Magnetic resonance techniques in the evaluation of the fetal and neonatal brain

Magnetic Resonance Techniques in the Evaluation of the Fetal and Neonatal Brain Barbara A. Bangert Magnetic resonance imaging (MRI) has contributed dramatically to our understanding of the newborn with neurologic problems. Recently developed magnetic resonance techniques, such as fetal MRI and MR spectroscopy, offer additional insight into normal and pathologic processes affecting the fetal and neonatal CNS. This article examines developmental abnormalities as reflected in neuroimaging studies and discusses some of the newer MR modalities and their capabilities.

Copyright 9 2001 by W.B. Saunders Company

' N THE NEARLY 20 years since becoming .clinically available, magnetic resonance imaging (MRI) has significantly advanced understanding of the neonatal brain and its pathologic manifestations. Organizing MRI findings according to a developmental framework enhances that understanding and helps to elucidate processes occurring in the fetal brain, as do some of the newer MR modalities.

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FETAL NEUROIMAGING

Ultrasonography has traditionally been and remains the modality of choice for fetal screening. A review of sonographic evaluation of the central nervous system (CNS) is beyond the scope of this article. However, diagnostic limitations to sonography may arise due to maternal body habitus, oligohydramnios, or prominent uterine fibroids. In addition, subtle brain malformations, particularly those involving the posterior fossa, may be overlooked or misinterpreted on a sonographic examination, a-3 Fast MRI is becoming increasingly popular as an adjunct to screening sonography. Using single-shot fast spin-echo technique to obtain images during maternal breath-holding obviates the need for maternal or fetal sedation. 4 Following acquisition of a scout film to determine fetal position, ultrafast Tz-weighted images are obtained in planes axial, coronal, and sagittal to the fetal brain. There has been no definitive evidence of any harmful effect on the developing fetus .5 The

From the Department of Radiology, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106. Address reprint requests to Barbara A. Bangert, MD, Department of Radiology, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106. Copyright 9 2001 by W.B. Saunders Company 1071-9091/01/0802-0003535.00/0 doi:l O.lO53/spen.2001.24838 74

possibility of injury to the fetal ear has been suggested but not confirmed by follow-up studies. 6 Nonetheless, fetal MRI is not used as a screening tool at this time but is reserved for cases in which pathology is suspected. In addition, scanning is not typically performed before 18 weeks' gestation. Fetal MRI has been proven useful both in confirming and refuting anomalies suspected by sonography. 7-13 Simon et al TM found that fetal MRI changed patient management in 24 of 52 clinical cases and increased the confidence of referring physicians in making management decisions in the remaining 28. In addition, advances in surgical techniques, such as in utero repair of myelomeningoceles, a5'16 have been facilitated in part by the high resolution and anatomic detail provided by fetal MRI. It is proving to be an invaluable tool for in vivo evaluation of the developing fetus. NEONATAL NEUROIMAGING

Ultrasonography comprises the mainstay of neonatal CNS evaluation because of its portability, low cost, and lack of ionizing radiation. As an initial neuroimaging study, sonography provides accurate information regarding the presence of hemorrhage, a mass, or extensive edema, that is, processes requiring immediate intervention. Sonography is not very sensitive to the detection of nonhemorrhagic injuryaT-19; however, nearly half of neonates with hypoxic-ischemic encephalopathy have normal ultrasound examinations. 2~ In addition, it lacks the sensitivity and specificity of MRI in terms of identifying more subtle lesions, 2~ particularly if they are situated over the convexity or in the posterior fossa. Computed tomography (CT) is also of limited value in evaluation of the neonate. Although CT is quite sensitive in demonstrating hemorrhage or bony abnormalities, the high water content of the neonatal brain significantly reduces overall contrast, thereby rendering focal nonhemorrhagic abSeminars in Pediatric Neurology, Vol 8, No 2 (June), 2001 : pp 74-88

