Overview ( Box 4.1 )

Completion of neural tube closure toward the end of four postconceptional (p/c) weeks is followed by the development of flexures in the anterior neural tube at around 5 weeks p/c (see Chapter 1 ), a developmental event that plays an important role in defining the territory of the future rhombencephalic structures ( Fig. 4.1 ). The pontine flexure causes a splaying and thinning of the dorsal hindbrain, site of the future fourth ventricular roof (see Box 4.1 ). Around the same time, the mesencephalic flexure appears at the border between the mesencephalon and rhombencephalon, the future midbrain-hindbrain (MHB) junction. The MHB junction defines the location of a critical organizer that orchestrates the patterning events required to define the territories of the cerebellar anlage and related structures. The primordia of the cerebellar hemispheres appear as bilateral thickenings in the lateral aspects of the dorsal surface of the rhombencephalon, known as the rhombic lips. Hereafter, a series of proliferative and migratory events in the germinal matrices along the fourth ventricular surface and rhombic lips lead to development of the cerebellar hemispheres and vermis, which become apparent by 12 to 13 weeks. Although there is overlap between these processes, we review them as three broad events in temporal sequence, that is, (1) patterning of the MHB junction and cerebellar anlage; (2) development of the fourth ventricular roof; and (3) development of the cerebellar hemispheres and vermis.

Human fetal brain stem at 7 weeks gestational age.

Note the kink formed by the mesencephalic, pontine, and cervical flexures.

(Image based on Stroustrup Smith et al. J Ultrasound Med . 2006; and image courtesy Veronika Doljenkova [Rhode Island School of Design, Providence, RI] with reference to Sarnat ¹ and Sadler ² .)

Patterning events define structural domains around the midbrain-hindbrain junction ( Fig. 4.2 ). Normal development of the cerebellum and various brain stem structures is critically dependent on a precise sequence of late first trimester events around the MHB junction. The initial critical event is the development and precise positioning of the isthmic organizer (IsO) at the MHB junction (see Fig. 4.2 ). This event is under the stewardship of two mutually suppressing homeobox transcription factors, Otx2 and Gbx2 . Specifically, the IsO develops at the interface between the expression domain of Otx2 in the caudal midbrain and that of Gbx2 in the rostral hindbrain. When Otx2 expression is suppressed by Gbx2 expression (see Fig. 4.2 ), the onset of cerebellar development is enabled. Conversely, suppression of Gbx2 expression by Otx2 permits development of the mesencephalic tectum (see Fig. 4.2 ). It is not surprising, therefore, that developmental anomalies in these structures may occur together (see later). Disturbed expression of either of these factors will lead to abnormal positioning of the IsO and subsequent increased or decreased growth or transformation of structures in the MHB region. Once established, the IsO begins to secrete fibroblast growth factors (FGFs). Secretion of Fgf8a supports the development of the mesencephalic tectum, while cerebellar development is dependent on Fgf8b (see Fig. 4.2 ). These factors set the stage for the subsequent developmental events (see later), including specific cell differentiation and migration in the mesencephalic tectum and cerebellum. Development of the medial cerebellar structures, especially the vermis, is exquisitely dependent on appropriate FGF8 expression. Consequently, lesions that include hypoplasia of the vermis likely involve early disturbances in IsO function.

Patterning events at the developing midbrain-hindbrain junction. IsO , isthmic organizer; Otx2 , homeobox protein encoded by the orthodenticle homeobox 2 (OTX2) gene; Gbx2 , homeobox protein encoded by the gastrulation brain homeobox 2 (GBX2) gene; FgF8a and b , fibroblast 8 growth factors a and b encoded by the FgF8 gene.

