advanced obstetrical ultrasound: fetal brain, spine, and limb abnormalities

Advanced Obstetrical Ultrasound: Fetal Brain, Spine, and Limb Abnormalities

Preface

Noam Lazebnik, MD

Ultrasound Clin 3 (2008) idoi:10.1016/j.cult.2008.101556-858X/08/$ – see fron

Roee S. Lazebnik, MD, PhD

Guest Editors

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Ultrasound imaging is relatively inexpensive, safe,real-time, and readily available in hospitals andclinics throughout the world. For almost fortyyears, sonography progressed steadily with ad-vances in both clinical application and equipmentperformance. It is truly an indispensable tool in ob-stetrics for the diagnosis and management ofmany diseases, encompassing three generationsof women and millions of studies.

At a given time, many new areas of ultrasoundimaging are under development and investigation.Of these, volumetric ultrasound (three-dimen-sional [3D]/four-dimensional [4D] US) generatedparticularly great interest by the clinical commu-nity. Yet, despite decades of exploration, only dur-ing the past five years has volume sonographyadvanced to a practical state for routine diagnosticand interventional applications. Recent advancesin computer technology and visualization tech-niques allow real-time reconstruction, visualiza-tion, and manipulation of volume data usinginexpensive desktop computers. These continueto enable many physicians to explore the full po-tential of this modality for a variety of diagnosticand therapeutic applications.

The most clinically mature applications for vol-ume ultrasound technology are within the realm ofobstetrics. Often, a volume approach provides in-formation that is not readily available using conven-tional two-dimensional (2D) imaging. Volume orsurface rendering, coupled with multiplanner refor-matted displays, allow a comprehensive review offetal organs and skeleton. The ability to rapidly reor-ient the active view for optimal visualization of thetarget anatomy permits rapid identification of nor-mal and abnormal structures. Numerous studies

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demonstrate the utility of volume ultrasound in ob-stetrics, often citing advantages compared withconventional 2D ultrasound. These include im-proved comprehension of fetal anatomy by the par-ents, allowing more informed decisions formanagement of the pregnancy; improved mater-nal/fetal bondingdue to intuitivevisualization of fetalfeatures; improved identification of fetal anomalies;and greater accuracy in volume measurements todetermine the size and extent of anomalies.

In this issue of Ultrasound Clinics, Bornstein andcolleagues extensively review the technical andclinical aspects of performing a fetal neuroscan.The interested reader is referred to practical ad-vice on imaging-based techniques and investiga-tions, a comprehensive review by Pilu andcolleagues, for additional information.1 In anotherarticle, Lazebnik and coauthors discuss the utiliza-tion and advantages of 3D ultrasound technologyin the evaluation of normal and common congeni-tal spine and vertebral anomalies.

Proper diagnosis of congenital brain anomaliesis challenging, even with the use of modern sono-graphic equipment. A high level of skill and exper-tise, as well as an understanding of the nature ofthe abnormality, are of utmost importance. Imag-ing-based information may drive the choice ofprenatal testing (chromosome, DNA, culture). Pre-natal diagnosis of neuronal migration disorders,while difficult, is possible using antenatal diagnos-tic sonography. Dr. Ritsuko Pooh, a leading re-searcher of sonographic fetal brain imaging,discusses neuronal migration disorders causedby the abnormal migration of neurons in the devel-oping brain and nervous system. These include fo-cal cerebrocortical dysgenesis, heterotopia,

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polymicrogyria, lissencephaly or pachygyria, andschizencephaly.

Intracranial cystic lesions are frequently diag-nosed using fetal ultrasound. Although the mostprevalent cysts are benign (choroid plexus andarachnoid cysts), the mere suspicion of a brain le-sion during fetal life raises serious concerns for theprospective parents regarding the neurodevelop-mental outcome of their child. Malinger and col-leagues review the diagnostic approach andparticularly the differential diagnosis and progno-sis of intracranial cystic lesions identified in uteroin the context of prenatal counseling.

Although fetal ultrasound is considered the stan-dard of care in the evaluation of fetal anomalies, anunderstanding of the technology’s limitations isimportant. These limitations include decreasedvisibility of fetal structures due to maternal bodyhabitus, position of the fetal head, ossification ofthe fetal skull, and, in some cases, oligohydram-nios. Fetal MR imaging is applied by many medicalcenters in addition to ultrasound in an attempt tofurther enhance the antenatal diagnostic process.The utilization of fetal brain MR imaging is dis-cussed by Smith and Glenn, and is particularlyhelpful in the diagnosis of anomalies of sulcation,periventricular nodular heterotopia, callosal agen-esis, periventricular white matter injury, cerebellardysplasia, germinal matrix, and intraventricularhemorrhage during the second and third trimes-ters. This approach provides additional informa-tion for prenatal counseling and delivery planning.

Anomalies of the fetal brain are relatively com-mon and have the potential to result in severe mor-bidity or mortality. Though much has beenpublished regarding the fetal brain, less has beendiscussed about the fetal skull. Images of the fetalskull are routinely obtained during ultrasound ex-amination. The frontal, parietal, thin squama ofthe temporal bones and occipital bones, whichtogether form the calvaria, are visualized. The car-tilaginous zones of articulation of these bones—the coronal, sagittal, and lamboid sutures—arevisible, as well as the fontanelles (mainly the ante-rior and the posterior). By combining 2D multiplan-ner display and 3D-rendered images in themaximum mode, the various bones and suturesof the skull are clearly defined. The article bySheiner and Abramowicz discusses the sono-graphic features of the normal and abnormal fetalskull utilizing 2D and 3D ultrasound technologies.

Fetal limb abnormalities are of utmost impor-tance for prenatal diagnosis of fetal disordersand appropriate genetic counseling. Limb abnor-malities may be isolated or found in associationwith other abnormalities. These may result frommalformations, deformations, or disruptions, aswell as a part of a dysplasia such as skeletal dys-plasia. Sonographic image quality depends onmany factors, including the patient’s body habitus,quality of the ultrasound equipment, and operatorskill. The article by Koifman and coworkers re-views a methodical approach to imaging the fetuswith prenatally diagnosed limb abnormalities. Thisprocess enables the medical team to provide themother and the family with information regardingthe nature of the abnormality, differential diagno-sis, prognosis, and management options.

Overall, ultrasound is an established and contin-ually evolving modality for the evaluation of the fe-tus across many organ systems. As ultrasoundtechnology evolves, so does our understandingof the diagnostic information it provides. We alsocontinue to discover new techniques for image ac-quisition and methods for data manipulation. Ulti-mately, these developments lead to increaseddiagnostic confidence and thus benefit both pa-tients and clinicians.

Noam Lazebnik, MDDepartment of Obstetrics and Gynecology

University Hospitals of Cleveland11100 Euclid Avenue

Cleveland, OH 44060, USA

Roee S. Lazebnik, MD, PhDSiemens Healthcare

Ultrasound Business Unit1230 Shore Bird Way

Mountain View, CA 94043, USA

E-mail addresses:[email protected] (N. Lazebnik)

[email protected] (R.S. Lazebnik)

REFERENCE

1. Pilu G, Ghi T, Carletti A, et al. Three-dimensional ultra-

sound examination of the fetal central nervous sys-

tem. Ultrasound in Obstetrics and Gynecology

2007;30(2):233–45.

mailto:[email protected]


The Utilization of 3Dand 4D Technology inFetal Neurosonology
Eran Bornstein, MD*, AnaMonteagudo, MD, RDMS,Ilan E.Timor-Tritsch, MD, RDMS
KEYWORDS� 3D ultrasound � Brain anomaly� Fetal brain � Neuroscan � Volume manipulation

om

This article discusses the clinical use of three-di-mensional (3D) technology while performing a fetalneuroscan. Before reading this article, one shouldfirst be familiar with the technical aspects ofperforming this type of fetal study. For completedetails and comprehensive discussion of the ad-vantages of 3D technique as well as technicalaspects of obtaining quality volume data and sub-sequently displaying quality images, the reader isreferred to ‘‘3D and 4D Fetal Neuroscan: Sharingthe Know-how and Tricks of the Trade’’ byBornstein and colleagues in this issue of theClinics.

HOW TO PERFORM THE 3D FETAL NEUROSCANVolume Acquisition

To perform fetal neuroscan, either the transabdo-minal or the transvaginal approach should beinstituted.1–4 The authors’ preference, if fetal posi-tion permits, is the transvaginal approach, usinga high-frequency probe aligned with the fontanellewhen possible or the sagittal or coronal sutures.Fig. 1 displays a surface rendering of the fetal sculldemonstrating the acoustic window, which is con-sistent with the anterior fontanelle and the sutures.After identification of the anterior fontanelle or thesuperior sagittal sinus, an adequate 2D-transvaginalpicture of the fetal brain is obtained (Fig. 2). The fe-tal head may be gently manipulated and controlledby the examiner’s free hand to perfectly align thefootprint of the probe with a fontanelle or a suture.Once the ultrasound beam has been aligned with

Division of Maternal Fetal Medicine, Department of ObsMedicine, 550 First Avenue, Room 9N26, New York, NY 1* Corresponding author.E-mail address: [email protected] (E. Bornstein).

Ultrasound Clin 3 (2008) 489–516doi:10.1016/j.cult.2008.09.0061556-858X/08/$ – see front matter ª 2008 Elsevier Inc. Al

the longitudinal axis of the fetal brain through theanterior fontanelle or the sagittal suture, anda clear and diagnostically good 2D image of thefetal brain is seen, the brain volume can beacquired in the sagittal plane. A second volumeshould be obtained in the coronal plane by rotat-ing the probe 90� from the median section of thefetal brain. These two volumes should be ac-quired using a 60� to 80� angle width to includethe whole fetal brain in the volume. The qualityof the image depends on the acquisition speed.The authors’ usually prefer slow acquisitionspeed, yielding a more detailed volume for imag-ing the fetal brain. Fast acquisition using the lowor medium resolution is more adequate foracquiring volumes from a moving fetus. Whenthe transvaginal approach is not possible, thetransabdominal approach is used to obtain twoacquisitions in two perpendicular planes. As thesagittal plane is usually hard to obtain transabdo-minally, the volume should be acquired in boththe axial and the coronal planes. The authorsusually acquire the volume with a mechanicalsweep of a 45� angle width during the secondtrimester scan. With advanced gestational ageduring the third trimester, the angle width shouldbe increased to about 60� to include the entirebrain in the acquired volume.5

Orientation within the Volume

Now that the volume has been acquired, the au-thors’ protocol is to first manipulate the volume to

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Fig. 1. The cranial bone is seen in this 3D surface ren-dering of the fetal scalp demonstrating the coronal(c) and sagittal (s) sutures, as well as the anterior fon-tanelle (f), which serves as a large acoustic window inthis 15-postmenstrual week’s fetus. The vaginal probeshould be directed toward the fontanelle to enablea high-resolution fetal neuroscan. The sagittal andcoronal suture may also be used if fetal positiondoes not facilitate the transfontanelle approach.

Fig. 2. Multiplanar image of the fetal brain acquired transabtoward the anterior fontanelle (Boxes A and B). Box 3D dearea to which the probe is directed. Even with a transabdoming the beam through the anterior fontanelle (f). The sagit

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a ‘‘starting position’’ so it is always displayed in thesame orientation in the multiplanar display boxes:

dommonsinaltal (s

The authors’ protocol consists of manipulat-ing the volume so that the coronal planeis displayed in Box ‘‘A,’’ the sagittal planein Box ‘‘B’’ and the axial plane in Box ‘‘C.’’

Box B should display the fetal head in thesagittal plane when the fetus ‘‘looks’’ tothe left of the screen. This way, in the cor-onal image in Box A, the right and leftsides will be displayed as in traditionalimaging. In Box C, the forehead will beon the bottom. Fig. 3 demonstratesa multiplanar display of the fetal afterthe initial acquisition (before manipula-tion). The arrows mark the manipulations,which were required and the order inwhich they were performed to positionthe volume in the correct orientation inthe three orthogonal planes, as is shown

inally. Note that the beam of the probe is directedtrates a surface rendering of the fetal scalp at theapproach, a good image can be achieved by direct-) and coronal (c) are also displayed (Box 3D).

Fig. 3. The multiplanar mode panel on the left side (before manipulation) displays the initial image of the acquiredbrain volume after the image was enlarged to fit the whole screen. Several steps were taken manipulating the vol-ume to obtain the desired orientation. (1) The marker dot in Box B was moved to the center of the fetal brain (cavumsepti pellucidi, in this case) (arrow). (2) The axial image in Box C was rotated 90� on the z-plane to place the fetal headin the axial plane, with the forehead pointing down (large curved arrow). (3) At this point, the mid-coronal positionwill be displayed in Box A, and only slight rotations may be required to fine-tune it in the perfect orientation (smallcurved arrow). The multiplanar display on the right side (after manipulation) demonstrates the same volume in thecorrect orientation after completing the above three steps. The authors prefer to display the images in the multi-planar mode, with the coronal plane in perfect alignment in Box A, in the median plane with the fetus ‘‘looking’’to the left in Box B, and the axial plane with the fetal forehead pointing downwards in Box C.

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in the multiplanar panel on the right sideof Fig. 3 (after manipulation).

Box A should now display a coronal section ofthe brain. At the same time, on the sagittalimage in Box B, the moving vertical linedisplays the level at which the picture inBox A is seen (see Fig. 3).

By moving the marker dot horizontally fromside to side on the coronal plane (Box A),successive sagittal sections from side-to-side (temporal-to-temporal) can be imagedin Box B following the planes of thesections in the coronal image. Thesesuccessive sagittal images are displayedin Fig. 4 by using the Tomographic ultra-sound imaging (TUI) mode.

Finally, moving the marker dot up and downon the coronal plane (Box A), successivehorizontal (axial) views of the brain fromthe base of the skull to the ‘‘top-of-the-head’’ can be imaged on Box C. Thesesuccessive axial planes are displayed inFig. 5 using the TUI display mode.

Manipulating the Volume to ObtainDiagnostic Planes

Manipulating the 3D-ultrasound volume in themultiplanar modeas described earlier enables a rel-atively easy reconstruction of several diagnosticplanes. However, before starting to navigate in

the acquired volume, one has to acknowledgethat the number of possibilities is virtually endless.One should remember that the display protocol ofdifferent manufacturers may be different. A repeti-tive manipulation of a volume is a good trainingtool to master the display technique of each spe-cific brand. In the authors’ experience, a completeneuroscan can be efficiently performed using fiveto seven continuous coronal sections, three sagittalsections (including the median and two parasagittalsections), and three axial sections. Recently, the In-ternational Society of Ultrasound in Obstetrics andGynecology (ISUOG) published guidelines recom-mending the necessary planes to be used in dedi-cated neurosonography, in addition to the axialplanes that are routinely performed. They includedfour coronal planes—the transfrontal, transcau-date, transthalamic and transcerebellar—as wellas three sagittal planes: median and two parasagit-tal.6 These recommendations did not includea 3D-brain scan; however, all these recommendedplanes can be visualized in few minutes after theperfect orientation of a good quality volume isobtained in the three orthogonal planes.

The median planeThe median plane is probably the most impor-tant plane, as it enables evaluation of severalimportant midline brain structures. The medianplane of the fetal brain can be used to assessthe corpus callosum, the cavum septi pellucidi,

Fig. 4. Tomographic display mode demonstrating multiple successive sagittal views of the fetal brain. Thesesuccessive sections can also be seen in the multiplanar mode Box B, when the marker dot (red dot) on the coronalview in Box A is moved horizontally from side to side on the initial orthogonal plane.

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the cavum vergae, the head of the caudate nu-cleus, the tela choroidea, the quadrigeminalplate, the quadrigeminal cistern, the cavum veliinterpositi, the brain stem, the pons, the thirdand fourth ventricles, the cerebellar vermis, thecisterna magna, and the nuchal fold. Fig. 6demonstrates a perfect median plane that wasobtained by 3D manipulation. This image is dis-played side by side with an identical image thathas several midline anatomic structures markedwith arrows. In the ‘‘perfect’’ median plane,one should not see the thalami. However, be-cause any ultrasound plane has a third plane(thin as it may be), it is possible to see slicesof the thalami that most of the time are so closeto each other that they touch. Depending on thefetal position, the acquisition of the medianplane may be impossible with 2D-transabdomi-nal ultrasound and require special expertise intransvaginal-transfontanelle scanning, as wellas prolonged examination time. Obtaining themedian plane by manipulation of 3D-ultrasoundvolume can be easily obtained by aligning all

three planes according to the previouslydescribed protocol and placing the marker dotin the center of the coronal plane.

The authors have previously demonstrated that3D reconstruction is useful in evaluating the integ-rity of the corpus callosum and in diagnosing com-plete or partial agenesis, as well as evaluating theentire lateral ventricles.7 Several other studies fo-cused on the median plane as a useful methodfor brain anomaly detection.8–10 The authorshave found the tomographic display mode to beextremely informative in the examination of the fe-tal brain by displaying consecutive parasagittalplanes with the midsagittal plane.

The three-horn view: parasagittalSeveral methods of evaluating the ventricular sys-tem have been described, with the standard mea-surement of the atrium (or body) of the lateralventricle in the axial plane being the most com-mon, as demonstrated in Fig. 7.2–4,9,11–13 Whenventriculomegaly occurs, the posterior horn isthe first to change in size and shape and the

Fig. 5. Tomographic display mode, demonstrating multiple successive axial views of the fetal brain. These succes-sive sections can also be seen in Box C of the multiplanar display mode by moving the marker dot in the coronalplane in Box A up and down on the initial orthogonal plane.

Fig. 6. These identical images of the ‘‘perfect’’ median plane obtained from a multiplanar display mode demonstratethe anatomic location of several midline brain structures. The arrows point to the corpus callosum (cc), cavum septipellucidi (csp), tela choroidea (tc), cavum vergae (cv), quadrigeminal plate (qp), quadrigeminal cistern (qc), thirdventricle (3v), fourth ventricle (4v), brain stem (bs), cerebellar vermis (V), and the cisterna magna (cm).


Fig. 7. Standard axial plane taken at the level of thelateral ventricles and cavum septi pellucidi, demon-strating measurements of the lateral ventricles. Notethat the proximal ventricle (left) is not clearly seen be-cause of ‘‘noise’’ and reverberations that decrease thequality of the image. Va, left lateral ventricle; Vp,right lateral ventricle.

Fig. 8. The three-horn view in this image enables theevaluation of all three components of the lateralventricles. The arrows point to the anterior horn(ah), posterior horn (ph), and inferior horn (ih).

Fig. 9. Multiplanar mode demonstrating the specific alignment of the three orthogonal planes necessary toobtain the 3HV. The marker dot is placed in the left anterior horn and the coronal plane (Box A) is tilted slightlyto the left on the z-axis. The axial plane (Box C) is also tilted slightly to the left on the z-axis. The sagittal plane inBox B than displays the 3HV.

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Fig.10. Tomographic display mode of multiple sagittal views including the median plane (middle) and the para-sagittal views, enabling evaluation of both lateral ventricles.


easiest to evaluate on the axial plane. The anteriorhorn is the last portion of the lateral ventricle todilate.14,15 The inferior horn is either barely visibleor not visible earlier in pregnancy. The parasagittalplane, which we have termed the ‘‘three-horn view’’(3HV), enables all three horns of the lateral ventricleto be displayed on one image (Fig. 8). The ventric-ular system is positioned obliquely within the brain,with the anterior horns closer to each other than thedistance between the posterior horns. Additionally,the distance between the inferior horns is evenlarger. Using 3D technique to obtain this view isboth simple and rapid, by tilting the volume on thecoronal plane using the y- and z-axis. Fig. 9 dis-plays a multiplanar mode that demonstrates thenecessary tilting in the coronal plane (Box A), andthe axial plane (Box C) to obtain the 3HV. An easyway to evaluate the lateral ventricles is by multiple,successive sagittal slices using the TUI mode(Fig. 10).

The three horns should be considered abnormalin several situations:11

If the anterior horn height is larger than8.7 mm at 14 weeks and 6.9 mm at 40

weeks (represent the 95th percentile forthese measurements);

If the posterior horn height is larger than11 mm at 14 weeks and 14 mm at 39 weeks(represent the 95th percentile for thesemeasurements);

If theposteriorhorn measurement fromthe pos-terior tip of the thalamus to the posterior tipof the horn is larger than 2.6 mm at 14 weeksto 3.4 mm at 40 weeks (represent the 95thpercentile for these measurements);

If the inferior horn is obvious to any degree.

The 3HV provides an objective measure evalu-ating both the severity of the ventricular dilatationand the progression of the pathology with suc-cessive measurements that are facilitated in thisplane. Another use of the 3HV is the recognitionof colpocephaly, a pathologic and persistent dila-tation of the posterior horn, which has been asso-ciated with agenesis of the corpus callosum andother syndromes affecting the midbrain, such asobstruction of the aqueduct.16 Some believethat not all cases of colpocephaly are a result ofpressure-related anomalies, but may be a result

Fig.12. TUI mode can be used to display the successive coronal planes. The operator can control for the numberand the thickness of the slices that are displayed as seen in this image. The successive coronal planes displayedfrom front to back include the four coronal planes recommended by ISUOG in the fetal neuroscan (see Fig.10).The transfrontal plane is seen in Box �3, the transcaudate plane is seen in Box �1, the transthalamic plane isseen in the box marked with *, and the transcerebellar plane is seen in Box 4.

Fig.11. Fetal head in the sagittal position, demonstrating the anatomic position of the successive coronal planesthat are recommended by the ISUOG during the fetal neuroscan. Transfrontal plane (a), transcaudate (b), trans-thalamic (c), and transcerebellar (d).

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Fig. 14. Examples of 3D ultrasoundreconstructions of the commonlyused axial planes: transventricular(A), transthalamic (B), and transcer-ebellar (C).

Fig.13. This diagram of a fetal head in the sagittal position illustrates the correct anatomic position of the threeaxial planes: the transventricular (a), transthalamic (b), and transcerebellar (c).


Fig. 15. Multiplanar display of a fetus with agenesis of the corpus callosum. The diagnosis can be made basedupon its direct signs on the ‘‘perfect median’’ plane in Box B, demonstrating the absence of the corpus callosum(arrow AGCC), and absence of the cavum septi pellucidi (Box B). The coronal image in Box A demonstrates thewidely spaced anterior horns (ah) showing the classic ‘‘Viking’s helmet sign,’’ and the interhemispheric fissureconnecting all the way to the upward displaced third ventricle (3v). The axial image in Box C demonstratesthe parallel lateral ventricles and the colpocephaly (c), which are characteristic to this anomaly.

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of an error in morphogenesis.17 Heinz and col-leagues18 were able to distinguish between ob-structive and atrophic dilatation of the lateralventricles in 92 infants and children using CT. Ob-structive dilatations showed a much larger mea-surement of the inferior and anterior horns thanthe posterior horn. However, in cases of atrophicdilatation, colpocephaly was more prominent. Itonly seems logical to employ the 3HV in differen-tiating the above-mentioned obstructive and atro-phic entities based on the ventricular horndilatation.

Another use of the 3HV is to compare the size andshape of the left lateral ventricle to the right lateralventricles in the same fetus. Although minimalasymmetry between the lateral ventricles may ex-ist,12,18,19 precise measurements of the size of theleft and right lateral ventricles in cases of lateral ven-tricular asymmetry contributed to an objective theidentification of pathologic unilateral dilatation.20

Coronal planeUsing the transvaginal-transfontanelle approach,diagnostic views of the fetal brain in the coronalplane can be obtained. Navigating through thebrain using the multiplanar display modality, themarker dot is moved on the axial plane in Box Cfrom the front of the head to the back of thehead along the midline, or on the B plane fromanterior to posterior. By doing so, continuoussections of the fetal brain in the coronal plane inBox A are obtained. The authors usually observefive to seven of these successive coronal planes,including the ones recommended by ISUOG: thatis, the transfrontal, transcaudate, transthalamicand transcerebellar planes (Fig. 11).6 These planescan be seen in the TUI display in Fig. 12. The trans-frontal plane demonstrates the uninterrupted inter-hemispheric fissure in the midline, with the anteriorhorns in the sides. The orbits and the sphenoidalbone may be seen as well.

Fig. 16. Tomographic display mode demonstrating successive coronal views of the same fetus with AGCC. Theabsence of the corpus can be diagnosed based on the ‘‘Viking’s helmet sign’’ and the upward displacement ofthe third ventricle that connects with the interhemispheric fissure. This modality is helpful in differentiatingpartial from total agenesis of the corpus callosum.

Fig. 17. Side-by-side displayof the tomographic displaymode may be used to enhancethe typical findings of AGCC inthese coronal and medianplanes.


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The transcaudate plane is taken at the level ofthe caudate nuclei, with the interhemisphericfissure interrupted by the genu of the corpuscallosum. The cavum septum pellucidi can beseen under the corpus callosum and the lateralventricles in each side.

The transthalamic plane is taken at the level ofthalami and can be used to evaluate its integrity.

The transcerebellar plane is frequently used toevaluate the posterior fossa, demonstrating theoccipital horns of the lateral ventricles, interhemi-spheric fissure, and the cerebellum.

Axial planesSimilarly to the 2D basic fetal brain evaluation, theaxial planes that are obtained during the 3D neuro-scan are the transventricular plane, the transcere-bellar plane (which is taken in a lower level witha posterior tilt), and the intermediate transthalamicbiparietal diameter plane (Figs. 13 and 14). Theseplanes provide information regarding various brainstructures, depending on the level in which it

Fig. 18. Multiplanar display focusing on the ventricular sywidely spaced anterior horns (Viking’s helmet sign). The axeral ventricles. The 3HV is obtained in Box B, demonstratinmark the anterior horn (ah), posterior horn (ph), and infe

crosses the brain. Among these structures are thefetal scull, falx cerebri, gyri and sulci, thalami, cavumsepti pellucidi, the posterior hornof the lateral ventri-cles, the choroid plexus, the cerebellum, cisternamagna, and nuchal fold. The evaluation of theseplanes using a 3D technique may be facilitated bythe simultaneous observation of the sagittal planeand the precise angle in which the axial is crossingit to achieve the desired planes. Of note, better qual-ity of the axial plane is achieved when the volume isacquired in this plane. In cases in which the axialplane is reconstructed, the quality will be inferior tothe one obtained by the 2D technique.

DETECTION OF FETAL NEUROPATHOLOGYBY 3D ULTRASOUND

This section presents several examples of how theauthors use 3D-ultrasound in the diagnosis andwork-up of several brain anomalies.

stem. The coronal plane in Box A demonstrates theial plane in Box C displays the abnormally parallel lat-g the abnormally dilated lateral ventricle. The arrowsrior horn (ih) that comprise the lateral ventricle.


Agenesis of the Corpus Callosum

The corpus callosum starts to form at around 12weeks of gestation and completes its anterior-to-posterior development at around 20 to 22 post-menstrual weeks. Failure of axons to cross themidline and form the corpus callosum results inpartial or total agenesis of the corpus callosum(AGCC) (absence of the entire corpus callosumor partial development of its anterior part only). Inspite of the fact that this diagnosis can be madebased upon axial and coronal sections revealingthe indirect signs of the malformation, the direct di-agnosis of the absence of the corpus callosum canonly be obtained by the median plane. The medianplane is obtained almost exclusively by the trans-vaginal scanning approach, provided the fetus is

in vertex presentation. The authors’ experience inevaluating patients referred for second-opinionfor hydrocephaly or ventriculomegaly has led tothe belief that many cases of AGCC are often mis-diagnosed. This might be because of the lack ofexpertise necessary to obtain the diagnostic me-dian plane performing a transvaginal neuroscan.As described earlier, the manipulation of the 3Dvolume is extremely useful in detecting midlinestructures and, hence, the application of this mo-dality in abnormalities of the corpus callosum isclinically helpful and may improve the detectionof this anomaly.

The median plane facilitates the inspection of theanatomic site of the corpus callosum, the cavumsepti pellucidi, and the pericallosal artery enablingthe diagnosis of AGCC. Additional indirect findings

Fig. 19. Angiographic demonstrations ofbrain vessels in AGCC. (A) Three-dime-sional power Doppler angiography-acquired median plane demonstratingthe anterior cerebral artery and theabsence of the pericallosal artery branch.(B) Three-dimesional power Dopplerangiography multiplanar display modedemonstrating the anterior cerebralartery (arrow) and the absence of thepericallosal artery. The ‘‘thick slice’’ tech-nique was used to obtain a 3D renderingof the brain vasculature (Box 3D) display-ing the anterior cerebral artery and theabsence of the pericallosal artery.

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associated with this anomaly may be seen on differ-ent diagnostic planes and include:

Fig. 2sencon thThe

Teardrop-shaped, parallel lateral ventriclesseen on the axial section;

Colpocephaly: a dilated posterior horn can beseen on the axial and 3HVs;

‘‘Sunburst sign’’: radial gyri and sulci onmedian surface (seen only after 26 to 28weeks when gyri/sulci are normally visible)on the median section;

‘‘Viking’s helmet sign’’: widely separated, ver-tically oriented lateral ventricles seen onthe anterior coronal sections;

Upward displacement of the third ventricleconnecting with the interhemisphericfissure on the coronal section.

Figs. 15 to 18 demonstrate a case of AGCC inwhich simple manipulation of the volume of thebrain enabled visualization of both the direct andindirect signs, leading to a clear diagnosis withinfew minutes. As described earlier, the appropriatevolume orientation is obtained using the multipla-nar mode to achieve the three orthogonal planes

0. Tomographic display mode showing multiple succeephaly diagnosed at 12 postmenstrual weeks. The arre posterior portion of the brain but not on the anter

typical hypotelorism can be seen in the anterior coro

perfectly placed in the midline position. Fig. 15demonstrates a multiplanar mode with the medianplane in Box B, providing direct sonographicevidence of the absence of the corpus callosum(arrow, AGCC) and the absence of the cavum septipellucidi. The image in the mid-coronal plane inBox A clearly demonstrates the widely displacedand upward pointing anterior horns (arrow, ah) ofthe lateral ventricles (Viking’s helmet sign), andthe elevation of the third ventricle (arrow, 3v),which is contiguous with the interhemisphericfissure. These findings can be further enhancedusing the tomographic display mode to obtainsuccessive coronal sections, which were ex-tremely helpful in providing MR imaging-like diag-nostic images (Figs. 16 and 17). Scrolling up anddown through the axial image in Box C of the multi-planar display mode (see Fig. 15), the authorscould appreciate the characteristic teardrop-shaped and parallel lateral ventricles with dilatedposterior horns, colpocephaly (arrow, c). This find-ing can be further enhanced by obtaining the 3HV(Fig. 18), in which the entire dilated lateral ventricleis evident with the overly dilated posterior hornknown as colpocephaly (Box B).

ssive coronal views in a fetus with semi-lobar holopro-ows point to the incomplete falx (Box �2) that is seenior portion (Box 1), and to the fused thalami (Box �1).nal view in Box 2 (arrow).


