton MRS volume of interest (VOI) is carefully plaved over fetal brain tissue (figure 9). The size of the nominal VOI is 4.5 cc. In our experience spectra are acquired immediately after HASTE, T1 and diffusion images, using spin echo sequence (PRESS)

FIG. 17. – Cavité kystique du parenchyme cérébral. Séquence HASTE, coupes axiale (a) et sagittale (b), chez un fœtus de 26 semaines exploré pour une infection toxoplasmique. Il existe une cavité kystique frontale en hypersignal T2. Notez la dilatation ventriculaire associée et les multiples foyers en hyposignal T2, suggérant la présence de calcifications (flèche sur la figure a).

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FIG. 17. – Cystic cavity of the cerebral parenchyma. Axial (a) and sagittal (b) HASTE images in a fetus of 26 weeks with toxoplasmosis infection. A small cystic cavity of bright signal is seen in the frontal are. Note the associated ventricular dilatation and multiple foci of low signal intensity suggestive of calcifications (arrow in a). FIG. 18. – Kystes épendymaires. Séquence HASTE, coupes axiales (a, b), chez un fœtus de 33 semaines. Il existe des kystes épendymaires bilatéraux apparaissant comme des p cavités péri-ventriculaires, notamment dans les régions frontales. Ces kystes épendymaires sont habituellement bordés par un revêtement épendymaire non identifiable en IRM.

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FIG. 18. – Ependymal cyst. Axial (a, b) HASTE images in a 33 weeks old fetus. Bilateral ependymal cysts manifest periventricular cavities predominantly in the frontal areas but not exclusively. Ependymal cysts are usually surrounded by ependymal lining that is generally not identified at MRI.

FIG. 19. – Calcifications. Séquences pondérées T1 (a) et T2 (b) dans le plan coronal, chez un fœtus de 26 semaines dans un contexte d’infection à cytomégalovirus. Des calcifications de la paroi ventriculaire sont visibles en hypersignal T1, mais sont plus difficiles à objectiver en pondération T2, où elles apparaissent en hyposignal et peuvent être confondues avec la matrice germinale normale, épaisse à cet âge. Il faut également noter que l’organisation normale en couches du cerveau foetal n’est plus visible. De plus, la gyration est absente, suggérant une nécrose diffuse et des lésions corticales de type micropolygyrie.

FIG. 19. – Calcifications. Coronal T1 (a) and T2 (b) WI in a 26 weeks old fetus with cytomegalovirus infection. Calcifications of the ventricular walls are seen and display bright signal intensity on T1 WI. The low signal intensity on T2 WI is difficult to identify and can be mistaken with a normal germinal matrix that is thick at that gestational age. Also note the absence of the normal contrast and layering of the cerebral mantle, of the developing gyration, suggestive of diffuse necrosis and cortical lesion such as micropolygyria.

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with short echo time (TE 30 ms) and long echo time (TE 135 ms) (figure 10). The following parameters are used for short echo time sequence: TE 30 ms, repetition time TR 1500 ms, number of acquisitions 256, total acquisition time 6 min 30 sec and for long echo time sequence TE 135 ms, repetition time TR 1500 ms, number of acquisitions 278, total acquisition time 7 min 03 sec. To optimize signal to noise ratio, the number of acquisitions has to be increased by a factor two, compared to the postnatal period because the filling factor of receiver coils is smaller than the filling factor of brain coil. For each sequence, six spectra are acquired simultaneously, 4 are obtained from the body phased array coils and 2 from the spinal coils; only one spectrum with best signal to noise ratio corresponding to the closest receiver coil is processed. From a metabolic point of view, peaks of NAA and creatine are increasing along with brain maturation whereas choline and myo-inositol peaks are decreasing [47]. In utero studies [45, 46] show that NAA signal increases significantly with advancing gestational age while no significant change is seen with Cr and inositol level. On the other hand the peak of choline tends to decrease without reaching significance. Figure 10 displays the brain spectra obtained from three fetuses of different age (22, 27 and 34 weeks of gestational age respectively) obtained at short and long echo time (TE=30 ms and TE=135 ms). This figure summarizes the major features of fetal brain evolution with increasing age. At 22 weeks of gestational age, the brain spectrum is essentially characterized by the presence of two prominent peaks assigned to myo-inositol, and choline. Creatine is clearly visible whereas N-acetylaspartate is barely detectable. With increasing age, myo-inositol and choline peaks tend to decrease, while N-acetylaspartate and creatine resonance peaks become well defined and more intense. At 34 weeks of gesta-

