CNS MALFORMATIONS

EARLY BRAIN DEVELOPMENT About the 15th day of life, ectodermal cells on the surface of the embryo proliferate to form a plate of tissue, the “primitive streak”. Rapidly proliferating group of cells, the “Hensen’s node” form at one end (cephalic end). From Hensen’s node, cells that form the notochord migrate rostrally and induce differentiation of the dorsal midline ectoderm into “neuroectoderm”. The plate like condensation of the neuroectoderm is the “neural plate”. At 17 days, lateral aspects of the neural plate thicken and neural folds bend medially, meeting in the midline around 20 days. As the neural tube closes, the neuroectoderm which will form the CNS separates from the overlying ectoderm, which will become the skin.

EARLY BRAIN DEVELOPMENT At the time of closure of the anterior neuropore, three dilatations or vesicles develop in the rostral cavity of the neural tube: prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). Rhombencephalon separated from the mesencephalon by the cephalic flexure and from the cervical cord by the cervical flexure. Prosencephalon is divided into the diencephalon (thalamus, hypothalamus, globus pallidus) and telencephalon (which will form the cerebral hemispheres, putamen, caudate). Diencephalon - cells originate in the germinal matrix of 3rd ventricle; telencephalon - cells originate in the germinal matrix in the walls of the future lateral ventricles Rhombencephalon will divide into myelencephalon (pons and medulla) and metencephalon (cerebellar hemispheres and vermis)

CNS DEVELOPMENT Primary neurulation: 3-4 gw Prosencephalic development: 2-3 mo Neuronal proliferation: 3-4mo Neuronal migration: 3-5 mo Organization: 5mo-yrs postnatal Myelination: IU-years postnatal

NORMAL DEVELOPMENT Primary neurulation (Dorsal induction) - inductive events in the dorsal aspect of the embryo resulting in the formation of brain and spinal cord, excluding segments caudal to lumbar region. Secondary neurulation - exclusive to lower sacral segments of the cord (caudal neural tube formation) - occurs later

PRIMARY NEURULATION CNS begins on dorsal aspect of embryo as a plate of tissue in the middle of the ectoderm; underlying notochord and chordal mesoderm induce formation of neural plate at 18 days. Neural tube - first folds neural folds occurs at lower medulla at 22 days; closure proceeds rostrally and caudally, but it is not a simple zipper like process Anterior end of NT closes at 24 days, posterior end at 26 days; posterior site of closure at lumbosacral level; more caudal segments formed by different process

SECONDARY NEURULATION Formation of caudal NT (lower sacral and coccygeal segments) occurs by sequential canalization (4-7gw) and retrogressive differentiation (7wks - birth+) At 28-32 days, aggregate of undifferentiated cells at caudal end (caudal cell mass) develop vacuoles - enlarge - coalesce - make contact with central canal; accessory lumina may remain Remaining structures are ventriculus terminalis (in the conus) and filum terminale

DISORDERS OF INDUCTIVE EVENTS IN ORDER OF DECREASING SEVERITY: Craniorachischisis totalis Anencephaly Myeloschisis Encephalocele Myelomeningocele/Chiari malformation

CRANIORACHISCHISIS TOTALIS There may be a neural plate like structure, but no axial skeleton or dermal covering Onset no later than 20-22 days Most aborted; some to early fetal stages

ANENCEPHALY Defect is failure of anterior neural tube closure Most severe case - defect from level of lamina terminalis to foramen magnum (holocrania/holoanencephaly); if defect does not extend to foramen magnum - meroacrania/meroanencephaly

ANENCEPHALY Most commonly - forebrain, variable amount of upper brainstem involved; exposed neural tissue represented by hemorrhagic, fibrotic, mass of neuroglial tissue - area cerebrovasculosa; anterior pituitary present, posterior pituitary usually absent Frontal bones above superciliary ridge, parietal bones, squamous part of occipital absent Onset no later than 24 days; polyhydramnios 75% SB; others can have brainstem function.

ENCEPHALOCELE Restricted disorder of neurulation, involving anterior neural tube closure 70-80% are occipital; frontal encephaloceles may protrude into nasal cavity (more common in SE Asia) Low occipital encephaloceles may have deformities of brainstem, cerebellum in the encephalocele, and abnormalities of skull base and cervical vertebrae (Chiari III) Timing around 26 days (time of closure of anterior neural tube)

MECKEL’S SYNDROME Constellation of occipital encephalocele, microcephaly, microphthalmia, cleft lip and palate, polydactyly, polycystic kidney, ambiguous genitalia

MYELOMENINGOCELE Restricted failure of posterior neural tube closure; 80% in lumbar area (last area of neural tube to close) Chiari II, hydrocephalus

