Approach to Congenital Malformations
Main Text
Preamble
A basic knowledge of normal brain development and maturation provides the essential foundation for understanding congenital malformations, the subject of the final part of this book.
Here, we briefly consider normal development of the cerebral hemispheres and cerebellum. We first focus on the basics of neurulation and neural tube closure, then turn our attention to how the neural tube flexes, bends, and evolves into the forebrain, midbrain, and hindbrain. Developmental errors and the resulting malformations that may occur at each stage are briefly summarized.
Cerebral hemisphere growth and elaboration into lobes, development of sulci and gyri, patterns of gray matter migration, and layering of the neocortex are all succinctly delineated.
Cerebral Hemisphere Formation
Preamble
The major embryologic events in brain development begin with neurulation, neuronal proliferation, and neuronal migration. The processes of operculization, gyral and sulcal development, and the earliest steps in myelination all take place later, between gestational week 11 and birth.
Neurulation
Neural Tube and Brain Vesicles
The neural plate develops at the cranial end of the embryo as a thickening of ectoderm on either side of the midline. The neural plate then indents and thickens laterally, forming the neural folds. The neural folds bend upward, meet in the midline, and then fuse to form the neural tube. The primitive notochord lies ventral to the neural tube. Neural crest cells are extruded and migrate laterally. The neural tube forms the brain and spinal cord, whereas the neural crest gives rise to peripheral nerves, roots, and ganglia of the autonomic nervous system (40-1).
The neural tube closes, beginning in the middle and proceeding bidirectionally in a zipper-like fashion along the length of the embryo (40-2).
As the neural tube closes, the neuroectoderm (which will form the CNS) separates from the cutaneous ectoderm in a process known as disjunction. Upon completion of disjunction, the cutaneous ectoderm fuses in the midline, dorsal to the closed neural tube. The brain grows rapidly and begins to bend, forming several flexures. The embryonic brain eventually has five definitive vesicles (40-3).
Neurulation Errors
Errors in neurulation result in a spectrum of congenital anomalies. The most severe is anencephaly (essentially complete absence of the cerebral hemispheres). Various types of cephaloceles also result from abnormalities of neurulation.
Incomplete closure of the posterior neuropore results in spina bifida. If the neuroectoderm fails to separate completely from the cutaneous ectoderm, myelomeningocele results.
Neuronal Proliferation
Embryonic Stem Cells
Pluri potent embryonic stem cells are derived from the inner cell mass of the 4- to 5-day blastocyst. These cells are able to proliferate and differentiate into all three germ layers (ectoderm, mesoderm, endoderm). MicroRNAs seem to play an important role as genetic regulators of stem cell development, differentiation, growth, and neurogenesis.
Histogenesis of Neurons and Glia
As the cerebral vesicles develop and expand, layers of stem cells arise around the primitive ventricular ependyma, forming the germinal matrix. These neural stem cells (NSCs) are multi potent cells that generate the main CNS phenotypes, i.e., neurons, astrocytes, and oligodendrocytes. NSCs are found primarily in the germinal zones.
Pluri potent NSCs in the germinal matrix give rise to “primitive” or “young”neurons that migrate outward to form the cortical mantle zone (precursor of the definitive cortex). Axons from the migrating neurons form an intermediate zone between the germinal matrix and cortical mantle that will eventually become the cerebral white matter.
Some NSCs become specialized radial glial cells (RGCs) that will eventually span the entire hemisphere from the ventricular ependyma to the pia. RGCs can give rise to both neurons and glia. Elongated cell bodies of the RGCs serve as a “rope ladder” that guides migrating neurons from the germinal matrix to the cortex.
Errors in Histogenesis
Errors in histogenesis and differentiation result in a number of embryonal neoplasms, including medulloblastoma and primitive neuroectodermal tumors. Problems with NSC proliferation and differentiation also contribute to malformations of cortical development (MCDs).