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tional age, the fetal cerebral metabolic pattern is already very similar to the neonatal spectrum, with three dominant peaks: choline, myo-inositol and Nacetylaspartate. The possibility to establish normative curves for each brain metabolite is of great potential value for the early detection of abnormal metabolic variations in fetuses with suspected brain damage. Figure 11 shows the brain spectrum of a fetus with unilateral mild ventricular dilatation characterized by an enormous increase in creatine seen on short echo time highly suggestive of gliosis that is not currently detectable on conventional MR images. Moreover, in certain conditions such as in isolated mild ventriculomegaly, MRS will help in distinguishing possible normal and abnormal brains in order to give additional information in term of prognosis that is still quite challenging [9].

WHAT IS FETAL BRAIN INJURY? Factors leading to pregnancy at risk of fetal brain damage are numerous and include maternal factors, obstetric factors and fetal factors. Fetal brain injury includes hypoxia-ischemia, congenital infections (especially toxoplasmosis and cytomegalovirus infections), brain damage due to malformation such as vascular brain malformation and heart malformation, pregnancies at risk of fetal brain damage, and even inherited metabolic diseases, especially mitochondrial diseases. Tumors are also part of acquired disorders but are uncommon and will not be described here. Fetal brain damage can manifest on ultrasound as fetal hypoxia; ultrasound criteria of fetal hypoxia include intrauterine growth retardation, abnormal doppler (especially umbilical), a bad score at biophysical profile which is dependant on fetal heart rate,

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FIG. 20. – Gliose de la substance blanche; association de réponses aiguës et chroniques du cerveau fœtal. Séquences pondérées T1 (a) et T2 (b) dans le plan axial chez un fœtus de 31 semaines. Examen histologique (c). Il existe une dilatation ventriculaire unilatérale avec hémorragie intra-ventriculaire responsable d’un hypersignal T1. Notez l’aspect irrégulier de la paroi ventriculaire (flèche sur la figure b), du à une abrasion épendymaire (flèche sur la figure c). Il existe une gliose de la substance blanche à l’examen histologique, non identifiable en IRM. FIG. 20. – White matter gliosis and combination of acute and chronic response of the fetal brain. Axial T1 (a) and T2 (b) WI obtained in a 31 weeks old fetus. Histology (c). Unilateral ventricular dilatation with intraventricular hemorrhage that displays a bright signal on T1 WI (a). Note the irregular ventricular wall (arrow in b) related to ependymal abrasion (arrow in c). Although no signal abnormality is seen in the adjacent white matter, histology on the other hand shows diffuse gliosis.

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FIG. 21. – Nécrose cérébelleuse. Séquence pondérée T2 dans le plan axial chez un fœtus de 22 semaines. Le signal normal du tronc cérébral et du cervelet n’est pas identifiable. La protubérance et les hémisphères cérébelleux sont en hypersignal, suggérant une nécrose étendue. FIG. 21. – Cerebellar necrosis. Axial T2 WI in a 22 weeks old fetus. The normal signal of the cerebellum and brainstem is not identified. The pons and cerebellar hemispheres show a diffuse bright signal compatible with extensive necrosis.

amniotic fluid volume, fetal breathing movements, gross body movements, fetal tone [24, 44, 56, 60, 70]. Pregnancies at risk of fetal brain damage consist of 1) toxic origin such as in carbon monoxide poisoning,