The use of 3D color Doppler is very helpful in di-agnosing AGCC and sometimes is the only directclue in cases with a challenging scan. Fig. 19demonstrates 3D volumes that were acquiredwith the power Doppler turned on, while focusingon the area of the corpus callosum in two differentcases of AGCC. Clearly, in both images, only theanterior cerebellar artery is detected and the peri-callosal artery was not seen branching from it,confirming the diagnosis of AGCC in these casesat 20 and 22 postmenstrual weeks, respectively.The power Doppler technique is especially impor-tant in cases of partial agenesis of the corpuscallosum detecting the anterior portion (but notthe entire) pericallosal artery branching off of theanterior cerebral artery. Additionally, a small ante-rior portion of the genu corporis callosi, as well asa small cavum septi pellucidi, may be seen insuch cases.

Using the 3D neuroscan to identify this anomaly,as well as other anomalies, it is important to obtaina perfect median plane. Correlation with other or-thogonal planes is required to ensure that the sec-tion is properly oriented and that the diagnosticimage is indeed in the true median plane.

Fig. 21. Tomographic display mode showing multiple suholoprosencephaly. The arrows point to the fused thalamiwith *). The massive hydrocephaly is very obvious.

Holoprosencephaly

Holoprosencephaly is associated with an inci-dense of 1 per 1,600 births, but is detected morefrequently when earlier sonograms are performed.The sonographic detection of the frequent forms,Alobar and Semilobar types, is relatively straightforward. Absence of the interhemispheric fissure(total or partial), nondisjunction of the thalami,absence of the corpus callosum and cavum septipellucidi, and various facial anomalies (cyclops,proboscis, median clefts, and other anomalies)are the most frequent sonographic features. Theauthors’ experience performing 3D neuroscanenabled accurate diagnosis of this complex syn-drome in several cases during the first trimester.The authors demonstrate a case of a fetus withsemi-lobar holoprosencephaly diagnosed at 12postmenstrual weeks. The manipulation of thebrain volume in this case was extremely helpful indisplaying the images in a diagnostic fashion.Fig. 20 is a TUI of multiple coronal sections demon-strating the falx (arrow in Box �2), which is not de-tected in the anterior section of the brain (Box 1),revealing the connection of the two ventricles atthe level of the anterior horns. The fused thalami

ccessive sagittal views in this fetus with semi-lobar(Box �1), and to the abnormal proboscis (Box marked

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is detected in Box �1 (arrow). The typical hypote-lorism can be also appreciated in the facial coronalview in Box 2 (see marker dot in Box 2). The sagittalTUI in Fig. 21 demonstrate the fused thalami (arrow,Box �1), and the facial proboscis (arrow in Box *).Fig. 22 is a multiplanar mode of the same casedemonstrating the anomaly in the three orthogonalplanes. An inversion mode is displayed in Box 3D,demonstrating the entire ventricular system. Themassive hydrocephaly can be appreviated, aswell as the two hemispheres that are partially sep-arated by the falx (arrow) in the opsterior part,whereas the anterior part of the ventricles is con-nected (double arrow). An example of inversionmode and multiplanar display in a case of alobarholoprosencephaly is shown in Fig. 23.

The lobar type has a more subtle sonographicfeatures, which are clustered around the corpuscallosum, cavum septi pellucidi, and the third ventri-cle.Thepresence of a box-shapedcavity in themid-brain below the corpus callosum, without the two

Fig. 22. Multiplanar mode of the same fetus with semi-lobseen in Box A. The incomplete falx is seen in Box B (see mwith a clear communication (arrow, C) making the diagnrendering is demonstrated in Box 3D identifying the tw(arrow, C) at the level of the anterior horns (ah). The blackthe posterior segment of the falx.

lateral walls of the septum pellucidum, suggeststhe presence of either lobar holoprosencephaly orsepto-optic dysplasia. The final diagnosis betweenthe two may not be made until after birth.

Cephalocele

This anomaly is characterized by herniation of in-tracranial structures through a skull defect. It wasreported to occur in approximately 1 to 3 out of ev-ery 10,000 live births. The most common form ofcephalocele is the encephalocele that consists ofboth brain and meninges herniating through theskull. Meningocele, however, is a less-severe de-fect in which only the meninges are herniatingthrough the skull defect to the para-cranial mass.There is large variation in the location and extentof this anomaly, which is usually associated withthe location of the scull sutures. About 80% of allcases among the white population in both Europeand North America are localized in the occipitalregion, with cases occurring in the temporal and

ar holoprosencephaly. The falx and fused thalami arearker dot) and the two lateral ventricles (LV) are seenosis of semi-lobar holoprosencephaly. Inversion mode

o dilated ventricles (LV) with their communicationline between the two ventricles (arrow, F) represents

Fig. 23. Multiplanar view of a case of alobar holoprosencephaly. The orthogonal planes display the fused thal-ami (arrow, T) and the markedly dilated and completely fused ventricles that are characteristic of holoprosen-cephaly (arrow, H). No falx is present, making the diagnosis consistent with the alobar form. The inversionmode is seen in Box 3D, demonstrating a superior view of the large fluid-filled space representing the fuseddilated ventricles.


frontal region less frequently. In contrast, amongthe Southeast Asian population, the most commonlocation is the fronto-ethmoidal region. Parietalcephaloceles are the least common and aremostly associated with significant underlying brainanomalies. Cephalocele should be suspectedwhen a para-cranial mass is detected on ultra-sound. In the authors’ experience, the additivevalue of 3D ultrasound in the diagnosis of theseanomalies lies mainly in the ability to navigatewith the marker dot through the skull defect anddemonstrate the connection of the brain to theadjacent cystic structure. In few difficult cases,where this connection was not detected by fetalbrain MR imaging, the authors were able to detectthe specific site of the communication using thistechnique (Fig. 24). In this case, the authors havealso used power Doppler angiography to demon-strate blood vessel crossing the cranial defect,confirming the diagnosis of occipital meningyo-cele, as can be seen in Figs. 25 and 26.

Arachnoid Cysts

Arachnoid cyst is a collection of cerebrospinalfluid within layers of arachnoid that is not con-nected with the ventricular system. It is a benignspace-occupying lesion, the significance of whichis dependent on its location and the extent of com-pression on the surrounding structures. It may belocated in various parts of the brain, such as inits surface, between the lobes, and even in thedepth of the brain originating at various sites. It ismore commonly detected on the left side of thebrain. In 5% to 10% of cases, the cyst may be lo-cated in the posterior fossa, resulting in upwarddisplacement of the tentorium and vermis. How-ever, in this case the anatomy of the cerebellumand the fourth ventricle remains normal, differenti-ating it from other posterior-fossa anomalies, suchas the Dandy Walker malformation. Many cysts re-main stable in size and do not compress vital brainstructures. Occasionally, large arachnoid cysts

Fig. 24. Tomographic display demonstrating multiple successive views through a posterior cranial mass. Note thescull defect (arrow) through which the meninges protrude, confirming the diagnosis of a meningocele.

Fig. 25. Tomographic display mode with power Doppler angiography, demonstrating a blood vessel (arrow)traversing the scull defect and supplying the herniated meninges.

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Fig. 26. A side-by-side Tomographic display view of the brain vessel (arrows) traversing the scull defect into themeningocele is shown in the coronal and axial views.

Fig. 27. Tomographic display mode, demonstrating multiple successive axial views through the entire height ofthe arachnoid cyst. The arrows point to the arachnoid cyst (Box *) and to a choroids plexus cyst (Box 1). Notethe ventriculomegaly that is the result of pressure caused by the large arachnoid cyst.


Fig. 28. Tomographic display mode, demonstrating multiple successive coronal views through the entire length ofthe arachnoid cyst, which is localized between the two brain hemispheres.

Fig. 29. Tomographic display mode, demonstrating multiple successive sagittal views through the entire width ofthe interhemispheric arachnoid cyst. The arrow points to the tela choroidea, which was considered to be theorigin of this arachnoid cyst.

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Fig. 30. Multiplanar display of the posterior fossa. The cerebellum can be easily seen and measured on both thecoronal plane (Box A) and the axial plane (Box C), demonstrating the entire cerebellar hemispheres. The medianplane (Box B) provides additional information enabling the evaluation and measurement of the cerebellar vermislength (1) and height (2), the cisterna magna (3), and the nuchal fold (4). Measurements of the cisterna magna (5)and nuchal fold (6) are also seen on the axial plane in Box C. One should be aware of the fine linear echoes of thearachnoid, which are sometimes visualized in the cisterna magna. These lines (Box C) are normal and should notbe confused with pathology.

Fig. 31. Median plane focused on the posterior fossa, demonstrating measurements of the cerebellar vermis height(1) and length (2), cisterna magna (3), and nuchal fold (4). The different lobes of the cerebellar vermis can be iden-tified in this plane. Additionally, the median plane can assist in the evaluation of the fourth ventricle (arrow, 4v), therelation of the vermis to the brain stem (bs), and the site and the position of the torcular (arrow, T).


Fig. 32. Median plane of the fetal brain focused onthe posterior fossa demonstrating the cerebellarvermis with its three lobes (marked as 1, 2, and 3),the cisterna magna (cm), the nuchal fold (nf), thefourth ventricle (4v), and the brain stem (bs).

Fig. 33. Multiplanar display of a case of Dandy Walker malflateral displacement of the cerebellar hemispheres (splayextremely informative, demonstrating the large posterior fmis, and the superior displacement of the tentorium anddemonstrates the classic view of this anomaly, demonstratstructure in the posterior fossa (arrow).

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can indent the underlying cortex and mimica picture of lissencephaly. As with other brainanomalies, the use of 3D ultrasound assists inthe orientation of the lesion within the volumeand can display it in a similar fashion to MR imag-ing, using the tomographic mode. Figs. 27 to 29demonstrate TUI display in different planes ina case of interhemispheric arachnoid cyst. Theextent of the lesion, as well as its impact on thesurrounding brain tissue, can be evaluated usingthe TUI mode in the different planes. The abilityto display the images in tomographic slices facili-tated the authors’ understanding regarding theorigin of the cyst, which appears to arise fromthe tela choroidea (Fig. 29, Box 1, arrow). Addi-tionally, the 3D images and the possibility of slicingwithin the volume gave important clinical informa-tion to the pediatric neurosurgeon and playeda practical role in counseling this patient.

ormation. The coronal plane (Box A) demonstrates theing of the cerebellum). The median plane (Box B) isossa cystic structure, the complete agenesis of the ver-the torcular herophili (arrow). The axial view in Box Cing the splaying of the cerebellum and the large cystic


Posterior Fossa and Related Anomalies

Three-dimensional evaluation of the posterior fossarequires both technical expertise and understand-ing of the normal development of the fetal brainalong gestation. Before 16 to 18 postmenstrualweeks, the cerebellar vermis is still not completelydeveloped and the fourth ventricle clearly commu-nicates with the cisterna magna through the widelyopen median aperture (foramen of magendie). Un-derstanding the timing of vermian development isthus crucial to avoid misdiagnosis of posterior-fossa anomalies at this gestational age.

Traditionally, posterior-fossa anomalies havebeen diagnosed and classified based on the axial(transcerebellar) view (see Fig. 14c). However,many important features of the posterior fossaanatomy, such as the position of the vermis, ten-torium, and the torcular (confluence of sinuses),cannot be adequately assessed using the axialview solely. Three-dimensional ultrasound en-ables the simultaneous evaluation of the three or-thogonal planes of the posterior fossa (Fig. 30).

Fig. 34. Tomographic display mode demonstrating multilength of the cerebellum. These views enhance our ability

The median plane (Figs. 31 and 32) is especially im-portant when establishing certain pathologies inthe posterior fossa, as it depicts the size (heightand length) and the orientation of the vermis, thecisterna magna, and the position of the torcular.

In the authors’ experience, the best image of theposterior fossa can be obtained by aligning the tipof the transvaginal transducer with the posteriorfontanelle. After acquisition of the volume in thismanner, the posterior fossa can be evaluated us-ing the coronal (occipital) plane, the traditionaltranscerebellar axial plane, and the median plane,which the authors’ find extremely informative.Vinals and colleagues21 reported the successfuluse of the volume contrast-imaging mode in theevaluation of the cerebellar vermis, which theauthors’ have also found useful.

The anomalies of the posterior fossa are a groupof fluid-containing malformations that share fewcommon features in their appearance and patho-logic definition. This group includes severalmalformations (listed as most-to-least severe):Dandy-Walker malformation, Dandy-Walker

ple successive coronal images taken throughout theto evaluate the extent of the cerebellar anomaly.

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variant, persistent Blake’s pouch cyst, and megacisterna magna. The previous confusing classifica-tion and nomenclature described the ‘‘Dandy-Walker continuum’’ and was based upon axial fetalultrasound. It is now thought that a more accuratedefinition and description of these entities isrequired, because their pathogenesis, their ana-tomic picture, their prognosis, and their treatmentare different. Therefore, the authors now approachthese anomalies as different entities rather thana continuum, making the correct diagnosisextremely important. Differentiation betweenthese malformations depends on the presenceand the severity of the vermian hypoplasia, thepresence or absence of posterior fossa cystic en-largement (the location of the torcular Herophili),abnormal communication between the fourthventricle and the posterior fossa cyst, and the rela-tionship between the position of the vermis and thebrain stem. Three-dimensional ultrasound wasfound to be of significant assistance in the

Fig. 35. Tomographic display mode, demonstrating multheight of the cerebellum. The lateral displacement of theent levels of the cerebellum.

diagnosis of these different entities.10 In the au-thors’ experience this technique, especially if ac-quired with a high-frequency vaginal transducerthrough the posterior fontanelle, is extremely use-ful in achieving a ‘‘posterior-fossa window,’’ en-abling the evaluation of the posterior fossa andits relation with the brain stem. As describedabove, the multiplanar display mode can be usedto easily detect the median plane. The authorsconsider it the plane of choice for evaluation ofthe vermis length and height, vermis position,and its relationship to the brain stem. When ananomaly is suspected, the median plane can fur-ther help in the evaluation of the size of the poste-rior fossa cyst, the superior displacement of thetorcular Herephili, the configuration of the fourthventricle, and measurement of the cisterna magna.

Dandy-Walker malformationThis severe malformation is characterized by anenlarged posterior-fossa fluid content and

iple successive axial views taken through the entirecerebellar hemispheres can be evaluated at the differ-


a complete or partial agenesis of the vermis. Thecerebellar hemispheres are laterally displaced(splaying of the cerebellum) and the tentoriumand the torcular herephili are displaced superiorly(Figs. 33–35). In this case of Dandy Walker malfor-mation, the multiplanar mode displays the extentof the anomaly, as it can be clearly identified oneach one of the three orthogonal planes simulta-neously. Despite the relative apparent sono-graphic findings, 20% to 40% of such cases areundetected antenatally. It is believed to have anincidence of 1 in 30,000 births, with most cases(50%–70%) associated with additional brainanomalies. In 50% to 70% of survivors, a poorneurodevelopment is observed. It is believed thatisolated cases carry a recurrence risk of 1% to5%.

Dandy-Walker variantThis anomaly consists of variable hypoplasia oragenesis of the vermis with or without enlargementof the cisterna magna, which communicates with

Fig. 36. Multiplanar mode of a fetus with Dandy Walkerspheres with the posterior fossa lesion seen in the coronal (hypoplasia of the superiorly displaced vermis (arrow, V) cmagna, which is seen communicating with the fourth vnormal size.

the fourth ventricle. The cerebellar hemispheresmaybe of normal size and frequently only subtlesonographic findings may be identified. At times,it is therefore a difficult prenatal sonographic diag-nosis to make. An example of such a case can beseen in the multiplanar mode in Fig. 36.

Genetic factors play a major role in the etiologyof both Dandy Walker malformation and variant.Agenesis of the vermis has been associatedwith a number of syndromes, such as Aicardisyndrome, chromosomal aneuploidy (trisomy 8and 9, triploidy) as well as Fry, Meckel-Grubber,Neu-Laxova, Smith-Lemli-Opitz, and Walker-Warburg syndromes. Therefore, whenever theseanomalies are detected, a genetic consultationand invasive genetic testing should be offeredto the patient.

Persistent Blake’s pouch cystThis pathology is thought to result from failure offenestration laterally through the lateral aperture(Luschka) and in the median plane through the

variant. Note the laterally displaced cerebellar hemi-Box A) and axial (Box C) views, respectively. Significantan be seen as well as the enlargement of the cisternaentricle. The cerebellar hemispheres appear to be of

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median aperture (Magendie), thereby preventingthe connection and fluid drainage between thefourth ventricle ‘‘so called cyst’’ and the subarach-noid space (Fig. 37).

Sonographic diagnosis is possible because thecyst wall is evident on the axial and the sagittalplanes. There is anechoic fluid inside the cystand slightly low-level echoic fluid in the surround-ing subarachnoid space. Additionally, the intactvermis may be displaced upward by the masseffect, which can also push the cerebellar hemi-spheres apart (splaying of the cerebellum), imitat-ing some of the findings in cases of Dandy Walkermalformation. Ventriculomegaly can sometimesbe seen if the mass effect obliterates the cerebro-spinal fluid drainage.

Fig. 37. Multiplanar mode of a case of Blake’s pouch cyst. Tthe fourth ventricle. The intact vermis can be seen on thethe mass effect. Additionally, the median plane assisted thas it is protruding into the cisterna magna. The Blake’s poThe coronal and axial views demonstrate splaying of theseen in Boxes A and C, respectively. In this case, without thpouch cyst would have been impossible.

The prognosis is relatively good because post-natal shunting leads to re-expansion of the dis-placed brain structures.

Mega cisterna magnaThis entity is characterized by an enlarged cisternamagna, measuring greater than or equal to 10 mm,with normally positioned and intact cerebellarvermis and fourth ventricle (Fig. 38). Its clinicalsignificance as an isolated finding is uncertain,and no clear-cut prognostic data are available.These fetuses may be totally asymptomatic;however, some cases are associated with othermalformations or chromosomal aberrations.

he cyst forms because of the accumulation of fluid insagittal plane in Box B (v), to be displaced upward by

e authors in identifying the posterior cyst wall (arrow),uch cyst is marked (BC) on the median plane in Box B.cerebellar hemispheres caused by the mass effect, ase image in the median plane, the diagnosis of Blake’s

Fig. 38. Multiplanar mode of a brain in a fetus with mega cisterna magna. The characteristically enlarged cisternamagna can be seen on all three orthogonal planes (Boxes A, B, and C). Measurements are provided in this case inthe median and the axial planes in Boxes B and C, respectively. Note the normally positioned and intact cerebellarvermis and fourth ventricle as seen on the median plane in Box B (marked with the red marker dot).


SUMMARY

In summary, the amazing technology of 3Dimaging enables the examination of the fetal brainsimultaneously in the three orthogonal planes, bet-ter defining the spatial relationship of brain struc-tures and malformations. The authors routinelyuse the multiplanar mode to navigate through thebrain volume, observing information on a specificstructure in all three orthogonal planes. Otherdisplay options, mainly the tomographic mode,are used to display the anomaly. The varieties ofdisplay modes and the infinite number of differentplanes that can be generated facilitate the diag-nostic process. Additional values of this technol-ogy include an off-line analysis of the volume bythe sonographer or sonologist to obtain the neces-sary planes, as well as an electronic transmittal foran off-site expert to provide a second opinionconsultation. This modality requires a short acqui-sition time, allowing high patient through-put andincreased patient satisfaction. In addition, it is anexcellent teaching tool and provides valuableinformation to consulting pediatric surgeons,

plastic surgeons, neonatologists, neurologistsand neurosurgeons.

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1. Goldstein I, Reece EA, Pilu G, et al. Sonographic

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3. Cardoza JD, Goldstein RB, Filly RA. Exclusion of

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6. International Society of Ultrasound in Obstetrics &

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7. Monteagudo A, Timor-Tritsch IE, Mayberry P. Three-

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fetal brain: ‘‘navigating’’ in the volume scan. Ultra-

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8. Timor-Tritsch IE, Monteagudo A, Mayberry P. Three-

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2000;16(4):302–6.

9. Correa FF, Lara C, Bellver J, et al. Examination of the

fetal brain by transabdominal three-dimensional ultra-

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ies. Ultrasound Obstet Gynecol 2006;27(5):503–8.

10. Pilu G, Segata M, Ghi T, et al. Diagnosis of midline

anomalies of the fetal brain with the three-dimen-

sional median view. Ultrasound Obstet Gynecol

2006;27(5):522–9.

11. Monteagudo A, Timor-Tritsch IE, Moomjy M. Nomo-

grams of the fetal lateral ventricles using transvagi-

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12. Wang PH, Ying TH, Wang PC, et al. Obstetrical

three-dimensional ultrasound in the visualization of

the intracranial midline and corpus callosum of

fetuses with cephalic position. Prenat Diagn 2000;

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13. Shapiro R, Galloway SJ, Shapiro MD. Minimal

asymmetry of the brain: a normal variant. AJR Am

J Roentgenol 1986;147:753–6.

14. Naidich TP, Schott LH, Baron RL. Computed tomog-

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North Am 1982;20:143–67.

15. Epstein F, Naidich T, Kricheff I, et al. Role of comput-

erized axial tomography in diagnosis, treatment and

follow-up of hydrocephalus. Child’s Brain 1977;3:

91–100.

16. Noorani PA, Bodensteiner JB, Barnes PD. Colpoce-

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17. Garg BP. Colpocephaly. An error of morphogenesis?

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18. Heinz ER, Ward A, Drayer BP, et al. Distinction be-

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3D and 4D FetalNeuroscan: Sharingthe Know-how andTricksof theTrade
Eran Bornstein, MD*, AnaMonteagudo, MD,Ilan E.Timor-Tritsch, MD
KEYWORDS� 3D Ultrasound � 4D Ultrasound� Fetal Brain � Neuroscan � Display modalities

.com

We live in a 3D world. It is obvious, therefore, thatvisual information that is obtained from 2D imagesmay be limited in reflecting the 3D structural real-ity. 2D ultrasonography (US) however, has beenestablished as the mainstay of fetal brain sono-graphic evaluation. It was first obtained by meansof conventional transabdominal scanning and,subsequently, the transvaginal-transfontanellarapproach was developed, simulating the neonatalneuroscan and applying it to fetal brain imaging.1–3

The addition of the transvaginal approach yieldedhigh-resolution coronal and sagittal ‘‘slices’’ ofany fetal organ but has been particularly helpfulin fetal brain study.4 The authors believe the sepa-ration of the two different approaches, the trans-abdominal and the transvaginal, has onlyhistorical significance. The two should be usedjointly to obtain a complete fetal study if needed.The transvaginal study of the fetal brain, however,mandates additional experience, skills, and under-standing of the structure or the brain malformationin question in order for diagnosticians to translatethe 2D images to a reconstructed 3D model in theirminds. Modern 3D techniques have emerged in re-cent years enabling acquisition of an entire volumeof spatial ultrasound information that can be usedin real time or stored for off-line analysis.5 The vol-ume can be analyzed and displayed in multipleplanes and display modes that exceed by far thedisplay capacities of 2D US and better reflect the3D nature of the structure or anomaly in question.

Division of Maternal Fetal Medicine, Department of ObFirst Avenue, Room 9N26, New York, NY 10016, USA* Corresponding author.E-mail address: [email protected] (E. Bornstein).


The unique features of 3D US have helped bringthe field of diagnostic fetal sonography to thenext level. Until recently, similar 3D display modeswere available only by the use of computed MRimaging . Thus, the use of 3D US in experiencedhands may provide useful information that canbe displayed without the need for high test costs,as MR imaging study is more expensive than fetalsonography. The authors believe that, in the nearfuture, 3D evaluation of the fetal body, includingthe brain, will not be considered a separate entityor technique but rather an inherent part of fetalstudy in cases where congenital anomaly, specifi-cally fetal brain abnormality, is suspected to obtainthe utmost relevant information without which anexamination would not be complete.

In the article by Bornstein and collegues, ‘‘TheUtilization of 3D and 4D Dimensional Technologyin Fetal Neurosonology’’, elsewhere in this issue,the use of 3D technology to study the normaland abnormal fetal brain is discussed; therefore,the fetal neuroscan imaging technique is referredto in this article. The value of this new and excitingtechnology is to supplement and enhance tradi-tional 2D technology in appropriate cases ratherthan replacing it.

s

TECHNICAL ASPECTS

The physics aspect of 3D US technology and thedifferent display modalities are beyond the scope

stetrics & Gynecology, NYU School of Medicine, 550


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of this article. Several texts are available, however,for readers who are interested.6,7

With the improvement in gray-scale (2D) tech-nology, excellent sectional images of the fetalbody with its internal organs can be generated.Because 3D US data in the volume are obtainedby a multitude of successive 2D US sectional im-ages, these data can be used to reconstruct anydesired plane by ‘‘slicing’’ the volume in various di-rections. Planes can be created that are virtuallyimpossible to obtain by 2D scanning because offetal position (abdominal probe) or limitations ofthe transducer (ie, when using a vaginal probe).With 2D scan alone, most of the time it is possibleto obtain any two of the three classical planes (cor-onal, sagittal, and axial) of the fetal head or thebrain; however, it is virtually impossible to obtainall three planes unless a fetus changes its positionsignificantly during the scan.

Analysis of a 3D voxel-based volume (voxel isthe smallest 3D US picture unit) allows a reviewof the volume in all directions and displaying it inthe various display modes (Fig. 1).

The core part of the 3D system used, regardlessof the differences in the display software, is thetransducer. Most transabdominal and transvaginaltransducers perform a mechanical sweep by anelectrical motor that moves the crystal array ina certain range (angle of rotation). The planes arescanned in the volume at fixed and precise time in-tervals enabling an operator to make accuratemeasurements in the volume itself. The operator

Fig.1. 3D image of fetal head acquired in the axial plane(A) is presented in the niche mode. Plane B is perpendic-ular to plane A and parallel to the ultrasound beam andplane C is the reconstructed plane which is perpendicu-lar to both planes (A and B). The red cubicle illustratesa voxel (the smallest unit of a 3D volume exactly asthe pixel is the smallest unit of a 2D picture) placed atthe point representing the transsection of the threeorthogonal planes. The real size of a voxel is far smallerthan the one displayed here.

controls the quality of the image in the acquisitionplane, the angle of rotation (section width), and thequality of the scan, which is dependent on the ac-quisition velocity. The final product of the process-ing module is displayed on the monitor and can bemodified using the master control panel of the unitor stored as a volume, enabling future datamanipulations.

Although 3D US is a static display of differentplanes within a volume of information, 4D US dis-plays a continuously updated and newly acquiredvolume creating the impression of a moving struc-ture. This is obtained by placing the region of inter-est (ROI) box over the structure to be scanned andinitiating the scan. Initially, a real-time 2D US im-age appears on the monitor alongside a 4D US im-age. An operator then can manipulate the imageusing the X, Y, and Z axes to obtain the optimizedrendered view and activate the full-screen displayoption to view the moving 3D image. The use of4D US techniques while performing fetal neuro-scan is not widespread and currently is limited toassessment of limb mobility.

DISPLAYMODALITIES

There are several ways of transforming voxel-based data to a 2D pixel-based image. Differentmanufacturers have software to analyze the 3DUS volume, including 4D View (GE), QLAB (Phil-lips), SonoView Pro (Madison), and 3D VolumeViewer (Siemens). The various available softwaredisplays the scanning planes on the screen in dif-ferent fashions. The descriptions, as well as thefeatured images in this article are the ones the au-thors prefer and have worked with over the years.

The Multiplanar or Orthogonal Display Mode

This specific display mode enables simultaneousdisplay of an image in the three orthogonal planes.The acquisition plane appears in the upper left cor-ner of the screen in box A. Box B displays the plane,which is perpendicular to the acquisition plane (A)but parallel to the ultrasound beam. Box C displaysthe reconstructed plane, which is perpendicular tothe acquisition plane and the ultrasound beam.With some manipulation of the data volume, displayof the three classical body planes (coronal, sagittal,and axial) can be achieved in these boxes. Fig. 2 isan example of a multiplanar view of a normal braindisplaying the three orthogonal planes (ie, coronalplane [box A], sagittal plane [box B], and axial plane[box C]). In the authors’ experience and others’, thismodality provides the mainstay of 3D US evaluationof the fetal brain.8–12 Not only can three orthogonalplanes be seen simultaneously but also this displaymodality can be used to scroll through the volume,

Fig. 2. Multiplanar display of the fetal brain in the three orthogonal planes: the coronal plane (box A), the me-dian plane (box B), and the axial plane (box C). Note the marker dot representing the intersection of the threeorthogonal planes, which is placed in this image in the cavum septi pellucidi.

3D and 4D Fetal Neuroscan 519

as the planes can be moved back and forth, up anddown, and from side-to-side within the volume.Thus, an operator can move freely (scroll or navi-gate) in the saved brain volume in all three planesto scrutinize it and obtain any desired diagnosticplane of the structure in question. An importanttool used in this display modality is (what the au-thors call) the marker dot (see Fig. 2). This dot isgenerated by the intersection of the three orthogo-nal planes marking the same spot (or technically thesame voxel) within the volume. The marker dot isfreely movable by the operator, who can use it topinpoint the same exact spot or structure on thethree planes, which are being displayed simulta-neously. For the authors, the liberal use of themarker dot constitutes the most valuable diagnos-tic feature of the software, enabling pinpointing theexact anatomic location of the structure of interestin one plane and having it displayed simultaneouslyin the other two orthogonal planes while navigatingthrough the volume.

The Tomographic Ultrasound Imaging Mode

This mode displays an image in a successivelysliced fashion, similar to the display in CT andMR imaging.13 It probably is the most useful static

display modality used during fetal neuroscan. Us-ing the multiplanar mode to navigate through thevolume and obtaining the desired plane, the tomo-graphic mode then can be used to display consec-utive sections of the area of interest in each one ofthe three orthogonal planes seen in boxes A, B,and C. The area of interest can be displayed asseveral reconstructed parallel 2D sections on a sin-gle panel. The operator has control over the thick-ness and the number of slices displayed. Anadditional option is to use the two-panel displayin which the chosen plane is displayed side byside with the tomographic slice enabling naviga-tion through both planes simultaneously. Fig. 3 isan example of a tomographic view displaying suc-cessive (front-to-back) coronal sections of a nor-mal fetal brain.