Neuronal Migration
Understanding how neurons are formed, migrate, organize, and then connect is essential to recognizing and understanding MCDs.
Genesis of Cortical Neurons
Once the “young” neurons have been generated in the germinal matrix, they must leave their “home” to reach their final destination (the cortex). The definitive cerebral cortex develops through a highly ordered process of neuronal proliferation, migration, and differentiation.
Neuronal Migration
Migration of newly proliferated neurons occurs along scaffolding provided by the RGCs. Neurons travel from the germinal zone to the cortical mantle in a generally “inside-out” sequence. Cells initially form the deepest layer of the cortex with each successive migration ascending farther outward and progressively forming more superficial layers. Each migrating group passes through layers already laid down by the earlier arriving cells.
Peak neuronal migration occurs between 11-15 fetal weeks, although migration continues up to 35 weeks. From 16-20 weeks, there is a three-layer pattern of the fetal brain on T2WI with germinal matrix, fetal white matter, and cortex from deep to superficial. From 20-30 weeks, there is a five-layer pattern of the fetal brain on T2WI with germinal matrix, subventricular-periventricular fiber-rich zone, subventricular cellular/intermediate zone, subplate, and cortical plate from deep to superficial.
Errors in Neuronal Migration and Cortical Organization
The primary result of errors at these stages are MCDs. Problems with NSC proliferation or differentiation, migration, and cortical organization can all result in developmental anomalies of the neocortex. Examples include microcephaly, megalencephaly, gray matter heterotopias, cortical dysplasias, and lissencephaly.
Operculization, Sulcation, and Gyration
Lobulation and Operculization
The hemispheres are initially almost featureless; the cortex is thin and smooth. As the hemispheres elongate and rotate, they assume a “C” shape with the caudal ends turning ventrally to form the temporal lobes.
Sulcation and Gyration
Sulcation and gyration occur relatively late in embryonic development. Shallow triangular surface indentations along the sides of the hemisphere—the beginnings of the lateral cerebral (sylvian) fissures—first become evident at ~ 16 weeks (40-4).
After the sylvian fissures form (40-6), multiple secondary and tertiary gyri begin to develop at 22- to 23-weeks gestation (40-5). The central sulcus is usually visible by 26 weeks. All major sulci are formed by ~ 34 weeks.
Anomalies in Sulcation and Gyration
Developmental errors in operculization, sulcation, and gyration are relatively common among congenital MCDs. Examples include microcephaly with simplified gyral pattern and polymicrogyria, which are representative anomalies that result from abnormal sulcation and gyration.
Myelination
Myelination occurs in an orderly, predictable manner and can be detected as early as 18 fetal weeks.
Imaging Approach to Brain Malformations
Technical Considerations
CT
Clinicians sometimes order NECT scans as an initial screening examination in a patient with seizures or suspected brain malformation. Although parenchymal calcifications, ventricular size/configuration, and major abnormalities can be identified, subtle abnormalities, such as cortical dysplasia, are difficult to detect and easy to overlook.
Bone CT is helpful in depicting midline facial defects, synostoses, and anomalies of endochondral bone.
MR
MR is the examination of choice. The two most important factors are gray matter-white matter differentiation and high spatial resolution. Many pediatric neuroradiologists recommend volumetric T1 sequences (e.g., MP-RAGE), and sagittal and coronal heavily T2-weighted sequences with very long TR/TEs. 3D imaging acquisitions allow isotropic orthogonal reformations. FLAIR can be very helpful in identifying focal cortical dysplasia (FCD), but only once the brain is fully myelinated (≥ 2 years).
A T2* sequence (GRE, SWI) can be a helpful addition if abnormal mineralization or vascular anomaly is suspected. DTI tractography is valuable when commissural anomalies are identified on initial sequences.
Contrast-enhanced T1WI generally provides little additional useful information in most congenital malformations, except in the case of associated vascular anomalies. DWI and MRS are useful in evaluating mass lesions and inborn errors of metabolism.