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fetal alcohol syndrome, cocaine exposure, 2) maternal/fetal coagulation disorders such as thrombocytopenia, alloimmunization, 3) maternal hypoxia such as trauma, sepsis, stroke, hemorrhage, cardiac arrest, 4) mechanic conditions such as placenta praevia, placental abruption, umbilical cord accident, 5) multiple pregnancy such as monochorionic twin pregnancy with twin-to-twin transfusion syndrome (TTTS), dichorionic twin pregnancy with death of a co-twin, 6) chorioamnionitis and prolonged rupture of membranes (PROM), alone or in combination. Risk of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) is increased in infants exposed to intrauterine infection [10, 19, 20]. PROM is also a known risk factor in developing leukomalacia [7, 8, 63, 71] and in adverse effect on development (cerebral palsy and/or mental delay) [14, 71]. Brain damage is thought to be related to cytokines mediated mechanisms. Cytokines contribute to the occurrence of IVH because of procoagulant activity and endothelial cell damage and is also involved in the induction of white matter damage. Monochorionic twin pregnancy with in utero death of one twin may lead to significant risks for the survivor such as brain damage [54]. In cases of TTS there is also a high risk of neurodevelopmental disorders for both the donor and the recipient [41, 48]. Fetal brain infections include the traditional TORCH (toxoplasmosis, rubella, cytomegalovirus and herpes simplex). However the range of possible infective agents is more extensive than that and human immunodeficiency virus (HIV), parvovirus,

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FIG. 22. – Nécrose cérébelleuse. Séquence HASTE dans le plan axial (a) et dans le plan coronal (b), chez un fœtus de 28 semaines. Puis, séquences pondérées T2 dans le plan sagittal (c) et coronal (e), T1 dans le plan axial (d), chez le même fœtus à 33 semaines.

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L’hémisphère cérébelleux droit est de petite taille. Noter la présence d’un limite nette de la zone nécrosée (flèches sur la figure b et sur la figure c) avec respect du cortex cérébelleux qui apparaît en hyposignal et linéaire (flèche sur la figure c).

FIG. 22. – Cerebellar necrosis; Axial (a) and coronal (b) HASTE images obtained at 28 weeks, and sagittal T2 WI (c), axial T1 WI (d), coronal (e) T2 WI acquired at 33 weeks. The right cerebellar hemisphere is small. Note the sharp limit of the necrosis (arrow in b and c) with preservation of part of the cortical ribbon that is seen as a linear area of low signal intensity (arrow in c).

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varicella, acute maternal sepsis (especially group B streptococcus infection) have also to be taken into account. Although inherited metabolic diseases are uncommonly detected in the prenatal period the onset of mitochondrial disorders can be seen in up to 36% of cases in neonates [53]. In utero brain damage such as venous thrombosis can be seen, probably related to hepatic failure and its consequent coagulation disorder [39]. Antenatal onset of other types of metabolic diseases exists, usually manifesting as nonspecific findings such as intrauterine growth retardation, polyhydramnios. This field of fetal expression of metabolic diseases remains poorly studied in term of fetal imaging and the exact metabolic defect is not always found postnatally, especially if the course of the disease is rapidly fatal.

MRI FINDINGS IN FETAL BRAIN INJURY MRI findings in fetal brain injury consist of acute or chronic lesions that can be seen alone or in combination. Cerebral abnormality can be found in up to 66.5% of hypoxic cases and up to 23% of fetal infection [28]. Calcifications and malformations, especially cortical malformation such as micropolygyria, are most likely seen in cases of congenital infection [5]. However cortical malformations can also be encountered in hypoxic cases such as in multiple pregnancy when death of a co-twin happened before 20 weeks since hypoxia-ischemia is known to interfere with cortical organization (figure 12). MR criteria of destructive lesions include abnormal ventricular morphology (irregular wall, asymmetry), abnormal appearance of the germinal matrix (asym-