Chiari malformation In 1891, Chiari described 3 malformations of the hindbrain associated with hydrocephalus. Chiari I: caudal cerebellar tonsillar ectopia, below the foramen magnum; association of chronic tonsillar herniation with syringomyelia Chiari II: complex malformation - myelomeningocele, hydrocephalus, hindbrain, spine abnormalities Chiari III: cervical spina bifida with cerebellar encephalocele

Chiari malformation Squamous bones of the vault have patches of irregular thickness - craniolacunia; shape does not correspond to gyri, not secondary to >ICP, can disappear. Falx is short and fenestrated Shallow posterior fossa, low position of torcular, low insertion of tentorium, tightly crowded brainstem and cerebellum displaced caudally and impacted into the foramen magnum Herniated cerebellar tissue protrudes into the cervical spinal canal and overrides the dorsal surface of the cord as a peg. Herniation originates from caudal vermis - tissue firm, sclerotic. In others, tonsils may herniate with vermis.

Chiari malformation Deformation of the brainstem- caudal shift of dorsal medulla, the 4th ventricle, choroid plexus - dorsal nuclear groups thus much more caudal to the ventral surface. The tissue caudal to the ventricle containing the gracile and cuneate nuclei form a hump which overrides and compresses the cervical cord. Beaking of the tectum Cervical spinal roots project cranially instead of taking their usual lateral or descending course Hydromyelia common in the cord Hydrocephalus with redundant cortical gyri (polygyria, microgyria, stenogyria), but normal lamination

Development of the cerebellum During the 5gw, a thickening occurs bilaterally in the alar plate of the rhombencephalon, forming the rhombic lips, containing the primordia of the cerebellar hemispheres and the germinal zones for the precursors of the granule cells. The neurons that form the deep cerebellar nuclei and Purkinje cells migrate radially outward from the germinal matrix in the wall of the 4th ventricle. Granule cells have a complex origin: at 11-13gw, precursor cells migrate tangentially from the germinal zone in the lateral portion of the rhombic lips, to form the external granular layer (EGL) over the surface of the cerebellum. From here, cells migrate inward past the Purkinje cells to form the granular layer. EGL attains maximum cell number in the first few postnatal months, then diminishes in size as the granule cells migrate inward. EGL disappears by about 13 months. Cerebellar vermis forms at the site of fusion of the developing hemispheres, begins superiorly at 9gw and continues inferiorly; entire vermis formed by end of 15gw - the cerebellar vermis cannot form in the absence of hemispheres.

DANDY-WALKER MALFORMATION Dandy-Walker malformation - enlarged posterior fossa, high position of the tentorium, hypogenesis or agenesis of the cerebellar vermis, cystic dilatation of the 4th ventricle that fills the posterior fossa, hydrocephalus Most common anomaly associated is callosal hypogenesis There may be dysplasias of the brainstem, especially abnormal inferior olives.

Malformations of the cerebellum Joubert syndrome Agenesis/hypogenesis of the cerebellar vermis with midline clefting, abnormal eye movements, periodic hyperpnea, ataxia, mental retardation Rhombencephalosynapsis - small cerebellar hemispheres fused in midline with sulci running across, agenesis of vermis Lhermitte Duclos syndrome (dysplastic cerebellar gangliocytoma): Mass effect, focal area of enlarged cortex, abnormal neurons in granule cell layer, hypermyelinated marginal layer; can be associated with Cowden disease (multiple hamartoma syndrome, other malignancies)

Occult dysraphic states Disorders of caudal neural tube formation (secondary neurulation, lower sacral and coccygeal segments); intact skin but dimples, abnormal hair tuft, sinus tract, cutaneous abnormalities Since the process results in formation of the conus and filum, common to find abnormalities of these structures: thickened filum Neural lesions: myelocystocele, diastematomyelia-diplomyelia, meningocele, lipomyelomeningocele, lipoma, dermal sinus with dermoid/epidermoid, tethered cord Lipomyelomeningocele may reflect focal premature dysjunction: focal separation of neuroectoderm from cutaneous ectoderm allows migration of periaxial mesoderm into the developing neural tube: mesoderm matures primarily into fat.

PROSENCEPHALIC DEVELOPMENT Peak period 2-3 months of gestation Prosencephalic development occurs by inductive interactions between the notochord/prechordal mesoderm and forebrain. This occurs ventrally at the rostral end of the embryo (ventral induction) This affects formation of the face as well as the brain.