MR EVALUATION OF FETAL AND NEONATAL BRAIN

normalities difficult to detect. The problem is particularly pronounced in the premature brain and in cases of white m a t t e r injury. 22"23 Anatomic detail is also limited due to the relatively poor resolution of CT. On the other hand, MR offers excellent contrast and resolution while affording visualization in three orthogonal planes. In addition to superior sensitivity and specificity, MRI provides the option of evaluating the intracranial or cervical vasculature with MR angiography and the dural venous sinuses with MR venography. Newer MR capabilities, such as diffusion-weighted imaging (DWI) and spectroscopy (MRS), enable earlier detection of acute ischemic injury and identification of various brain metabolites, respectively. Standard MRI evaluation of the neonate should include Tl-weighted images in at least two planes, including the sagittal plane, as well as axial T zweighted and proton-density images. The midline sagittal image is particularly useful in the assessment of suspected structural anomalies. In general, Ta-weighted images are necessary for evaluation of myelin maturation during the first 6 to 8 months of life. 23 Tz-weighted images often provide more information regarding sulcal and gyral abnormalities in neonates. DWI is an MRI technique that can detect parenchymal changes caused by severe ischemia within minutes of the event. 24-26 Infarcts are generally not apparent on T2-weighted MR images until 12 hours or more following injury. In addition, infarcts are even less conspicuous in neonates compared with adults due to the higher water content in the neonatal brain. The apparent diffusion coefficient (ADC), a quantitative measure of the diffusion rate of water molecules in brain parenchyma, may be diminished by 50% in ischemic brain tissue relative to normal brain. Areas of decreased diffusion appear bright on diffusion weighted images (Fig 1A). However, because diffusion-weighted images are Te-weighted, foci of hyperintense signal on any Tz-weighted images will appear bright on DWI. This problem is resolved by also generating ADC images, which are essentially maps of ADC values throughout the parenchyma. A focus of acutely decreased diffusion will appear dark on the ADC images (Fig 1B). Although there is an extensive body of research focusing on DWI of the adult brain, relatively little has been published regarding DWI in the neonate.

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Fig 1. Diffusion-weighted axial image (A) of a 2-month-old with congenital heart disease presenting with seizures demonstrates bright foci throughout the right hemisphere (short arrows) and in the left centrum semiovale (long arrow). Corresponding ADC image (B) shows a similar pattern of dark signal in the right hemisphere (short arrows) and left centrum semiovale (long arrow), confirming acute ischemic injury. Normal signal is seen in the right frontal cortex anteriorly (open arrow), suggesting that the bright signal in this region on 1A is artifactual. T2-weighted and FLAIR images were normal.

A number of studies have found that DWI depicts areas of infarction earlier than T2-weighted or fluid-attenuated inversion recovery (FLAIR) images and with greater conspicuity. 25'27-3~ Other

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studies suggest that the sensitivity of DWI in neonates may depend on the pattern o f injury. 30-32 For example, DW1 may more consistently detect focal cortical infarcts than diffuse hypoxic-ischemic injury. An early period of "false negativity" has been noted in some neonates, a phenomenon not commonly described in adult patients. A number of possible explanations have been proposed for the differences, including relative absence of myelination and its effect on diffusion rates, selective vulnerability of certain parts of the brain, regional variation in progression to cell death, and temporal variation in the compartmentalization of intracellular versus extracellular brain water. 3~ Neonatal animal models suggest a biphasic pattern of diffusion abnormalities 33 that may extend to human neonates, that is, there may be a transient period of normalization following the hyperacute phase during which DWI is falsely negative. If that is the case, timing of the examination relative to the ischemic event becomes of paramount importance. Clearly, DWI is potentially useful not only in terms of identifying an acute infarct but also in its capacity to establish time of injury. However, further research examining asphyxiated neonates will be necessary before the temporal relationship and other aspects of the process are entirely understood. MR spectroscopy (MRS) is a modality that facilitates noninvasive, in vivo measurement of brain metabolites. A complete discussion of this technique is beyond the scope of this article, but a number of excellent reviews are available. 26"34"35 Acquisition of information in MRS is similar to that of MRI except that the MR signal is used to generate a spectrum in MRS rather than the images that result from MRI. MR scout images are obtained in three planes and either a single voxel in single-voxel spectroscopy (SVS) or multiple contiguous voxels in chemical-shift imaging (CSI) are selected within the field of interest (Fig 2A). Data are then obtained using either a short TE (10 or 20 ms) or a long TE (135 or 270 ms) depending on the specific metabolites relevant to the investigation, and a spectrum is generated (Fig 2B). Peaks in the spectrum are identified by their characteristic location and configuration. The area beneath each peak is approximately proportional to the number of nuclear spins creating the signal. Spectra obtained using a long TE include N-acetylaspartate (NAA), a neuronal marker; creatine (Cr), a bioenergetic

BARBARA A. BANGERT

Fig 2. (A) A single voxel positioned over left basal ganglia region in child with suspected Leigh's disease. Spectrum (B) includes abnormal lactate doublet (arrow) supportive of diagnosis.

metabolite; choline (Cho), an indicator of membrane disruption; and lactate (Lac), a metabolite that accumulates following tissue damage. Short TE spectra include the additional metabolites glutamine/glutamate (Glx), myo-inositol (mI), and lipids, all of which prove useful in investigation of metabolic disorders and neoplasms.