Inversion Mode

This unique modality, inversion mode, is a datamanipulation that can be applied to the renderedvolume to image sonolucent structures better.This technique inverts anechoic structures thatare displayed as black on the customary 2Dgray-scale ultrasound picture into a white, cast-like appearance (as in the negative of a film). This

Fig. 3. Tomographic ultrasound image obtained on a fetal head in the sagittal position demonstrating successivecoronal planes displayed from front to back. The coronal planes correspond to the planes that are marked cross-ing the brain on the sagittal image. The operator has control over the number and the thickness of the slices thatare displayed as seen in the ultrasound image.

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mode recently was described in the evaluation ofthe ventricular system in both—in normal casesstudying the developing brain and in cases compli-cated by ventriculomegaly and holoprosence-phaly.14 The authors also have found thismodality useful in such cases. Fig. 4 demonstratesthe use of the inversion mode to image the ventric-ular system in a fetus with hydrocephalus.

Thick-Slice Mode

The software collapses a preselected number ofsuccessive pictures (slices) and displays them ina 2D picture to enhance edge detection. Theoperator can adjust the slice thickness modifyingthe number of cuts that are compressed into the fi-nal rendered image. An example of a thick slice ispresented in Fig. 5. This technique was furtherperfected and named volume contrast imaging(VCI) technology. The thick-slice technique stillcan be used; however, it requires several stepsin contrast with the newer VCI, which is a one-step display mode.

Static Volume Contrast Imaging

VCI is a modality aimed at improving the resolutionof the rendered image by displaying a thin slice ofthe acquired volume decreasing the ultrasound ar-tifacts. By adding successive and defined numberof tissue layers, ultrasound artifacts, such asspeckles and noise pixels, are decreased or totallyeliminated so that anatomic structures and theiredges are enhanced, resulting in an increasedcontrast resolution. Several users apply the staticVCI as a processing tool for the saved volumewith a slice thickness of 1 to 3 mm as the modalityof choice in analyzing the fetal brain.12 Fig. 6 en-ables comparison between traditional gray scaleand VCI of the same brain image acquired in theaxial plane.

Surface Rendering

Surface rendering is by far the most recognizablefeature of 3D US and 4D US, which drew the initialattention of the industry, software developers,

Fig. 4. These three images 4 A, B, and C are examples of the use of the inversion mode to image the fetal ven-tricular system in a case of hydrocephalus. This modality provides a cast-like pattern of the ventricular system.The inversion mode in Fig. 4A (box 3D) displays a sagittal view of the grossly dilated lateral ventricles. The arrowspoint to the anterior horn (ah), posterior horn (ph), and the inferior horn (ih). In Fig. 4B the inversion mode (box3D) displays a posterior view of the dilated ventricular system. The falx (arrow F) can be seen as the black lineseparating the two lateral ventricles. The communication of the lateral ventricles with the third ventricle alsocan be seen (arrow 3v). The inversion mode in Fig. 4C (box 3D) demonstrates a view of the superior aspect ofthe lateral ventricles with a complete falx (arrow F) separating them. The falx (arrow F) and the dangling choroidplexus (arrow cp) also are seen on the coronal and axial planes in boxes B and C, respectively. The complete falx isimportant in this case to differentiate it from the various degrees of holoprosencephaly.


Fig. 4. (continued).

Fig. 5. Multiplanar mode of the fetal spine with the sagittal plane in (box A) and axial plane in (box B)demonstrating the complete vertebrae and the coronal longitudinal plane in (box C). The thick-slice techniquewas applied to obtain the rendered image in the maximum mode (box 3D). Using this technique, the slicethickness can be adjusted, controlling the numbers of slices that are compressed into the final rendered image.

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Fig. 6. Image enhancement software: comparison of the same image of a fetal brain in the axial transventricularplane is displayed in normal gray-scale (A) and in VCI mode (B). This modality may improve the resolution of therendered image by displaying a thin slice of the acquired volume decreasing the ultrasound artifacts.


physicians, and patients to use of this technique.To obtain such an image, a well-defined interface(eg, tissue/fluid) is required. The volume then canbe rotated in all three axes, X, Y, and Z, to achievethe right plane. The light mode of the surface ren-dering displays the body surface as it would ap-pear if illuminated by a light source. This mode isnot used frequently while imaging a brain duringfetal neuroscan. It is an extremely useful mode,however, for detecting anomalies of the fetalface, which frequently are seen in cases of brainanomaly. Fig. 7 demonstrates the use of surfacerendering in the detection of unilateral cleft lip.

Transparency Mode

This modality, transparency mode, also called thex-ray mode or the maximum mode, was designed

Fig. 7. Surface rendering of the fetal face demonstrat-ing unilateral cleft lip.

to retain only strong US echoes. Because weakertissue echoes are suppressed and the bonesusually provide the strongest echoes, imagesresemble x-ray pictures. This mode is helpful par-ticularly for enhancing the evaluation of the skull incases of microcephaly; skull defect, such as ceph-alocele; abnormality of the skull sutures; and eval-uation of the fetal skeleton (eg, in examining thespine for neural tube defects). Fig. 8 demonstratesthe entire fetal spine and rib cage rendered in themaximum mode. Imaging the ribs can assist in lo-calizing the precise level of vertebrae associatedwith the spine anomaly, thus having an importantprognostic role.

Fig. 8. The entire fetal spine and rib cage is displayedin this image, which was rendered in the transparency(maximum) mode. The evaluation of the fetal bonystructures can be enhanced with this mode by provid-ing precise localization of the exact level of the verte-bra. The marked area shows the cervical spine (C),thoracic spine (T), lumbar spine (L), and sacrum (S).

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3D Angiography

Similarly to using 2D gray-scale ultrasound, powerangiography or color Doppler mode detects bloodflow and can be used while acquiring a 3D US vol-ume. These are useful imaging options of 3D USequipment while performing fetal brain scan-ning.15–17 In selected cases, volume scans canbe obtained using power angiography to imagevarious main vessels in the brain. The authorsare interested mainly in the course of the perical-losal branch of the anterior cerebral artery. Thecourse of this vessel and its branches are demon-strated in Fig. 9. The technique of volume acquisi-tion and manipulation is the same as with other 3DUS modes. This mode of the 3D US machine mayassist tracing a deviant course of any arterythrough the combined use of power angiographyand the marker dot. Another common helpful useof power Doppler while performing fetal neuroscanis imaging the circle of Willis. The clinical impor-tance of this technique is largely in cases wherea middle cerebral artery Doppler study is required.Fig. 10 displays a multiplanar mode using thethick-slice technique to image the circle of Willis.

SPECIAL CONSIDERATIONSOF 3D FETAL ULTRASOUND

The advantages and disadvantages of 3D ultra-sound in general and during fetal neuroscan in par-ticular have to be considered.

Fig. 9. 3D volume acquired with power Doppler posi-tioned at the median plane demonstrating the branch-ing of the complete pericallosal artery from theanterior cerebral artery. The presence of the entire peri-callosal artery confirms the presence of a normal corpuscallosum. The arrows point to the anterior cerebral ar-tery (a), frontopolar artery (fp), callosomarginal artery(cm), the pericallosal artery (P), the precuneal artery(pr), and the vein of Galen (G).

Advantages of 3D Ultrasound

1. As described previously, the major advantageof 3D US is the ability to view a structure or or-gan of interest simultaneously in the three per-pendicular planes, rotate the image, and freelynavigate through the volume in endless optionsof angles. This enhances the assessment ofmalformations by allowing images to be re-sliced and viewed from angles that are notavailable with 2D imaging alone and displaythem tomographically in fashion similar to CTand MR imaging.

2. The volume can be stored for future off-lineevaluation, enabling further manipulations, re-slicing, and displaying modes not performedat the time of examination or initial evaluation.

3. Electronic means of communication enablesending the volumes to specialists anywherein the world for second-opinion evaluation orconsultation. Recipients then can manipulatethe volume independently to obtain the desiredsections and planes. The authors have been us-ing this advantage successfully in the past fewyears by providing consultations to several col-leagues after reviewing the volumes they savedin an Internet-based file transfer protocol.

4. Another advantage is that the surface-rendering mode produces an image similarto a photograph, which is especially usefulin patient education and counseling. Patientsviewing a small fetal omphalocele, encephalo-cele, or facial abnormality, such as a cleft lip,may be better informed as they note the ap-pearance and size of the anomaly. The sameapplies for medical consultants, such as pedi-atric surgeons, neurosurgeons, and plasticsurgeons, who may obtain important clinicalinformation regarding the in utero anomaly,assisting them in early counseling of patientsand planning postpartum management beforea fetus is born. Fig. 11 is a multiplanar modewith surface rendering of a unilateral cleft lip.This image provides reassurance to parentsand plastic surgeons as to the extent of ananomaly and the likely favorable cosmeticprognosis.

5. Scanning time may be reduced significantlywith 3D US scanning allowing processing thevolume after a patient has left the examinationsuite. This may result in a better safety profilebecause of reduced exposure time, allowingfor more efficient use of staff and equipmentand increased patient satisfaction.

6. Positive influence on maternal-fetal bondinghas been described after obtaining 3D US.18

Fig. 10. The use of power Doppler is shown in this multiplanar image demonstrating the circle of Willis onthe axial plane (box A). Thick-slice technique was used to obtain a rendered image of the circle of Willis(box 3D). The arrows point to the anterior cerebral artery (a), middle cerebral artery (m), and the posterior cere-bral artery (p).


Specific Advantages of 3D UltrasoundDuring Fetal Neuroscan

1. The main advantage of 3D US in performing a fe-tal neuroscan, in the authors’ experience, is theuse of the multiplanar orthogonal display modeto navigate through the volume. By doing so,views can be obtained that are impossible (orextremely difficult) to obtain by traditional 2DUS. As discussed previously, after achievingthe specific plane using this technique, addi-tional display modes can be applied to obtaina diagnostic image with the tomographic modethe most useful during the fetal neurosonogram.

2. The sections recreated from the 3D US volumeare parallel to each other and do not radiatefrom a common point (the fontanelle) as is thecase in conventional 2D transvaginal transfon-tanellar neurosonography and neonatal neuro-scan. This makes 3D scanning of the fetalbrain similar to conventional imaging using CTand MR imaging. Fig. 12 demonstrates thedifferent angles in which the coronal views areobtained with transvaginal neuroscan and with3D reconstruction, respectively.

3. As discussed previously, the power angiogra-phy mode can be used in selected cases to ob-tain a volume imaging of various main vessels inthe brain. The authors are interested mainly inthe course of the pericallosal branch of the ante-rior cerebral artery. In cases of space-occupy-ing lesions, the anatomy of the vessels may beof use in determining the size and extent of thelesion. In cases of brain tumor, its vascularityhelps to evaluate the nature of the lesion. Using2D US to obtain the ‘‘perfect’’ median (midsag-ittal) plane requires experience in transvaginalbrain scan and at times may not be obtained be-cause of unfavorable fetal position or presenta-tion. Manipulating the 3D US to obtain the‘‘perfect’’ median plane can be achieved easilyby aligning the axial and coronal planes in theright position (discussed later). In some cases,in which the artery deviates from the midline be-cause of pressure from a structure (such asa cyst), the course of the displaced artery canbe followed using 2D US scans only with greatdifficulty or not at all. 3D angiography may assistin tracing the deviant course of the artery withthe combined use of the marker dot.

Fig.11. Multiplanar image of fetal face after manipulation of the volume to display the fetal profile in box A. Aunilateral cleft lip is seen in the 3D rendered box. This image may assist the plastic surgeon in counseling thepatient and planning the postpartum management before the baby is born.

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Limitations of 3D Ultrasound

1. In general, the limitations of 3D US are few andmainly reflect lack of adequate experience be-cause of its long learning curve.19

2 The quality of an image displayed in the orthog-onal planes (or any other render or display) canbe only as good as the 2D US image in the ac-quisition plane. In addition, the reconstructedthird plane (C plane) always will have lower res-olution and an increased level of artifacts. Thequality may be improved somewhat by usingthe thick-slice or the VCI application (discussedpreviously).

3. Acoustic shadowing in 2D US image in theacquired plane results in fixed acoustic shadowalso limiting the 3D volume. For example, a 2DUS image of the fetal brain obtained throughthe occipital bone may have poor quality of theintracranial structures as the thick bone createsan acoustic shadow. Similarly, a 3D volume ob-tained in this manner includes this fixed acousticshadow embedded in the volume. Therefore,the prerequisite for a good 3D US image is togenerate good-quality 2D US image.

4. Fetal motion is a major limitation causing arti-facts that may preclude the acquisition ofa good 3D US volume making it necessary toobtain additional volumes. This usually is over-come by decreasing the acquisition time of thevolume using the low- or medium-quality sweepand by obtaining the volume in a time periodwith no fetal or maternal movements. The au-thors frequently instruct patients to hold theirbreath at the time of volume acquisition to limitany possible movement. This is true for volumesrequiring long acquisition times, such as thosecontaining color or power Doppler information.

5. The surface-rendering mode requires a fluid-tissue interface that sometimes may becompromised by an unfavorable fetal position,a fetal hand over the fetal face, or a fetal facetoo close to the anterior placenta. The elec-tronic scalpel or the lectronic eraser may assistin eliminating structures that are not desired orthat block the target structure.

6. Additional drawbacks that apply to 3D US justas in 2D US are the difficulty of obtaininga good image in patients who are obese or pres-ent with oligohydramnios and a nonfavorable

Fig. 12. The diagrams demon-strate the different angles inwhich the coronal views areobtained with transvaginaland with 3D neuroscans,respectively. The sections recre-ated from the 3D volume areparallel to each other and notradiating from a commonpoint (the anterior fontanelle)as is the case with conventional2D transvaginal neurosonogra-phy and neonatal neuroscan.


fetal position limiting the acquisition of thevolume.

7. 3D US requires more expensive, updated ultra-sound machines and software and is regardedas experimental by most health care carriers.For now, its use is limited by availability, finan-cial aspects, and inexperienced users.

Limitations Unique to the 3D Neurosonogram

Specific limitations to the use of 3D US during fetalneuroscan are few. Generally, a high-frequencytransvaginal ultrasound probe produces better im-ages with higher resolution. The fetus must be invertex presentation and the probe should be di-rected to perform a transvaginal transfontanellarneuroscan. In cases of breech presentation, ac-quisition of the volume should be attemptedthrough the fontanelles, the sutures, or the thinnertemporal bone to obtain a better view of the intra-cranial structures. At times, external version of thefetus into vertex presentation is warranted in fe-tuses with strong suspicion of a brain anomaly. Im-aging the posterior fossa may be compromised bythe acoustic shadow of the thick petrous ridge ofthe skull limiting the ability to image the brainstem.Volume acquisition through the posterior fonta-nelle or the posterior section of the sagittal suturemay assist in overcoming this problem. Anotherlimiting factor is the rare case of craniosynostosisin which the early fusion of the sutures limitseasy scanning access to the brain that may be par-tially overcome by using the higher-frequencytransvaginal transducer.

REFERENCES

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11. Pilu G, Segata M, Ghi T, et al. Diagnosis of midline

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13. Monteagudo A, Timor-Tritsch IE, Mayberry P. Three-

dimensional transvaginal neurosonography of the

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14. Kim MS, Jeanty P, Turner C. Benoit B.Three-dimen-

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15. Pooh RK, Pooh K. Transvaginal 3D and doppler

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Gynecol 1998;178:1199–206.

The Utility of VolumeSonography for theDetection of Fetal SpineAbnormalities
Noam Lazebnik, MDa,*, Eran Bornstein, MDb,Ilan E.Timor-Tritsch, MD, RDMSb
KEYWORDS� Volume ultrasound � Fetal spine abnormalities� Technical principals

m

Sonographic evaluation of the fetal vertebral col-umn is essential for fetal central nervous systemevaluation and valuable for ruling out genetic con-ditions. The development of volume ultrasound inthe early 1990s1–4 led several groups to studythe fetal skeleton using the maximum intensityprojection (MIP) mode, also termed ‘‘maximumtransparency’’ or the ‘‘X-ray’’ mode.5–12 Johnsonand coworkers8 performed three-dimensionalstudies of the fetal spine on 28 fetuses (16 normaland 12 abnormal). Fifteen of the 16 normal fetalspines were visualized completely. In cases ofneural tube defects, a three-dimensional approachwas superior for identifying the specific vertebrallevel of the lesion and recognizing the presenceof scoliosis. Pilu and colleagues,13 however, deter-mined that a normal three-dimensional evaluationof the bony spine is not always reassuring, andmay miss small, subtle, and low localized spinabifida. Similarly to others, they did recognize theadditive value of the three-dimensional scan foridentifying the precise location of a spinal lesionusing the twelfth rib as a marker for T12.13,14

This article provides an overview for obtainingand manipulating fetal vertebrae three-dimen-sional data to obtain the necessary diagnosticviews. Additional technical information is providedelsewhere in this issue. This discussion is limitedto include only the most common fetal vertebralabnormalities. The same technical principals,

a Department of Obstetrics and Gynecology, Case WCleveland, 11100 Euclid Avenue, Cleveland, OH 44106, Ub New York University School of Medicine, 550 First Ave* Corresponding author.E-mail address: [email protected] (N. Laze


however, enable detection of many additionalabnormalities.

o

PROPER TECHNIQUE

Both transabdominal and transvaginal studies arepractical for volume acquisition depending on theorientation of the fetal spine and the fetal size. Ac-quisition is best performed along the median planeof the trunk with beam origin at the posterior of thefetus. The authors generally use a 30- to 40-de-gree angle sweep to include the entire fetus withina single frame. If acquisition is not performedwithin the median plane, the volume may bemanipulated to obtain appropriate sagittal andcoronal planes. MIP mode rendering facilitatesdetection of skeletal anomalies, such as hemiver-tebra, sacral agenesis, and agenesis of ribs, andenables evaluation of the three ossification centersof each vertebra.14,15

The three-dimensional approach is extremelyuseful for studying the spine, vertebrae, ribs, pelvicbones, and the spinal cord. Not only can one si-multaneously visualize three orthogonal planes,but also scroll through the volume along any givenorientation. Through this one may confirm the pre-cise anatomic location of a vertebral abnormality,using known anatomic landmarks for reference.Another extremely important tool is the ‘‘markerdot.’’ Typically, this dot is located at the

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intersection of three orthogonal planes and isfreely movable by the user to pinpoint a givenstructure on three planes simultaneously.

Fig. 1 demonstrates multiplanar images of thefetal spine with the ‘‘thick slice’’ rendering tech-nique and MIP mode (Fig. 1D). In Fig. 1E a differentcolor scheme was used to enhance further the fe-tal bony structures. Fig. 2 demonstrates the fetalspine rendered using MIP mode, demonstratingthe three processes of the vertebrae and the rib

Fig.1. Multiplanar display of the fetal spine with the sagittaplete vertebrae and the coronal longitudinal plane (C). Thedered image in the MIP mode (D). Using this technique, thwidth that is visualized by the final rendered image. (E) Rvertebra, ribs, and the pelvic bones. The MIP mode and ubony structures.

cage and iliac bones. It is important to note thatthe use of real-time three-dimensional, also knownas four-dimensional, may be useful for performingthe skeletal evaluation during fetal motion.

NEURALTUBE DEFECTS

Neural tube defects occur if there is interferencewith physiologic closure of the neural tube aroundthe 28th day postfertilization. The normal brain and

l plane (A) and axial plane (B) demonstrating the com-‘‘thick slice’’ technique was applied to obtain the ren-

e slice thickness can be adjusted, controlling the tissueendered three-dimensional image of the fetal spine,nique color scheme are used to document better the

Fig. 2. The fetal spine rendered using MIP mode anddemonstrating the three processes of each vertebra(the two lateral processes and the posterior processare marked with arrows). The rib cage can also beevaluated and assist in precise localization of verte-bral defects. The twelfth rib is marked with an arrowand correlates with the level of T12. The iliac crests isalso seen (arrow).

Fig. 3. Rendered three-dimensional image of the pro-file of an anencephalic fetus at 19 weeks. The entirefrontal bone is missing and disorganized brain tissueis seen superior to the eyes.

Fig. 4. The three orthogonal planes and a rendered three-dimensional image of the fetus seen in Fig. 3. Thecoronal image (C) demonstrates lack of calvarial bones.

3D Image of Fetal Spine 531

Fig. 5. Thin-sliced rendered three-dimensional imageshowing a posterior skull defect through which me-ninges and brain tissue herniated for this 20-week fe-tus with posterior encephalocele and final diagnosisof Walker-Warburg syndrome.

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spinal cord develop as a groove, which folds overto become a tube (the neural tube). Layers of tis-sues that normally emerge from this tube formthe brain and spinal cord and their covering tis-sues, including parts of the spine and meninges.Failure of the neural tube to develop normally

Fig. 6. The three orthogonal views and a rendered threencephalocele can be seen only on the coronal view.

may affect the brain, spinal cord, and meninges.The severity of the abnormality differs betweenaffected fetuses and the incidence of neuraltube defects is approximately 1 to 3 per 1000worldwide.

The spectrum of neural tube defects includesthree types of defects: (1) anencephaly, (2) ence-phalocele, and (3) spina bifida.16 The most severeform is anencephaly, which occurs when the ‘‘ce-phalic’’ or head end of the neural tube fails toclose, resulting in absence of a major portion ofthe brain, skull, and scalp. Infants with this disor-der are born without a forebrain and cerebrum.The remaining brain tissue is often exposed andnot covered by bone or skin (Figs. 3 and 4).

Encephaloceles are rare neural tube defectscharacterized by sac-like protrusions of the brainand the membranes that cover it through openingsin the skull. These defects are caused by failure ofthe neural tube to close completely during fetaldevelopment. The result is a groove down themidline of the upper part of the skull, the area be-tween the forehead and nose, or the back of theskull (Figs. 5 and 6). Encephaloceles are oftenassociated with neurologic problems and may beassociated with known genetic conditions, suchas Walker-Warburg syndrome. Usually,

e-dimensional image of the fetus seen in Fig. 5. The

Fig. 7. A fetus with anterior encephalocele (arrows). The sagittal view shows the skull defect. Only the meningesare seen herniating out.

Fig. 8. A 22-week fetus with sacral open neural tube defect (meningocele). The anomaly in the axial (A), thesagittal (B), and the coronal planes (C) is clearly seen.


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encephaloceles are dramatic deformities diag-nosed in utero using an ultrasound study, but oc-casionally a small encephalocele in the nasal andforehead region is undetected (Fig. 7). Encephalo-celes are often accompanied by craniofacialabnormalities or other brain malformations. Symp-toms and associated abnormalities for encephalo-celes may include hydrocephalus, spasticquadriplegia, microcephaly, ataxia, developmen-tal delay, vision problems, mental and growthretardation, and seizures. There is a genetic com-ponent to the condition; it often occurs in familieswith a history of spina bifida and anencephaly infamily members or might be a phenotypic expres-sion of an unrelated genetic syndrome, such asMeckel-Gruber syndrome.

There are four types of spina bifida. They differ inseverity and the tissue involved. Spina bifidaocculta is the mildest and most common form inwhich one or more vertebrae are malformed. Thename ‘‘occulta,’’ which means ‘‘hidden,’’ indicatesthat the malformation, or opening in the spine, iscovered by a layer of skin. This form of spina bifidararely causes disability or symptoms.

Fig. 9. Tomographic display mode demonstrating multiplwidth of the spine defect. The lateral displacement of theent levels of the cerebellum. Only the meninges are hern

Closed neural tube defects make up the secondtype of spina bifida. These are a diverse group ofdefects in which the spinal cord is affected bya malformation of fat, bone, or membranes. Insome patients there are few or no symptoms; inothers the malformation causes incomplete paral-ysis with urinary and bowel dysfunction.

The third type of defect, meningocele, is charac-terized by the meninges protruding from the spinalopening. This malformation may or may not becovered by a layer of skin. Some patients with me-ningocele may have few or no symptoms, whereasothers experience symptoms similar to those ofclosed neural tube defects.

Myelomeningocele, the fourth form, is the mostsevere and occurs when the spinal cord is ex-posed through the opening in the spine, resultingin partial or complete paralysis of the parts of thebody below the level of the spinal opening. The pa-ralysis may be so severe that the affected individ-ual is unable to walk and may have urinary andbowel dysfunction.16

An example of a fetus with spina bifida detectedat 22 weeks is demonstrated in Figs. 8 and 9. The

e successive sagittal views taken through the entirecerebellar hemispheres can be evaluated at the differ-iating out.

Fig. 11. The typical abnormalities associated withspinal open neural tube defect of the fetal skull(lemon sign) and the pulled down cerebellum (ba-nana sign).


sonographic volume was displayed in three or-thogonal planes to visualize the anomaly in boththe axial and the sagittal planes. Tomographic ul-trasound imaging mode displays successive sagit-tal planes, improving delineation of extent of theanomaly and the nature of the tissue herniatingthrough the defect to be meninges, suggestingmeningocele. The vertebral column can be ren-dered using MIP mode for cases where the spe-cific level of the spine defect cannot bedetermined easily using two-dimensional imagingand to illustrate the etiology of the herniating tissue(Fig. 10). Additionally, clinically significant openneural tube defects typically exhibit pathology ofthe posterior fossa (ie, the impacted cerebellumgives rise to the ‘‘banana sign,’’ which is an indi-rect consequence of the vertebrae anomaly wherethe entire spinal cord is pulled downward)(Fig. 11).

Fig. 10. The fetus seen in Figs. 8 and 9. The vertebralcolumn can be rendered using MIP mode to demon-strate the spine defect (A) and to illustrate the natureof the tissue herniating out (B).

HEMIVERTEBRAE

The congenital vertebral anomalies are classifiedbased on failure of formation; failure of segmenta-tion; and a combination of the two (mixed).17 Themost common failure of formation anomaly isa hemivertebra. In this form, a portion of the verte-bra is missing resulting in a small, triangularshaped ‘‘half vertebra’’ or hemivertebra. Congeni-tal scoliosis is one type of structural spine defor-mation and hemivertebra is the most commonanomaly causing congenital scoliosis (Fig. 12).18

Hemivertebrae is associated with continued pro-gression of scoliosis in extrauterine life.

Hemivertebrae may be isolated or may occurat multiple levels. It is frequently associatedwith other congenital anomalies.18,19 Theseinclude other musculoskeletal anomalies, suchas those of the spine, ribs, and limbs. Cardiacand genitourinary tract anomalies are the morecommon extramusculoskeletal anomalies seenwith hemivertebrae. Anomalies of the central ner-vous system and gastrointestinal tract are alsoreported. Hemivertebra may be part of a syn-drome including Jarcho–Levin, Klippel-Feil, andVACTERL association (Vertebral anomalies, Analatresia, Cardiovascular anomalies, Tracheoeso-phageal fistula, Esophageal atresia, Renal[kidney] or radial anomalies, preaxial Limbanomalies).

Coronal display of the vertebral column facili-tates easy visualization of the vertebral bodiesincluding the three ossification centers and theribs (Fig. 13). As with other skeletal anomalies,use of the MIP mode may assist in diagnosingthis condition by demonstrating absence of partof the vertebra or one of its processes.

Fig. 12. A 23-week fetus diagnosed with VACTREL association. The spinal defect is clearly seen on the three or-thogonal planes (A–C) and the three-dimensional rendered image (D) using MIP mode. Significant scoliosisalso is seen.

Fig.13. The three orthogonal planes are used to show the failure of lateral vertebral formation resulting in a hemi-vertebra anomaly.

536


TETHERED SPINAL CORD OR OCCULT SPINALDYSRAPHISM

Tethered spinal cord or occult spinal dysraphismis likely the result of improper growth of the neuraltube during fetal development, and is closelylinked to spina bifida. It is a rare neurologic disor-der (occurring in 0.05–0.25 of 1000 births) andcaused by tissue attachments that limit the move-ment of the spinal cord within the spinal column re-sulting in abnormal stretching of the spinal cord.Tethered spinal cord may go undiagnosed untiladulthood, when sensory and motor problemsand loss of bowel and bladder control emerge.The delayed presentation of symptoms is relatedto the degree of strain placed on the spinal cordover time. In children, symptoms may includelesions, hairy patches, dimples, or fatty tumor onthe lower back; foot and spinal deformities; weak-ness in the legs; low back pain; scoliosis; andincontinence.20

Closed spinal defects, such as ‘‘subtle skin-cov-ered spinal dysraphism,’’ are difficult to detect inutero by a routine two-dimensional ultrasoundstudy. This group of anomalies includes a tethered

Fig.14. A 36-week fetus. The sagittal plane demonstrates thconfirm the location by using the coronal plan to identifyThe marker dot identifies the location of the distal end o

cord (tight filum terminale syndrome); diastemato-myelia; subcutaneous or interspinal lipoma; andepidermoid and dermoid cysts.

During normal fetal development, the conus me-dullaris (CM), which is situated at the sacral regionof the vertebral column, ascends to its final loca-tion at birth. Review of the literature demonstratesa limited number of studies focused on the CM.Wilson and Prince21 used MR imaging to deter-mine the anatomic location of the normal CMthroughout childhood and demonstrated it is prox-imal to the L2 vertebra. Robbin and colleagues22

studied the fetal CM using two-dimensional ultra-sound techniques. In a recent study by Zalel andcolleagues,23 the researchers describe the normallocation of the CM and determined the timeline ofits ascent during human gestation using two-di-mensional imaging. To locate the CM precisely,they obtained sagittal and coronal longitudinalviews identifying known anatomic landmarks.The upper pole of the kidney was considered theT11 vertebra, and the lower rib was T12. Verifica-tion was done by counting the vertebra from thelumbosacral junction upward. Zalel and col-leagues23 concluded that the CM could be

e distal end of the CM (A). The other two planes (B, C)the twelfth rib/T12 and count the vertebra caudally.

f the CM on all three planes.

Fig.15. The tomographic display mode is used to verify that neural tissue is not seen distal to L4. The marker dotidentifies the location of the distal end of the CM on all tomographic slices.

Lazebnik et al538

sonographically identified and followed through-out pregnancy and a significant ascent of the CMwas detected between 13 and 40 postmenstrualweeks from the level of L4 or more caudally, be-tween 13 and 18 postmenstrual weeks of preg-nancy, to the level of L1 to L2 at approximately40 weeks. They also suggested that in fetuseswhose CM termination levels are equivocal (L3)or abnormal (lower than L3–L4), a follow-up ultra-sound study and additional work-up are indicatedin early life.

