01 -NORMAL BRAIN DEVELOPMENT and GENERAL CLASSIFICATION of CONGENITAL MALFORMATION

P A R T O N E Brain development and congenital malformations with: Richard S Boyer Normal brain development and general classification of congenital malformations Disorders of neural tube closure Disorders of diverticulation and cleavage, sulcation, and cellular migration Posterior fossa malformations and cysts Disorders of histogenesis: neurocutaneous syndromes C H A P T E R Normal Brain Development and General Classification of Congenital Malformations Normal Brain Development Neurulation Neural Tube Closure Formation of Brain Vesicles and Flexures Disjunction of Cutaneous and Neural Ectoderm Forebrain Formation Neuronal formation Neuronal migration Cerebral commissures Midbrain Formation Hindbrain Formation Spine and Spinal Cord Formation General Classification of CNS Malformations Formation of the human central nervous system (CNS) is a continuous, immensely complicated process with repeated cycles of development, modeling and remodeling, and modification and modulation that begin in early fetal life.1 Knowledge of basic CNS development is essential for understanding congenital malformations of the brain and spine encountered in modern clinical radiology practice An in-depth discussion of neuroembryology is beyond the scope of this text For a more detailed, concise delineation, Keith L Moore’s basic embryology textbook, The Developing Human2 is suggested Dr Moore has generously permitted use of the drawings reprinted in this chapter NORMAL BRAIN DEVELOPMENT The basic events of CNS cytogenesis morphogenesis are summarized in the box, p and Neurulation At its very early stages the human embryo is basically a simple bilaminar disk At about weeks of embryonic life the neural plate appears on the dorsal aspect of the disk as an area of focal ectodermal proliferation (Fig 1-1, A) At approximately 18 days of gestation the neural plate invaginates, forming the neural groove (Fig 1-1, B) The lateral portions of this groove then thicken and proliferate, forming paired elevations called the neural folds (Fig 1-1, C and D) The edees of these folds bend medially toward each other, eventually making contact and closing over the top of the neural groove to form the neural tube (Fig 1-1, C to F) 4 PART ONE Brain Development and Congenital Malformations Fig 1-1 Diagrams illustrating formation of the neural crest and folding of the neural plate into the neural tube A, Dorsal view of an embryo of about 18 days, exposed by removing the amnion B, Transverse section of this embryo showing the neural plate and early development of the neural groove The developing notochord is also shown C, Dorsal view of an embryo of about 22 days The neural folds have fused opposite the somites but are widely spread out at both ends of the embryo The rostral and caudal neuroyores are indicated Closure of the neural tube occurs initially in the region corresponding to the future junction of the brain and spinal cord D to F, Transverse sections of this embryo at the levels shown in C illustrating formation of the neural tube and its detachment from the surface ectoderm Note that some neuroectodermal cells are not included in the neural tube but remain between it and the surface ectoderm as the neural crest These cells first appear as paired columns on the dorsolateral aspect of the neural tube, but they soon become broken up into a series of segmental masses (From K.L Moore, The Developing Human, W.B Saunders, 1988) Chapter Normal Brain Development and General Classification of Congenital Malformations The proximal two thirds of the neural tube thickens to form the future brain; the caudal one third represents the future spinal cord The neural tube lumen will become the brain ventricular system (see subsequent discussion) and the central canal of the spinal cord.2 Neural Tube Closure flaring cephalic end of the CNS constricts to form the primary brain vesicles.1 Failure of neural tube apposition in concert with fluid pressure that is inadequate to enlarge and form the ventricles properly is thought to result in the Chiari II malformation (see Chapter 2) Closure of the neural tube begins in the hindbrain region and proceeds in a "zipperlike" fashion toward both ends of the embryo3 (Fig 1-1, C) Ciliated epithelial cells lining the neural tube begin to secrete a watery liquid that distends the brain cavity, while the After the rostral neuropore closes, three hollow fluid-filled expansions are formed: the forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon) (Fig 1-2) The hindbrain continues caudally into a tubelike cylinder with a narrow central lumen, the future spinal cord.4 Subsequent constriction and bending of the cephalic end of the neural tube forms the telencephalon (future cerebral hemispheres), diencephalon (thalamus, hypothalainus), mesencephalon (tectum, midbrain), metencephalon (pons, cerebellum), and myelencephaIon (medulla) (Fig 1-2) Three major flexures, the midbrain, pontine, and cervical flexures, divide the developing brain into cerebrum, cerebellum, and spinal cord (Fig 1-3).4a Neuroembryology in a Nutshell Neural plate forms Neural plate invaginates, producing neural folds Neural folds appose in rnidline to form neural tube Tube closes like zipper, beginning in hindbrain area Tube constricts and bends, forming: Telencephalon (future hemispheres) prosencephalon diencephalon (thalamus hypothalamus) mesencephalon mesencephalon (tecturn, midbrain) metencephalon (pons, cerebellum) rhombencephalon myelencephalon (me dulla) Formation of Brain Vesicles and Flexures Disturbance in the