MR EVALUATION OF FETAL AND NEONATAL BRAIN

Clinical pediatric applications of MRS include evaluation of inborn errors of metabolism, 36-44 infection, 45,46 neoplasm, 47-5~ trauma, 51 epilepsy, 52 and ischemic injuryY However, in the neonate, much of the research has focused on prognostic implications of spectra obtained following perinatal hypoxia. Elevated lactate levels and depressed NAA levels have been found to be predictive of a poor clinical outcome. 54-58 As the technique becomes more widely used and post-processing algorithms necessary to generate the spectra are simplified, MRS should contribute significantly to the overall understanding of the neonatal brain. DEVELOPMENTAL STAGES AND THEIR CHARACTERISTIC DISORDERS

Standard MR images of the neonatal brain already provide a wealth of information pertaining to fetal CNS development and the effects of injury or insult during different developmental stages. Van der Knaap and Valk 59 have devised a classification system for CNS congenital anomalies that is based on time of onset of morphologic derangement. This system does not address causes, which may be quite varied, even when they result in a similar malformation. For example, polymicrogyria may be attributed to infectious, 6~ ischemic, 61 or genetically determined events, although the time of development and the morphologic end result are the same. In addition, anomalies formed during different developmental periods may occur in the same patient, either because successful completion of one phase is necessary for a subsequent developmental process or because a single aberrant gene may be responsible for the formation of different structures at different times. The van der Knaap system is nonetheless extremely useful in terms of organizing congenital abnormalities according to a developmental framework.

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flect defective neural tube closure at either the rostral or caudal end, that is, encephalocele, chiari II malformation, or myelomeningocele. 59"62 Encephalocetes consist of bony defects in the skull through which dura and brain parenchyma protrude. Although somewhat simplified for the purpose of this classification system, encephaloceles actually comprise a diverse group of anomalies that vary in their location and, possibly, in their embryogenesis. 62'63 Encephaloceles are typically identified in terms of the location of their bony defects. The four most common locations are fronto-ethmoidal, 64 also referred to as sincipital and most common in southeast Asia, occipital, 65 which account for approximately 80% of the encephaloceles seen in western Europe and North America, parietal 66 and sphenoidal. 67 The sphenoidal variant is unusual in that it is not immediately obvious clinically and may present later in childhood as a nasopharyngeal mass. MRI is the preferred modality for evaluation of encephaloceles, although high-resolution CT scans are helpful in delineating the extent of the bony abnormality. MR images demonstrate brain tissue and CSF extending through the defect (Fig 3) and also allow for assessment of occasional dural venous sinus involvement and identification of other midline anomalies often associated with encephaloceles. The Chiari II malformation, almost always associated with spinal myelomeningocele, is a complex hindbrain deformity consisting of caudal displacement of the medulla, pons, and portions of the

DORSAL INDUCTION

The CNS originates as the notochordal process that induces formation of a neural plate, a thickened strip of embryonic ectoderm. The neural plate folds over on itself and fuses in a zipper-like fashion to form the neural tube, which will ultimately give rise to the brain and spinal cord. These initial inductive events are referred to as dorsal induction and occur during the third and fourth weeks of gestation. An insult during the dorsal inductive period may result in anomalies that re-

Fig 3. Fronto-ethmoidal encephalocele. Tl-weighted sagittal image shows parenchyma and CSF extending through bony defect (curved arrow).