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metry in thickness, nodular and irregular appearance), loss of cell layer visibility, loss of normal signal contrast, loss of maturation milestones and evidence of abnormal signal such as hemorrhage, edema, cystic cavitation and necrosis (figure 12). Acute response of the fetal brain consists of 1) hemorrhage which can be intraventricular, within the cerebral parenchyma, of the germinal matrix, and in the subdural spaces (figure 13), 2) white matter signal abnormality such as edema, loss of the intermediate layer in young fetuses, leukomalacia, 3) infarction, diffuse necrosis, 4) venous thrombosis. Hemorrhage generally manifests bright signal on T1 WI and low signal on T2 WI. Tiny foci of old hemorrhage can be difficult to identify and usually present as focal lesions of low signal on T2 WI with no signal abnormality on T1 WI. As already mentioned T2 echo planar images are useful in detecting such lesions made of old hemorrhage. Leukomalacia of acute stage characterized by periventricular nodules of bright signal on T1 WI and low signal on T2 WI is not commonly seen in utero [33, 34]. Subcortical leukomalacia is more frequent and manifests a bright signal on T2 WI and low signal on T1 WI (figure 14). The absence of the intermediate layer of the white matter can be the only MRI finding in young fetuses [33, 34]. White matter edema may be transient or lead to necrosis. Infarction of arterial distribution as seen in neonates is rare in utero. More common is diffuse necrosis of the cerebral parenchyma [34]. Selective neuronal necrosis as seen in hypoxic-ischemic encephalopathy of the neonate [6, 22, 35] which manifests T1 shortening (high signal intensity on T1 WI) within the cortex and/or the basal ganglia has not been encountered in our experience of prenatal

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FIG. 23. – Dysplasie cérébelleuse. Séquence HASTE dans le plan axial (a, b) et dans le plan sagittal (d). L’hémisphère cérébelleux droit est de petite taille. Remarquez l’irrégularité de la surface cérébelleuse qui présente un aspect nodulaire (flèches sur les figures a, b, d), suggérant davantage une dysplasie qu’une nécrose.

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FIG. 23. – Cerebellar dysplasia. Axial (a, b), coronal (c) and sagittal (d) HASTE images. The right cerebellar hemisphere is small. Note the irregular and nodular appearance of the cerebellar surface (arrow in a, b, d) that is more suggestive of dysplasia than necrosis.

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FIG. 24. – Atrophie ponto-cérébelleuse. Séquences pondérées T2 (a) et T1 (b) dans le plan sagittal, T2 dans le plan axial (c). Examen histologique (d). Le cervelet est de petite taille, de même que le tronc cérébral. Le relief antérieur de la protubérance est à peine visible. En histologie il existe une atrophie de la partie antérieure du tronc cérébral au niveau du pont.

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FIG. 24. – Pontocerebellar atrophy. Sagittal T2 (a) and T1 (b) WI, axial T2 WI (c), histology (d). The cerebellum is small with a shallow brainstem. The anterior pontine bulging is barely seen. Histology shows atrophy of the anterior brainstem at the level of the pons.

d fetal brain MRI. This is probably due to the greater resistance of neurons to hypoxia earlier in gestation and also to less acute events during the prenatal period compared to the peri and neonatal periods. Acute response of the fetal brain is encountered in 33% of hypoxic cases and in 22% of cases of infections with brain abnormality [28]. Chronic response of the fetal brain is more common and is seen in 67% of hypoxic cases and in 78% of cases of infections with brain abnormality [28]. This type of response consists of 1) ventricular dilatation, 2) thickened/irregular germinal matrix or ventricular wall (figure 15), 3) white matter gliosis [15], 4) atrophy (figure 16), 5) parenchymal cystic cavity (figure 17), 6) ependymal cyst (figure 18), 7) calcifications (figure 19), 8) malformations especially cortical malformations such as micropolygyria, schizencephaly (figure 12). Hydranencephaly represents the ultimate stage of diffuse necrosis. White matter gliosis is extremely difficult to detect at MRI in utero. Indirect features are usually seen such as ventricular dilatation and irregular ventricular wall (figure 20). As already mentioned MRS can be helpful in showing stigmata of parenchymal gliosis (figure 11). Irregular ventricular wall is a common MRI finding. This appearance usually corresponds to ependymal abrasion and white matter gliosis at autopsy (figure 20). Loss of volume is generally encountered in diffuse necrosis. Atrophy usually manifests ventricular dilatation and prominent subarachnoid spaces associated or not to signal