PROSENCEPHALIC FORMATION Begins at the rostral end of the neural tube after anterior neuropore closes, at the end of the 1st month and beginning of 2nd month

PROSENCEPHALIC DEVELOPMENT Three sequential events: Prosencephalic formation Prosencephalic cleavage midline prosencephalic development

PROSENCEPHALIC CLEAVAGE 5-6 gw, includes 3 basic cleavages: Horizontally to form paired optic vesicles, olfactory bulbs and tracts Transversely to separate telencephalon from diencephalon (thalamus, hypothalamus) Sagittally to form from the telencephalon the paired cerebral hemispheres, lateral ventricles

Disorders of prosencephalic development Prosencephalic formation (aprosencephaly/atelencephaly) Prosencephalic cleavage (holoprosencephaly) Midline prosencephalic development (agenesis of corpus callosum, agenesis of septum pellucidum, septo-optic dysplasia)

APROSENCEPHALY/ATELENCEPHALY Most severe disorder of telencephalic development - 2nd month Aprosencephaly - lethal - absence of both telencephalon/diencephalon, with rudimentary brainstem (distinguished from anencephaly by intact skull, scalp) Atelencephaly - diencephalon may be relatively preserved (can survive for even a year with little neurological function except breathing)

HOLOPROSENCEPHALY Disorder of prosencephalic cleavage (5-6 wks) alobar, semilobar, lobar alobar - most severe form, univentricle, membranous roof over 3rd ventricle (dorsal cyst), absence of olfactory bulbs/tracts, hypoplasia of optic nerve/single optic nerve, absent corpus callosum, falx cerebri, interhemispheric fissure; azygous anterior cerebral artery with single trunk supplying branches to the ACA territories in both hemispheres

HOLOPROSENCEPHALY Facial anomaly: single median eye (cyclops), no eye with rudimentary nasal structure (proboscis), marked ocular hypotelorism with or without a proboscis (ethmocephaly), and ocular hypotelorism with a flat single nostril nose (cebocephaly), cleft lip/palate, absent philtrum Eye abnormalities: cataract, retinal dysplasia, colobomas

Semilobar holoprosencephaly Brain less dysmorphic than alobar form Interhemispheric fissure and falx cerebri partially formed in the posterior portions of the brain; anterior frontal region may be fused and underdeveloped Corpus callosum may be present with posterior part in the absence of anterior callosal formation (exception to anteroposterior rule) Thalami partially separated, but may be fused into a single mass Syntelencephaly - variant of semilobar type

CEREBRAL COMMISSURES At 7gw, dorsal part of lamina terminalis (the rostral most end of the neural tube) undergoes a generalized thickening - called lamina reuniens or commissural plate. Lamina reuniens develops a groove which is filled with material originating in the meninx primitiva - this material probably in conjunction with glial cells in the developing hemispheres secrete molecules that guide axons across the midline (cell adhesion molecules, axonin 1 involved) These bundles of axons form the cerebral commissures: the anterior commissure, the hippocampal commissure, and the corpus callosum.

MIDLINE PROSENCEPHALIC DEVELOPMENT 2-3 months Important in formation of corpus callosum and septum pellucidum, the optic nerve-chiasm, and hypothalamic structures Corpus callosum - earliest appearance at 9 wks, by 12 wks definable as a commissural plate, completed by approximately 20 weeks of gestation

CORPUS CALLOSUM Corpus callosum composed of 4 sections - rostrum, genu, body, splenium If normal development disturbed, corpus callosum may be completely absent or partially formed. In hypogenesis of CC, the anterior portion of CC will be formed (anterior body, posterior genu), but the posterior part (posterior body, splenium) will be absent. This anterior to posterior rule helps to differentiate a hypogenetic CC from one that is secondarily destroyed. Exceptions to this rule are seen in holoprosencephaly, where splenium may be present without a normal genu or body, or body and splenium may be present without genu, or in interhemispheric fusion cases, genu and splenium may be present without the body.

CALLOSAL ANOMALIES Corpus callosum formed around 8-20 gw. Anomalies of corpus callosum may be isolated or associated with other anomalies. Aicardi syndrome - X-linked dominant disorder with infantile spasms, callosal hypo or agenesis, chorioretinopathy. Almost exclusively in females (need 2 X), but can be in Klinefelter’s (47XXY). Intracranial anomalies include callosal hypo/agenesis, interhemispheric cysts, polymicrogyria, heterotopia, cerebellar hypoplasia, choroid plexus cysts/papillomas, retinal dysplasia, chorioretinal colobomas.