Image Analysis
The following approach to analyzing imaging studies is modified and adapted from A. James Barkovich’s guidelines on imaging evaluation of the pediatric brain.
Sagittal Images
Begin with the midline section and examine the craniofacial proportion. At birth, the ratio of calvarium:face should be 5:1 or 6:1. At two years, it should be 2.5:1. In adults and children over the age of 10 years, it should be ~ 1.5:1. Assess myelination of midline structures, such as the corpus callosum and brainstem.
The most common of all brain malformations are anomalies of the cerebral commissures (especially the corpus callosum), which can be readily identified on sagittal T1 scans (40-7A). Commissural anomalies are also the most common malformation associated with other anomalies and syndromes, so, if you see one, keep looking! Look for abnormalities of the pituitary gland and hypothalamus. Evaluate the size and shape of the third ventricle, especially its anterior recesses.
Look for other lesions, such as lipomas and cysts. These are often midline or paramidline and can be readily identified. The midline sagittal scan also permits a very nice evaluation of the posterior fossa structures. Does the fourth ventricle appear normal? Can you find its dorsally pointing fastigium? Evaluate the position of the tonsils and the craniovertebral junction for anomalies.
If the lateral and third ventricles are large and the fourth ventricle appears normal, look for a funnel-shaped aqueduct indicating aqueductal stenosis. If you see aqueductal stenosis in such instances, look for rhombencephalosynapsis, which is seen in ~ 50% of aqueductal stenosis cases.
Sagittal images are also especially useful in evaluating the cerebral cortex. Is the cortex too thick? Too thin? Irregular? “Lumpy-bumpy”? MCDs, such as pachygyria and polymicrogyria associated with brain clefting (“schizencephaly”), are often most easily identified on sagittal images. Finally, note the position and size of the vein of Galen, straight sinus, and torcular Herophili.
Coronal Images
MCDs are often bilateral. Polymicrogyria may occur anywhere but has a strong predilection for the perisylvian region. Coronal scans make side-to-side comparison relatively easy. Follow the interhemispheric fissure (IHF) all the way from front to back. If the hemispheres are in contiguity across the midline, holoprosencephaly is present. If the IHF appears irregular and the gyri “interdigitate” across the midline, the patient has a deficient falx, which is most commonly encountered in a Chiari 2 malformation.
Evaluate the size, shape, and position of the ventricles. In callosal dysgenesis/agenesis, the third ventricle appears “high riding” and the frontal horns of the lateral ventricles often look like a “Viking helmet”(40-7B).
If the frontal horns appear squared-off or box-like, look carefully for an absent cavum septi pellucidi, a finding seen in septo-optic dysplasia and sometimes associated with polymicrogyria or schizencephaly.
Carefully evaluate the temporal horns and hippocampi to make sure that they are normally folded and oriented horizontally (not vertically, as occurs in many MCDs).
Axial Images
The combination of a true T1WI together with a long TR/TE T2WI is necessary in evaluating all cases of delayed development to assess myelin maturation. The thickness and configuration of the cortical mantle are well seen (40-8). The size, shape, and configuration of the ventricles are easily evaluated on these sequences.
Isolated FCD and cortical dysplasias associated with tuberous sclerosis complex are often best seen on T1WI in the first few months of life as hyperintense areas in the background of unmyelinated white matter. From approximately a few months of life into the second year of life, such abnormalities can be difficult to identify. Once myelination is complete, FCD is typically best seen on T2 FLAIR imaging (40-9).
Do not forget the posterior fossa! The fourth ventricle in the axial plane is normally shaped like a kidney bean on its side. If the vermis is absent and the cerebellar hemispheres appear continuous from side-to-side, rhombencephalosynapsis is present (40-10). If the fourth ventricle and superior cerebellar peduncles resemble a molar tooth, then a molar tooth malformation is present, suggesting Joubert syndrome and related disorders (40-11).
Selected References: The complete reference list is available on the eBooks+ version included with purchase.