Development of structures in and around the fourth ventricle roof , the second broad event in development of the cerebellum, is complex ( Fig. 4.3 ), and developmental disturbances in this region account for many of the posterior fossa lesions seen in clinical practice. As mentioned earlier, the physical forces exerted on the neural tube during formation of the pontine flexure widen its central lumen, forming the fourth ventricle, and stretch the dorsal rhombencephalon into the thin diamond-shaped fourth ventricle roof (see Fig. 4.3 ). At about 10 weeks p/c, the fourth ventricle roof is transected by a transverse crease, the plica choroidea (the future fourth ventricular choroid plexus), into the anterior and posterior membranous areas (AMA and PMA, respectively). The roof of the fourth ventricle has two layers: inner ependymal and outer pial. The AMA also contains neurons while the PMA does not. During normal development, the vermis overgrows and incorporates the AMA; the PMA persists and undergoes a series of perforations. Around 10 weeks p/c the outer pial layer becomes fenestrated in the midline just caudal to the plica choroidea, followed soon thereafter by perforation of the underlying ependymal layer, to form the foramen of Magendie. If there is a delay in ependymal perforation, a small pouch of ependyma, the Blake pouch (a normal structure), herniates through the pial perforation, and then subsequently perforates. More delayed perforation of the Blake pouch may lead to increasing encysted fluid (Blake pouch cyst) in the posterior fossa (discussed later; Figs. 4.13 to 4.15 ). Usually by around 14 to 17 weeks, but as late as 26 weeks, the foramina of Luschka develop in the lateral angles of the PMA (see Fig. 4.3 ).

Normal landmarks of the developing fourth ventricular roof.

Blake pouch is a normal feature of posterior membranous area. Failure or delay of the foramen Magendie to open leads to cyst formation.

Blake pouch cyst.

Fetal ultrasound axial view in a 23-week old fetus showing the septa (solid arrows) of the Blake pouch (asterisk) with the subarachnoid space on both sides (dashed lines) . The Blake pouch cerebrospinal fluid space is usually more echolucent than the adjacent subarachnoid space, which is bridged by pial-arachnoid septations.

Signaling support for developmental events in and around the fourth ventricular roof comes, in part, from genetic expression in the overlying mesenchyme. Forkhead box ( Fox ) genes are expressed by the mesenchymal tissues, but not by the underlying rhombencephalic tissues. Nonetheless, mutations in the Forkhead box gene C1 (Fox c1) are associated (see later) with cerebellar hypoplasia, hypoplasia and dysplasia of the vermis, mega cisterna magna, and the Dandy-Walker syndrome. Furthermore, disturbances in these signaling pathways may underlie conditions in which mesenchymal and neuroepithelial defects are associated (discussed later).

Development of the cerebellar hemispheres (see Box 4.1 ). Although earlier investigators proposed that up to one-third of the cerebellum derives from the rostral mesencephalon, it is now known that all cell types composing the cerebellum are derived from the alar plate at the junction of the IsO and the first rhombomere (R1). With the fundamental structures of the cerebellar anlage in place, the growth and development of the cerebellar hemispheres and vermis unfold through a complex series of programmed neuronal proliferation, migration, and differentiation. The major events in cerebellar histogenesis are illustrated in Fig. 4.4 .

Major events in the histogenesis of the cerebellum in four major time periods from 9 weeks of gestation to 7 months postnatal (pn). The two zones of proliferation are the ventricular zone (VZ) and the external granule cell layer (EGL). Three directions of migration are indicated by arrows; that is, radial from the VZ, tangential over the surface of the cerebellum to form the EGL, and later, inward to form the internal granular layer (IGL). Proliferation in the outer half of the EGL is under positive control by Sonic hedgehog (Shh) secreted by Purkinje cells (P-cells). Note the markedly active proliferation and migration of the granule precursor cells of the EGL during the premature period. Not shown is the marked increase in size of the molecular layer (ML) during the postnatal period. De , dentate; IZ , intermediate zone; WM , white matter.

(From Limperopoulos C, Soul JS, Gauvreau K, et al. Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics . 2005;115:688-695, with permission.)