AGENESIS OF CORPUS CALLOSUM Axons that would normally cross to opposite hemisphere through the CC turn at the interhemispheric fissure and run parallel to that fissure forming the longitudinal bundle of Probst. Probst bundles invaginate the medial borders of the lateral ventricles, giving the ventricles a crescentic shape (batwing), more so frontally. When the callosal body is absent, the bodies of the lateral ventricles are straight and parallel. Interhemispheric surface shows gyri perpendicular to roof of 3rd ventricle (radial pattern) Corpus callosum is the most tightly packed bundle of axons in the brain; this compactness gives the lateral ventricles their shape. In callosal agenesis, posterior portions of ventricles expand, resulting in dilatation of the trigones and occipital horns of lateral ventricles (colpocephaly). Colpocephaly refers to massive dilatation of occipital horns with normal size of frontal horns. Nature not well understood, and used loosely in the literature

INTRACRANIAL LIPOMAS Malformations resulting from abnormal differentiation of the meninx primitiva, the undifferentiated mesenchyme that surrounds the developing brain. Meninx differentiates into fat. As they are formed from the meninx, intracranial lipomas almost always in the subarachnoid space and blood vessels and cranial nerves may course through them. Most common site: deep interhemispheric fissure 40-50% Interhemispheric lipomas almost always associated with hypogenesis of corpus callosum; calcification in lipoma

Septo-optic dysplasia Syndrome named by De Morsier - hypoplasia of optic nerves, hypoplasia or absence of septum pellucidum, 2/3rds with hypothalamic/pituitary dysfunction

Development of the cortex At 7 gw, proliferation of young neurons occurs in the subependymal layer of the walls of the lateral ventricles (germinal matrix). Here stem cells undergo mitoses to produce neurons and glia. After mitoses, some of the newly generated cells will remain in the germinal zone and undergo further divisions, while others will migrate outward to their final destinations. At 8 gw, the first young neurons begin to migrate outward. Initially, simple process - cells in the germinal zones elongate, with nucleus moving to end of the cell farthest from the ventricular surface. Contact with the ventricular surface is terminated, and remainder of the cell joins the nucleus. As cerebral hemispheres enlarge and distance to be traveled increases, specialized radial glia guide the migrating neurons. In the cortex, “inside out” sequence, with deeper layers formed before superficial layers. An exception is the neurons of the molecular layer which arrive first.

Cortical malformations Any event that inhibits neuronal or glial proliferation, neuronal migration, or subsequent organization can cause a cortical malformation. Abnormal proliferation: micrencephaly, hemimegalencephaly Abnormal migration and organization: classical lissencephaly, cobblestone lissencephaly, heterotopias, agyria/pachygyria, polymicrogyria, schizencephaly Tuberous sclerosis and focal cortical dysplasia also show cortical malformation

Microcephaly and Micrencephaly Microcephaly - smallness of the cranial vault; may be induced either by hypoplasia of brain tissue, or by a variety of lesions (infarcts, atrophy etc) Micrencephaly - subnormal size of the brain, thickened scalp, thickened bones of cranial vault, severe intellectual impairment, delayed motor function, autosomal recessive, hypoplasia of cortex and white matter, cerebellum may be spared Small brain may be part of other malformations

SCHIZENCEPHALY Gray matter lined clefts extending from the ependymal lining of the lateral ventricles to the pial covering of cortex Both genetic and acquired causes Gray matter lining the clefts is dysplastic

LISSENCEPHALY Lissencephaly/agyria - “smooth brain” Pachygyria - focal broad gyri Classical lissencephaly - arrest of migration of neurons, eg, Miller Dieker syndrome Cobblestone lissencephaly - eg, Walker Warburg syndrome, muscle eye brain disease - overmigration of neurons, polymicrogyria, muscle/eye disease, abnormal myelination, hydrocephalus

Agyria/Pachygyria Cortex much thicker than normal, volume of white matter reduced, large ventricles Abnormal cortex with 4 layers: 1. molecular layer, 2. thin superficial layer of nerve cells, 3. tangential plexus of myelinated fibers, 4. thick cellular layer of neurons in disorganized arrangement Agyria dates much earlier (11-13gw) than polymicrogyria which dates near 20-24gw.

Walker Warburg syndrome Cobblestone lissencephaly, polymicrogyria, congenital hydrocephalus, severe eye malformations (retinal dysplasia, persistent primary hyperplastic vitreous, retinal nonattachment, optic nerve hypoplasia), hypomyelination, callosal hypogenesis, cerebellar polymicrogyria, dysplasia, other associated anomalies (eg, Dandy Walker, encephalocele), muscular dystrophy Neuroglial heterotopias in the subarachnoid space

Neuronal heterotopia Collections of gray matter in abnormal locations: subependymal, subcortical, band heterotopia (double cortex - homogeneous band of gray matter between cortex and ventricle, complete or partial, female preponderance)

TORCH INFECTIONS CMV - transplacental congenital infection - IUGR Microcephaly, meningoencephalitis, periventricular calcification, disturbances of neuronal migration chorioretinitis, hepatosplenomegaly, petechia, anemia