Figs. 14 and 15 demonstrate the CM of a 36-week fetus suspected of having tethered spinalcord. The CM is seen lower than expected be-tween L3to L4. The use of the three orthogonalplanes and the tomographic display modeenabled precise localization of the CM to be equiv-ocal (L3–L4) late in gestation. The diagnosis wasconfirmed at 6 months of age.

SUMMARY

Volumetric sonography is extremely useful for ex-amining the fetal spine, individual vertebrae, pelvicbones, and the spinal cord. By scrolling throughthe volume one may confirm the exact location

of a vertebral abnormality using known anatomiclandmarks as a reference point. The preferredthree-dimensional rendering mode of the vertebralcolumn is the MIP mode, which provides valuableinformation complementary to a conventional two-dimensional examination.

REFERENCES

1. Mueller GM, Weiner CP, Yankowitz J. Three-dimen-

sional ultrasound in the evaluation of fetal head

and spinal anomalies. Obstet Gynecol 1996;88:

372–8.

2. International Society of Ultrasound in Obstetrics &

Gynecology Education Committee. Sonographic ex-

amination of the fetal central nervous system: guide-

lines for performing the basic examination and the

fetal neurosonogram. Ultrasound Obstet Gynecol

2007;29(1):109–16.

3. Merz E, Bahlmann F, Weber G, et al. Three-dimen-

sional ultrasonography in prenatal diagnosis. J Peri-

nat Med 1995;23(3):213–22.

4. Steiner H, Spitzer D, Weiss-Wichert PH, et al. Three-

dimensional ultrasound in prenatal diagnosis of skel-

etal dysplasia. Prenat Diagn 1995;15:373–7.


5. Platt LD, Santuli T Jr, Carlson DE, et al. Three-dimen-

sional ultrasonography in obstetrics and gynecol-

ogy: preliminary experience. Am J Obstet Gynecol

1998;178:1199–206.

6. Nelson TR, Pretorius DH. Visualization of the fetal

thoracic skeleton with three-dimensional sonogra-

phy: a preliminary report. Am J Roentgenol 1995;

164:1485–8.

7. Riccabona M, Johnson D, Pretorius DH, et al. Three

dimensional ultrasound: display modalities in the fe-

tal spine and thorax. Eur J Radiol 1996;22:141–5.

8. Johnson DD, Pretorius DH, Riccabona M, et al.

Three-dimensional ultrasound of the fetal spine. Ob-

stet Gynecol 1997;89:434–8.

9. Schild RL, Wallny T, Fimmers R, et al. Fetal lumbar

spine volumetry by three-dimensional ultrasound.

Ultrasound Obstet Gynecol 1999;13:335–9.

10. UlmMR, KratochwilA, Oberhuemer U, et al.Ultrasound

evaluation of fetal spine length between 14 and 24

weeks of gestation. Prenat Diagn 1999;19:637–41.

11. Garjian KV, Pretorius DH, Budorick NE, et al. Fetal

skeletal dysplasia: three-dimensional US: Initial ex-

perience. Radiology 2000;214:717–23.

12. Lee W, Chaiworapongsa T, Romero R, et al. A diag-

nostic approach for the evaluation of spina bifida by

three-dimensional ultrasonography. J Ultrasound

Med 2002;21(6):619–26.

13. Pilu G, Ghi T, Carletti A, et al. Three-dimensional ul-

trasound examination of the fetal central nervous

system. Ultrasound Obstet Gynecol 2007;30(2):

233–45.

14. Esser T, Rogalla P, Sarioglu N, et al. Three-dimen-

sional ultrasonographic demonstration of agenesis

of the 12th rib in a fetus with trisomy 21. Ultrasound


15. Kalache KD, Bamberg C, Proquitte H, et al. Three-

dimensional multi-slice view: new prospects for

evaluation of congenital anomalies in the fetus.

J Ultrasound Med 2006;25(8):1041–9.

16. National Institute of Neurological Disorders and Stroke.

Spina bifida fact sheet. Available at: http://www.ninds.

nih.gov/disorders/spina_bifida/detail_spina_bifida.htm.

Accessed November 7, 2008.

17. Erol B, Kusumi K, Lou B, et al. Etiology of congenital

scoliosis. UPOJ 2002;15:37–42.

18. McMaster MJ, David CV. Hemivertebra as a cause

of scoliosis. J Bone Joint Surg Br 1986;68:588–95.

19. Connor JM, Conner AN, Connor RAC, et al. Genetic

aspects of early childhood scoliosis. Am J Med

Genet 1987;27:419–24.

20. National Institute of Neurological Disorders and

Stroke. NINDS tethered spinal cord syndrome infor-

mation page. Available at: http://www.ninds.nih.gov/

disorders/tethered_cord/tethered_cord.htm. Accessed

November 7, 2008.

21. Wilson DA, Prince JR. MR imaging determination of

the location of the normal conus medullaris through-

out childhood. AJR Am J Roentgenol 1989;152:

1029–32.

22. Robbin ML, Filly RA, Goldstein RB. The normal loca-

tion of the fetal conus medullaris. J Ultrasound Med

1994;13:541–6.

23. Zalel Y, Lehavi O, Aizenstein O, et al. Development

of the fetal spinal cord: time of ascendance of the

normal conus medullaris as detected by sonogra-

phy. J Ultrasound Med 2006;25(11):1397–401.

http://www.ninds.nih.gov/disorders/spina_bifida/detail_spina_bifida.htm

http://www.ninds.nih.gov/disorders/spina_bifida/detail_spina_bifida.htm

http://www.ninds.nih.gov/disorders/tethered_cord/tethered_cord.htm

http://www.ninds.nih.gov/disorders/tethered_cord/tethered_cord.htm

Fetal Neuroimagingof Neural MigrationDisorder
Ritsuko K. Pooh, MD, PhD
KEYWORDS� Fetus � Prenatal � Neuroimaging � Migration disorder� Lissencephaly � Cortical development

Many brain malformations are closely related toneuronal migration disorders.1 Neuronal migrationdisorders include focal cerebrocortical dysgenesis,heterotopia, polymicrogyria, lissencephaly or pa-chygyria, and schizencephaly. These disordersare caused by the abnormal migration of neuronsin the developing brain and nervous system.Neurons must migrate from their origin areas totheir final anatomic location within the centralnervous system (CNS) where they must settle intoproper neural circuits. Neuronal migration, whichoccurs as early as the second month of gestation,is controlled by a complex assortment of chemicalguides and signals. When these signals are absentor incorrect, neurons do not migrate appropriately.

Fetal neuroimaging, through advances in ultra-sound and MR imaging, has contributed to the fieldof fetal medicine in prenatal detection of many con-genital CNS anomalies, such as prosencephalicdisorders, neurulation disorders, intracranial tumors,cysts, and brain damage attributable to intrauterineinsults. In addition, prenatal imaging assessment ofthe fetal CNS contributes to more effective prena-tal/postnatal management. Although migration dis-orders occur during early gestational stage, theirphenotypic expression appears in late pregnancy,when sonographic assessment of the cortical devel-opment is difficult because of fetal cranial ossifica-tion. Antenatal cortical assessment is, at present,one of the most challenging fields of fetal medicine.

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NORMAL CORTICAL DEVELOPMENT

Neuronal migration occurs between 3 and 5months’ gestation. In early brain development,

CRIFM Clinical Research Institute of Fetal Medicine PMCE-mail address: [email protected]

Ultrasound Clin 3 (2008) 541–552doi:10.1016/j.cult.2008.09.0071556-858X/08/$ – see front matter ª 2008 Published by E

nerve cells migrate to their final anatomic destina-tions to populate and form the six layers of the ce-rebral cortex. When the brain first forms, neuronsare generated in a region of the ventricular zoneand ‘‘crawl’’ to the cortical surface. There are twomodes of cell migration: tangential migration andradial migration.2 The first and earlier mechanismis movement by translocation of the cell body.3

This movement results in the prepalate formation.The second mechanism is radial migration, in whichmigrating cells are generated by the radial glial pro-genitors. Travel instructions and guides are servedto migrating cells and are controlled by compli-cated molecular machinery.

Owing to recent advanced sonographic technol-ogy and fast MR technology, detailed morphologicstructures of the fetal brain are detectable as earlyas the late first and early second trimesters. Pheno-typic expression of migration disorders appears inlate pregnancy and therefore seems difficult to de-tect by the end of the second trimester. Duringpregnancy, one of the most comprehensive imag-ing planes for evaluation of fetal cortical develop-ment is the anterior coronal section, in which thebilateral sylvian fissures are well demonstrated, asshown in Fig. 1. This plane is acquired sonograph-ically by way of the anterior fontanelle window. Dur-ing the latter half of the second trimester, thecortical structure macroscopically develops. Themost distinct morphologic alteration seems toaffect the structure of the sylvian fissure betweenapproximately 20 and 30 weeks. The sylvian fissureis thus one of the morphologic landmarks indicatingcortical development through normal neuronal mi-gration. Developmental delay of the sylvian fissures

, 3-7, Uehommachi, Tennoji, Osaka #543-0001, Japan

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Fig.1. Changing appearance of sylvian fissure in the anterior coronal section by transvaginal sonography. At 20weeks of gestation, the bilateral sylvian fissures (arrowheads) appear as indentations (left, A). With cortical de-velopment, sylvian fissures are formed during the latter half of the second trimester (middle, B) and become thelateral sulci (right, C). Sylvian fissure appearance is one of the most reliable ultrasound markers for the assessmentof cortical development.

Fig. 2. Abnormal sulcal formation at 31 weeks and 5 days of gestation. (Upper) Transvaginal ultrasound images.Sagittal (left, A) and posterior coronal (right, B) sections. Arrowheads indicate abnormal sulcal formation.(Lower) MR images for the same gestation. Same findings as shown by sonography were confirmed by the sag-ittal (left, C) and posterior coronal (middle, right, D, E) sections.

Pooh542

Fetal Neuroimaging of Neural Migration Disorder 543

during the second and third trimesters should bringsuspicion for migration disorder.

MIGRATION DISORDERS

Migration disorder can result in structurally abnor-mal or missing areas of the brain in the cerebralhemispheres, cerebellum, brainstem, or hippo-campus. Disorders of neuronal migration, in orderof increasing severity, include focal cerebrocorticaldysgenesis, heterotopia, polymicrogyria, lissence-phaly or pachygyria, and schizencephaly.

In migrational disorders, hypoplasia or agenesisof the corpus callosum often accompanies gyralabnormality.2 The causes of disorders of migrationare varied and include environmental toxic condi-tions or genetic metabolic disorders.

Detection of polymicrogyria as early as 24weeks has been reported4 but more commonlyprenatal sonographic suspicions for migration dis-order arise during the third trimester.

Fig. 3. Abnormal sulcal formation with agenesis of the corptrasound images. Sagittal (upper left, A) and anterior coseen. Arrowhead indicates abnormal sulcal formation. Mshown by sonography were confirmed by the sagittal (lowe

FOCAL CEREBROCORTICAL DYSGENESIS

Migration disorders associated with cerebrocorti-cal dysgenesis may occur anywhere intracranially.The prognosis varies with the specific disorder, de-gree of brain abnormality, and subsequent neuro-logic deficiencies. Occasionally minor gyral/sulcalabnormality is detectable using ultrasound studyof the fetal brain as shown in Figs. 2 and 3. Figs.4 and 5 demonstrate unilateral maldevelopmentat 20 weeks’ gestation as detected by ultrasonog-raphy and MR imaging because of unilateral hemi-spheric migration disorder of the brain. Histologicfindings subsequent to termination of pregnancyshowed the distinct differences in brain structurebetween the right and left hemispheres (seeFig. 5). Figs. 6 and 7 demonstrate asymmetric de-velopment of the ventricular zone and corticalstructure between hemispheres. Postnatal multipleheterotopias were confirmed by MR imaging alongwith intractable convulsions.

us callosum at 36 weeks of gestation. Transvaginal ul-ronal (upper right, B) sections. No corpus callosum isR images for the same gestation. Same findings asr left, C) and anterior coronal (lower right, D) sections.

Fig. 4. Migration disorder of unilateral hemisphere at 18 weeks of gestation. (upper six images, A) Tomographiccoronal image of the brain. Note the markedly different appearance of the bilateral hemispheres. (Lower fourimages, B) MR images of the same gestational age. Anterior-coronal, posterior-coronal, parasagittal and mid-sag-ittal sections (left to right). Unilateral abnormal brain development was caused by the migration disorder.

Pooh544

LISSENCEPHALY

Lissencephaly is characterized by lack of gyral de-velopment. Previously lissencephaly was classi-fied into two types. In type I the surface of thebrain is smooth, whereas in type II the surfacedemonstrates a cobblestone appearance. A re-cent classification is based on associated malfor-mations and genetic causes.5 Five major groupsof lissencephaly are recognized: (1) Classic lissen-cephaly (previously known as type 1 lissence-phaly), including lissencephaly due to the LIS1gene mutation, which subdivides into type 1 iso-lated lissencephaly and the Miller-Dieker syn-drome, lissencephaly due to the doublecortin(DCX) gene mutation, (2) X-linked lissencephalywith agenesis of the corpus callosum, linked tothe ARX gene, (3) lissencephaly with cerebellar

hypoplasia, including the Norman-Robertssyndrome linked to mutation in the reelin gene,(4) micro-lissencephaly (lissencephaly and micro-cephaly), and (5) cobblestone lissencephaly,including the Walker-Warburg syndrome, alsoknown as HARD � E syndrome (hydrocephalus,agyria, retinal dysplasia, with or without encepha-locele), Fukuyama syndrome, and muscle-eye-brain (MEB) disease.

Several reports of prenatal diagnosis of lissen-cephaly are available.6–8 Fig. 8 shows the lissen-cephalic brain with abnormal brain circulationdue to chromosomal aberration at 29 weeks anddemonstrates bilateral shallow sylvian fissures,premature brain structure, and mild ventriculome-galy. Pachygyria in the third trimester from un-known cause is shown in Fig. 9. Classic

Fig. 5. Specimen from aborted fetus at 21 weeks of gestation and histologic findings (the same case as Fig. 4). (Leftupper, A) Prenatal MR imaging, coronal section. (Right upper, B) Macroscopic intracranial finding at autopsy.(Left lower, C) Maldevelopment of the other hemisphere due to the migration disorder. (Right lower, D) Normalcerebral structure of normal hemisphere.


Fig. 6. Ultrasound and MR imaging of migration disorder at 25 weeks of gestation. (Upper left, A) Ultrasoundanterior coronal section. Abnormal gyri and sulcus (arrowhead) are seen in the unilateral hemisphere. (Upperright, B) Tomographic ultrasound imaging, sagittal section. Abnormally asymmetrical shape of the ventricles (ar-rowheads) is demonstrated. (Lower) Fetal MR imaging at the same gestational age. In the sagittal (left, C) andaxial (middle, D) sections, abnormal protrusion of the unilateral anterior lobe (circle) is seen. In the posteriorcoronal section (right, E), abnormal gyral formation (oval) is seen.

Pooh546

Fig.7. Ultrasound imaging of abnormal cortical formation at 29 weeks of gestation. (the same case as Fig. 6). Para-sagittal ultrasound image of the surface of left hemisphere (upper left, A) and right hemisphere (lower left, B).Note the marked difference in cortical formation between hemispheres. The right figure (C) demonstrates thesurface anatomy of hemispheres by 3D ultrasound in parietal view. The different formation of gyrus and sulcusbetween hemispheres is clearly demonstrated.

Fig. 8. Lissencephalic brain with abnormal brain circulation due to chromosomal aberration at 29 weeks. (Upper)Fetal MR images. Coronal, axial and mid-sagittal sections from left, (A–C). In coronal and axial sections, shallowsylvian fissures, premature brain structure, and mild ventriculomegaly are demonstrated. (Lower) Fetal bloodflow waveforms. Umbilical artery flow is normal (left, A), but internal carotid artery (ICA, B) and middle cerebralartery (MCA, C) demonstrate reverse end-diastolic flow.


Fig. 9. Lissencephaly (pachygyria) at 33 weeks of gestation. (Upper) Transvaginal ultrasound pictures. Posteriorcoronal (left, A) and parasagittal (middle, B) sections show the smooth surface of the cerebral hemispheres. (Up-per right, C) Surface anatomy of the cerebral superficial structure by 3D ultrasound in parietal view. (Lower) MRimages for the same gestation. Parasagittal sections (lower left and middle, D, E) shows pachygyria. Anterior cor-onal section (lower right, F) demonstrates bilateral shallow sylvian fissures (arrowheads) with wide subarachnoidspace around the hemispheres.

Pooh548

Fig.10. Classical lissencephaly (type I lissencephaly) at 31 weeks of gestation. (Upper three images, A) Coronal to-mographic ultrasound images. Note the smooth premature appearance of the bilateral hemispheres with ventri-culomegaly. (Middle three images, B) Sagittal tomographic ultrasound images. Small cerebellum (whitearrowhead) and smooth cerebri are demonstrated. (Lower three images, C) MR image for the same gestation.Coronal, parasagittal and mid-sagittal sections (left to right). The brain appearance is similar to that of a 10-to 12-week-brain. The cerebellar hemispheres also appear premature (white arrowheads). Prematurity of thebrainstem (black arrowheads) may predict postnatal respiratory difficulty.


Fig.11. Cobblestone lissencephaly (classical type II lissencephaly) with agenesis of the corpus callosum and cere-bellar hypoplasia at 36 weeks of gestation. (Upper) Sonographic pictures of the posterior coronal (left, A) andmidsagittal (middle, B) sections. Abnormal gyral formation is demonstrated. (Upper right, C) Fetal flat face bythree-dimensional ultrasound. (Lower, C–E) Fetal MR images at the same gestation. Cobblestone lissencephalywith hypoplastic cerebellum, shallow sylvian fissures and agenesis of the corpus callosum is clearly demonstrated.

Pooh550


lissencephaly of the third trimester, similar to the10- to 12-week brain, is shown in Fig. 10. The ap-pearance of cobblestone lissencephaly with agen-esis of the corpus callosum and hypoplasticcerebellum in late pregnancy is shown in Fig. 11.For specifying the type of disease, genetic muta-tional analysis is required to correlate betweenthe abnormal sonographic/MR imaging findingand possible genetic cause. Significant overlapbetween the various phenotypic expressions ofthe above-listed categories exists and well-de-fined phenotype–genotype correlation is presentlyunavailable.

Fig.12. Bilateral schizencephaly at 33 weeks of gestation. (Ulined by pia-ependyma, is clearly demonstrated. (Upper riaxial and (lower right, D) coronal images.

SCHIZENCEPHALY

This rare abnormality is characterized by congen-ital clefts in the cerebral mantle, lined by pia-epen-dyma, with communication between thesubarachnoid space laterally and the ventricularsystem medially. Sixty three percent of cases areunilateral and 37% bilateral. The frontal region isaffected in 44% of cases and the frontoparietal re-gion in 30% of cases.9,10 Few reports of prenatalsonographic diagnosis of schizencephaly areavailable.11 Fig. 12 demonstrates typical bilateralschizencephaly with the MR image clearly depict-ing gray matter lining the lesion.

pper left, A) MR axial image. Bilateral schizencephaly,ght, B) MR coronal image. (Lower left, C) Sonographic

Pooh552

SUMMARY

Prenatal diagnosis of migration disorder is amongthe most difficult challenges of an antenatal sono-graphic examination. Anterior coronal demonstra-tion of the sylvian fissures is recommended as thescreening of cortical development and maldevel-opment. Once suspicion of a migration disorderdevelops, MR imaging is the preferred modalityfor demonstration of cortical development. Con-sidering that migration disorders occur before fetalviability but detection of brain lesions is most com-monly performed in the third trimester, this pres-ents a diagnostic dilemma. Early detection ofmigration disorder with severe prognosis is amongthe central missions of fetal neuroimaging.

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The DifferentialDiagnosis of FetalIntracranial CysticLesions
Gustavo Malinger, MDa,b,*, Edgardo Corral Sere~no, MDc,Tally Lerman-Sagie, MDb,d
KEYWORDS� Intracranial cysts � Prenatal diagnosis � Ultrasound

Intracranial cystic lesions are frequently diagnosedby fetal ultrasound scan. They may come frommany sources and involve different brain compart-ments. Although the most prevalent cysts are be-nign (choroid plexus cyst and arachnoid cyst) anddo not affect development, the mere suspicion ofa brain lesion during fetal life raises serious con-cerns in the prospective parents regarding the neu-rodevelopmental outcome of their child. It istherefore important to diagnose these lesions pre-cisely and accordingly offer accurate counseling.The diagnosis and particularly the differential diag-nosis and prognosis of intracranial cystic lesionsidentified in utero have not been studied as exten-sively as other more frequent brain anomalies (ie,ventriculomegaly), because of late development insome cases and presence in places that are notpart of the routine ultrasound examination of thebrain, such as the Sylvian fissure or ambiens cistern.

The purpose of this review is to present thedifferential diagnosis of intracranial cystic lesionsin the context of prenatal counseling andprognostication.

Intracranial cysts may be classified into threedifferent categories according to their place oforigin: extra-axial, intraparenchymal, or intraven-tricular (Table 1).

a Prenatal Diagnosis Unit, Department of Obstetrics andIsraelb Sackler School of Medicine, Tel-Aviv University, Tel-Avic Unidad de Ultrasonografia y Medicina Fetal, Servicio dgua, Chiled Pediatric Neurology Unit, Edith Wolfson Medical Cent* Corresponding author. Prenatal Diagnosis Unit, DeparMedical Center, Holon, Israel.E-mail address: [email protected] (G. Malinger).


CYSTS OF EXTRA-AXIAL ORIGIN

Arachnoid cysts are the most common type of cystsfound on the brain surface. Usually the surface ofthese cysts is in contact with the dura and the exter-nal wall of the arachnoid. Arachnoid cysts are filledwith cerebrospinal fluid, but they are usually notconnected to the subarachnoid space. The wallsof the cyst contain a thick layer of collagen and hy-perplastic arachnoid cells but lack the trabecularprocesses characteristic of the normal arachnoid.1

They may be found anywhere over the brain surfaceand also inside the ventricular system.

In children, common locations are the temporalfossa, the Sylvian fissure, and suprasellar or infra-tentorial regions. Interhemispheric cysts generallyare associated with agenesis of the corpuscallosum.

The prenatal diagnosis of arachnoid cysts hasbeen reported on several occasions, includingtwo large series.2,3 Pierre-Khan and Sonigo3 pub-lished their experience with 54 patients with arach-noid cysts; in 63% of their patients, the cysts weresupratentorial, mostly placed in the interhemi-spheric fissure (25%), other common sites werethe infratentorial region (22.2%) and the base ofthe cranium and the incisure. All the cysts werediagnosed after 20 weeks of gestation: 55%

Gynecology, Edith Wolfson Medical Center, Holon,

v, Israele Obsteticia y Ginecologia, Hospital Regional, Ranca-

er, Holon, Israeltment of Obstetrics and Gynecology, Edith Wolfson


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Table1Differential diagnosis of fetal intracranialcystic lesions

Extra-axial cystsArachnoid cystDural separationGlioependymal cystEndodermal cystCystic teratoma

Intraparenchymal cystsPeriventricular pseudocystCystic periventricular leukomalaciaPorencephalic cystBrain cystic tumor

Intraventricular cystsChoroid plexus cystChoroid plexus hemorrhage

Malinger et al554

between 20 and 30 weeks of gestation and theremaining 45% only after 30 weeks. In all theircases the initial suspicion was made by ultra-sound, but they preferred magnetic resonance(MR) imaging to better delineate the structureand its surroundings and also to differentiatebetween malformative and acquired cysts. Theauthors stated that in the majority of the casesMR imaging did not modify the original diagnosis.

Diagnosis before 20 weeks of gestation hasonly been reported in infratentorial locations(Fig. 1).4,5 Hogge and coworkers reported theprenatal diagnosis of an infratentorial arachnoidcyst in an 18-week fetus associated with an

Fig. 1. Transvaginal midsagittal plane of the brain ina 15-week fetus shows a large infratentorial arach-noid cyst causing anterior displacement of the brainand the vermis. The white arrows show the positionof the cystic wall; V, vermis.

unbalanced X;9 translocation.4 Bertelle and co-workers reported the presence of an isolated in-fratentorial cyst in a 13-week fetus withpathologic confirmation after termination ofpregnancy at 15 weeks.5

Both the above-mentioned prenatal studies aswell as postnatal studies found that the prognosisof these patients is generally good, even in thosewith hydrocephalus and requiring surgical drain-age.6,7 Although most arachnoid cysts are isolatedfindings (including secondary development ofhydrocephalus) (Fig. 2), they may sometimes beassociated with malformations of cortical develop-ment8 (Fig. 3); metabolic diseases (glutaric acidu-ria type 1) or congenital hypothyroidism (personalexperience). The prognosis will be according tothe associated abnormalities. Therefore, in casesof prenatally diagnosed arachnoid cysts, it isimportant to follow-up longitudinally throughoutthe pregnancy, search for other brain anomaliesconsidering MR imaging and check for glutaricaciduria type1 when the arachnoid cyst is in theopercular area.

The differential diagnosis includes neuroecto-dermal cysts, also known as glioependymalcysts,9,10 endodermal cysts,11 and even cystic ter-atoma.12 All these diagnoses are extremely rare,and the working diagnosis in most cases of a cysticfinding involving the brain meninges should be anarachnoid cyst. Even with the use of MR imaging,a correct diagnosis may be difficult to obtain asrecently shown in a case report by Muhler andcoworkers.13 The authors suspected the presenceof a porencephalic cyst in a fetus with unilateralventriculomegaly, microcephaly, and a midline

Fig. 2. Transvaginal axial plane of the brain in a 22-week fetus shows a prepontine arachnoid cyst. Thesize of the cyst remained stable throughout preg-nancy, and the child was asymptomatic after birth.

Fig. 3. Fetus at 40 weeks with periventricular heterotopia, pachygyria, and arachnoid cyst. (A) Transvaginalultrasound scan shows the interhemispheric bilobate cyst. (B) MR imaging in a similar plane.

Diagnosis of Fetal Intracranial Cystic Lesions 555

interhemispheric cyst, but the pathologic exami-nation proved that the cyst was actually a glioe-pendymal cyst.

INTRAPARENCHYMAL CYSTS

Cystic brain lesions may be the result of differenttypes of insults (see Table 1). Cysts may developas a consequence of hemorrhagic, ischemic,infectious, or tumoral processes. The prognosisdepends on the presence of associated findingsand on the extent and place of the insult.

Periventricular pseudocysts (PVPCs) usually arefound at the level of the caudo-thalamic groove orclose to the caudate nuclei; they may be unilateralor bilateral and unilocular or multilocular (Fig. 4).14

These cysts probably develop after a small hemor-rhagic event in the germinal matrix that upon resolu-tion liquefies. PVPCs may be found in 1% of

Fig. 4. Periventricular pseudocyst at 33 weeks of gesta-tion (white arrow). Note the presence of mild ventri-culomegaly. LV, lateral ventricle.

newborns, their diagnosis should prompt an investi-gation to rule out cytomegalovirus infection. Otherless common etiologies found in association withPVPCs include cardiac malformations, chromosomalmicrodeletions (4p-), and metabolic or mitochondrialdisorders. At least 50% of the cases represent iso-lated germinolytic events without development ofany handicap in the affected children.

Prenatal diagnosis of PVPCs is possible basedon the demonstration of the cysts adjacent to thelateral ventricle.15 Although transabdominal axialplanes generally are sufficient to raise the suspicionof the presence of PVPCs, transvaginal coronal andsagittal planes are more informative and help par-ticularly in the differential diagnosis between thiscondition and periventricular leukomalacia.15 Incases of associated growth retardation, fluores-cent in situ hybridization for 4p- deletions is indi-cated; other tests should include maternal and, ifnecessary, amniotic fluid cytomegalovirus (CMV)status. Unfortunately, the prenatal diagnosis ofmost of the metabolic and mitochondrial disordersin which PVPCs may be present is not possible, andthe suspicion of these diseases relies on familialhistory or the presence of associated anomalies.

Cystic periventricular leukomalacia (PVL) ismost common in premature newborns, but itmay occur also in full-term newborns after hyp-oxic–ischemic events.16 Cystic PVL is the resultof focal necrosis of the periventricular white mat-ter, when the area of focal necrosis is large; theend result of the clastic process is cyst formation.The association between PVL and antenatal infec-tion and inflammation has been studied exten-sively during the last decade;17,18 maternalinfection during pregnancy has been found to bevery common among children developing cerebralpalsy;17 furthermore, histologic chorioamnionitis

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and congenital infection-related morbidity aremore common among neonates with PVL thanamong those without PVL.18

Cystic lesions resembling PVL have beendescribed in fetuses by the use of ultrasoundscan and MR imaging,19,20 but the differentialdiagnosis with PVPCs may be difficult as seen intwo patients with pyruvate carboxylase deficiencyin whom the investigators considered the cysts tobe cystic PVL, whereas the actual diagnosis wasPVPCs.21 It is important to remember that PVLcysts are characteristically found on top of the lat-eral ventricles and not on their sides (Fig. 5).15

The authors have observed periventricular cystsin fetuses with metabolic, infective (mainly CMV)22

and vascular conditions. The prognosis in thesecases is usually reserved but some exceptionsmay occur.

Porencephalic cystic lesions occur after focalnecrosis as a result of an ischemic event involvingthe vascular distribution of a single major cerebralvessel.16

Pilu and coworkers described the prenatal diag-nosis of severe porencephaly in 10 fetuses diag-nosed during the second half of pregnancy; innine fetuses the cysts were connected with the lat-eral ventricles.2 Termination of pregnancy was per-formed in three fetuses, perinatal death occurred inanother three, and the remaining four children weredelivered and suffer from severe neurodevelop-mental delay.2 Our group has recently reportedthe natural history of a probable focal arterial strokediagnosed at 23 weeks evolving into a porence-phalic cyst that eventually communicated with thelateral ventricle. After birth the child was found tohave a familial leukoencephalopathy.23 In another

Fig. 5. Periventricular leukomalacia in a fetus referredat 28 weeks of gestation because of mild ventriculo-megaly. Midsagittal plane shows the presence oftwo cysts on top of the lateral ventricles (whitearrows).

case, a large porencephalic cyst was found in asso-ciation with brain disruption after a life-threateningcar accident (Fig. 6).

Brain cystic tumors without the presence ofsolid components are extremely rare. A possibleexample of this type of tumor is the intraparenchy-mal choroid plexus papilloma (Fig. 7).