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Fig 4. Chiari II malformation. Tl-weighted sagittal image demonstrates marked tonsillar ectopia (short arrow), cervicomedullary kinking (long arrow), tectal beaking (curved arrow), and low tentorium causing small posterior fossa (black arrow). The fourth ventricle is compressed (black arrowhead).

cerebellum through an enlarged foramen magnum into the spinal canal (Fig 4). 68-70 The spectrum of associated structural stigmata include callosal dysgenesis, hydrocephalus, tectal "beaking," interdigitation of the falx, a prominent massa intermedia, cerebellar dysplasia, and luckenschfidel, a lobular irregularity of the inner and outer tables of the skull. 62 Ta-weighted midline sagittal images best demonstrate the primary deformity, which presents as a small posterior fossa, flattening of the fourth ventricle, and displacement of cerebellar tonsils and brainstem into the spinal canal. A characteristic cervicomedullary kink, caused by the medulla stretching caudally further than the cervical cord allows, is seen in most cases. VENTRAL INDUCTION

Following completion of dorsal induction, three vesicles (the prosencephalon or forebrain, the mesencephalon or midbrain, and the rhombencephalon or hindbrain) form at the rostral end of the neural tube. During the fifth week of fetal life, the prosencephalon divides by axial cleavage into the diencephalon and the telencephalon. The diencephalon ultimately becomes the thalami, hypothalami, and globi pallidi. The telencephalon, by virtue of sag-

ittal cleavage, ultimately develops into the cerebral hemispheres, putamina, and caudate nuclei. As the hemispheres increase in size, they coil over on themselves to form the temporal lobes. The corpus callosum begins to develop and to unite the hemispheres at 8 weeks of gestation. During approximately the sixth week of fetal life, the rhombencephalon divides into the myelencephalon, which will develop into the pons and medulla, and the metencephalon, which will ultimately form the cerebellar hemispheres and vermis. These events comprise the stage of ventral induction, which occurs between the fifth and tenth week of gestation. Congenital anomalies, which have their time of onset during ventral induction, include holoprosencephaly, Dandy-Walker syndrome, and callosal dysgenesis/agenesis. 59'62 Holoprosencephaly is characterized by failure of the prosencephalon to cleave both laterally and transversely, resulting in varying degrees of hemispheric and ventricular fusion. 71"72 Depending on the extent of cerebral cleavage, holoprosencephaly may be subdivided into three subtypes: alobar, semilobar, and lobar. In alobar holoprosencephaly, the most severe form, there is total lack of cleavage. MR findings include a single cerebrum lacking an interhemispheric fissure or flax, a horseshoe-shaped monoventricle, which is usually contiguous with a dorsal "cyst" or CSF collection, and absence of the corpus callosum (Fig 5). In semilobar holoprosencephaly, there are rudimentary temporal or occipital lobes as well as mild differentiation of the ventricular system, although there may still be a dorsal cyst. The mildest form, lobar holoprosencephaly, often has a nearly normal appearance on MR images. Because the anterior portions of the brain are the most severely affected in holoprosencephaly, lobar holoprosencephaly may merely present with hypoplastic frontal horns or underdevelopment of the anterior aspect of the falx. The Dandy-Walker complex is actually a spectrum of hindbrain anomalies ranging from the Dandy-Walker malformation, the most severe derangement, to Dandy-Walker variant to mega cisterna magna, the mildest form of the complex. 73'74 During ventral induction, the vermis forms in a rostral-caudal fashion. The severity of the malformation is therefore partly reflected by the degree of caudal vermian hypoplasia. In the true DandyWalker malformation, there is generally severe

MR EVALUATION OF FETAL AND NEONATAL BRAIN

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anterior to posterior fashion. 75 Specifically, formation of the genu anteriorly is followed by development of the body and, finally, the splenium. The only exception to the pattern is the rostrum, a small slip of commissural fibers just inferior to the genu, which is generally thought to develop after the spenium is completed. The pattern of callosal genesis is important because timing of an insult to the developing brain may be estimated by the extent of the corpus callosum that is present, that is, an event occurring at 8 weeks gestational age may result in total agenesis of the corpus callosum while injury taking place midway through development will result in formation of the genu and body but not the splenium o r r o s t r u m . 76'77 On MR examination, total absence of the corpus callosum presents as lateral ventricles with a parallel orientation on axial images (Fig 6A), a ventricular "staghorn" appearance on coronal slices (Fig 6B) and absence of both callosal fibers and a cingulate gyrus on midline sagittal images. In milder callosal dysgenesis, there may only be colpocephaly, or focal dilatation of the atria and occipital horns of the lateral ventricles, on a x i a l images. 62'76'77 Fig 5. Alobar holoprosencephaly. Tl-weighted axial image shows fused cerebral hemispheres and a monoventricle contiguous with a dorsal "cyst."