process of differentiating the cerebral vesicles results in the spectrum of holoprosencephalies, whereas anomalies in cerebellar hemispheric growth and development results in various forms of cerebellar dysgenesis and, probably, the Dandy-Walker spectrum as well It is worth noting that the cerebellar vermis is formed from midline fusion of the hemispheric primordia, S beginning superiorly and continuing inferiorly Therefore when the vermis is hypoplastic (as S~in Dandy-Walker malformations), only its superior lobules are present Fig 1-2 Diagrammatic sketches of the brain vesicles indicating the adult derivatives of their walls and cavities The rostral (anterior) part of the third ventricle forms from the cavity of the telencephalon; most of the third ventricle is derived from the cavity of the diencephalon (From K.L Moore, The Developing Human, W.B Saunders, 1988) PART ONE Brain Development and Congenital Malformations Fig 1-3 A, Sketch of the developing brain at the end of the fifth week showing the three primary divisions of the brain and the brain flexures B, Transverse section through the caudal part of the myelencephalon (developing closed part of the medulla ).C and D, Similar sections through the rostral part of the myelencephalon (developing “open” part of the medulla) showing the position and successive stages of differentiation of the alar and basal plates The arrows in C show the pathway taken by neuroblasts from the alar plates to form the olivary nuclei (From K.L Moore, The Developing Human, W.B.Saunders, 1988) Disjunction of Cutaneous and Neural Ectoderm Immediately after neural tube closure, the superficial ectoderm of each side separates from the underlying neural ectoderm and then closes over it (Fig 1-1, F) This separation of ectodermal from neural tissue is extremely important and is known as disjunction The two portions of superficial ectoderm then fuse to establish the integrity of the superficial ectoderm (future skin).5 The future meninges, neural arches, and paraspinal muscles are formed from mesenchyme that migrates dorsally between the neural tube and the skin Premature separation or nondisjunction both result in severe anomalies If the disjunction of the neural and cutaneous ectoderm occurs too early, adjacent mesenchyme can enter the neural groove These mesenchymal cells give rise to spinal cord lipornas and participate in forming lipomyelomeningoceles More focal failure of disjunction results in a persisting epithelial-lined communication between the ectoderm and neural tube derivatives, i.e., a dermal sinus A larger area of nondisjunction results in an open neural tube that is continuous dorsally with cutaneous ectoderm, i.e., myelocele or myelomeningocele Forebrain Formation Formation and maturation of the brain neocortex is a complex but orderly process that involves neuronal proliferation, differentiation, and migration The cerebral hemispheres first appear as bilateral outpouchings, or diverticulae, of the telencephalon at approximately 35 days of gestation (Fig 1-4) As, these cerebral vesicles expand, cellular layers develolp within their walls to form the germinal matrix from which the neurons and glial cells will arise Swellings around the third ventricle form the diencephalon i.e., the thalamus and hypothalamus (Fig 1-5) Neuronal formation Formation of the embryonic cortex begins with production of neuronal and glial precursors in the germinal zones that line the lateral and third ventricles.6 The germinal matrix forms at about weeks’ gestational age and involutes at about Chapter Normal Brain Development and General Classification of Congenital Malformations lateral ventricle Fig 1-4 A, Sketch of the dorsal surface of the forebrain indicating how the ependymal roof of the diencephalon is carried out to the dorsomedial surface of the cerebral hemispheres B, Diagrammatic section of the forebrain showing how the developing cerebral hemispheres grow from the lateral walls of the forebrain and expand in all directions until they cover the diencephalon The arrows indicate some directions in which the hemispheres expand The rostral wall of the forebrain, the lamina terminalis, is very thin C, Sketch of the forebrain, as viewed anteriorly, showing how the ependymal roof is finally carried into the temporal lobes as a result of the C-shaped growth pattern of the cerebral hemispheres (From K.L Moore, The Developing Human, W.B Saunders, 1988.) 28 to 30 weeks, although it persists in the form of focal cell clusters up to weeks 36 through 39.7 Cells form in the germinal matrix, differentiate, and then migrate peripherally along specialized radial glial fibers that span the entire thickness of the hemisphere from the ventricular surface to the pia.6 Neuronal migration With the exception of the outer layer, neurons migrate from the germinal matrix to cortex in an "inside-out" sequence: those that will form the deepest cortical layer (layer 6) migrate first, followed by layers 5, 4, 3, and, finally, layer This migration and layering process occurs from weeks to through 24 to 26, when the full six layered cortex is achieved.7 A brain insult during neuronal migration can result in abnormalities ranging from lissencephaly (smooth brain) to schizencephaly (split brain), polymicrogyria, and laminar or focal heterotopias Cerebral commissures As the cerebral cortex is developing, commissural fibers connect corresponding areas of the cerebral hemispheres with each other These commissures develop between approximately and 17 weeks gestation, contemoraneous with many other major cerebral structures.8 The most important of the