INTRAVENTRICULAR CYSTS

The most common type of intraventricular cysts ischoroid plexus cysts (CPC). The choroid plexus iscomposed of secory neuroepithelium and is re-sponsible for the production of cerebrospinal fluid(CSF). The choroid plexus epithelium is present allthrough the ventricular system but is more promi-nent in the lateral ventricles and usually is easilyrecognized by the use of ultrasound scan as a hy-perechogenic structure starting from 8 weeks ofgestation.24

Choroid plexus cysts are relatively common,and their prevalence ranges from 1% to 3.6% ofpregnancies.25 CPCs are sonolucent findingsmost commonly found in the body of the lateralventricle choroid plexus (see Fig. 1), but havebeen described in other parts of the lateral ventri-cles and also in the third ventricle. Characteristi-cally, they are not observed before 17 weeks,and in the majority of patients they disappearbefore 26 weeks of gestation. They may be unilat-eral or bilateral, nonseptated or septated. CPCsare not lined by epithelium but consist of a dis-tended mesenchymal stroma with distended angi-omatous interconnecting thin-walled capillaries.26

According to the current literature, CPCs areconsidered benign findings, and when isolatedthey do not increase the risk for chromosomalabnormalities. The observation of such a cystshould prompt the physician to perform a complete

Fig. 6. Large porencephalic cyst at 31 weeks of gesta-tion as a result of a car accident at 16 weeks.

Fig. 7. Intraparenchymal cystic choroid plexus papil-loma diagnosed at 35 weeks with normal develop-ment at the age of 20 months after surgery.

Diagnosis of Fetal Intracranial Cystic Lesions 557

search for associated anomalies with particularattention to the heart, brain, and hands, becausein cases caused by trisomy 18 there are malforma-tions in these organs.27 A possible associationbetween CPC and trisomy 21 has been ruled outby almost all the well-designed publishedstudies.28

Follow-up until their disappearance may be indi-cated because of the very rare possibility of thedevelopment of obstructive hydrocephaly causedby occlusion of CSF drainage through the Foram-ina of Monro in case of a large cyst.29 The differen-tial diagnosis should include the possibility of anintraventricular hemorrhage penetrating into thechoroid plexus and other rare types of cysts thatare seldom diagnosed in utero like colloid orependymal cysts.

SUMMARY

Fetal intracranial cysts can be diagnosed duringpregnancy by the use of ultrasound scan. The cystscan be found in different brain compartments andmay be of diverse origins. Choroid plexus andarachnoid cysts are the most commonly diagnosedlesions and when isolated carry a good prognosis.Intraparenchymal cysts may have different etiolo-gies, and the prognosis depends largely on the lo-cation and the extent of the lesion.

To give accurate counseling, it is fundamental toperform a detailed ultrasonographic examination,including multiplanar ultrasound scan of the brain,to search for additional anomalies. Fetal brain MRimaging may be complementary in difficult cases.

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17. Bax M, Tydeman C, Flodmark O. Clinical and MRI

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like brain lesions in two sibs with the acute neonatal

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22. Malinger G, Lev D, Zahalka N, et al. Fetal cytomega-

lovirus infection of the brain: the spectrum of

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Magnetic ResonanceImaging FollowingSuspicion for FetalBrain Anomalies
Alice B. Smith, Lt. Col, USAF, MCa,b,*, Orit A. Glenn, MDc
KEYWORDS� Fetal MR imaging � CNS anomalies� Fetal brain � Sulcation � Ventriculomegaly� Cortical malformation

Fetal ultrasound is considered the standard of carein the evaluation of fetal anomalies; however, limi-tations exist, including decreased visibility of fetalstructures because of maternal body habitus,position of the fetal head, ossification of the fetalskull, and, in some cases, oligohydramnios. Onthe identification of a fetal brain anomaly by ultra-sound, further evaluation is necessary to betterdefine the anomaly and to rule out other associ-ated anomalies. In the developing fetus, manybrain structures are forming at around the sametime; thus, the detection of one anomaly necessi-tates the evaluation for others. Fetal MR imagingis a complement to ultrasound and has several ad-vantages, including visualization of the entire brain(as opposed to ultrasound where the upside cere-bral hemisphere is often shadowed because of re-verberations from overlying structures). MRimaging is also capable of assessing the sulcationpattern and developing cortex, which is difficult tovisualize on ultrasound.1–6 In addition, when ananomaly is detected, fetal MR imaging mayprovide better definition of the lesion because of

The opinions and assertions contained herein are the privas official or as reflecting the view of the Departments oa Department of Radiologic Pathology, Armed Forces Inton, DC, USAb Department of Radiology and Radiological Sciences, U4301 Jones Bridge Road, Bethesda, MD 20814, USAc Department of Radiology, Diagnostic Neuroradiology, U505 Parnassus Avenue, San Francisco, CA 94143-0628, US* Corresponding author. Department of Radiology and Rthe Health Sciences, 4301 Jones Bridge Road, Bethesda,E-mail address: [email protected] (A.B. Smith).

Ultrasound Clin 3 (2008) 559–582doi:10.1016/j.cult.2008.09.0081556-858X/08/$ – see front matter. Published by Elsevier

improved contrast resolution and identify otherlesions not visible on ultrasound.

Fetal MR imaging has been demonstrated toaccurately detect anomalies within the secondand third trimesters, providing additional informa-tion for prenatal counseling and delivery planning.In a study by Levine and colleagues of the centralnervous system (CNS) of 145 fetuses, additionalfindings were found on MR imaging in 32%.Another study by Simon and colleagues7 of 73fetuses found that in 46% of cases the finding onfetal MR imaging changed patient managementfrom what it would have been based on the ultra-sound findings alone. When CNS anomalies areidentified by ultrasound, MR imaging may demon-strate additional findings that may alter patientmanagement.6,8,9 Several studies have identifiedanomalies by MR imaging that were not visualizedon ultrasound, including anomalies of sulcation,periventricular nodular heterotopia, callosal agen-esis, periventricular white matter injury, cerebellardysplasia, germinal matrix, and intraventricularhemorrhage.7,10–14

ate views of the authors and are not to be construedf the Army, Navy, Air Force, or Defense.

stitute of Pathology, 6825 16th Street NW, Washing-

niformed Services University of the Health Sciences,

niversity of California, San Francisco, Box 0628, L358,Aadiological Sciences, Uniformed Services University ofMD 20814.

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FETALMR IMAGING TECHNIQUEAND LIMITATIONS

The use of fetal MR imaging began in the early1980s in Europe, at which time fetal sedation wasused. Since that time, improvements in techniquehave resulted in our ability to image the fetal brainwithout maternal or fetal sedation and thus in its in-creasing clinical use in the United States. Currently,most fetal MR imaging is performed using ultrafastT2-weighted MR imaging techniques known as sin-gle-shot fast spin echo (SSFSE) or half-Fourier ac-quired single-shot turbo spin echo (HASTE). Theserapid pulse sequences allow acquisition of a singleimage in less than 1 second, reducing the artifactfrom fetal motion. In addition, T1-weighted imagesare used to visualize fat and hemorrhage, and gra-dient echo T2 images are used to visualize hemor-rhage. Diffusion-weighted MR imaging can alsonow be performed in fetal MR imaging and is helpfulin cases of suspected parenchymal injury, such asstroke or periventricular white matter injury. Diffu-sion-weighted MR imaging is also sensitive to mat-urational changes in the microstructure of fetalbrain tissue, a process that normally occurs with in-creasing gestational age.15,16 Diffusion tensor MRimaging provides even more information concern-ing tissue microstructure and maturational pro-cesses, although further technical advances arerequired before it can be successfully applied to fe-tuses.17–19 MR spectroscopy is being investigatedfor the assessment of brain maturation and alter-ations in brain metabolism,20–22 although it is lim-ited by long acquisition time (4.5 minutes) andcurrently is only performed in the third trimesterwhen the head is larger and engaged in the mater-nal pelvis.23 Functional MR imaging is also beingused in research protocols, but is not used in rou-tine practice.24–26 Fetal MR imaging is usually per-formed around 22 weeks’ gestation, to decreasethe effect of fetal motion that occurs with youngerfetuses and the brain is larger, and, therefore,more easily assessed than at a younger gestationalage.

A study by Blaicher and colleagues27 found thatthe diagnostic accuracy increases with gestationalage, and concluded that fetal MR imaging shouldbe performed from 20 weeks onward, althoughwe have found 22 weeks to be the optimal agefor performing fetal MR imaging.

Patients are imaged on a 1.5 Tesla scannerusing an eight-channel torso phased array coil,which is placed over the mother’s abdomen. Pref-erably, the patient is imaged in the supine position,allowing for optimal coil geometry. UltrafastSSFSE images (TR 4000, TE 90, FOV 24 cm,matrix 192 � 160) are obtained in coronal, axial,

and sagittal planes, and 3-mm slice thickness isused for the brain (2 mm for the spine). No seda-tion is given to the mother, but she is instructednot to eat for 4 hours before the examination,because this tends to decrease the frequency offetal movement. In addition, the patient isscreened for any contraindications to MR imagingbefore the examination.

In addition to fetal motion, limitations of fetal MRimaging include the small size of the structurebeing evaluated combined with increaseddistance of the structure from the receiver coil,which limits the resolution. Improvements in coiltechnology, such as parallel imaging withincreased number of channels, are resulting inthe reduction in these limitations. Maternal claus-trophobia and discomfort from lying still for thestudy period are also problems, because the MRimaging examination typically lasts at least 45 min-utes. If the mother cannot lie on her back, she canbe imaged in the left lateral decubitus position,which may ease discomfort, although this doesresult in decreased image quality.

MR IMAGING SAFETY

MR imaging of the fetus is considered to be safe;however, studies on the safety of MR imaging inpregnant women are limited. Follow-up studiesof children who underwent fetal MR imaginghave thus far demonstrated no long-term adverseeffects; however, these studies have been limitedby small sample size.28–30 Because the effect ofMR imaging on the developing fetus has notbeen determined, it is not recommended in thefirst trimester to avoid the potential risk for themagnetic fields interfering with organogenesis.Biologic effects, miscarriage, acoustic noise expo-sure, and heating effects are the potential risksfrom exposure to the magnetic field. Studies usingpregnant animals and animal fetuses have not pro-vided a consensus as to risk, and whether or notthe information can be applied to humans is uncer-tain because the equipment and scanner parame-ters were variable in these studies.31–35 To provideguidance for imaging, a 2002 American College ofRadiology white paper states, ‘‘Pregnant patientscan be accepted to undergo MR images at anystage of pregnancy if, in the determination ofa Level Two MR Personnel –designated attendingradiologist, the risk-benefit ratio to the patient war-rants that the study be performed.’’36 All pregnantwomen should undergo counseling and sign a con-sent form before MR imaging.

In addition, the use of gadolinium for fetal MRimaging has been avoided. Gadolinium is a ‘‘rareearth’’ element, which is toxic when it is in an

MR Imaging for Fetal Brain Anomalies 561

unbound state. When bound to a chelating agent itis no longer toxic, as in the form used as an intra-venous contrast agent (gadolinium-DTPA). Gadoli-nium crosses the placenta, is exced in the urine ofthe fetus, and can then be swallowed.37 It thus re-mains within the fetal environment where there isthe potential for it to become unbound, and thereis concern that in the unbound form it may havea teratogenic effect. Gadolinium is labeled asa pregnancy category C by the Food and Drug Ad-ministration because of lack of epidemiologicstudies evaluating exposure in the first trimester.A recent study reported by De Santis and col-leagues38 in 2007 of 26 women who received ga-dolinium during the first trimester found noadverse pregnancy or neonatal outcome. The cur-rent recommendation for using gadolinium duringpregnancy is only when the potential benefit tothe mother outweighs the potential risk to the fe-tus. There are few, if any, situations in which gado-linium would provide additional useful informationin the evaluation of fetal brain anomalies and itsbenefit would outweigh its risk.

ABNORMALITIES OF THE FETAL BRAIN

An understanding of the normal development ofthe fetal brain on MR imaging is essential for theidentification of anomalies and several excellentreviews are available.39–46 In brief, the formationof sulci occurs in an organized and time-specificmanner, with primary sulcation complete by about32 to 34 weeks. The appearance of the sulci on fe-tal MR imaging lags behind that seen in fetal au-topsy by a mean of 1.9 � 2.2 weeks, which mostlikely reflects the limitations of MR resolution.40,41

In addition, the depth and complexity of a sulcusprogresses with increasing gestational age, andthus it is important to evaluate the appearanceand the morphology of the sulci on fetal MR imag-ing (Fig. 1; Table 1).

In addition to evaluating the sulcation pattern,fetal MR imaging also allows evaluation of thebrain parenchyma. Normally, a multilayered pat-tern is present in the developing parenchymafrom about 20 to 28 gestational weeks, which rep-resents different developing layers in the fetal brain(Fig. 2). The multilayered pattern disappears ina topographically and timely organized mannerthat corresponds to known histologic changes indeveloping brain layers with increasing gestationalage. It disappears from the depths of the sulci andthen from the crests of the gyri and from differentregions of the brain in time-specific fashion asthe sulci form.47,48 Prominent subarachnoidspaces are also normally noted in the fetus, espe-cially before 30 weeks, in comparison with the

term infant. A complete discussion of the matura-tional changes of the fetal brain is beyond thescope of this article, but it is important to stressthat knowledge of the gestational age of the fetusis critical to proper image interpation.

Developmental anomalies of the fetal brain havevarious causes, including chromosomal, infec-tious, and destructive. Fetal brain structures aredeveloping at approximately the same time; there-fore, the presence of one anomaly should promptthe search for others. Primary indications for MRimaging of the fetal brain are for the evaluation ofventriculomegaly and other CNS anomalies visual-ized on prenatal ultrasound, and to assess the fetalbrain when there is a risk for fetal brain damage,such as in complicated monochorionic twin preg-nancies.49–51

VENTRICULOMEGALY

Ventriculomegaly is defined as enlargement of theventricular atrium greater than 10 mm at the levelof the thalami in the axial plane with the measure-ment being made through the posterior aspect ofthe glomus.52 The size of the ventricular atria re-mains relatively constant from 15 to 35 weeks;the brain, however, enlarges so the relative sizeof the ventricles compared with the brain de-creases. Ventriculomegaly is the most frequentlydetected intracranial anomaly on prenatal ultra-sound, and frequently results in referral for furtherevaluation by MR imaging, which may be able de-termine the cause or associated anomalies not de-tected on ultrasound.53 A study by Levine andcolleagues54 of the similarity of ventricular sizemeasured on ultrasound compared with MR imag-ing in the axial plane demonstrated minimal differ-ences with the measurements being within 2 mmof each other. In a study by Garel and Alberti,55

measurements of ventricular size in the coronalplane on ultrasound and MR imaging were similar.

There are numerous causes of ventriculome-galy, and prognosis is related, at least in part, tothe presence of other anomalies. The cause maybe obstruction, destructive processes, or develop-mental or chromosomal abnormalities. In mild ven-triculomegaly (atrial size 10–15 mm), reportedassociated anomalies, both neuronal and somatic,may be present in up to 75% of cases.53,56 Theseanomalies include neuronal heterotopia, lissence-phaly, intraventricular hemorrhage, and neuraltube defects. In a study by Bromley and col-leagues57 of patients who had borderline mild ven-triculomegaly (10–12 mm), the frequency ofassociated anomalies decreased to 39%. Fre-quently, the ventriculomegaly is isolated (ie, noother additional extra- or intracerebral anomalies),

Fig.1. Progression of normal sulcation. (A) Coronal T2 SSFSE of a 23-week estimated gestational age (EGA) fetusdemonstrates formation of the sylvian fissure (arrow), and hippocampal sulcus (arrowhead). Note the promi-nence of the cerebrospinal fluid (CSF) space. (B) Coronal T2 SSFSE of a 29-week EGA fetus reveals further devel-opment of the sylvian fissure. In addition, the cingulate sulcus is identified (arrow) and further definition of thehippocampal sulcus. (C) Coronal T2 SSFSE of a 34-week EGA fetus shows the complete primary sulcation pattern.Note the decreased prominence of the CSF space.

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and, to date, the impact on the fetus’s postnatalneurodevelopmental outcome for mild, isolatedcases is still not completely understood. Previousstudies reported the incidence of developmentaldelay in cases of prenatal isolated mild ventriculo-megaly (IMVM) to range from 0% to 36%.56,58–61 Incases in which the atrial diameter is less than 12mm, several studies have found a lower risk for de-velopmental delay, especially if the fetus ismale.56,59,61,62 In a more recent study by Falipand colleagues63 of postnatal clinical and imagingfollow-up of 101 infants who had isolated mild ven-triculomegaly on prenatal ultrasound and fetal MRimaging, 94% of infants who had ventricular size of10 to 11.9 mm had favorable outcome, and 85% ofthose who had ventricular size of 12 to 15 mm had

a favorable outcome, although the difference be-tween the two groups was not statistically signifi-cant. No difference in prognosis was foundbetween uni- and bilateral IMVM or between sta-ble, progressive, and resolved IMVM, and progno-sis was independent of the gestation age atdiagnosis and gender. In addition, they reportedwhite matter abnormalities detected only on post-natal MR imaging in two thirds of the infants whohad poor outcome.63

Because the prognosis for fetuses who haveventriculomegaly is related to the presence ofother anomalies, a search for associated anoma-lies is necessary. Studies have shown a false-neg-ative rate for detection of associated anomalieswith prenatal ultrasound in experienced prenatal

Table1Expected normal appearance of primary sulci for gestational age

Sulcus Gestational Age (wk)

Parietoccipital sulcus 20–23

Calcarine sulcus 24–25

Callosal sulcus 22–23

Hippocampal sulcus 22–23

Cingulate sulcus 24–25

Central sulcus 27

Superior temporal sulcus 27

Precentral sulci 27

Postcentral sulci 28

Gestational age at which sulci are present in R75% of fetuses.Data from Garel C, Chantrel E, Brisse H, et al. Fetal cerebral cortex: normal gestational landmarks identified using

prenatal MR imaging. AJNR Am J Neuroradiol 2001;22(1):184–9.


diagnostic centers to be 10% to 25%.56,64 Exam-ples of sonographically occult lesions include de-velopmental anomalies, such as agenesis of thecorpus callosum, cerebellar dysplasia, and corti-cal dysplasia, and the sequelae of destructiveprocesses, such as periventricular leukomalacia,and subependymal and intraventricular

Fig. 2. Multilayer pattern. Coronal T2 SSFSE of a 23-week EGA fetus demonstrates the multilayer pattern.The germinal matrix (thin arrow) is the deepest layer.The periventricular zone (arrowhead) is adjacentto the germinal matrix. The more superficial layersare the subventricular and intermediate zones (thickarrow), and the subplate, which is recognized asa band of high signal (double arrows). The developingcortex and marginal zone are the most superficiallayers.

hemorrhage.6,11,12,65 In addition, sonography hasbeen noted to be limited in its ability to detect as-sociated anomalies in the presence of ventriculo-megaly.61,66 Fetal MR imaging is capable ofidentifying additional anomalies in up to 50% ofcases of fetal ventriculomegaly, thereby providingadditional information for the parents.6,8–10

CALLOSAL AGENESIS

Fetal MR imaging provides an excellent means forevaluation of the corpus callosum because of itscapability of imaging it in the sagittal and coronalplanes. It has better specificity in evaluation ofthe corpus than ultrasound. One study demon-strated that an intact corpus was identified in20% of fetuses who were suspected to have anabnormal corpus on ultrasound.11 Ultrasoundidentifies agenesis by the characteristic parallelconfiguration of the lateral ventricles and colpoce-phaly,67 and by the absence of a cavum septumpellucidum. Occasionally, on second and third tri-mester ultrasounds, the fornix mimics the cavumseptum pellucidum resulting in a missed diagnosisof callosal agenesis.68

In addition to absence of the corpus callosum,other associated findings on fetal MR imaging in-clude colpocephaly, abnormal configuration ofthe frontal horns of the lateral ventricles thathave a ‘‘steer’s horns’’ appearance on the coronalview, and, in older fetuses, a radial pattern of themedial sulci with extension to the third ventricle,which results from a persistent eversion of the cin-gulate gyrus (Fig. 3). The corpus callosum de-velops from the commissural plate, as do theanterior and hippocampal commissures; there-fore, anomalies of the corpus callosum are

Fig. 3. Agenesis of the corpus callosum. (A) Axial T2 SSFSE of a 22-week EGA fetus demonstrates a parallel con-figuration of the lateral ventricles. (B) Axial T2 SSFSE of a 22-week EGA fetus reveals prominence of the occipitalhorns of the lateral ventricles consistent with colpocephaly. (C) Sagittal T2 SSFSE of a 34-week EGA fetus demon-strates absence of the corpus callosum. (D) Coronal T2 SSFSE of a 22-week EGA fetus reveals absence of the corpuscallosum with the resultant abnormal configuration (‘‘steer’s horns’’) of the frontal horns. (E) Sagittal T2 SSFSE ofa 34-week EGA fetus demonstrates absence of the corpus callosum. At this gestational age the radial pattern ofthe sulci extending to midline is appreciated.

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frequently associated with anomalies of the ante-rior and hippocampal commissures. Typically,these are aplastic or hypoplastic, but occasionallythey may be enlarged; enlargement of the hippo-campal commissure may be mistaken for the sple-nium of the corpus callosum.39 In addition,knowledge of the normal development of the cor-pus callosum helps differentiate a hypoplastic cor-pus callosum from one that is secondarilydestroyed. In general, the corpus develops ina front-to-back pattern with the genu forming first,then the body, splenium, and, finally, the rostrum.A deviation from this pattern may indicate thepresence of holoprosencephaly (dysplasia of thecorpus callosum with only the posterior aspectformed), or cerebral lesions in regions sending fi-bers across the corpus callosum (porencephalies,schizencephaly). The presence of callosal/com-missural anomalies is an important clinical finding.The belief that isolated callosal agenesis is of noclinical significance has been challenged. Ina study by Moutard and colleagues69 of childrenwho had prenatally diagnosed isolated agenesisof the corpus callosum, behavioral and cognitiveabnormalities became more apparent as the chil-dren reached school age. In the future, diffusion-tensor MR imaging may provide a means forfurther evaluation of callosal agenesis.

Agenesis of the corpus callosum is associatedwith other CNS anomalies and more than 70 differ-ent syndromes, and identification of associatedanomalies is greater with fetal MR imaging than ul-trasound.14,70 In a study of children by Hetts andcolleagues,71 agenesis of the corpus callosumwas frequently (>50%) associated with reductionin white matter volume and cortical malformations,the most frequent of which is heterotopia. Hetero-topia was identified on postnatal imaging in 29%of these patients, and hypogenesis of the corpuscallosum was associated with heterotopia in21%. Autopsy studies have demonstrated addi-tional CNS anomalies in up to 85% of patientswho have callosal agenesis.72 In addition to graymatter heterotopia, these include Chiari II malfor-mation, schizencephaly, Dandy-Walker malforma-tion, and encephaloceles.73 Evaluation for theseassociated anomalies is critical, because theirpresence is associated with a higher incidenceof neurodevelopmental disability, and if findingsare present that suggest a genetic syndrome thisprovides important information for counselingthe parents regarding future pregnancies.14,73,74

Abnormalities of the hippocampi are also associ-ated with callosal agenesis. Incomplete inversionof the hippocampal formation may be seen. Thetemporal horns may develop a keyhole shapeas a result of deficiency of the hippocampal

formation, which can be seen in older fetuseswith callosal agenesis.

ABNORMALITIES OF CORTICAL DEVELOPMENT

Cortical malformations are important imaging find-ings that are frequently associated with neurode-velopmental abnormalities, and studies havedemonstrated that fetal MR imaging has the abilityto detect cortical malformations that are not de-tected on ultrasound.6,13,14 Abnormalities of corti-cal development can be classified by the stage ofdevelopment during which they occur as abnormalneuronal and glial proliferation or apoptosis (in-cluding focal transmantle cortical dysplasia withballoon cells, microlissencephaly, schizencephaly,and hemimegalencephaly), abnormal neuronalmigration (lissencephaly, heterotopia, polymic-rogyria, and congenital muscular dystrophy), orabnormal cortical organization (polymicrogyriaand focal cortical dysplasia without balloon cells).Other causes of cortical malformations includeexogenous (maternal alcohol or drug abuse) orendogenous (metabolic disorders) toxins, the se-quelae of infection (cytomegalovirus) or ischemia(monochorionic twinning complications). Classifi-cation of anomalies can be problematic becauseof the likelihood of multiple anomalies. Identifyingmalformations of cortical development by MR im-aging may be difficult in fetuses less than 25weeks, because few sulci and gyri are normallyseen at this stage.1 When assessing cortical mal-formations it is beneficial to obtain follow-up MRimaging, because the appearance of cortical mal-formations changes with increased fetal age.

ABNORMAL NEURONAL AND GLIALPROLIFERATION OR APOPTOSISTransmantle Cortical Dysplasiawith Balloon Cells

In cases of focal transmantle cortical dysplasiawith balloon cells there is a focal region of abnor-mal cortical lamination in which the normal six-layered appearance of the cerebral cortex isdisturbed. The abnormality extends through theentire cerebral mantle, and on histologic examina-tion abnormal cells, including balloon cells, atypi-cal glia, and large dysplastic neurons, are seenwithin the cerebral cortex and underlying whitematter.6,75 On imaging, focal transmantle corticaldysplasia can be visualized as an area of low sig-nal on T2 SSFE that is wedge-shaped and extendsfrom the pial surface to the ventricular surface.

Tuberous sclerosis is an autosomal dominantphakomatosis (80% of cases are de novo muta-tions) in which there are transmantle dysplasias

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and cortical tubers that on imaging and pathologyare identical to focal cortical dysplasia with ballooncells (Fig. 4).39 Referral to a geneticist for a patientwho has evidence of transmantle cortical dyspla-sia is indicated to rule out the possibility of tuber-ous sclerosis. A search for other manifestationsof tuberous sclerosis, such as subependymal nod-ules, should be undertaken. MR imaging can alsobe used to evaluate the heart, because rhabdo-myomas may be seen in at least 60% of patientswho have tuberous sclerosis.76,77

Microlissencephaly

Fetuses who have microlissencephaly demon-strate a small head circumference (more thanthree standard deviations from normal) resultingfrom a reduction in proliferation of neurons andglia in the germinal zones.39 These fetuses havetoo few gyri and shallow sulci, and the volume ofwhite matter is reduced. When suspected, it isnecessary to evaluate for genetic causes and po-tential acquired causes, such as infection, ische-mia, inborn errors of metabolism, toxins, andradiation exposure.

Schizencephaly

Schizencephaly is a term to describe a gray mat-ter–lined cleft extending from the brain surface tothe ependymal lining that may result from a geneticanomaly (mutation of the EMX2 homeobox gene—although this has been disputed recently) ora transmantle injury occurring in the second

Fig. 4. Tuberous sclerosis. Coronal T2 SSFSE of a 26-week EGA fetus demonstrates a focal wedge-shapedarea of low signal extending from the cortex to thelateral ventricle. Both focal cortical dysplasia with bal-loon cells and the subcortical tubers of tuberous scle-rosis have this imaging appearance. In this case, thepatient had tuberous sclerosis.

trimester (Fig. 5).39,78 When open lipped it is easilyidentified, but closed-lipped schizencephaly maybe more difficult to visualize, although it is typicallyassociated with dimpling of the ventricular surfaceat the site of the schizencephaly. When unilateral,assessment of the contralateral cortex is impor-tant, because there may be an associated mirrorimage cortical malformation. The septum pelluci-dum is almost always absent when the clefts arebilateral. The severity of the patient’s symptomsdepends on the amount of involved brain.

Hemimegalencephaly

Hemimegalencephaly is a hamartomatous over-growth of all or part of a cerebral hemisphere, inwhich the affected portion has little or no function.Affected children typically have intractable epi-lepsy and severe developmental delay.79 Hemime-galencephaly can be difficult to detect prenatallyand slight brain asymmetry may not be detectedby ultrasound.43 Fetal MR imaging may be moresensitive to the detection of hemimegalencephalybecause abnormal signal within the white matterand an overlying abnormal gyral pattern may beseen.43

ABNORMAL NEURONAL MIGRATIONClassical Lissencephaly

Lissencephaly is a paucity of gyral and sulcal de-velopment, resulting from the arrest of normal neu-ronal migration. Patients have either agyria (nogyration) or pachygyria (broad, simplified gyri).

Fig. 5. Schizencephaly. Coronal T2 SSFSE of a 33-weekEGA fetus reveals bilateral, symmetric clefts involvingthe frontal lobes consistent with open-lippedschizencephaly.


Agyria is seen in the Miller-Dieker syndrome,which is linked to chromosome 17 and involvesthe LISI gene. Posterior pachygyria is also associ-ated with chromosome 17 deletions, and anteriorpachygyria is seen in the X-linked form (associatedwith mutations of the doublecortin gene located onchromosome X). Fetal MR imaging is beneficial inpatients who have a family history of lissence-phaly. In the normal development of the fetus,the sulci are visualized at predictable times byMR imaging (see Table 1). Knowledge of the esti-mated gestational age is critical when assessingsulcal development. A delay in sulcation shouldraise the suspicion of lissencephaly and a follow-up fetal MR imaging may be indicated to confirmpersistent sulcation delay. In classical lissence-phaly, normal sulcation is not visualized and the

Fig. 6. Classical lissencephaly. (A) Axial T2 SSFSE of a 34-w(arrows) and paucity of the other primary fissures. Notice tof the same fetus demonstrates shallow sylvian fissures andtilayer pattern with thick band of low signal in the develogross specimen of a brain with lissencephaly from an autoof normal sulcation. (D) Coronal T2 SSFSE of a 34-week EGfor this stage of gestation.

sylvian fissures remain shallow (Fig. 6).23 There isalso a thickened deep cortical layer, representinga band of arrested neurons, which is separatedfrom a thin outer cortical layer by a zone of whitematter.39,40 Histologically, a thick four-layer cortexis noted consisting of the cortical plate and a thicklayer of heterotopic cells.43

Heterotopia

Gray matter heterotopia result from under-migra-tion of neurons; they can be described as nodularor laminar and by their location (periventricular orsubcortical). Subependymal heterotopia can beidentified as focal or diffuse areas of low signalalong the ventricular lining (Fig. 7). These protrudeinto the ventricles, and should not be confused

eek EGA fetus demonstrates a shallow sylvian fissurehe prominence of the CSF spaces. (B) Coronal T2 SSFSEabsence of the other primary sulci. An abnormal mul-

ping white matter is seen (arrows). (C) Photograph ofpsy at 38 gestational weeks demonstrates the absenceA fetus reveals the normal sulcation pattern expected

Fig. 7. Subependymal heterotopia. Coronal (A) and axial (B) T2 SSFSE of a 22-week EGA fetus demonstrates nod-ularity along the ventricular surface (arrows) consistent with subependymal heterotopia.