abnormality (figure 16). True ependymal cysts can be seen in hypoxia as well as in infection [49]. MRI is known to be extremely helpful in evaluating for associated brain abnormality with ventriculomegaly compared to ultrasound scan [30, 52]. Our experience shows that the percentage of cases with ventriculomegaly considered as isolated decreases from 84% to 42% after fetal brain MRI [30]. MRI is therefore part of the prenatal screening of ventriculomegaly besides maternal serological tests, amniotic fluid studies, karyotype. Ventricular dilatation is more likely unilateral in cases of destructive brain compared to bilateral ventriculomegaly either caused by CNS malformation or related to genetic origin [30]. Greater vulnerability of differentiating oligodendrocytes manifests as gliosis explaining the MRI features with a high incidence of ventricular dilatation, irregular germinal matrix or ventricular wall which is known to correspond to glial nodules of the matrix and/or ependymal lining at histology. Neuropathologically, ependymal reactions to injury include atrophy, discontinuity, subventricular gliosis, ependymal rosettes, inflammation with lack of regenerative or repair capacity of the fetal ependyma leading to abnormal developmental processes [59]; this contributes also to the high rate of chronic response of the fetal brain to injury. A combination of acute and chronic response is commonly seen (figure 20) in fetal brain injury probably related to repetitive insults to the fetal brain.

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Fetal brain injury of the posterior fossa can also be seen. Acute changes of diffuse necrosis of the cerebellum are easy to identify (figure 21) since edema usually shows a low signal on T1 WI and bright signal on T2 WI. On the other hand cerebellar hypoplasia is a challenge because of the difficulty in distinguishing malformation from necrosis (figure 22). Indeed pontocerebellar hypoplasia can be related to genetic, infectious, ischemic or dysplastic etiologies [1, 52]. However the non visibility of the cerebellar cortical ribbon and sharp limits of the cerebellar hemisphere are more likely related to brain injury (necrosis) than to malformation that generally manifests irregular cortical ribbon (figure 23). On the other hand abnormal pontine flexures, lack of the anterior pontine bulging, shallow brainstem are MRI findings suggestive of posterior fossa malformation (figure 24).

RÉFÉRENCES [1] ADAMSBAUM C, MOREAU V, BULTEAU C, BURSTYN J, LAIR MILAN F et al. Vermian agenesis without posterior foss a cyst. Pediatr Radiol 1994; 24: 543-546. [2] ADAMSBAUM C, GELOT A, ANDRE C, BARON J. Atlas d’IRM du cerveau fœtal. 1er ed., Paris, Masson, 2001. [3] BAETHMANN M, KAHN T, LENARD HG, VOIT T. Fetal CNS damage after exposure to maternal trauma during pregnancy. Acta Paediatr 1996; 85: 1331-1338. [4] BALDOLI C, RIGHINI A, PARAZZINI C, SCOTTI G, TRIULZI F. Demonstration of acute ischemic lesions in the fetal brain by diffusion magnetic resonance imaging. Ann Neurol 2002; 52: 243-246. [5] BARKOVICH AJ, GIRARD N. Fetal brain infections. Child Nerv Syst in press.

[15] BURKE CJ, TANNENBERG AE, PAYTON DJ. Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction. Dev Med Child Neurol 1997; 39: 726-730. [16] BYDDER GM, RUTHERFORD MA. Diffusion weighted imaging of the brain in neonates and infants. Magn Reson Imaging Clin N Am 2001; 9: 83-98. [17] BYDDER GM, RUTHERFORD MA, COWAN FM. Diffusionweighted imaging in neonates. Child’s Nerv Syst 2001; 17: 190-194. [18] CHABROL B, VION-DURY J, CONFORT-GOUNY S, COZZONE PJ. Magnetic resonance spectroscopy: a new technique for brain metabolism exploration in children. Arch Pediatr 1995; 2: 783-792. [19] DAMMAN O, LEVITON A. Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Seminars in Pediatric Neurology 1998; 5: 190201. [20] DAMMAN O, LEVITON A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997; 42 : 1-8. [21] DE LAVEAUCOUPET J, AUDIBERT F, GUIS F, RAMBAUD C, SUAREZ B, BOITHIAS-GUÉROT C et al Fetal magnetic resonance imaging (MRI) of ischemic brain injury. Prenat Diagn 2001; 21: 729-736. [22] FELDERHOFF-MUESER U, RUTHERFORD MA, SQUIER WV, COX P, MAALOUF EF, COUNSELL SJ et al. Relationship between MR imaging and histopathologic findings of the brain in extremely sick preterm infants. AJNR Am J Neuroradiol 1999; 20: 1349-1357. [23] FOLKERTH RD, MCLAUGHLIN ME, LEVINE D. Organizing posterior fossa hematomas simulating developmental cysts on prenatal imaging. J Ultrasound Med 2001; 20: 1233-1240. [24] GHIDINI A, SALAFIA CM, KIRN V, DORIA V, SPONG CY. Biophysical profile in predicting acute ascending infection in preterm rupture of membranes before 32 weeks. Obstet Gynecol 2000; 96: 201-206. [25] GAREL C. Le dévelopement du cerveau fœtal. Atlas IRM et biométrie. Montpellier, Sauramps Medical, 2000.