NEURONAL PROLIFERATION, HISTOGENESIS, MIGRATION, AND ORGANIZATION

hypoplasia of the inferior vermis, which is rotated superiorly, creating continuity between the fourth ventricle and a retrocerebellar CSF collection. The tentorium is elevated, resulting in an enlarged posterior fossa. Hydrocephalus is present in approximately 75% of cases, although it often does not develop until 3 months of age or later. The degree of vermian hypoplasia is less in the Dandy-Walker variant and the tentorium is not elevated, although there is still a posterior CSF collection contiguous with the fourth ventricle. On the other hand, a mega cisterna magna, consists primarily of a retrovermian CSF collection, without any vermian hypoplasia. Other midline anomalies such as encephalocele, holoprosencephaly, and callosal dysgenesis may coexist with the Dandy-Walker spectrum. These are more likely to occur at the severe end of the spectrum; however, they are extremely rare in the case of mega cisterna magna, which is often an incidental finding. Callosal development occurs between 8 and 20 weeks of fetal life and proceeds primarily in an

Once dorsal and ventral induction have resulted in establishment of the overall external structure of the brain, complex processes that will culminate in formation of the cortex and hemispheric white matter are initiated. Van der Knaap and Valk 59 divide these processes into two categories: (1) neuronal proliferation, differentiation, and histogenesis, and (2) migration. Both periods are described as occurring somewhat simultaneously, between 2 and 5 months' gestation. Barkovich et a178 propose a classification scheme for malformations of cortical development that combines van der Knaap's two categories and is based on three embryologic stages of cortical formation: (1) cellular proliferation within the germinal zone, which occurs between 7 and 16 weeks' gestational age, (2) migration of neuroblast cells from the germinal matrix to the developing cortex, occurring between 12 and 24 weeks' gestational age, and (3) vertical and horizontal organization of cells within the cortex with establishment of axonal and dendritic ramifications, which begins at approximately 22 weeks' gestational age and continues beyond the birth process.

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The first category of the Barkovich classification model includes anomalies caused either by diminished or abnormal cell proliferation within the germinal zones, which are situated at the ventricular surfaces and in the subventricular region immediately superficial to the ventricle. Most neurons as well as glial cells originate from the germinal zones. Entities included in this category include radial microbrain, microcephalia vera, tuberous sclerosis, focal cortical dysplasia of Taylor, hemimegalencephaly, and focal transmantle dysplasia.61, 78

Fig 6. Agenesis of the corpus calloaum. Tl-weighted axial image (A) illustrates parallel orientation of the lateral ventricles and colpocephaly. Coronal image (B) demonstrates characteristic "staghorn" configuration of lateral and third ventricles (arrows).

A paucity of neuroblasts within the germinal zones may result in radial microbrain or microcephalia vera. Radial microbrain, sometimes referred to as lissencephaly Type IV, consists of a brain that is dramatically reduced in size but possessed of a normal gyral configuration and cortical thickness. The overall number of neurons may be reduced to as much as 30% of normal. Patients present with severe microcephaly and multiple non-CNS anomalies. Microcephalia vera, also called lissencephaly Type III in the literature, encompasses several genetic and sporadic abnormalities that occur secondary to severe depletion of neurons in cortical layers two and three. Histopathologic examinations of such brains demonstrate a severely comprised germinal zone and no evidence of any migratory disorder. On magnetic resonance examination, thin cortices and underdeveloped sulci are seen. Patients with microcephalia vera tend to present with moderate developmental delay but no focal neurologic findings. 6a Tuberous sclerosis is a complex, multisystem disorder of cellular proliferation that results in hamartomatous growths and, in some cases, neoplasms. 79 The most commonly encountered cerebral lesion in tuberous sclerosis is the cortical tuber, a hamartoma composed of bizarre giant cells, heterotopic neurons, and glial tissue, which is evident in approximately 95% of patients. In neonates, tubers appear hyperintense on Tl-weighted images and slightly hypointense on T2-weighted images. There may be associated widening of the involved gyrus. Subependymal nodules or hamartomas are visualized nearly as frequently as cortical tubers in tuberous sclerosis. They are typically bilateral and situated along the ventricular surface of the candate nucleus, although they may be present anywhere along the ventricular ependymal