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with germinal matrix, which is also low in signal butdoes not protrude into the ventricle. In addition,the germinal matrix begins to involute after 26 to28 weeks. If the subependymal heterotopia isbilateral and diffuse, this is associated with anX-linked disorder that is lethal in males. Presenceof heterotopia should be confirmed in two imagingplanes. In addition, subependymal heterotopia areindistinguishable from the subependymal nodulesseen in tuberous sclerosis; therefore a thoroughsearch for other manifestations of tuberous sclero-sis (cortical tubers, transmantle dysplasia, andcardiac rhabdomyoma) is necessary. Heterotopia,however, are much more common than tuberoussclerosis. Band heterotopia is frequently notimaged because of lack of ultrasoundabnormalities.43

Polymicrogyria

Polymicrogyria results when neurons distributeabnormally in the cortex resulting in multiple smallgyri. Suspicion of polymicrogyria should occurwhen sulci are present that are not expectedaccording to gestational age, and if an irregularsurface of the brain is noted.43 Polymicrogyria isfrequently perisylvian, and the appearance ofa thickened cortex in this region may be a clue toits presence. In other regions an appearance oftoo many sulci in a less mature fetus or too fewsulci or abnormally located sulci in a more maturefetus should be a clue to the presence of polymi-crogyria (Fig. 8).23,80 Two forms of polymicrogyriahave been described based on microscopy and in-clude a four-layered form and an unlayered form.81

The layered form of polymicrogyria is believed tobe attributable to postmigrational events, whereas

the unlayered form is believed to be attributable toevents that occur before the end of neuroblast mi-gration (before 17 weeks).81 Currently, imagingfeatures cannot distinguish layered from unlayeredpolymcirogyria. Polymicrogyria is frequently asso-ciated with chromosomal anomalies. Other causesof polymicrogyria include the sequelae of infection(cytomegalovirus), ischemia (as can occur inmonochorionic co-twin demise), exposure toexogenous toxins, and endogeneous toxins (inher-ent metabolic disorders).39,43

Congenital Muscular Dystrophy

Congenital muscular dystrophies are a heteroge-neous group of disorders characterized by hypo-tonia, weakness, and, frequently, congenitalcontractures with an autosomal recessive modeof inheritance. Brain involvement in these disor-ders occurs in approximately 50%, and includescobblestone (type II) lissencephaly that resultsfrom a disorder in neuronal migration in whichthe migrating neurons are not able to dissociatefrom the radial glial fibers that guide them to theirfinal location, leading to an overmigration of neu-rons.82 The most severe form, Walker-Warburgsyndrome, demonstrates a cobblestone cortexand has a classic dorsal ‘‘kink’’ at the pontome-sencephalic junction along with fusion of the supe-rior and inferior colliculi, which can be identified byfetal MR imaging (Fig. 9). Prenatally, ventriculome-galy with cerebellar hypoplasia are the most com-mon findings on ultrasound.83 A variable degree ofcallosal hypogenesis is also present and can bedetected prenatally. Fetal MR imaging can identifythe lissencephaly and cerebellar and brainstemabnormalities. These patients also have

Fig. 8. Polymicrogyria. (A) Axial SS-FSE T2-weighted image of a 30-week EGA fetus demonstrates dysplastic-ap-pearing sylvian fissures with multiple abnormal small infoldings of the cortex (arrows) consistent with perisylvianpolymicrogyria. (B) Photograph of a gross specimen from a term infant with history of in utero CMV infectiondemonstrates numerous small irregular gyri consistent with polymicrogyria.


abnormalities of the cerebral and cerebellar whitematter that are seen postnatally.39 Associatedeye anomalies, including subinal hemorrhagesand microphthalmia, can occasionally be identi-fied prenatally.84

CEPHALOCELES

Fetal MR imaging is valuable in the evaluation ofcephaloceles because it can identify the portionof brain involved, and in older fetuses may evenbe able to identify involvement of the dural venoussinuses in cases of occipital and parietal encepha-loceles. It is also capable of evaluating associatedanomalies, such as anomalies of the corpuscallosum, Chiari malformations, and corticalmalformations. In the rare case of Chiari III malfor-mations, in which there is a defect in the lower oc-cipital bone and upper cervical spine, involvementof the brainstem and cerebellum can be assessed(Fig. 10).85

HOLOPROSENCEPHALY

Holoprosencephaly results from a failure of differ-entiation and cleavage of the prosencephalon.These can be the result of teratogens (maternal di-abetes) and genetic factors (trisomy 13 and 18).These disorders all have in common some degreeof callosal dysgenesis, along with absence of theseptum pellucidum.86 The holoprosencephaliesrepresent a continuum and difficulty exists in

determining a clear distinction between cate-gories. Alobar holoprosencephaly is the mostcommon form of holoprosencephaly identified onfetal ultrasound. It is easily assessed by fetal ultra-sound, and the typical appearance is of a largemonoventricle communicating with a dorsal cyst,fused thalami and basal ganglia, and a fused cor-tical mantle anteriorly without any interhemi-spheric fissure. No corpus callosum is identifiedin these patients. Because of the poor prognosis(most die shortly after birth or are stillborn) andeasy identification of alobar holoprosencephalyby fetal ultrasound, other imaging studies are typ-ically not performed. Semilobar and lobar holopro-sencephalies are more difficult to detect on fetalultrasound.87 In semilobar holoprosencephaly,the interhemispheric fissure and falx cerebri arepartially formed. There is still some degree of in-complete separation of the basal ganglia, anda third ventricle and incompletely formed lateralventricles may be seen. Incomplete separation ofthe frontal lobes is still present, and only the sple-nium of the corpus callosum with or without a por-tion of the posterior body of the corpus callosummay be seen (Fig. 11). In lobar holoprosencephalythe ventricular system is further formed with iden-tifiable frontal horns of the lateral ventricle,although they may be rudimentary. The degree ofnonseparation of the forebrain is also mild, and inthe mildest form only the hypothalamus is not sep-arated. The body and splenium of the corpus cal-losum can be visualized.88,89 Fetal MR imaging

Fig. 9. Walker-Warburg syndrome. (A) Axial T2 SSFSE of a 31-week EGA fetus demonstrates ventriculomegaly. Inaddition, shallow, irregular sulci are noted. (B) Sagittal T2 SSFSE from the same fetus demonstrates a ‘‘kink’’ (ar-row) at the pontomesencephalic junction and cerebellar vermian hypoplasia. (C, D) Photograph of a gross spec-imen (C) from a different patient who had Walker-Warburg syndrome demonstrates the abnormal appearance ofthe cortex and marked hydrocephalus. On the magnified image (D) irregular projections of cortex into the whitematter can be seen (arrow).

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can assess the degree of callosal developmentand separation of the frontal lobes and deep graynuclei. In addition, associated anomalies of corti-cal development may be seen.

Associated eye and facial anomalies can beidentified on fetal ultrasound and on fetal MR im-aging. In alobar holoprosencephaly, severe mid-line facial deformities (cleft lip, cleft palate) arepresent because of absence or hypoplasia of thepremaxillary segment of the face. In the extremeforms the orbits and globes fuse resulting in cyclo-pia. Facial abnormalities in semilobar holoprosen-cephaly are mild or absent.

Middle interhemispheric (MIH) variant, alsoknown as syntelencephaly, is another form of hol-oprosencephaly. Unlike the classical holoprosen-cephaly, which is believed to be attributable to

lack of expression of genes in the notochord orfloor plate, MIH variant is believed to be the resultof underexpression of genes involved in the devel-opment of the roof plate.90 The result is a lack ofinduction of dorsal midline structures. There is fu-sion of the sylvian fissure across the midline withthe posterior frontal and parietal lobes. The inter-hemispheric fissure is formed in the anterior frontaland in the occipital lobes. The callosal genu andthe splenium are formed, but the body is absent.90

Patients usually have mild to moderate cognitiveimpairment, mild visual impairment, and spastic-ity. Seizures may be seen in up to 40%, which issimilar to the incidence in classic holoprosence-phaly, but they do not demonstrate the endocrinedysfunction found in patients who have classicholoprosencephaly.89 Distinguishing the MIH

Fig.10. Chiari III malformation. Sagittal SSFSE in a 23-week EGA fetus demonstrates a low occipital, highcervical bony defect through which neural tissue her-niates into a cystic structure consistent with anencephalocele.


variant from other holoprosencephalies or midlinemigrational anomalies may be difficult by ultra-sound, but is possible with fetal MR imaging.91

HEMORRHAGE ANDVASCULARMALFORMATIONS

Fetal MR imaging can be useful for the assess-ment of intracranial hemorrhage, and T1-weightedimages and gradient echo T2-weighted imagesare beneficial in this regard. Hemorrhage is typi-cally low in signal on T2 and high in signal on T1.Although the MR appearance of hemorrhage inchildren and adults typically depends on the ageof the hemorrhage,92 the signal patterns for evolv-ing hemorrhage in the fetal brain are not well de-fined. Typically only one fetal MR is performedduring gestation, and no complete studies havebeen performed. In addition, fetal hemoglobinhas a higher affinity for oxygen, and the degrada-tion process may be quicker in the fetus.40

Germinal matrix hemorrhages can be observedin the fetus. In term neonates, germinal matrixhemorrhage is associated with anoxia, acidosis,and changes in blood pressure associated withdelivery. The pathophysiologic mechanisms offetal germinal matrix hemorrhage are still un-clear.93,94 The detection of small germinal matrix

hemorrhages is difficult because the germinal ma-trix has a similar signal to blood on both T1- andT2-weighted images. A T2*-weighted gradient im-age may be helpful to confirm blood, which mayappear more hypointense than the germinal ma-trix.95 These hemorrhages often originate fromthe anterior ganglionic eminence, which is a highlyproliferative portion of the germinal matrix. Rup-ture of the ependyma in association with the ger-minal matrix hemorrhage leads to intraventricularhemorrhage (Fig. 12). Compression of medullaryveins draining into the ventricular system by thehemorrhage can also lead to injury of the adjacentperiventricular white matter with development ofintraparenchymal hemorrhage A study by Moriokaand colleagues93 found that neurodevelopmentaloutcome in fetuses with germinal matrix hemor-rhage depended on the presence and severity ofparenchymal damage.

A potential cause of fetal intracranial hemor-rhage is a vascular malformation. Dural arteriove-nous fistulas are rare congenital malformationsand are often located medially and posteriorly,and typically involve the torcula herophili.95 Onultrasound, they typically appear as a heteroge-neous mass posterior to the vermis and may con-tain a more hyperechoic nodule centrally.95

Characteristic MR imaging findings consist of a du-ral-based mass centered at the torcula that dem-onstrates heterogeneous signal on T1-weightedimages (Fig. 13).95 On imaging follow-up themass becomes more heterogeneous and concen-tric rings typical of thrombosis may be seen. Com-plications include hydrocephalus and infarction,and fetal MR imaging is beneficial for assessingfor parenchymal injury.96 Dural arteriovenous fistu-las are considered to be associated with a poorneurologic outcome; however, favorable outcomehas been reported when they thrombose inutero.95,97,98 Malformations of the vein of Galenare also rare, and consist of abnormal connectionsoccurring between intracranial arteries and thepersistent median prosencephalic vein of Markow-ski. These malformations are visualized on ultra-sound as a cyst-like structure in the region of thevein of Galen, and the vascular nature can be con-firmed by Doppler. Vein of Galen malformationmay result in a steal of blood flow from the sur-rounding brain parenchyma leading to ischemia(Fig. 14). The main differential diagnosis is an arte-riovenous malformation (AVM) draining into thevein of Galen, and differentiating between thetwo is important because the outcomes can differ.The vein of Galen can be treated postnatally andhave a good outcome, whereas an AVM typicallyhas a worse prognosis.99 Fetal MR imaging canbe useful for identifying the exact nature of the

Fig.11. Semilobar holoprosencephaly. (A) Axial T2 SSFSE in a 33-week EGA fetus demonstrates fusion of the cere-bral hemispheres anteriorly. (B) Sagittal T2 SSFSE from the same fetus demonstrates formation of the spleniumand posterior body of the corpus callosum (arrow). The anterior aspect of the corpus callosum is not formed.(C, D) Photographs of a gross specimen (C is ventral, D is dorsal view) from a 22-week fetus with semilobar hol-oprosencephaly from showing absence of the interhemispheric fissure anteriorly (C) but it is present posteriorly(D). The olfactory bulbs were also absent.

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malformation and resultant intracranial complica-tions, such as areas of encephalomalacia andhemorrhage.

VASCULAR INSULTS AND TWIN^TWINTRANSFUSION

Monochorionic twins are at risk for developing is-chemic parenchymal insults. The fetuses sharethe same placenta and there is increased likeli-hood of abnormal vascular connections resultingin abnormal blood flow to the fetuses. Twin–twintransfusion syndrome results when blood abnor-mally flows from one twin (donor) to the other re-cipient twin. The donor twin is smaller and

develops oligohydramnios, the recipient twin de-velops volume overload and polyhydramnios,and both twins are at risk for cerebral ischemia.There is a 10-fold reported increased risk for thedevelopment of white matter injury in monochor-ionic twins compared with dichorionic twins(33% versus 3.3%).100 Co-twin demise is anothercomplication of monochorionic twin pregnancies,and is associated with a greater risk for neurologicimpairment in the surviving twin (Fig. 15).101 Thisimpairment may result from thromboembolicevents in the surviving twin or result from hypoper-fusion.101 Fetal MR imaging is valuable in assess-ing for regions of ischemic parenchymal injury,which appear as regions of increased T2 signal

Fig.12. Germinal matrix hemorrhage with rupture into the lateral ventricle. Axial (A) and coronal (B) T2 SSFSE ofa 33-week EGA fetus with hemorrhage adjacent to the right caudothalamic notch (arrow). Intraventricular exten-sion and hydrocephalus with diffuse edema and or injury are present. (C) Axial T1-weighted image from the samepatient. The intraventricular hemorrhage demonstrates T1 hyperintense signal (arrows).


within the white matter, cerebral cortex, or germi-nal matrix.23 The identification of such areas of en-cephalomalacia and periventricular white matterinjury is important because they are associatedwith long-term neurodevelopmental deficits.93 Dif-fusion-weighted MR imaging may lead to earlierdetection of areas of ischemia in fetuses at riskfor brain injury.102

Other causes of fetal ischemic insult include pla-cental insufficiency, infectious causes, or maternalcomplications, including hypovolemic shock, ab-dominal trauma, hypoxia, hypertension, or druguse. Ischemic injuries have also been identified ad-jacent to mass lesions, such as neoplasms andsubdural hematomas, and may result from com-pression. A study by Garel and colleagues103

found that MR was a valuable tool in detectingthe sequelae of ischemia involving the cortex,which was demonstrated by the presence of lam-inar necrosis or polymicrogyria and white matterlesions. Laminar necrosis and calcified leukomala-cia are well demonstrated using T1-weightedsequences, and T2* imaging can be used to dem-onstrated regions of previous hemorrhage. In thefuture diffusion-tensor MR imaging may be of ben-efit in identifying the microstructural damage re-sulting from ischemic insult.103

ABNORMALITIES OF THE POSTERIOR FOSSA

Abnormalities of the posterior fossa are one of themost common findings on fetal imaging.104

Fig.13. Dural arteriovenous fistula. Sagittal (A) and axial (B) T2 SSFSE images of a 22-week EGA fetus demonstrateventriculomegaly and an isointense, subdural mass within the posterior fossa (arrow). This mass was determinedto be a hematoma, and was surgically evacuated shortly after birth. Abnormal vasculature consistent with a duralarteriovenous fistula was noted by the neurosurgeon. (C) Axial T1-weighted image obtained at 1 day of age dem-onstrates hematomas involving the posterior and middle cranial fossas (arrows).

Smith & Glenn574

Posterior fossa evaluation may be limited on ultra-sound, especially in the third trimester secondaryto ossification of the skull. Fetal MR imaging allowsdirect visualization of the posterior fossa struc-tures, such as the vermis, cerebellar hemispheres,and brainstem. Posterior fossa abnormalities areheterogeneous and complex, and the evaluationof these anomalies by fetal MR imaging has beencomplicated by false-positive and false-negativediagnoses.105–111

One of the more common sonographic diagno-ses is the Dandy-Walker complex, which is a con-tinuum of posterior fossa cystic anomalies andconsists of varying degrees of cerebellar or ver-mian hypoplasia, including the Dandy-Walker mal-formation, vermian hypoplasia, and mega cisterna

magna (Fig. 16). Some authors use the termDandy-Walker variant, which leads to confusionbecause some may use this to refer to a hypoplas-tic cerebellar vermis and a large cistern magna,whereas others may use it to refer to the Dandy-Walker malformation in which one or more of thefourth ventricular outflow foramina are patent.Because of the marked heterogeneity of brain ab-normalities in both ‘‘Dandy Walker malformation’’and ‘‘Dandy Walker variant,’’ the effect of theseabnormalities on neurodevelopmental outcome ispoorly understood. Adopting a more descriptiveapproach of the findings as detected by eitherprenatal ultrasound or MR imaging (rather thanclassifying the abnormality into Dandy-Walkermalformation or Dandy-Walker variant) will assist

Fig.14. Sagittal (A) and coronal (B) T2 SSFSE demonstrates a large flow void in the expected region of the vein ofGalen (arrow) and continuing into the straight sinus.


in our eventual understanding of these complexabnormalities, their embryology, etiology, andneurodevelopmental outcome.

Hypoplasia or absence of the cerebellar vermis,hypoplasia of the cerebellar hemispheres, andenlargement of the posterior fossa and fourth ven-tricle have been classically described as theDandy-Walker malformation. The enlargement ofthe posterior fossa results in an elevation of thetorcula that is nicely demonstrated on the sagittalimages, and is frequently associated with hypopla-sia of the brainstem. Additional CNS anomalies,such as agenesis of the corpus callosum,

Fig.15. Co-twin demise. Axial (A) and coronal (B) T2 SSFSE ochorionic twin. There is massive diffuse loss of supratentonoted, which is consistent with either a hemorrhage or ca

holoprosencephaly, schizencephaly, andheterotopia, are associated with a worse progno-sis112–114 and are typically better evaluated by fetalMR imaging.

Vermian hypoplasia is a more subtle abnormalityand is typically identified by incomplete coveringof the fourth ventricle on ultrasound. Patients areoften referred for fetal MR imaging to determineif the vermis is small or if there is a prominent cis-terna magna. On fetal MR imaging, the vermis canbe directly measured and the cerebellar hemi-spheres and brainstem can also be evaluated. Inabout one third of cases with presumed diagnosis

f a 25-week EGA fetus status post demise of the mono-rial brain parenchyma. Periventricular low T2 signal islcification.

Fig.16. Spectrum of posterior fossa anomalies. (A) Sagittal T2 SSFSE of a 23-week EGA fetus demonstrates vermianhypoplasia, enlargement of the posterior fossa, and elevation of the tentorium (arrow) consistent with Dandy-Walker malformation. (B) Photograph of a gross specimen of a different patient who had Dandy-Walker malfor-mation demonstrates absence of the vermis and hypoplasia of the cerebellar hemispheres (arrows). (C) Sagittal T2SSFSE of a 23-week EGA fetus demonstrates mild vermian hypoplasia demonstrated by a lack of complete cover-age of the fourth ventricle (arrow). (D) Sagittal T2 SSFSE of a 29-week EGA fetus demonstrates a prominent pos-terior fossa fluid collection (arrow), but the vermis is normal in configuration and the tentorium is normallylocated, consistent with mega cisterna magna.

Smith & Glenn576

of inferior vermian hypoplasia on prenatal ultra-sound and fetal MR imaging, the vermis appearsnormal on postnatal imaging.104,105 This findinghas important implications because some studieshave shown neurodevelopmental abnormalities inchildren who have inferior vermian hypoplasia.106

Although rare, hemorrhage can occur within thecerebellum, and may result from infection, such ascytomegalovirus. The presence of cerebellar hem-orrhage should, therefore, raise the suspicion ofa congenital infection and a search for associatedanomalies, such as intrauterine growth ardation,calcifications, and microcephaly, should be under-taken.115,116 Other causes of cerebellar hemor-rhage include immune and nonimmune hydrops,which may result from associated hematologic

abnormalities.117 Germinal matrix hemorrhagewithin the cerebellum may also occur.

Chiari II

Myelomeningoceles are one of the most commonspinal anomalies detected on fetal ultrasound.They are almost always seen in associated withhindbrain malformation referred to as Chiari II,which consists of the findings of a small posteriorfossa and herniation of the cerebellar tissue intothe cervical subarachnoid space (Fig. 17). ChiariII malformations are easily assessed by fetalultrasound, but fetal MR imaging has the benefitof assessing for other associated anomalies,such as callosal agenesis or hypogenesis,

Fig.18. Teratoma. Sagittal (A) and axial (B) T2 SSFSE in a 28mass. No normal brain parenchyma is identified, and therethe gross specimen obtained at autopsy from the same pa

Fig.17. Chiari II malformation. Sagittal T2 SSFSE imageof a 22-week EGA fetus demonstrates a defect in thelumbosacral region (thin arrow) consistent with a mye-lomeningocele. A small posterior fossa is noted alongwith low-lying cerebellar tonsils (thick arrow) andmarked ventriculomegaly.


cerebellar dysplasia, periventricular heterotopia,syringohydromyelia, and diastematomyelia.23,118

Currently, several centers perform fetal surgeryfor repair of myelomeningoceles.119

CONGENITAL NEOPLASM

Intracranial neoplasms occurring during fetal lifeare rare, and account for approximately 0.5% to1.9% of pediatric neoplasms.120–122 The progno-sis is typically poor, with postnatal survivalreported around 28%.123,124 Teratomas accountfor 50% and gliomas are the second most com-mon (25%).40 Other reported neoplasms includecraniopharyngioma, hamartomas, choroid plexuspapilloma, and hemangioblastoma.125 Intracranialteratomas are heterogeneous in appearance. Theyare composed of solid and cystic components,and when the cystic component predominatesthey may be difficult to distinguish from an arach-noid cyst (Fig. 18). The imaging findings of glialneoplasms, craniopharyngiomas, and hamarto-mas are variable; however, craniopharyngiomas

-week EGA fetus demonstrates a large heterogeneousis an enlarged head circumference. (C) Photograph oftient demonstrates a multilobulated mass.

Fig.19. Craniopharyngioma. (A) Sagittal T2 SSFSE in a 34-week EGA fetus demonstrates a midline heterogeneousmass in the suprasellar region (arrow). There is associated hydrocephalus. On autopsy, this was found to be a cra-niopharyngioma. (B) Photograph of gross specimen cut in the sagittal plane from the same patient demon-strates the large size of the lesion in comparison with the brain. The brainstem is visible in the lower aspectof the image (arrow).

Smith & Glenn578

tend to be located in the sellar region in the midline(Fig. 19). A study by Cassart and colleagues125

found that fetal MR imaging was able to betterdetermine the extent of tumoral extension than ul-trasound, allowing them to assess the degree ofinvolvement of adjacent structures, thus providinginformation concerning likelihood of surgicalresection and prognosis.

CONGENITAL INFECTIONS

Various infections can involve the fetal nervoussystem, including the TORCH infections (toxoplas-mosis, rubella, cytomegalovirus, and herpes sim-plex infections) and HIV, varicella, and acutematernal sepsis (typically group B streptococcus).The most common of these infections are cyto-megalovirus and toxoplasmosis.50,126–130 Theeffect of an infection of the fetal nervous systemdepends on the stage of development duringwhich it occurs. Those infections occurring in thefirst two trimesters typically result in congenitalmalformations, whereas those occurring in thethird trimester result in destructive lesions.50 Thefindings of intrauterine growth retardation, intra-cranial and intrahepatic calcifications, ventriculo-megaly, hyperechogenic bowel, or hydropsfetalis on ultrasound should raise the suspicion offetal infection.128 Intracranial hemorrhage hasbeen reported as a complication of intracranialinfections, especially in association with cytomeg-alovirus.1 Other sequelae, such as cortical malfor-mations, including lissencephaly and

polymicrogyria, and delayed cortical maturationare well assessed on fetal MR imaging, and fetalMR imaging is an important adjunct to ultrasoundwhen infection is suspected because it gives thebest evaluation of the extent of parenchymaldamage.50

SUMMARY

Fetal MR imaging provides a useful adjunct in theevaluation of anomalies of the fetal brain notedon ultrasound. The higher resolution of fetal MRimaging allows for improved assessment of corti-cal malformations and other anomalies. The useof fetal MR imaging is relatively new, however,and understanding of the imaging findings con-tinues to evolve. In addition, the improvement ofnewer techniques, such as diffusion-weightedMR imaging, should lead to improved understand-ing of the developing fetal brain and the impact ofischemic, infectious, and developmental insults.

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Ultrasound of the FetalCranium: Review ofCurrent Literature
Eyal Sheiner, MD, PhDa, Jacques S. Abramowicz, MDb,*
KEYWORDS� Fetal cranium � Fetal anatomy � Ultrasound� Craniosynostosis � Neural tube defects

Among the core goals of the prenatal ultrasoundexamination is characterization of the fetal organsas anatomically normal or abnormal. Deviationsfrom normal require detailed specialized examina-tion. Anomalies of the fetal brain are relativelycommon and have the potential to result in severemorbidity or mortality. Although much has beenpublished regarding the fetal brain, less has beendiscussed about the skull. This article discussesnormal and abnormal fetal skull anatomy asobserved using ultrasound technology.

m

NORMAL SKULL AND SHAPE VARIATIONS

The skull bones are formed from mesenchymalcondensations that develop into connective tissueand subsequently ossify (ie, membranous ossifica-tion).1 Prenatal ultrasound study is able to depictossified portions of the fetal skeleton as early asthe late first trimester.2 Ossified bones appearechogenic compared with hypoechoic cartilage.

Images of the skull are routinely obtained duringultrasound examination. The frontal, parietal, thinsquama of the temporal bones, and occipitalbones, which together form the calvaria, shouldbe visualized. The cartilaginous zones of articula-tion of these bones, the coronal, sagittal, and lam-boid sutures, are visible, along with thefontanelles, mainly the anterior and posterior(Fig. 1).3,4

The biparietal diameter (BPD) was the first re-ported related sonographic fetal measurement5

and is considered a relatively accurate parameter

a Department of Obstetrics & Gynecology, Soroka UnivNegev, Beer Sheva, Israelb Department of Obstetrics & Gynecology, Rush UniversitIL 60612, USA* Corresponding author.E-mail address: [email protected] (J.S. Abra


for gestational age determination between 14and 26 weeks of gestation, with variation of plusor minus 7 to10 days. The BPD is preferably mea-sured on the transverse plane, from the outer edgeof the proximal skull to the inner edge of the distalskull. The BPD is measured at the widest area onthe skull and demonstrates the thalamic nucleiand the cavum septi pellucidi. The occipitofrontaldiameter is measured from mid-echo to mid-echo (ie, the anteroposterior measurementobtained from outer skull to outer skull, excludingthe skin). The cephalic index is the ratio of thebiparietal to occipitofrontal diameters reported asa percentage (short axis/long axis � 100). Normalintrauterine cephalic index is 80%. The head cir-cumference (HC) should always be measured,because most of the time it better reflects gesta-tional age. This measurement is done eitherthrough tracing with digital calipers or calculationfrom the above two diameters. The cranium is con-sidered to be brachycephalic (from the Greekbrachys, meaning short) if the cephalic index isgreater than 85% (ie, the head shape is roundedbecause the BPD is relatively large, whereas theoccipitofrontal diameter is somewhat short)(Fig. 2), and dolichocephalic (from the Greek doli-khos, meaning long and thin, also known as sca-phocephaly or boat-shape [Greek: scaphe]) ifless than 75% (ie, the head shape is elongated).6,7

Dolichocephaly is more common in pretermfetuses presenting as breech and more commonin fetuses who have oligohydramnios of long-standing duration.8 From 14 to 40 weeks’

ersity Medical Center, Ben Gurion University of the

y Medical Center, 1653 W Congress Parkway, Chicago,

mowicz).


asou

nd.th

ecli

nics

.co



Anterior

MS

CSCS

AF

LS

SS

PF LS

Fig.1. Fetal cranium sutures and fontanelles. AF, ante-rior fontanelle; CS, coronal suture; LS, lambdoidal su-ture; MS, metopic suture; PF, posterior fontanelle; SS,sagittal suture.

Fig. 2. Severe brachycephaly. Note that the BPD is con-sistent with a gestational age of 34 and 4/7 weeks ina 32-week fetus.