[6] BARKOVICH AJ. Pediatric neuroimaging, Third edition. Lippincott Williams and Wilkins, Philadelphia; 2000.

[26] GAREL C, BRISSE H, SEBAG G, ELMALEH M, OURY JF, HASSAN M. Magnetic resonance of the fetus. Pediatr Radiol 1998; 28: 201-211.

[7] BAUD O, FOIX-L’HELIAS L, KAMINSKI M, AUDIBERT F, JARREAU PH, PAPIERNIK E et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999; 341: 1190-1196.

[27] GAREL C, CHANTREL E, BRISSE H, ELMALEH M, LUTON D, OURY JF et al. Fetal cerebral cortex: normal gestational landmarks identified using prenatal MR imaging. AJNR Am J Neuroradiol 2001; 22: 184-189.

[8] BAUD O, VILLE Y, ZUPAN V, BOITHIAS C, LACAZE-MASMONTEIL T, GABILAN JC et al. Are neonatal brain lesions due to intrauterine infection related to mode of delivery? Br J Obstet Gynaecol 1998; 105 : 121-124.

[28] GIRARD N, GIRE C, SIGAUDY S, PORCU G, d’ERCOLE C, FIGARELLA-BRANGER D et al. MR imaging of acquired fetal brain disorders. Child’s Nerv Syst 2003; In press.

[9] BLOOM SL, BLOOM DH, DELLANEBIA C, MARTIN LB, LUCAS MJ, TWICKLER DM. The developmental outcome of children with antenatal mild isolated ventriculomegaly. Obstet Gynecol 1997; 90: 93-97. [10] BOUBRED F, TAUZIN L, DERHI SS, RAMELLA F, LACROZE V, MILLET V et al. Brain injury after premature rupture of membranes: magnetic resonance imaging (MRI) findings at 4 months corrected postnatal age. Pediatr Res 2002; 51: 439440. [11] BOUJRAF S, LUYPAERT R, SHABANA W, DE MEIRLEIR L, SOURBRON S, OSTEAUX M. Study of pediatric brain development using magnetic resonance imaging of anisotropic diffusion. Magn Reson Imag 2002; 20: 327-336. [12] BRISSE H, FALLET C, SEBAG G, NESSMANN C, BLOT P, HASSAN M. Supratentorial parenchyma in the developing fetal brain: in vitro MR study with histologic comparison. AJNR Am J Neuroradiol 1997; 18: 1491-1497. [13] BRISSE H, SEBAG G, FALLET C, ELMALEH M, GAREL C, ROSSIER L et al. Prenatal MRI diagnosis of corpus callosum agenesis: study of 20 cases with pathologic comparisons. J Radiol 1998; 79: 659-666. [14] BURGUET A, MONNET E, PAUCHARD JY, ROTH P, FROMENTIN C, DALPHIN ML et al. Some risk factors for cerebral palsy in very premature infants: importance of premature rupture of membranes and monochorionic twin placentation. Biol Neonate 1999; 75: 177-186.