MR EVALUATION OF FETAL AND NEONATAL BRAIN

lining. The nodules are isointense or hypointense relative to white matter on T~-weighted images and hypointense on T2-weighted images in older infants and children, but a relative signal reversal is present in the neonate. Giant cell tumors arise from subependymal nodules in 5% to 10% of tuberous sclerosis patients. 79'8~ Curvilinear streaks of disorganized white matter, hypointense on Tz-weighted images in neonates and hyperintense on Tz-weighted images in older infants and children, may also be visualized extending across the white matter, usually in proportion to the number of cortical tubers. Nonetheless, tuberous sclerosis is thought to be a disorder of proliferation, rather than a true migratory disorder. Stefansson et a181 suggest that defective stem cells in all germ cell layers underlie the CNS manifestations of tuberous sclerosis. The stem cells apparently differentiate into astrocytes and neurons, which lack the ability to integrate themselves further into the brain structure. Some remain in the germinal zone, resulting in subependymal hamartomas, whereas others migrate along glial fibers in the white matter to the cortex, where they form disorganized cellular clusters (tubers). Van der Knaap includes other phakomatoses, such as Von Recklinghausen disease, Sturge-Weber disease, Von Hippel-Lindau disease, and ataxia-telangiectasia in the category of abnormalities of neuronal proliferation, differentiation, and histiogenesis. 59 Focal cortical dysplasia of Taylor (FCDT), balloon cell subtype, shares a similar histology and developmental etiology with tuberous sclerosis. It has, in fact, been designated a forme fruste tuberous sclerosis by some authors. 82 Although both entities are associated with seizures, balloon cell FCDT is a solitary cerebral lesion that has no associated cutaneous manifestations. On MR images, balloon cell FCDT is associated with focal gray matter thickening contiguous with a linear, hyperintense signal extending through the subcortical white matter on Tz-weighted images. The lesion tapers in dimension as it nears the lateral ventricle. The characteristic balloon cells of this anomaly have components of both neurons and astrocytes. The absence of complete differentiation in these cells is indicative of an abnormality that occurs in pluripotent brain cells, such as in the first trimester. 78 Hemimegalencephaly, also an anomaly in the

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category of abnormal neuronal/glial proliferation, consists of unilateral cerebral enlargement with associated hamartomatous parenchymal overgrowthY Patients present with developmental delay and intractable seizure. There is some association with linear sebaceous nevus syndrome and unilateral hypomelanosis of Ito. 62 The MR appearance of hemimegalencephaly includes an enlarged hemisphere with a dysplastic cortex and variably abnormal signal in the white matter (Fig 7). The involved lateral ventricle tends to be enlarged in proportion to the degree of hemispheric hypertrophy. Hemimegalencephaly is not entirely understood, and there is some controversy as to the timing of the insult. However, because of its bizarre, hamartoma-like features, it is often thought to occur secondary to proliferation of abnormal cells rather than during or after migration. 78 Similarly, focal transmantle dysplasia, which is characterized by abnormal cortical lamination, white matter astrogliosis, and balloon cells, is clas-

Fig 7. Hemimegalencephaly. Tl-weighted axial image demonstrates enlarged left hemisphere with prominent lateral ventricle and diffusely abnormal gyral pattern,