Sheiner & Abramowicz584

gestation, there is no significant change in thecephalic index with gestational age.9

Variations in the shape of the fetal skull (eg, dol-ichocephaly, brachycephaly) may adversely affectthe accuracy of the BPD measurement in estimat-ing fetal age.9,10 Controversy exists regarding theassociation between variation in shape and chro-mosomal abnormalities. Although Borenstein andcolleagues7 found an association betweenbrachycephaly and trisomy 21 at 11 plus 0/7 to13 plus 6/7 weeks of gestation, such associationwas not confirmed by others.11 Borrell and col-leagues11 determined the cephalic index in 555consecutive chromosomally normal fetuses andin 38 chromosomally abnormal fetuses beforeamniocentesis. A cephalic index greater than0.85 was observed in 14% of fetuses who hadDown syndrome and in 11% of normal fetuses.The authors concluded that brachycephaly is nota useful marker for Down syndrome in early mid-trimester fetuses. Preliminary experience indicatesthat a cephalic index greater than 1 SD from themean (less than 74% or greater than 83%) maybe associated with significant alteration of theBPD measurement expected for a given gesta-tional age, and therefore the head circumferencecan be used effectively as an alternative andmore accurate means of establishing gestationalage.9

Fetal head measurements can be correlatedwith the abdominal circumference (AC) or the fe-mur length (FL). The normal head circumference/

abdominal circumference ratio (HC/AC) is gesta-tional age dependent and ranges between 1.07and 1.26.12 Alterations in this ratio may suggesta cranial anomaly. The normal femur length/bipar-ietal diameter ratio (FL/BPD) is 0.71 to 0.87. Thisratio may be altered when there is a change ineither of these measurements.12 Fetuses affectedwith Down syndrome demonstrate normal biparie-tal diameter (BPD), but high BPD/FL ratio, second-ary to shortened femur length.13

The association between the second-trimesterfetal biparietal diameter/nasal bone length (BPD/NBL) ratio and trisomy 21 was previously evalu-ated.14 Thirty-one cases of trisomy 21 were com-pared with 136 matched euploid fetuses formaternal age, indication for referral, and gesta-tional age. The mean NBL was shorter (mean �SD, 2.3 � 1.7 mm versus 3.9 � 1.2 mm; P<.001)and the BPD/NBL ratio was greater (17.7 [range,6.2–114] versus 11.7 [range, 5.8–80]; P<.001) forfetuses who had trisomy 21. The risk for trisomy21 increased 2.4-fold (95% CI, 1.7–3.4) with every1-mm decrease in NBL and increased 1.08-fold(95% CI, 1.03–1.12) with each unit increase inthe BPD/NBL ratio (P<.001). The BPD/NBL ratiowas found to be an independent predictor of tri-somy 21 (odds ratio, 1.08; 95% CI, 1.03–1.11) ina multiple logistic regression model. The authorsconcluded that second-trimester BPD/NBL ratiowas a significant and independent predictor of tri-somy 21. An assessment of the BPD/NBL ratiomay improve the detection rate of trisomy 21cases when incorporated with current prenatalsonographic and maternal serum screeningprotocol.14

Head size should be carefully measured relativeto the established gestational age, to determinethe appropriateness of head size or the presenceof micro- or macrocephaly. The shape of the

Ultrasound of the Fetal Cranium 585

head should be evaluated also. Anomalies of theskull have been observed using ultrasound studyduring the early second trimester.15 Ossificationcenters become visible near the end of the first tri-mester. At 16 weeks a three-dimensional (3D) sag-ittal scan displays the cranium and the echo-freefontanels and the cranial sutures (Fig. 3).16 On anaxial sonogram at the beginning of the second tri-mester, the head should be oval. The optimal timefor viewing the cranial sutures is between14 weeksand 16 weeks, and the earliest described cranialchanges included abnormalities in biparietaldistance.17,18

ABNORMAL SKULLCraniosynostosis

Craniosynostosis is the premature fusion of a sin-gle or multiple cranial sutures.12 It may occur eitherprenatally or perinatally.19 This premature fusionrestricts and distorts the growth of the skull, oftenresulting in increased intracranial pressure. The fi-nal abnormal skull shape depends on the specificsuture fused and whether unilateral or bilateral su-tures are involved.20

Fig. 3sounsagitfontMS,tal s

Premature fusion of the coronal sutures com-pels the skull to grow wide relative to itslength, resulting in brachycephaly.

Premature fusion of the sagittal suture forcesthe skull to grow long relative to its width,resulting in dolichocephaly.

Premature fusion of the metopic suture resultsin a narrow, triangular forehead with con-cavity of the temples, known astrigonocephaly.

. Sutures and fontanelles, as imaged by 3D ultra-d reconstruction. Note the metopic, coronal, andtal sutures and anterior fontanelle AF, anterioranelle; CS, coronal suture; LS, lambdoidal suture;metopic suture; PF, posterior fontanelle; SS, sagit-uture.

Fig. 4Irregof mfetu

Premature fusion of either the coronal orlambdoid sutures results in asymmetrical,flat skull shape or plagiocephaly (‘‘oblique’’skull).

Premature fusion of both the coronal and sag-ittal sutures causes an abnormally highconical skull shape, known as oxycephaly(also known as turricephaly or high-head).

Premature fusion of the coronal, lambdoidand posterior sagittal sutures results ina cloverleaf skull, also known as kleeblatt-schadel, the most common sonographi-cally diagnosed craniosynostosisreported in the literature because of its ab-normal skull shape.

Sonographic features of the kleeblattschadelskull abnormality include an enlarged trilobed skull(Fig. 4), hydrocephaly, and polyhydramnios. Acommon error in diagnosis may be due to misinter-pretation of this skull anomaly as encephalocele.21

Kleeblattschadel abnormality is usually associatedwith thanatophoric dysplasia, a lethal disorder ofendochondral ossification, with chondrocytesthat are either decreased in number, absent, ordisorganized. Thanatophoric dysplasia is consid-ered the most common skeletal dysplasia with in-cidence of 1/6000 to 1/17,000 births.22–26 There isabnormal mesenchymal-like tissue in the growthplate and periosteum, which may account for theabnormal bone formation. A far less common ge-netic syndrome associated with the kleeblattscha-del abnormality is type II Pfeiffer syndrome, whichin addition includes severe ocular proptosis,severe central nervous system involvement, andbroad thumbs and great toes.

. Cloverleaf skull, kleeblattschadel malformation.ular shape of the skull, secondary to synostosisultiple sutures. Hydrocephaly is also present. Thes had thanatophoric dysplasia, type II.


Craniosynostosis occurs in isolation in 85% ofcases but is in general described in associationwith several syndromes, including cranial shapeabnormalities and severe malformations of thedigits and grouped together under the term acro-cephalosyndactyly (ACS). The Online MendelianInheritance in Man database contains 120 entrieswith craniosynostosis as an abnormal feature.27

Five major subtypes are recognized but someoverlap may exist between the various types,which makes a definite diagnosis difficult withoutdocumentation of the specific gene mutationinvolved.

ACS type I, also known as Apert syndrome, isthe most severe form. Findings includebicoronal facial craniosynostosis, hyperte-lorism, exophthalmos, midface hypoplasia,a narrow palate, and osseous or membra-nous syndactyly of all four extremities.There is often complete fusion of boneswithin the second to the fourth fingersand the presence of a single commonnail, resulting in the appearance of ‘‘mit-ten’’ hands and feet. Mutations in the fibro-blast growth factor 2 gene (FGFR2), whichmaps to chromosome 10q25-10q26,cause Apert syndrome.

ACS type II, Crouzon syndrome, with coronalsuture synostosis and facial hypoplasia.Mutations in the fibroblast growth factor2 gene (FGFR2), which maps to chromo-some 10q25-10q26, are responsible forabout 90% of Crouzon syndrome, whereasabout 10% of mutations in the fibroblastgrowth factor 3 gene (FGFR3) result inCrouzon syndrome with acanthosisnigrans. Another ACS type II form featuringsagittal, coronal, and lambdoid suturessynostosis is called Carpenter syndromewith preaxial polydactyly. Mutations in theRAB 23 gene, which is a RAS oncogene,cause this syndrome.

ACS type III, Saethre-Chotzen syndrome withptosis of eyelids and ears and syndactylyof second and third fingers. Mutations inthe TWIST gene, which maps to chromo-some 7p21-7p22, are responsible for thissyndrome. Sakati-Nyhan syndrome isa variant with polysyndactyly. Advancedparental age supported new dominantmutation as the cause. No specific genehas yet been found. The Baller-Gerold syn-drome shares phenotypic overlap withACS type III but includes radial defectsand is thus considered by some to be a var-iant. Baller-Gerold syndrome is caused by

mutations in the RECQL4 gene and mapsto chromosome 8q24.3.

ACS type IV, Goodman syndrome with cleftpalate, heart defects, and hermaphrodit-ism. Goodman syndrome is believed tobe a variant of Carpenter syndrome (acro-cephalopolysyndactyly type II).

ACS type V, Pfeiffer syndrome with brachy-cephaly, syndactyly of fingers and toes,and enlargement of the thumbs and bigtoes. Mutations in fibroblast growth factor1 gene (FGFR1), which maps to chromo-some 8p11.22-p12, cause Pfeiffer syn-drome type I, whereas mutations in thefibroblast growth factor 2 gene (FGFR2),which maps to chromosome 10q25-10q26, cause Pfeiffer syndrome type II. Ab-normalities in the hands and feet tend to beless severe in Pfeiffer syndrome type I.

Other syndromes with craniosynostosis includeShprintzen-Goldberg with craniosynostosis, withsevere exophthalmos, maxillary and mandibularlyhypoplasia, arachnodactyly, abdominal hernias,and developmental and mental delays resultingfrom mutations in the FBN1 gene (the same generesponsible for Marfan syndrome). Jackson-Weisssyndrome with midfacial hypoplasia and footanomalies (possibly a variant of Pfeiffer) is causedby mutations in the fibroblast growth factor 2 gene(FGFR2), which maps to chromosome 10q25-10q26. Antley-Bixler syndrome is caused by muta-tion in the fibroblast growth factor receptor geneFGFR2 with trapezoidocephaly, midface hypopla-sia, humeroradial synostosis, bowing of femora,fractures, and other abnormalities. Opitz-C (alsoknown as Opitz trigonocephaly) syndrome resultsfrom an autosomal recessive disorder caused byan as-yet unknown gene, with microcephaly,peculiar facies, strabismus, short limbs, heartdefects, and cryptorchism. There are also lesserknown, multiple case reports of single patientswho had craniosynostosis and a unique additionalfindings, named after the individual who publishedthe case.

The diagnosis of craniosynostosis is mostlymade secondary to observing other anatomicabnormalities.12 Turribrachycephaly was identi-fied using ultrasound study at 16 to 17 weeks ina child who had Apert syndrome, whose motherwas similarly affected.28 In these cases, typicalfacies may be a telltale sign (Fig. 5). Unilateral cor-onal suture synostosis, which appeared as anasymmetric multilobulated skull at 31.8 weeks’gestation, was also reported.29 Sagittal suturecraniosynostosis (scaphocephaly) was also diag-nosed prenatally using ultrasound.30–32

Fig. 5. Craniosynostosis. (A) Note the unusual skull shape, secondary to abnormal closure of sutures. (B) Abnormalfacies, with high, prominent forehead, down-slanting eyes, exophthalmos, and bulging tongue. In addition thefetus also has low-set ears (not visible in picture). These are typical findings of Apert syndrome.

Fig. 6. Strawberry-shaped skull in a case of trisomy 18.


Miller and colleagues12 examined prenatal ultra-sound images of patients who had craniosynosto-sis to determine the extent to which prenataldiagnosis is possible. Prenatal ultrasound imagesof 19 patients who underwent 26 ultrasoundexaminations, with postnatally diagnosed metopicor coronal suture craniosynostosis, werereviewed. Diagnosis was not possible in the firsttrimester. All aspects of pregnancy seemed nor-mal. In the second trimester, kleeblattschadel skullabnormality was diagnosed at 20.5 weeks, whena multilobular shape of the skull and diastasis ofthe frontotemporal suture was identified. Inanother child who had kleeblattschadel skullabnormality, the cephalic index was above normalat 86.4 and the head circumference to abdominalcircumference ratio was increased. Brachyceph-aly was diagnosed during the second trimester.During the third trimester, the head shape defor-mation was more obvious.12 The diagnosis ofcraniosynostosis using ultrasound may be chal-lenging. Only 15 of 26 (58%) cases were correctlydiagnosed.12 In the same study the diagnosis ofcraniosynostosis was not possible during the firsttrimester. Diagnosis of malformations, such askleeblattschadel, trigonocephaly, brachycephaly(bilateral coronal suture craniosynostosis), andplagiocephaly (unilateral coronal suture craniosy-nostosis), is possible during the second and thirdtrimesters. Generally, craniosynostosis has anincidence rate of 52 per 100,000.33

An additional abnormal skull shape is describedas strawberry-shaped (Fig. 6). This abnormal skullshape results from flattening of the occiput withpointing of the frontal bones.34 This abnormalityis commonly associated with other fetal malforma-tions, trisomy 18, and triploidy. The ultrasono-graphic finding of a strawberry-shaped skullshould therefore initiate a diligent search for thepresence of additional markers of trisomy 18 and

is a strong indication for fetal chromosomestudy.34

Abnormal Skull Findings in NeuralTube Defects

Neural tube defects (NTD) are a group of malfor-mations resulting from incomplete closure of theneural tube by the sixth week of gestation. Suchmalformations are generally associated with cra-nial abnormalities.

Spina bifidaSpina bifida is an opening of the vertebra throughwhich a meningeal sac may herniate out. Meningo-cele is defined as the meningeal sac alone; onceneural elements are included in the sac the findingis referred to as meningomyelocele. Classically,fetuses who have spina bifida have one or moreof the following cranial signs: small BPD, ventricu-lomegaly, frontal bossing (‘‘lemon sign,’’ ie, frontalbone scalloping),35 elongation and downward dis-placement of the cerebellum (‘‘banana sign,’’ ie,the cerebellum is impacted deep into the posteriorfossa),36,37 and effacement or obliteration of thecisterna magna (Fig. 7). Examination of the fetal

Fig. 7. Cranial signs in open spina bifida. Note in-cav-ing of the frontal bones, resulting in the lemon shape(arrows), the abnormal shape of the cerebellum or ba-nana sign (arrowheads) and obliteration of the poste-rior fossa (asterisk).


cranium and its contents can thus assist the in thediagnosis of open spina bifida. The sensitivity ofabnormal cranial findings in correctly diagnosingspina bifida is about 99%.37,38 The lemon sign,however, might also be present in 1% or 2% ofnormal fetuses. Although in most cases of spinabifida the malformation is isolated, the abnormalitymight be associated with chromosomalabnormalities.39

The incidence and diagnostic accuracy of thelemon skull deformity and the abnormal cerebellarultrasonographic findings, as well as head size andventriculomegaly, were evaluated in a study of1561 patients at high risk for fetal neural tubedefects.40 In the 130 fetuses who had confirmedopen spina bifida there was a gestational age–re-lated correlation between gestational age andthe presence of each of these abnormal findings.The lemon sign was present in 98% of fetuses at

Fig. 8. Encephalocele. (A) Sonographic image. Note openincontent (arrowheads). (B) Fetus after termination of preg

less than or equal to 24 weeks’ gestation but inonly 13% of the same fetuses at greater than24 weeks’ gestation. Cerebellar abnormalitieswere present in 95% of fetuses irrespective of ges-tational age; however, the cerebellar abnormalityat less than or equal to 24 weeks’ gestation waspredominantly the banana sign (72%), whereasat gestations greater than 24 weeks it was cerebel-lar ‘‘absence’’ (81%). Growth restriction and cere-bral ventriculomegaly significantly worsened withgestation, whereas the head circumferenceremained disproportionately small throughoutgestation.40

CephaloceleCephalocele is defined as herniation of meningeswith brain tissue through a bony defect in the skull.In most cases the lesion arises from the midline, inthe occipital area, and less frequently from theparietal or frontal bones. Commonly associatedconditions are either hydrocephalus due toimpaired cerebrospinal fluid circulation, or micro-cephaly, as is the situation in massive encephalo-cele, when brain tissue is present inside the sac.Fetal cephalocele should be suspected whenevera para-cranial mass is seen using ultrasound. Itis also commonly associated with ventriculome-galy. Because cephalocele is often associatedwith other malformations, detailed ultrasoundexamination is warranted. Proper diagnosis is pos-sible when demonstrating the bony defect of theskull (Fig. 8). Nevertheless, the defect might beextremely small and impossible to demonstrate.

Neonatal mortality rate is about 40%, and men-tal retardation and other neurologic impairmentsare common among these cases.41–45 The prena-tal diagnosis of cephalocele was reported among15 fetuses who had this skull defect. In 13 fetusesthe defect was occipital, and in 1 case each with

g in occipital region (arrow) with extrusion of cerebralnancy.


ethmoidal frontoparietal cephaloceles.42 Theprognosis for these fetuses was generally poor.Only 21% (3/14) were born alive, and all werehandicapped. Abnormal chromosome study wasnoted in 44% (4/9). Associated cranial abnormali-ties observed in various numbers of fetusesincluded ventriculomegaly, the lemon sign, a flatbasioccipital, ‘‘beaked’’ tectum, and bony defect.Likewise, in another series of 15 fetuses diag-nosed with cephalocele, 11 were located in theoccipital region and 2 each at the vertex and thefrontonasal region.43 Eleven fetuses were diag-nosed before 24 weeks’ gestation. Nine familiesopted for an interruption. Of the 2 pregnanciesthat continued to term, 1 had a benign meningo-cele and the other died in the neonatal period ofassociated cardiac anomalies. Of the 4 fetusesdiagnosed after 24 weeks, 1 was normal (after sur-gery) at 9 months, 2 were severely handicapped,and 1 died in the immediate postpartum period.

Two genetic syndromes are important to men-tion in any discussion related to cephalocele:Meckel-Gruber syndrome (MKS) and Walker-War-burg syndrome. MKS is a lethal, rare, autosomalrecessive condition mapped to chromosomes17q21-24, 11q13, and 8q24. This mapping sug-gests genetic heterogeneity in MKS. The triad ofoccipital encephalocele, large polycystic kidneys,and postaxial polydactyly characterizes MKS.Associated abnormalities include oral clefting,genital anomalies, CNS malformations, and liverfibrosis. Pulmonary hypoplasia is the leadingcause of death. Improvements in ultrasonographyhave enabled prenatal diagnosis as early as 10weeks’ gestation. The clinical features of Walker-Warburg syndrome are congenital cataracts, mi-crophthalmia, occipital encephalocele, fusion ofthe hemispheres, and absence of the corpus cal-losum. Mutations in two genes, POMT1 andPOMT2, were found in some but not all affected

Fig. 9. (A, B) Acrania (exencephaly), 2D and 3D images andnium and amorphous brain material above the orbits.

cases. Additional genes coding for glycosyltrans-ferases, yet to be identified, are believed to bethe major cause of this disorder.

AnencephalyAnencephaly is a lethal defect characterized byabsence of the brain and cranium above thebase of the skull. It is considered by some as thefinal stage of acrania (aka, exencephaly).46 In acra-nia, the upper part of the calvaria is absent withabnormal brain substance visible (Fig. 9). It isbelieved to occur during the beginning of weekfour of the pregnancy. At that time the anteriorneuropore is expected to close. The membranethat is normally destined to become the epidermisremains membranous and normal migration ofmesenchymal tissue does not occur. The resultis normal base but absent calvarial bones of theskull and dura mater. The brain tissue that is nowunprotected by the calvaria is disrupted, resultingin anencephaly.47–50 In anencephaly, no anatomicstructure is visible above the forehead line(Fig. 10). Amniotic bands may occasionally be animportant etiologic factor.51 Associated malforma-tions are extremely common with anencephalyand include spina bifida, cleft lip and palate, clubfoot, omphalocele, and hydramnion. Acrania andanencephaly can be reliably diagnosed at the rou-tine 10- to 14-week ultrasound scan, providedstudy includes demonstration of a normal-appear-ing fetal brain and skull.52 Before 10 weeks of ges-tation, diagnosis may be difficult because of lackof adequate calcification of the calvaria.

MICROCEPHALY

Microcephaly (ie, severely small head) is definedas head circumference at least 3 SDs below themean.53–56 It is primarily a brain development dis-order with secondary deficient growth of the skull.

gross pathology. Note the absence of upper the cra-

Fig.10. Anencephaly. Note absence of cranium and contents above the eye-line. Compare with Fig.9. (A) 2D imageof the fetal head. (B) 3D reconstructed image. (C) The fetus following termination of pregnancy.


This condition is commonly associated with envi-ronmental insults (alcohol, radiation, tolueneabuse, anorexia, infections) or genetic disorders(trisomies 18 and 13 and other chromosomeabnormality and genetic syndromes).53,56,57 Tol-mie and colleagues56 described a series of 29 iso-lated cases of microcephaly and 9 families withrecurrent microcephaly. The recurrence risk forsibs was 19%, which reflects the high incidenceof autosomal recessive disorders associated withmicrocephaly in this study and in other studies.Anatomic shortening of the fetal frontal lobe seemsto precede microcephaly.53 Brain size determinesthe size of the calvaria.58 Biometry of the frontallobe of the fetal brain may be a valuable tool forthe identification of the fetus at risk for microceph-aly.53 Careful study of the of the developing fetalbrain is necessary in suspicious cases, becauseabnormalities of neurocranial architecture occurin approximately two thirds of cases.53

MR imaging can add significant information tothe ultrasound examination.59 Steinlin and

colleagues59 found MR imaging revealed signifi-cant abnormalities in the majority of infants whohad primary microcephaly and neurodevelopmen-tal delays, and seems to be more sensitive thancranial ultrasound and CT. Interestingly, the under-lying conditions that may predispose to brainatrophy may be recognizable using Doppler ultra-sonography, suggesting the usefulness of brainvasculature imaging.60

THE ABNORMAL SKULL IN OTHERGENETIC DISORDERSOsteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heterogeneousgenetic disorder with defective type 1 collagen at-tributable to mutations in two type 1 collagengenes, COL1A1 and COL1A2. The disorder ischaracterized by osteopenia, bone fractures, andblue sclera.61,62 Nonlethal forms are associatedwith impaired hearing, poor dentition, and hyper-mobile joints. Ultrasound examination


demonstrates variable hypomineralization andin utero bone fractures in some but not all formsof OI.63 Hypomineralization of the skull may besevere, resulting in complete absence of posterioracoustic shadowing, leading to easy sonographicdemonstration of the ventricles and choroidsplexus. Additional findings may include microme-lia, irregularity and bowing of bones, and bell-shaped thorax. A peculiar finding is indentationof the fetal skull secondary to the hypomineraliza-tion and caused by transducer pressure (Fig. 11).The differential diagnosis should include othermicromelic dysplasias and conditions leading tohypomineralization of the bones, such as hypo-phosphatasia or achondrogenesis.

Congenital Hypophosphatasia

Although formal diagnostic criteria are not estab-lished, all forms of hypophosphatasia (exceptpseudo-hypophosphatasia) share in commonreduced activity of unfractionated serum alkalinephosphatase (ALP) and presence of either one ortwo pathologic mutations in ALPL, the geneencoding alkaline phosphatase, tissue-nonspe-cific isozyme (TNSALP). Perinatal and infantilehypophosphatasia are inherited in an autosomalrecessive manner. The milder forms, especiallyadult and odontohypophosphatasia, may be in-herited in an autosomal recessive or autosomaldominant manner depending on the ALPL muta-tion effect on TNSALP. Because of deficiency inalkaline phosphatase activity, the phenotypic ab-normalities result from impaired ossification.64–66

Ultrasound might demonstrate profound under-ossification of bones, a hypoechogenic skull, bow-ing and shortening of long bones, and severemicromelia.64–66 Severe under-ossification of theskull may result in a membranous skull, which iscompressible and may be mistaken for acrania.67

Fig.11. A case of perinatal lethal (type II) osteogenesisimperfecta. Note depression of proximal skull (arrow)secondary to transducer pressure.

Radiologic examination can occasionally help inthe diagnosis of the under-ossification.67

Abnormal Ossification

Abnormal skull ossification can be attributed tovarious drugs, and specifically angiotensin-con-verting enzyme (ACE) inhibitors and folic acid an-tagonists.68,69 ACE inhibitors are widely used forcontrolling hypertension.70 Their use in pregnantwomen increases the risk for fetotoxicity.71 ACEinhibitor fetopathy is characterized by hypoplasticskull bones (hypocalvaria),70,71 in addition to fetalhypotension, oligohydramnios, growth restriction,pulmonary hypoplasia, and renal tubular dyspla-sia. Although the true frequency of adverse fetaleffects is unclear, because of the debilitating andlethal nature of the fetal damage it is highly recom-mended to avoid exposure to ACE inhibitors dur-ing pregnancy, particularly during the secondand third trimesters.

THREE-DIMENSIONAL ULTRASOUNDOF THE FETAL CRANIUM

Three-dimensional ultrasound technology can bea useful adjunct to two-dimensional (2D) examina-tion and for parental counseling.72–78 The stereo-scopic display of rendered 3D ultrasound dataadds valuable information that assists in identifica-tion of fetal bony structures, such as cranialsutures, particularly in complex formations. The in-creasing availability of stereoscopic visualizationworkstations will offer an additional tool for fetaldiagnosis and evaluation.3

Roelfsema and colleagues79 explored the devel-opment of the fetal skull base using 3D sonogra-phy. The researchers performed serial 3Dsonographic measurements of the anterior skullbase length, posterior cranial fossa length, andskull base angle in 126 normal singleton pregnan-cies at 18 to 34 weeks of gestation. Measurementswere technically successful in 69% to 94% ofcases. A statistically significant gestational age-re-lated increase was established for both the ante-rior skull base length and the posterior cranialfossa length. The skull base angle showed a smallbut significant flexion of about 6 degrees. The re-producibility was acceptable for all fetal skullbase measurements.79 Three-dimensional ultra-sound was also used to describe patterns of ab-normal development of the metopic suture inassociation with fetal malformations during thesecond and third trimesters of pregnancy.75

A cross-sectional study of the frontal bones andmetopic suture in 11 fetuses at 17 to 32 weeks ofgestation was performed. Cases were selectedbecause obvious abnormalities in the metopic

Fig.12. Abnormal metopic suture. In addition, the fe-tus was found to have club feet, cerebellar hypopla-sia, intracranial cyst, and agenesis of the corpuscallosum. (Courtesy of Dr. Bernard Benoit, Nice,France.)


sutures were noted. In each case, the malforma-tion was initially detected by 2D ultrasound studyand subsequently 3D ultrasound technology usingtransparent maximum imaging mode was applied.Four patterns of abnormality in the metopic suturewere identified:

Delayed development with a V- or Y-shapedopen suture, which is found in normalfetuses at 12 to 16 weeks.

U-shaped open suture, presumably becauseof upward growth of the frontal boneswith delayed closure.

Premature closure of the suture, which is nor-mally observed after 32 weeks.

The presence of additional bone between thefrontal bones (Fig. 12).75

Premature closure of the suture or the finding ofadditional bone between the frontal bones wasobserved in fetuses who had holoprosencephalyand abnormalities of the corpus callosum,whereas the V-, Y-, and U-shaped metopic sutureswere observed in fetuses who had facial defectsinvolving the orbits, nasal bones, lip, palate, andmandible, in the absence of holoprosencephalyand abnormal corpus callosum.75

SUMMARY

Fetal cranial defects and abnormal skull shape areamenable to ultrasound study diagnosis. Correctidentification of the nature of the abnormality isextremely important and helpful in establishingdiagnosis and long-term prognosis. In addition itmight direct the care provider to apply the correctgenetic study, chromosome or DNA related, forfinal diagnosis confirmation. The astute operator

is likely to immediately suspect a problem in theface of fetal microcephaly, ossification abnormal-ity, bone fractures, and abnormal skull shape sec-ondary to craniosynostosis or brain structureabnormality. Although most of these abnormalitiesare amenable to 2D ultrasound study detection,3D ultrasound and infrequently fetal MR imagingcan be an adjunct for delineation of cranial abnor-malities and may be useful in demonstrating theextent of the abnormality and in parentalcounseling.

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Diagnostic Approach toPrenatally DiagnosedLimb Abnormalities
Arie Koifman, MDa,b,c, Ori Nevo, MDd, AntsToi, MDe,David Chitayat, MDa,b,c,*
KEYWORDS� Detection and diagnosis of limb abnormalities using

prenatal ultrasound

The prevalence of limb abnormalities is approxi-mately six in 10,000 live births, with higher inci-dence in the upper limbs compared with thelower limbs (3.4 of 10,000 and 1.1 of 10,000,respectively).1 Unilateral limb abnormalities aremore common than bilateral and are morefrequent in the right limb compared with the left.2

Limb formation occurs early in embryogenesis(4–8 weeks’ gestation), whereas primary ossifica-tion centers are present in all the long bones ofthe limbs by the 12th week of gestation. Develop-ment of the upper and lower limbs is similar ex-cept that the morphogenesis of the lower limblags approximately 1 to 2 days behind that of theupper limb. The molecular regulation of limb for-mation is complex and involves different genefamilies. The homeobox (HOX) gene family hasa key role in the positioning of the limbs alongthe craniocaudal axis in the flank regions of theembryo. Limb outgrowth is tightly regulated by fi-broblast growth factor (FGF) genes along with thebone morphogenetic proteins (BMPs). Patterningof the anteroposterior axis of the limb is regulatedby sonic hedgehog (SHH) genes, contributing tothe correct order of appearance of digits. SHH

a The Prenatal Diagnosis and Medical Genetics ProgramOntario Power Generation Building, 700 University Avenb Department of Obstetrics and Gynecology, Mount SinToronto, ON, Canada M5G 1L4c The Hospital for Sick Children, Division of Clinical aUniversity Avenue, Toronto, ON, Canada M5G 1X8d Department of Obstetrics and Gynecology, SunToronto, 76 Grenville Street (at Women’s College Hospite Department of Diagnostic Imaging, Mount Sinai HoGeneration Building, 700 University Avenue, Rm. 3292, T* Corresponding author. The Prenatal Diagnosis and MOntario Power Generation Building, 700 University AvenE-mail address: [email protected] (D. Chitayat).


genes are under different regulatory transcriptionfactors (BMPs, EN1, WNT7a, and others),3,4,5

and the transcription factors TBX5 and TBX4regulate the differentiation of upper from lowerlimbs.6

The detection and diagnosis of limb abnormali-ties using prenatal ultrasonography depends onpatient body habitus, quality of the ultrasoundmachine, and operator skill and capabilities.7

Studies have shown that limb abnormalities werediagnosed more accurately when associatedwith other abnormalities and when detected aspart of a known syndrome (chromosomal or singlegene), whereas isolated limb defects were lesslikely to be diagnosed prenatally.7,8 Holder-Espi-nasse and colleagues,9 in their series of 107 casesof limb abnormalities detected prenatally, con-cluded that diagnosis was reached in 79% of theoverall cases, whereas only 29% were diagnosedas isolated limb malformations. The limb abnor-mality was not diagnosed in 21% of the cases.The authors concluded that familiarity with geneticsyndromes is very helpful in reaching a diagnosis,particularly if the anomaly is associated with othermalformations.

, Mount Sinai Hospital, University of Toronto, Theue, Rm. 3292, Toronto, ON, Canada M5G 1X5ai Hospital, University of Toronto, 92 College Street,

nd Metabolic Genetics, University of Toronto, 555

nybrook Health Sciences Centre, University ofal), Toronto, ON, Canada M5S 1B2spital, University of Toronto, The Ontario Poweroronto, ON, Canada M5G 1X5edical Genetics Program, Mount Sinai Hospital, Theue, Rm. 3292, Toronto, Ontario, Canada, M5G 1X5.


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Koifman et al596

Upper and lower limb abnormalities are a mor-phologically and etiologically heterogeneous groupof abnormalities. They include malformation, defor-mation, or disruption and can be limited to one limbor part of a limb. Limb anomalies may affect only theupper or the lower limbs, or all four limbs and can beisolated or associated with other abnormalities.These defects are frequently acquired or multifacto-rial in origin but are occasionally inherited. Althoughsingle gene disorders,9,10,11 chromosomal abnor-malities,5 intrauterine factors,12 vascular events,3,13

maternal diseases,14 and maternal exposures8,15

are all known causes of limb abnormalities, inmany cases the etiology remains unknown.