[29] GIRARD N. Fetal MR Imaging. Eur Radiol 2002; 12: 18691871. [30] GIRARD N, GIRE C, MANCINI J, MILLET V, LETHEL V, SIGAUDY S et al. Ventriculomegaly. J Neuroradiol 2002; 29: 8. [31] GIRARD N, GAMBARELLI D. Normal fetal brain. Magnetic resonance imaging. An atlas with anatomic correlations. Brunelle F, Shaw D (eds), Rickmansworth, UK, 2001. [32] GIRARD NJ, RAYBAUD CA. Ventriculomegaly and pericerebral CSF collection in the fetus: early stage of benign external hydrocephalus? Child’s Nerv Syst 2001; 17: 239-245. [33] GIRARD N, RAYBAUD C, GAMBARELLI D. Pediatric neuroimaging: Fetal MR imaging. In: Recent advances in diagnostic neuroradiology, Demaerel Ph (ed), Springer-Verlag, Berlin, 2001; 373-398. [34] GIRARD N, RAYBAUD C, GAMBARELLI D, FIGARELLABRANGER D. Fetal brain MR imaging. Magn Reson Imaging Clin N Am 2001; 9: 19-56. [35] GIRARD N, MILLET V, RAYBAUD C. MRI assessment of prognosis in neonatal disorders. Child’s Nerv Syst 2000; 16: 52. [36] GIRARD N, RAYBAUD C, PONCET M. In vivo MR study of brain maturation in normal fetuses. AJNR Am J Neuroradiol 1995; 16: 407-413. [37] GIRARD N, RAYBAUD C, D’ERCOLE C, BOUBLI L, CHAU C, CAHEN S et al. In vivo MRI of the fetal brain. Neuroradiology 1993; 35: 431-436.

FETAL BRAIN INJURY

137

[38] GIRARD NJ, RAYBAUD CA. In vivo MRI of fetal brain cellular migration. J Comput Assist Tomogr 1992; 16: 265-267.

A review of magnetic resonance studies. Brain Res Bull 2001; 54: 255-266.

[39] GIRE C, GIRARD N, NICAISE C, EINAUDI MA, MONTFORT MF, DEJODE JM.Clinical features and neuroradiological findings of mitochondrial pathology in six neonates. Child’s Nerv Syst 2002; 18 : 621-628.

[56] PAVLOVA NG, KONSTANTINOVA NN, ARUTJUNYAN AV. Functional and biochemical criteria for investigation of brain development disorders. Int J Devl Neuroscience 1999; 17: 839-848.

[40] GUO WY, CHANG CY, HO DMT, WONG TT, SHEU MH, CHENG HC et al. A comparative MR and pathological study on fetal CNS disorders. Child’s Nerv Syst 2001; 17: 512-518.

[57] PRAYER D, PRAYER L. Diffusion-weighted magnetic resonance imaging of cerebral white matter development. Eur J Radiol 2002; In press.

[41] HAVERKAMP F, LEX C, HANISCH C, FAHNENSTICH H, ZERRES K. Neurodevelopmental risks in twin-to-twin transfusion syndrome: preliminary findings. Eur J Paediatr Neurol 2001; 5 : 21-27.

[58] RAYBAUD C, GIRARD N. Cerebral development and MRI. In: Neuroimaging in child neuropsychiatric disorders, Garreau B (ed): Springer-Verlag, Berlin, 1998; 59-88.

[42] HEERSCHAP A, VAN DEN BERG PP. Proton magnetic resonance spectroscopy of human fetal brain. Am J Obstet Gynecol 1994; 170: 1150-1151. [43] INDER TE, VOLPE JJ. Mechanisms of perinatal brain injury. Sem Neonatal 2000; 5: 3-16. [44] JAMES D. Assessing fetal health. Current Obstet Gynaecol 2002; 12: 243-249. [45] KOK RD, VAN DEN BERG PP, VAN DEN BERG AJ, NIJLAND R, HEERSCHAP A. Maturation of the human fetal brain as observed by 1H MR spectroscopy. Magn Reson Med 2002; 48: 611-616. [46] KOK RD, VAN DEN BERGH AJ, HEERSCHAP A, NIJLAND R, VAN DEN BERG PP. Metabolic information from the human fetal brain obtained with proton magnetic resonance spectroscopy. Am J Obstet Gynecol 2001; 185: 1011-1015. [47] KREIS R, ERNST T, ROSS BD. Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy. Magn Reson Med 1993; 30: 424-437. [48] LARROCHE JC, GIRARD N, NARCY F, FALLET-BIANCO C. Abnormal cortical plate (polymicrogyria), heterotopias and brain damage in monozygous twins. Biol Neonate 1994; 65: 343-352. [49] LARROCHE JC. Developmental pathology of the neonate. Elsevier/North-Holland Biomedical Press, Amsterdam; 1977. [50] LEVINE D, BARNES PD. Cortical maturation in normal and abnormal fetuses as assessed with prenatal MR imaging. Radiology 1999; 210: 751-758. [51] LIU AY, ZIMMERMAN RA, HASELGROVE JC, BILANIUK LT, HUNTER JV. Diffusion-weighted imaging in the evaluation of watershed hypoxic-iscemic brain injury in pediatric patients. Neuroradiology 2001; 43: 918-926. [52] MERZOUG V, FEREY S, ANDRE CH, GELOT A, ADAMSBAUM C. Magnetic resonance imaging of the fetal brain. J Neuroradiol 2002; 29: 76-90. [53] MUNNICH A, ROTIG A, CHRETIEN D, SAUDUBRAY JM, CORMIER V, RUSTIN P. Clinical presentation and laboratory investigations in respiratory chain deficiency. Eur J Pediatr 1996; 155: 262-264. [54] NICOLINI U, POBLETE A. Single intrauterine death in monochorionic twin pregnancies. Ultrasound Obstet Gynecol 1999; 14: 297-301. [55] PAUS T, COLLINS DL, EVANS AC, LEONARD G, PIKE B, ZIJDENBOS A. Maturation of white matter in the human brain:

[59] SARNAT HB. Ependymal reactions to injury. A review. J Neuropathol Exp Neurol 1995; 54: 1-15. [60] SEYAM YS, AL-MAHMEID MS, AL-TAMIMI HK. Umbilical artery doppler flow velocimetry in intrauterine growth restriction and its relation to perinatal outcome. Int J Gynecol Obstetrics 2002; 77: 131-137. [61] SIMON M, GOLDSTEIN R, COAKLEY F, FILLY R, BRODERICK K, MUSCI T et al. Fast MR imaging of fetal CNS anomalies in utero. AJNR 2000; 21: 1688-1698. [62] SONIGO PC, RYPENS FF, CARTERET M, DELEZOIDE AL, BRUNELLE FO. MR imaging of fetal cerebral anomalies. Pediatr Radiol 1998; 28: 212-222. [63] SPINILLO A, CAPUZZO E, STRONATI M, OMETTO A, ORCESI S, FAZZI E. Effect of preterm premature rupture of membranes on neurodevelopmental outcome: follow up at two years of age. Br J Obstet Gynaecol 1995; 102: 882-887. [64] STAZZONE MM, HUBBARD AM, BILANIUK LT, HARTY MP, MEYER JS, ZIMMERMAN RA et al. Ultrafast MR imaging of the normal posterior fossa in fetuses. AJR Am J Roentgenol 2000; 175: 835-839. [65] STEHLING MK, MANSFIELD P, ORDIDGE RJ, COXON R, CHAPMAN B, BLAMIRE A et al. Echo-planar imaging of the human fetus in utero. Magn Reson Med 1990; 13: 314-318. [66] VAN DER KNAAP MS, VALK J. Magnetic resonance of myelin, myelination and myelin disorders, 2nd edition. SpringerVerlag, Heidelberg, 1995. [67] VION-DURY J, SALVAN AM, CONFORT-GOUNY S, COZZONE PJ. Atlas of brain proton magnetic resonance spectra. Part II: Inheritited metabolic encephalopathies. J Neuroradiol 1998; 25: 281-289. [68] VOLPE JJ. Brain injury in the premature infant– from pathogenesis to prevention. Brain Dev 1997; 19: 519-534. [69] YAMASHITA Y, NAMIMOTO T, BE Y, TAKAHASHI M, IWAMASA J, MIYAZAKI et al. MR imaging of the fetus by a HASTE sequence. AJR Am J Roentgenol 1997; 168: 513519. [70] ZELOP CM, RICHARDSON DK, HEFFNER LJ. Outcomes of severely abnormal umbilical artery doppler velocimetry in structurally normal singleton fetuses. Obstet Gynecol 1996; 87: 434-438. [71] ZUPAN V, GONZALEZ P, LACAZE-MASMONTEIL T, BOITHIAS C, D’ALLEST AM, DEHAN M et al. Periventricular leukomalacia risk factors revisited. Dev Med Child Neurol 1996; 38: 1061-1067.