commidssural fibers cross in the lamina terminalis, the rostral end of the forebrain2 (Fig 1-6) The largest of the interhemispheric communications is the corpus callosum, connecting neocortical areas The corpus callosum forms from front to back except for the rostrum, which forms last An insult to the developing brain can result in complete or partial callosal agenesis When partial, the splenium and rostrum are always affected.9 Midbrain Formation The midbrain (mesencephalon) undergoes less change than any other part of the developing brain, excepting the caudal hindbrain.2 The neural canal narrows and becomes the cerebral aqueduct (Fig 1-7, D) Neuroblasts from the alar plate of the micibrain form the tectum and colliculi; those from the basal plate form the tegmentum (Fig 1-7, B).2 Hindbrain Formation The hindbrain (rhombencephalon) is composed of a rostral segment (metencephalon) and a caudal segment (myelencephalon) The metencephalon gives rise to the pons and cerebellum, and the myelencephalon becomes the medulla.2 Development of the pons and cerebellum is illustrated in Figure 1-7 Spine and Spinal cord Formation The spinal cord and spinal canal are formed by a complex process called canalization and retrogressive PART ONE Brain Development and Congenital Malformations Fig 1-5 A, External view of the brain at the end of the fifth week B, Similar view at weeks C, Median section of this brain showing the medial surface of the forebrain and midbrain D, Similar section at weeks E, Transverse section through the diencephalon showing the epithalamus dorsally, the thalamus laterally, and the hypothalamus ventrally (From K.L Moore, The Developing Human, W.B Saunders, 1988) Chapter Normal Brain Development and General Classification of Congenital Malformations Fig 1-6 A, Drawing of the medial surface of the forebrain of a 10-week embryo showing the diencephalic derivatives, the main commissures, and the expanding cerebral hemispheres B, Transverse section through the forebrain at the level of the interventricular foramen showing the corpus striatum and the choroid plexuses of the lateral ventricles C, Similar section at about 11 weeks showing division of the corpus striatum into caudate and lentiform nuclei by the internal capsule The developing relationship of the cerebral hemispheres to the diencephalon is also illustrated (From K.L Moore, Pte Developing Human, W B Saunders, 1988) 10 PART ONE Brain Development and Congenital Malformations Fig 1-7 A, Sketch of the developing brain at the end of the fifth week B, Transverse section through the metencephalon (developing pons and cerebellum) showing the derivatives of the alar and basal plates C and D, Sagittal sections of the hindbrain at and 17 weeks, respectively, showing successive stages in the development of the pons and cerebellum (From K.L Moore, The Developing Human, W.B Saunders, 1988) differentiation (the latter applies only to the distal cord) A caudal cell mass forms and then cavitates If the caudal cell mass fails to form properly, sacral agenesis and caudal regression syndromes result If it forms but differentiates abnormally, teratomas and spinal canal lipomas occur Abnormal retrogressive differentiation results in the spectrum of tethered cord, ranging from simple low-lying conus to thick filum and fatty filurn with liporna GENERAL CLASSIFICATION OF CENTRAL NERVOUS SYSTEM MALFORMATIONS Congenital malformations of the brain, spine, and spinal cord are numerous; over 2000 different congenital cerebral malformations have been described One third of all major embryologic anomalies involve the CNS; over 75% of fetal deaths have cerebral malformations.10 Various chromosomal and DNA repair disorders that result in CNS anomalies have been identified; the neurogenetics and imaging findings in the more common syndromes have been delineated by Kumar et al.11 These are summarized in Table 1-1 Several different systems have been developed to categorize and classify CNS congenital malformations but most are based on the system devised by DeMye and modified by Volpe,12 arranging disorders according to the estimated time of onset of morphologic derangements Useful modifications have been made by van der Knaap and Valk,13 as well as Boyer.14 All these systems divide malformations according to the major developmental stages of the human brain: dorsal and ventral induction, neuronal proliferation, migration, organization, and myelination Thus specific congenital CNS anomalies that can often be recognized on neuroirnaging studies are related to the timing of specific neuroembryologic events Therefore we will discuss the major identifiable CNS congenital anomalies in this manner The major events in normal CNS development with anomalies resulting from disruptions at various embryonic stages are listed in Table 1-2 A simplified classification is presented in the box Chapter Normal Brain Development and General Classification of Congenital Malformations 11 Table 1-1 Chrornosomal, DNA repair disorders Type CN5 manifestations Associated anomalies Comments Autosomal aberrations Trisomies 21 (Down syndrome) Mental retardation, generalized brain atrophy; Alzheimer’s; underdeveloped temporal inferior frontal gyri Brachycephaly; hypotelorism; hypoplastic maxillae, nose; skull base deformities; cervical spinal stenosis, atlantoaxial dislocation Most common chromosomal disorder 18 (Edwards syndrome) Gyral dysplasias (microgyria), hyperplasias; cerebellar hypoplasia; sometimes callosal agenesis, Chiari II; choroid plexus cysts Dolichocephaly; lowset ears; microphthalmia; micrognathia; hypertelorism Second most common trisomy,