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sifted as an anomaly originating in the maldifferentiation of germinal zone stem cells. Patients with focal transmantle dysplasia tend to present with seizures, most often simple or complex partial in nature, as well as occasional hemiplegia. MRI demonstrates a focal dysplasia extending radially from the ventricular surface to the cerebral cortex with an indistinct cortical gray matter--white matter junction and varying degrees of abnormal white matter signal. 84 Following neuroblast proliferation in the germinal zone, neuroblast nuclei migrate toward the pial surface along specialized radial glial fibers during the neuronal migration phase of development, which occurs between 12 and 24 weeks' gestation. The migration occurs in six successive waves, normally resulting in a six-layer cortex. 85 Upon reaching their cortical destination, the nuclei divide and grow axonal processes back toward the ventricular surface, resulting in progressive widening and organization of the white matter. Generalized abnormalities occurring within this time frame include the lissencephalies and diffuse heterotopia. Classical (Type I) lissencephaly, also called agyria-pachygyria, refers to absent or markedly undeveloped gyri and sulci. Histologically, the cortex, although thickened in appearance, consists of only four layers; migration is postulated to have been arrested sometime between 12 and 16 gestational weeks in the lissencephalic brain. 61 Patients are generally hypotonic at birth with subsequent development of spasticity and seizures. However, a spectrum of severity is seen with the worst clinical presentations occurring in patients with Miller-Dieker Syndrome and relatively milder manifestations in cases of isolated lissencephaly. MR images of the lissencephalic brain demonstrate an "hourglass-shaped" brain with a thick cortex having few if any sulci and underdeveloped white matter (Fig 8). 61'62 Type II lissencephaly is characterized by a severely disorganized, thickened cortex lacking a normal layered pattern. The cortex is sometimes described as having a "cobblestone" appearance, although it is thinner than in Type I lissencephaly. There is considerable clinical overlap between Type II lissencephaly, Walker-Warburg syndrome, and Fukuyama's congenital muscular dystrophy. The imaging appearance of Type II lissencephaly includes a thickened, disorganized cortex with

BARBARA A. BANGERT

Fig 8. Type I lissencephaly. Tl-weighted axial image shows "hourglass" hemispheric configuration, thickened cortex with absence of sulci, and a paucity of white matter.

shallow sulci and hypomyelinated white matter. 61,62

Gray matter heterotopia are foci of normal neurons situated in abnormal locations secondary to an arrest in the migration process. Heterotopia may be diffuse or focal. Subependymal and band heteropia are examples of neuronal migration anomalies that may be diffuse. 86-s9 Subependymal heterotopia are small, ovoid masses of gray matter located along the lateral ventricular walls (Fig 9). 85-s7 Patients with subependymal heterotopia often present with a relatively mild clinical course with normal development and seizure onset after the first decade of life. The imaging hallmark of all heterotopia, including the subependymal form, is isointensity with gray matter on all sequences, that is, on both T 1weighted and T2-weighted images. This becomes particularly important when differentiating subependymal heterotopia from the subependymal nodules of tuberous sclerosis, which are isointense to hypointense compared with white matter on both sequences. It is also important to note that heterotopia do not enhance following contrast or

MR EVALUATION OF FETAL AND NEONATAL BRAIN

Fig 9. Subependymal heterotopia. Tl-weighted sagittal image shows multiple gray-matter nodules lining the lateral ventricle (arrows).

gadolinium administration, as do many of the nodules of tuberous sclerosis as well as metastatic foci in neoplastic CSF dissemination. Band heterotopia, also referred to as "double cortex" heterotopia, consist of large circumferential layers of heterotopic neurons that have failed to reach the cortex during the course of their radial migration, ss's9 The resulting gray matter band is uniform, diffuse, and bilateral. Because the neurons have aberrant axonal connections with the rest of the brain, patients with this anomaly typically present with moderate to severe developmental delay and intractable seizures. On imaging studies, the heterotopia appear as circumferential bands of gray matter separated from the cortex by a thin zone of white matter (Fig 10). Neuronal migration anomalies may also be focal, but the abnormalities then typically represent localized collections of the above-described malformations. For example, focal areas of agyria/ pachygyria may occur, and in some cases they are referred to as partial lissencephaly. However, whether focal or diffuse, the migratory defect is still postulated to have occurred between 12 and 16 gestational weeks. Similarly, a subependymal het-

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erotopia may exist as a single nodule or as scattered few heterotopia situated unilaterally or bilaterally along the ventricular surface. Finally, an additional focal anomaly in the category of migrational abnormalities is the subcortical heterotopia, which exists as an irregular, lobulated mass of gray matter situated in the subcortical white matter. 9~ These heterotopia tend to be bulky, often extending from the frontal lobe to the parietooccipital region. The overlying cortex appears thin with shallow sulci on imaging studies, and there are often associated dysplastic basal ganglia. Patients present with developmental delay, mild hemiplegia or hemihypesthesia, and partial epilepsy. By 24 weeks of fetal development, a six-layered cortex has formed. Cortical organization, which is in turn dependent on normal migration, begins at approximately 22 weeks' gestational age and continues throughout the first 2 years of life. Abnormalities occurring within this period include focal or diffuse polymicrogyria and schizencephaly.