One of the challenges in providing medical carefor patients with fetal limb anomaly is to define theetiology of the disorder and thus the prognosis andrecurrence risk for future pregnancies. Thisknowledge will provide the parents with accurateinformation regarding the possibilities for prenataldiagnosis for their future pregnancies and, if possi-ble, options for prevention of recurrence. The ef-fort to delineate the etiology of a limb defectshould involve a multidisciplinary approach includ-ing the obstetrician, radiologist/sonologist, clinicalgeneticist, neonatologist/pediatrician, and a pedi-atric orthopedic surgeon. Other specialties maybe needed if other abnormalities are noted.

The aim of this review is to describe the diag-nostic approach to prenatally detectable limbabnormalities using detailed fetal ultrasonography.

STEPWISE APPROACH TO THE FETUSWITH PRENATALLY DIAGNOSED LIMBABNORMALITIESçASSEMBLING THE PUZZLEStep I—Describe the Limb AbnormalitiesUsing Appropriate Terms

Once a limb abnormality is identified, the firststep in the clinical workup is careful descriptionof the abnormality using established nomencla-ture (Table 1). Stoll and colleagues,16 publisheda useful classification and description of limb de-fects in the European Surveillance of CongenitalAnomalies (EUROCAT) guide. This classificationscheme is based on a descriptive rather than eti-ologic approach, although a specific conditioncan fit more than one category.

The operator should strictly adhere to thebelow-listed definition of malformation, deforma-tion, or disruption to correctly categorize thedefect from a pathogenetic point of view becausethis has utmost importance in determiningetiology, prognosis, and recurrence risk.

� Malformation: A morphologic defect at anorgan, part of an organ, or larger region ofthe body resulting from an intrinsically

abnormal developmental process (eg, ec-trodactyly, phocomelia, polydactyly).� Deformation: An abnormal form, shape, or

position of part of the body caused bymechanical forces (eg, clubfeet, genurecurvatum).� Disruption: A morphologic defect of an

organ, part of an organ, or a segment ofthe body resulting from the extrinsic break-down of, or an interference with, anoriginally normal developmental process(eg, amniotic band sequence).

Step II—Look for Other Abnormalities(Isolated versus Nonisolated LimbAbnormalities)

When limb abnormalities are associated with otherdetectable abnormalities they are more likely toresult from chromosomal abnormalities, singlegene disorders, or teratogenic exposure and areless likely the result of a multifactorial conditionor vascular injury. However, because not all fetalabnormalities can be detected by fetal ultrasonog-raphy, what is thought to be an isolated limbabnormality prenatally may actually be multipleabnormalities noted postnatally. Moreover, anapparently mild single abnormality may later beestablished as a major disorder (eg, clubfeet thatare associated with brain abnormalities or meta-bolic disorder). If there is a family history of a med-ical condition, it is important to provide thisinformation to the sonologist, along with a list ofthe abnormalities associated with the condition,in an attempt to help detect subtle and uncommonbut important findings. For example, the standardultrasound examination is unlikely to detect epiph-yseal calcifications. However, these are visible ifspecifically sought.

The sonologist should try to further define thenature of the limb abnormality by adhering to thefollowing pattern of abnormalities:

� Dysplasia: An abnormal organization of cellsinto tissue(s) and its morphologic result(s).In other words, a process (and the conse-quence) of dishistiogenesis.� Sequence: A pattern of multiple anomalies

derived from a single known or presumedprior anomaly or mechanical factor.� Syndrome: A recognized pattern of devel-

opmentally independent malformationshaving one etiology.� Association: Nonrandom concurrence of

independent malformations, the etiology ofwhich (single or multiple) is unknown. Thisincludes the VACTERL association: Verte-bral defects, Anal atresia, Cardiac

Table1Nomenclature used in defining the type of limb defect

Acheiria Absence of Hand(s)

Acromelia Shortening of a distal segment in hands/feet

Adactyly Absence of fingers/toes

Amelia Absence of a limb(s)

Apodia Absence of foot/feet

Brachydactyly Abnormally short fingers

Camptomelia Bent limb

Clinodactyly Inturning of a finger

Hemimelia Absence of a longitudinal segment of a limb

Mesomelia Shortening of a middle segment in hands/feet

Micromelia Shortening of all long bones

Oligodactyly Partial loss of fingers

Phocomelia Hypoplasia of the limbs (hands attached toshoulders, feet to hips)

Polydactyly Supernumerary digits

Rhizomelia Shortening of a proximal segment in upper/lowerlimbs (humeri/femurs)

Syndactyly Fused digits

Terminal Transverse defects Absence of distal structures of the limb with normalproximal structure

Proximal intercalary defects Absence or severe hypoplasia of proximalintercalary parts of the limb where the distal partsof the limb (normal or malformed), are present

Longitudinal absence or severe hypoplasiaof a lateral part of the limb

Absence of a lateral component of a limb

Split hand/foot (ectrodactyly) Absence of central digits with or without absence ofcentral metacarpal/metatarsal bones. Usuallyassociated with syndactyly of other digits.

Multiple types of reduction defects More than one defect of those listed above in thesame individual

Prenatally Diagnosed Limb Abnormalities 597

abnormalities, T-E fistula, Esophageal atre-sia, Renal dysplasia, and Limb/radialabnormalities.

Step III—Obtain the Pregnancy History

The pregnancy history should include informationregarding maternal diseases such as diabetesmellitus, hypercoagulability, systemic lupus eryth-ematosus and other autoimmune diseases, myo-tonic dystrophy, high blood pressure, andexposure to teratogens such as medications,infections, alcohol, and cigarette smoke.

Step IV—Obtain the Family History

A three-generation family history should beobtained, using standardized pedigree symbols,15

that contains critical medical data and biologicalrelationships. Information regarding family

members with congenital limb or other abnormali-ties, recurrent miscarriages, stillbirths, mental re-tardation, inherited conditions, and consanguinityshould be included. Obtaining medical recordsfrom specific family members for documentationand accurate counseling may be required. In gen-eral, a family pedigree is a tool for making a medicaldiagnosis, deciding on testing strategies, estab-lishing the pattern of inheritance, identifying at-risk family members, calculating risks, determiningreproductive options, distinguishing genetic fromother risk factors, making decisions on medicalmanagement and surveillance, developing patientrapport, educating the patient, and exploring thepatient’s understanding.1 If new and important in-formation becomes available, it may be worthwhilerepeating the ultrasound examination because itmay detect abnormalities that were not specificallysought during the initial examination.

Table 2Chromosomal disorders associatedwith limb abnormalities

Chromosome Abnormality Limb Abnormalities

Trisomy 21 Short broad hands, clinodactyly and short fifth fingers, ‘‘sandal gap,’’slightly short femur and humerus

Trisomy 13 Postaxial polydactyly, clenched hands, overlapping fingers, prominentheels

Trisomy 18 Radial ray defects, hypoplastic thumbs, clenched hands, overlappingfingers, ‘‘rocker bottom feet,’’ clubhand, clubfeet, ectrodactyly,prominent heels, dislocated hips

del(4) (p16.3) Clubfeet

del(5) (p15.3) Clinodactyly of the fifth fingers, clubfeet, syndactyly of the second andthird fingers and toes, oligosyndactyly, hyperextensible joints

Trisomy 8 Camptodactyly of second to fifth fingers, joint contractures

Triploidy Syndactyly of the third to fourth fingers, ‘‘sandal gap’’, clubfeet

Del(3) (p25-pter) Postaxial polydactyly

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Step V—Compile the Informationand Form a Differential Diagnosis

The existence of a limb abnormality on fetal ultra-sound scan may be an unexpected finding duringa routine ultrasound scan or can be detected dur-ing a targeted ultrasound scan indicated by thefinding of intrauterine fetal growth restriction, shortlong bones suggestive of a skeletal dysplasia, orother major fetal abnormalities. In these cases,the finding of limb abnormality can help in narrow-ing the differential diagnosis and directing addi-tional investigation. Certain limb abnormalitiescan direct us toward a specific diagnosis:clenched hands in trisomy 18 and in other neuro-logic abnormalities, ‘‘hitchhiker’’ thumbs in dia-strophic dysplasia, bent tibia and femur incamptomelic dysplasia, and sacral agenesis andabsent/hypoplastic femurs in fetuses with diabeticembryopathy. Furthermore, the family history canindicate a recurrence when a limb abnormality isdetected. Thus, thumb abnormality can indicatea recurrence in a family with a previous child withFanconi’s anemia and stippled epiphysis witha family history of chondrodysplasia punctata.When a limb abnormality is detected on fetal ultra-sound scan, a referral should be made to a tertiarycenter with expertise in prenatal diagnosis of fetalanomalies. Fetal echocardiography should also beinitiated. The approach should be multidisciplinaryand include a medical geneticist, perinatologist,neonatologist, and fetal pathologist (if the preg-nancy is being interrupted).

Etiologically, fetal limb abnormalities, as otherabnormalities, can be divided into six categories:

1. Chromosome abnormalities (Table 2)2. Single gene disorders (Table 3)3. Multifactorial (Box 1)4. Maternal diseases and exposures/teratogens

(Table 4)

Detailed description of all types of limb abnor-malities and the conditions associated with themis beyond the scope of this review. Some of themore common findings/diagnoses will thus be out-lined. The nomenclature used in describing thetype of limb abnormalities is outlined in Table 1.

MALFORMATION^DEFORMATIONPositional Abnormalities

Positional abnormalities can be classified as a de-formation or a malformation. Thus, clubfeet canresult from oligohydramnios or uterine septumand can also be the result of an abnormality inthe formation of the feet. Positional abnormalitiesdetected on fetal ultrasound scan includecommon abnormalities such as clinodactyly,camptodactyly, clenched fingers, and clubbedhands/feet. Almost all these conditions havea multifactorial mode of inheritance.

Clinodactyly

Clinodactyly is a fixed deviation of the fingers ortoes. Clinodactyly of the toes is difficult to detecton fetal ultrasound scan; thus, the review concen-trates on clinodactyly of the fingers. This abnor-mality affects each of the fingers but is mostcommonly seen as fifth finger clinodactyly. Thisabnormality results from asymmetrical hypoplasia

Table 3Single gene disorders associatedwith limb abnormalities

Condition Limb Abnormalities Gene

Autosomal Dominant

Holt Oram Syndrome Upper limb only. Thumbs digitalized, absent, hypoplastic, triphalangeal, or, rarely, bifid;oligodactyly, syndactyly, and clinodactyly of fingers; limb reduction

TBX5

Okihiro syndrome Thenar eminence hypoplasia, limitation in flexion of the first interphalangeal joint, absent,triphalangeal or hypoplastic thumbs, clubhand, spine abnormalities, lower limbabnormalities

SALL4

Cornelia de Lange Micromelia, oligodactyly, limb reduction, clinodactyly of the fifth fingers, proximally placedthumbs, partial syndactyly of the second to third toes, limitation of elbow extension

NIPB1

Apert syndrome Syndactyly of digits two through five and occasionally the thumbs—mitten hand (thefingernails might be fused), syndactyly of toes, preaxial polydactyly of the feet, shorthumeri, limited mobility of the shoulder and elbow joints.

FGFR2

Autosomal Recessive

Fraser syndrome Syndactyly of the fingers and toes FRAS1, FREM2

Smith-Lemli-Opitz syndrome Syndactyly of second to third toes, postaxial polydactyly DHCR7

Fanconi pancytopenia Thumb hypoplasia, triphalangeal/digitalized, supernumerary; clubhand; radial hypoplasia FANC-A, C, D2,E, F, G and BRAC2

TAR syndrome Radial aplasia with preservation of the thumbs, clubhand Microdeletion 1q21.1

X-linked

Goltz syndrome Syndactyly of third to fourth fingers, polydactyly, ectrodactyly, oligodactyly, limb reduction PORCN

Chondrodysplasiapunctata - CDPX2

Stippled epiphyses, brachytelephalangy, short stature, rhizomelic shortening of the limbs ARSE

Split-hand/footmalformation type 2

Syndactyly, median clefts of the hands and feet, aplasia or hypoplasia of the phalanges,metacarpals, and metatarsals

SHFM2

OPD (Oto-Palato-Digital)type I and II

Limited elbow and knee extension; radial head dislocation; mild lateral femoral bowing;short, broad distal phalanges, especially thumbs; short square nails; short third, fourth,and fifth metacarpals; supernumerary carpal bones; fusion of hamate and capitate; short,broad halluces toe syndactyly; anomalous fifth metatarsal; extra calcaneal ossificationcenter; gap between first and second toes; dense long bones; radial, ulnar, femoral, andtibial bowing; small to absent fibula; subluxed elbow, wrist, and knee. Type II is allelic totype I but showed more severe findings including flexed overlapping fingers (trisomy18–like); postaxial polydactyly and syndactyly of the fingers and toes; second fingerclinodactyly; hypoplastic irregular metacarpals; short, broad hallucis; rockerbottom feet;‘‘Tree-frog’’ hands and feet; hypoplastic metatarsals.

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Box1Multifactorial conditions affecting the limbs

Congenital dislocation of the hips (CDH)

Clubfeet

Scoliosis

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of the mid-phalanx with the medial part beingshorter than the lateral part, resulting in radialangulation of the distal phalanx. In many cases,the clinodactyly is familial and isolated and hasan autosomal dominant mode of inheritance withincomplete penetrance.17 It is of utmost impor-tance to recognize that clinodactyly exists in18% of the normal population and has been re-ported in up to 60% of infants with Down syn-drome. Thus, it is not a reliable sign for thedetection of Down syndrome on fetal ultrasoundscan when isolated.18 However, when seen, otherultrasound findings suggestive of trisomy 21should be looked for (thickened nuchal fold, heartdefect, ventriculomegaly, hypoplastic nasal bone,short humerus and femur, and renal pelvisdilation).

Clubfeet

Clubfoot or talipes equinovarus is characterized bya foot fixed in adduction, supination, and varusposition. There is subluxation of the talo-calca-neo-navicular joint, with underdevelopment of thesoft tissues on the medial side of the foot andfrequently of the calf and peroneal muscles.19 Asa result, the foot typically is turned inward, givingthe foot a clublike appearance. This is one of themost common congenital birth defects and has

Table 4Maternal diseases and exposures associatedwith fetal lim

Maternal Diseases andTeratogens Associatedwith Fetal Limb Abnormalities

Valproic Acid

Carbamazepine

Hydantoin

Thalidomide

Imipramine

Nortriptyline

Azathioprine

Cocaine

Maternal insulin-dependent diabetes mellitus

Maternal autoimmune diseases

been diagnosed as early as 13 weeks’ gestationby transvaginal sonography20,21 and at 16 weeksby transabdominal ultrasound scan.22 Approxi-mately one third of cases are isolated; however,many are associated with other abnormalitiessuch as central nervous system abnormalities, themost common being neural tube defect. Thus,a thorough fetal ultrasound examination is impor-tant in prenatally diagnosed clubfeet (Fig. 1). Theassociation of clubfeet with chromosome abnor-mality prompts the question of performing fetal kar-yotyping in isolated cases of clubfeet. In mostcases of fetal chromosomal abnormalities, theclubfeet are not isolated. Because not all abnormal-ities are detectable by fetal ultrasound scan, fetalkaryotyping should be offered.23,24,25,26

Clenched Hand

Clenched hand (the second and fifth fingers over-lap the third and fourth with an adducted thumb)seen on fetal ultrasound scan must be evaluatedcarefully to determine that it is a persistent andnot a temporary finding. When constant, it sug-gests the possibility of chromosomal abnormali-ties, particularly trisomy 18, as well as othercauses of fetal akinesia sequence/arthrogryposismultiplex congenita. Both conditions are associ-ated with poor prognosis (Figs. 2 and 3).27,28

Camptodactyly

Camptodactyly is a flexion contracture of one ofthe interphalangeal joints. Prenatally, only affectedfingers can be diagnosed. Camptodactyly may beassociated with chromosomal abnormalities, par-ticularly when multiple fingers are affected (trisomy18 and 13) as well as with inherited conditions such

b abnormalities

Limb Abnormalities

Hypoplasia of distal phalanges



Limbs reduction

Limbs reduction (Amelia in one case)

Limb reduction defects (not confirmed)

Preaxial polydactyly (not confirmed)

Limb reduction—vascular disruption

Sacral agenesis/femoral hypoplasia unusual facesyndrome/caudal regression

Chondrodysplasia punctata

Fig.1. Clubfoot. Foot has ‘‘hockey stick’’ configuration.

Fig. 3. Ultrasound scan shows finger clenching in fetuswith trisomy 18.


as Tel-Hashomer camptodactyly syndrome.29 Inmany cases, it is part of a condition associatedwith arthrogryposis multiplex congenital, whichcan be a noninherited as in amyoplasia, or a varietyof inherited conditions such as Larsen syndrome(autosomal recessive or dominant)30 and geleo-physic dysplasia (autosomal recessive).31

MALFORMATION^DISRUPTIONAbnormalities of Size and Number

This category includes abnormalities involvinglength or width. Abnormalities in width, such asmacrodactyly, are known to be associated withconditions such as Proteus syndrome and are dif-ficult to detect using fetal ultrasound scan. Lengthabnormalities are seen in different skeletal dyspla-sia and can be rhizomelic (short femurs or humeri),mesomelic (short forearms or calves), or acromelic(involving the hands or the feet). It is beyond thescope of this review to discuss the different typesof skeletal dysplasia; therefore, this review fo-cuses on isolated short long bones. These abnor-malities can be caused by disruption, as inamniotic band sequence, or malformation, suchas thalidomide teratogenicity.

Fig. 2. Three-dimensional view of finger clenching infetus with trisomy 18.

Phocomelia

In phocomelia, the hands or feet are present, but thearms/forearms and thighs/calves are missing orforeshortened. The hands/feet may be normal orabnormal. The condition can be sporadic as welland associated with single gene disorders such asRobert syndrome, TAR (thrombocytopenia absentradius) syndrome, Grebe syndrome (see below)and teratogens such as thalidomide (Fig 4).32

Clubhand

This condition is divided into radial clubhand andulnar clubhand. Radial and ulnar clubhand are fre-quently associated with radial ray and ulnar ray

Fig. 4. Prenatal ultrasound scan of a fetus at 14 weekswith tetramelia and hydrops. Thin arrow, scapula;thick arrows, absent upper limbs; arrowhead, leftpleural effusion.

T ble 5C nditions associatedwith radial ray defect

C ndition OtherManifestations

A tosomal recessiveR thmund-Thomson

syndromePoikiloderma congenita, alopecia, photosensitivity, dystrophic nails, abnormal teeth, cataracts, short stature, and

hypogonadism. Short and stubby hands and absent thumbs, eye abnormalities including iris dysgenesis, porokeratosisand cataracts, annular pancreas, duodenal stenosis. Thirty-two patients were screened for cataracts.

T R syndrome Bilateral absent radii but existent thumbs, ulnar and humeral hypoplasia, lower limb abnormalities have beenreported but rare. Association with a submicroscopic deletion at 1q21.1 in some cases.

F nconi anemia IUGR; bone marrow failure; abnormalities of the eyes, kidneys, urinary tract, ear, heart, gastrointestinal system, oralcavity, and central nervous system; hearing loss; hypogonadism; developmental delay; and increased riskof malignancy. Genetically heterogenous.

K utel syndrome Microcephaly, occipital meningocele, dysplastic ears, optic atrophy, vertebral abnormalities, limb problemsincluding radiohumeral synostosis, subluxation of one hip, joint contractures, and focal femoral hypoplasia.

R berts and/or SCphocomeliasyndrome

IUGR, tetraphocomelia, or hypomelia caused by mesomelic shortening of the limbs with radial defects and oligodactylyor syndactyly (the upper limbs are more severely affected than lower limbs), cleft lip/palate, large genitalia, congenitalheart defects, cystic kidneys, characteristic face with hypertelorism, a prominent premaxilla, a mid-face capillaryhemangioma, cloudy corneas or cataracts and dysplastic or small ears, micrognathia, beaked nose, ear malformations,and mental retardation

A tosomal DominantD amond-Blackfan

syndromeDevelopmental delay, triphalangeal thumbs, hypoplastic anemia, hypertelorism, retinopathy, cleft palate, short webbed neck,

parietal foramina, scoliosis.

H lt-Oramsyndrome

Cardiac abnormalities including atrial septal defect (ostium secundum type), ventricular septal defect, hypoplastic left heart,and patent ductus arteriosus. Upper limb abnormalities can be asymmetrical and include absent, bifid, or triphalangealthumbs; carpal bone anomalies; phocomelia;and radial-ulnar anomalies

O ihiro syndrome Uni- or bilateral radial ray malformation including thenar hypoplasia, thumb hypoplasia/aplasia, triphalangeal, preaxialpolydactyly, clubhand, deviation of the forearms, Duane anomaly, sensorineural or conductive deafness, andrenal abnormalities

d Lange syndrome Upper limb reduction defects ranging from subtle phalangeal abnormalities to oligodactyly, IUGR, micrognathia,cardiac abnormalities, microcephaly, and ambiguous genitalia

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Chromosomal abnormalitiesTrisomy 13 Profound mental retardation, scalp defects, holoprosencephaly, sloping forehead, anophthalmia/microphthalmia,

absent nose, cyclopia, proboscis, bulbous nose, cleft lip/palate, cardiac abnormalities, omphalocele, ambiguousgenitalia, postaxial polydactyly, neural tube defects

Trisomy 18 IUGR; microcephaly; choroid plexus cysts; facial dysmorphism; cleft lip; micrognathia; ear, nose, and throat abnormalities;cataract, microphthalmia cardiac anomalies; diaphragmatic hernia; omphalocele; clenched hand; clubhand; rockerbottom feet; prominent heels

TeratogensThalidomide

embryopathyLimb abnormalities including phocomelia, amelia, clubfeet, polydactyly, microtia, facial palsy, orofacial cleft,

microphthalmia, cardiac defect, IUGR, urogenital, gastrointestinal, and spinal defects

Varicella embryopathy IUGR, clubfeet, abnormal position of the hands, limitation of limb extension, limb hypoplasia,chorioretinitis, cataracts, microphthalmia, microcephaly

OthersKlippel-Feil

syndromeCervical vertebral fusions, microtia, conductive deafness, restriction of supination of the forearms, thenar hypoplasia,

thumb hypoplasia, radial aplasia, absence of metacarpals, humerus, and ulnar hypoplasia. Unknown inheritance

VACTERLassociation

Vertebral defects, anal atresia/stenosis, cardiac abnormalities, tracheo-esophageal fistula/esophageal atresia,radial and other limb defects, and renal anomalies

Abbreviation: IUGR, intrauterine growth restriction.

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Fig. 6. Clubhand. Humerus is normal. Forearm has sin-gle short bone. Hand and wrist are flexed acutelyand lie along anterior aspect of forearm. Fetus hastrisomy 18.

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abnormalities, respectively.32–34 Radial clubhand isthe more common abnormality detected prenatallyand in most cases is associated with other abnor-malities, many of them inherited (Table 5).

Ulnar clubhand is secondary to ulnar ray defi-ciency. This is a rare anomaly and is usually non-syndromic, although it can occur in associationwith conditions such as Larsen syndrome or TAUsyndrome (thrombocytopenia and absent ulnawith mental retardation and facial dysmorphism).35

The condition may be associated withskeletal dysplasia and arthrogryposis. Prenatal dif-ferentiation between ulnar clubhand and radialclubhand is difficult, and in many cases ulnar club-hand is associated with a radial ray defect also(Figs. 5–7).

Thumb Anomalies

Thumb anomalies deserve special attention inview of the important differential diagnosis associ-ated with these conditions (see Table 5). The pre-natal diagnosis of thumb abnormalities includesthumb hypoplasia, triphalangeal thumb, broadthumb, and hitchhiker thumb. Thumbabnormalities may be isolated but in most casesare associated with other body organ or limbabnormalities. The extremely rare hitchhikerthumb deformation corresponds to the abnormallyabducted position of a more proximally insertedthumb.32,36,37 This constant malposition is sug-gestive of diastrophic dysplasia, a rare skeletaldysplasia with an autosomal recessive mode of in-heritance that is amenable to prenataldiagnosis.32,36,37

Polydactyly

Polydactyly is frequently detected using fetal ultra-sound scan as the presence of extra digit/s in the

Fig. 5. Clubhand. Humerus adjacent to fetal trunk isnormal. Hand and fingers are markedly flexed at wristand lie along forearm.

upper or lower extremities. The extra digits mayvary in their developmental maturity. The extradigit can appear on the radial side (preaxial) oron the ulnar side (postaxial) polydactyly. Meso-ax-ial polydactyly is less frequent than pre-/postaxialpolydactyly. Postaxial polydactyly is morefrequent than preaxial polydactyly, particularlyamong Africans. The incidence of polydactyly isone in 700 pregnancies.38 Postaxial polydactylycan be an isolated finding, usually with an autoso-mal dominant mode of inheritance with incompletepenetrance or part of a syndrome. Several familial

Fig. 7. Bilateral clubhands. Forearms are short. Handsare acutely flexed at wrists and only three digits.Also bilateral cleft lip.

Fig. 8. Forearm amputation. Left imageshows radius and ulna amputated atmid-forearm. Right image shows normalhumerus.


cases of mutations in the GLI3 gene mapping to7p1339 have been as well as other genes reported.

Preaxial polydactyly is a highly variable condi-tion ranging from broad thumb to duplication ofthe thumb and can be isolated (autosomal domi-nant) or part of a syndrome. Mutations of regula-tory genes affecting the SHH pathway40 havebeen reported in some families with isolated pre-axial polydactyly.

Terminal Transverse Limb Defects

Generally, terminal transverse defects are morecommon in the upper limbs than the lower limbs;they may be isolated or part of syndromes andare likely to be associated with other abnormali-ties. The condition is thought to result from a vas-cular injury and has been found in association withcoagulation defects13 as well as conditions caus-ing fetal hypoxemia, such as a-thalassemia homo-zygous state,41 or after chorionic villus sampling.42

In many cases the condition is the result of con-striction band sequence/amniotic band sequence,

Fig. 9. X-ray of arm amputation at mid-forarm.

caused by early rupture of the amnion and forma-tion of fibrous bands that can trap, constrict, anddisrupt fetal parts. The presentation can varyfrom a simple circumferential groove to ring con-striction, amputation of part of a finger resultingin whole-limb amputation, or severe malforma-tions including syndactyly, pterygium, and lethalcraniofacial or thoraco-abdominal destructive pos-sesses. Disruptions caused by amniotic bands arecharacteristically asymmetrical and are amenableto ultrasound detection, but the wide range of ab-normalities makes the diagnosis challenging. Thedifferential diagnosis of this condition includesAdams-Oliver syndrome (aplasia cutis congenita,limb defects)43 with an autosomal dominant modeof inheritance (Figs. 8 and 9).

Ectrodactyly (Split Hand/Split Foot)

Split hand/foot deformity, also known as lobsterclaw hand/foot, results from a deficiency of thecentral digits/toes with a deep V- or U-shapedcentral cleft. The main pathogenic mechanism ismost probably a failure of the median apical

Fig. 10. Ectrodactyly X-ray. Only thumb and little fin-ger have phalanges, and these are abnormal. Middlethree metacarpals are short, and phalanges aremissing.

Fig. 11. Ectrodactyly on ultrasound scan at 20 weeks.Hand has a V-deformity with thumb on one side andtwo fingers with syndactyly on the other. Middlemetacarpals and phalanges are missing.

Fig.12. Ectrodactyly on ultrasound scan. Thumb is vis-ible on one side of the V defect. Malformed fingers onthe other side.

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ectodermal ridge in the developing limb bud.44 Itmay be isolated or associated with other abnor-malities such as in EEC syndrome (ectrodactyly,ectodermal dysplasia, cleft lip/palate) and syndac-tyly, absence, or hypoplasia of the residual phalan-ges; metacarpals/metatarsal can also be seen(Figs. 10–12). The severity of the malformation isvariable, and the inheritance can be autosomal re-cessive, autosomal dominant, or X-linked.45

Syndactyly

Syndactyly is a condition in which two or moredigits are fused together. It is the most commoncongenital malformation of the limbs, with an inci-dence of 1 in 2000 to 3000 live births.46,47 The con-dition is the result of failure of separation of thefingers or toes into individual appendages, whichusually occurs between the sixth and seventhweek postconception.

Syndactyly is defined as simple when it involvessoft tissue only or complex when it involves thebone or nail of the adjacent fingers or toes thatare joined side by side. It can be complete whenthe fusion extends to the tip of the finger or toeor incomplete when the soft-tissue union doesnot extend to the fingertips. Complex syndactylyrefers to fingers joined by bone or cartilaginousunion, usually in a side-to-side fashion at the distalphalanges. The most severe form of syndactyly isclassified as complicated syndactyly which refersto fingers joined by bony fusion other thana side-to-side and can include bony abnormalitiessuch as extra, missing, or duplicated phalangesand abnormally shaped bones such as delta pha-langes. The complex type of syndactyly may beassociated with other finger or toe abnormalitiesincluding polydactyly, oligodactyly, or duplicatedphalanges as well as abnormally shaped bones.The condition can be an isolated finding or associ-ated with other abnormalities, and more than 30syndromes with syndactyly have been reported,

Fig.13. Fetal ultrasound scan and autopsyshow complex, complete syndactyly.


including Poland, Apert, Fraser and Holt-Oram syn-dromes. Simple syndactyly is more common be-tween the third and fourth fingers and the secondand third toes. In 50% of the cases it is bilateral.

Prenatal diagnosis of simple toe syndactyly is al-most impossible, whereas prenatal diagnosis offinger simple syndactyly is possible but very chal-lenging. The diagnosis is easier when the syndac-tyly is complete and complex because it isassociated with bony changes in shape and re-sults in synchronous movements of the affecteddigits. In cases of mitten hand deformity as seenin Apert syndrome, the fingers and toes cannotbe seen individually, which makes the prenataldiagnosis easier (Fig. 13).48

SUMMARY

The detection of fetal limb abnormalities, using ul-trasonography, is of utmost importance for prena-tal diagnosis of fetal anomalies and for providingaccurate genetic counseling. Limb abnormalitiesmay be isolated or associated with other abnor-malities and can be the result of malformation, de-formation, or disruption, as well as part ofa dysplasia such as skeletal dysplasia. When thelimb anomaly is a malformation and associatedwith other abnormalities, it is usually the result ofa chromosomal abnormality or single gene disor-der. The prenatal diagnosis and management oflimb abnormalities is complex and requires a multi-disciplinary approach of radiologists, perinatolo-gists, medical geneticists, neonatologists, andorthopedic surgeons to provide the couple/woman with information regarding the nature ofthe abnormality, differential diagnosis, prognosis,and options related to the pregnancy.

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