Fig 10. Band heterotopia. "Double cortex sign" consisting of thick bands of gray matter on Tl-weighted axial image.

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Fig 11. Diffuse polymicrogyria. Small, disorganized gyri throughout both hemispheres on Tl-weighted axial images.

Polymicrogyria results when neurons reach the cortex but distribute in an abnormal fashion, creating multiple small gyri with a deranged sixlayered cortex. Polymicrogyria may be diffuse (Fig 11), 91 symmetrical and bilateral as in bilateral opercular syndrome, 92-95 or focal and unilateral. 96 It may occur anywhere but is most commonly seen in the perisylvian region. The clinical presentation is qttite variable, depending on the location and extent of involvement, although seizures are present in 70% to 80%. On imaging studies, polymicrogyria appears as cortical thickening with multiple small gyri. In some cases, the gyri are so small that the appearance is one of broad, flat gyri with shallow sulci, which are similar to pachygyria. In general, however, the polymicrogyric cortex, which usually measures 5 to 7 mm in thickness, is narrower than the pachygyric cortex, which averages a cortical thickness of greater than 8 ram. 6a Although polymicrogyria is isointense to cortex on all MRI sequences, there is abnormal hyperintense bright signal in the underlying white matter on Tz-weighted images in 20% of patients. Prominent vessel flow voids are often seen in loci of polymicrogyria. These represent anomalous venous drainage and should not be mistaken for vascular malformations. 97 Angiography should not be undertaken in such cases.

BARBARA A. BANGERT

Barkovich et a178 also classify schizencephaly as a malformation due to abnormal cortical organization because there is at least some evidence that it may represent an extreme form of polymicorgyria. However, Van der Knaap and Valk 59 place schizencephaly earlier in the migrational sequence than polymicrogyria, proposing a time of onset of 2 months' gestational age for schizencephaly and 5 months for polymicrogyria. Schizencephaly consists of gray-matter lined clefts that extend through the full thickness of the hemisphere from the cortex to the ependymal lining of the ventricles. 98 The gray matter lining the clefts is often polymicrogyric. Schizencephaly is divided into "open-lip" and "closed-lip" subtypes, depending on whether the walls of the clefts are fused or not. The clinical course, which often includes seizures, hemiparesis, or motor delay, tends to be milder in cases of "closed-lip" or fused schizencephaly. 99 On MR images, a cleft lined with thickened, disorganized gray matter can be seen extending from cortex to ventricle (Fig 12). True schizencephaly, as opposed to a focus of polymicrogria with partial-thickness cleft, typi-

Fig 12. Open-lip schizencephaly. Full-thickness open cleft lined by polymicrogyric gray matter on T2-weighted axial image.

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cally has a tethering effect on the ventricle, resulting in a small dimple where the cleft comes in contact with the ventricle. Schizencephaly may be bilateral, and in cases of unilateral schizencephaly, there is often a contralateral focus of cortical dysplasia. 62 Absence of the septum pellucidum is nearly always noted. SECONDARILY ACQUIRED INJURY Finally, van der Knaap defines a category encompassing secondarily acquired injury of normally formed structures including abnormalities related to ischemic damage, such as porencephaly, hydranencephaly, and multicystic encephalomalacia. 59 Because these are destructive disorders, they are difficult to date precisely. However, the developing brain's response to injury provides some basis for determining time of onset. The brain cannot mount an astrocytic-gliotic reaction to damage until the late second or early third trimester. 95 Porencephaly, a smooth-walled cyst often contiguous with the lateral ventricle and usually repre-

sentative of prior ischemic injury, is therefore presumed to have occurred before second trimester's end. 1~176 Hydranencephaly, 1~ a condition in which most of the cerebral hemispheres have been replaced by fluid-filled sacs, is also assumed to have evolved before the third trimester. However, multicystic encephalomalacia is characterized by glial septations and reactive astrocytic proliferation, rendering it somewhat shaggy and heterogeneous in appearance. The presence of an astrocytic response in multicystic encephalomalacia is indicative of a third trimester process. 1~176 CONCLUSION

MRI provides the clinician with information regarding existing malformations as well as keys to understanding the developmental derangements underlying the abnormalities. Newer adjunct techniques, such as DWI, MRS, and fetal MRI, may be expected to contribute more to the existing body of knowledge in the future.

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