Neural progenitors originate in two proliferative zones ( Fig. 4.5A ). Specifically, the inhibitory GABAergic neurons of the future cerebellum proliferate in the primary subependymal neuroepithelium (dorsomedial ventricular zone) around the fourth ventricle (see Fig. 4.5B ). Proliferation of these inhibitory neurons and their expression of Ptfa1 is stimulated by the diffusible mitogen, sonic hedgehog ( Shh ). Neuronal proliferation in the subependymal ventricular zone accelerates around 7 to 8 weeks p/c, followed by radial migration into the body of the future cerebellar anlage where these cells make up the inhibitory interneurons of the deep cerebellar nuclei and the Purkinje cell layer (see Fig. 4.5B ), that is, the primary efferent neurons of the cerebellum. Later, this zone generates the inhibitory GABAergic neurons that become the Golgi cells of the internal granular layer and the basket and stellate cells of the molecular layer. Proliferation of the future excitatory glutamatergic neurons of the cerebellum occurs in the rhombic lips ( Fig. 4.5C ), neuroproliferative zones along the dorsolateral margins of the fourth ventricle, comparable to the subventricular zones of the developing cerebrum (see Chapter 5 ). These excitatory glutamatergic neurons express Atoh1. It is of interest that the origin of the glutamatergic and GABAergic neurons differs in the cerebellum and cerebrum where glutamatergic neurons originate from the ventricular zone, and the GABAergic neurons from the subventricular zone (see Chapter 5 ). The first cells to leave the rhombic lips are those migrating into the substance of the future cerebellum to become glutamatergic projection neurons of the cerebellar nuclei (see Fig. 4.5C ). These cells only briefly express Atoh1 and do not have a prolonged clonal expansion phase (see the section on transit amplification later). From about 12 weeks p/c, proliferation accelerates in the dominant cell population in the rhombic lips, the granule cell precursors. The rhombic lips are the sole source of granule cell precursors. Once these cells begin expressing Atoh1 , they leave the rhombic lips and embark on a complex tangential migration pathway over the subpial surface of the cerebellum. Given the configuration of the developing cerebellum and the fourth ventricle, the lateral subventricular zone origin of these future granule cells is in close proximity to the subpial spaces along which they migrate away from the rhombic lips. By 29 weeks p/c the external granule precursors cover the entire surface of the developing cerebellum. The initial thin layer of cells undergoes waves of symmetric cell division that results in an exponential expansion of the external granular layer, a process recently termed transit amplification . The external granular layer develops an outer zone of active proliferation and an inner zone of postmitotic cells. From the inner zone, postmitotic granule cells migrate radially into the cerebellum along the Bergmann glial cells, crossing the Purkinje cell layer to form the (internal) granular layer of the mature cerebellum (see Fig. 4.5D ). During and after this inward migration, important connections are made by the granule cells. As they pass through the Purkinje cell layer they extend horizontal parallel fibers to contact the dendrites of the Purkinje cells, and soon after arrival at the internal granular layer, they link with the mossy fibers ascending from the pontine nuclei. Between 24 and 40 weeks, this external granular layer proliferation is largely responsible for the fivefold volumetric growth of the cerebellum ( Fig. 4.6 ). As discussed later, the close proximity of the actively proliferating outer layer of granule cells to the subarachnoid space (separated only by the thin pial layer) may expose this crucial neuroproliferative zone to potentially noxious substances circulating in the cerebrospinal fluid (CSF), including the products of prematurity-related forms of brain hemorrhage.

(A) Cerebellar primary and secondary neuroproliferative sites. (B) Neuronal migration of GABAergic cells from the primary ventricular neuroepithelium. (C) Neuronal proliferation and migration of glutamatergic neuronal precursors from the rhombic lips into the secondary neuroproliferative zone of the external granular layer. (D) Internal migration of the granule cells from the external granular layer through the Purkinje cell layer to form the internal granular layer.

Volumetric magnetic resonance imaging studies of 169 preterm infants and 20 healthy term-born infants. Cerebellar volumetric volume (in cc) between 26 and 44 weeks (A) and cerebellar/total brain volume (%) in B.

(From Limperopoulos C, Soul JS, Gauvreau K, et al. Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics . 2005;115:688-695, with permission.)

The dorsal rhombic lips also generate neurons that follow a different, caudal migrational path along the ventrolateral of the pons and rostral medulla to form specific brain stem nuclei, including the pontine and inferior olivary nuclei, among others. These nuclei subsequently generate important afferent input to the cerebellum, the pontine nuclei connecting to the internal granule cells through the mossy fibers, and the inferior olivary nuclei connecting to the Purkinje cells through the climbing fibers. This common origin of cellular precursors underlies the association between malformations in the cerebellum and other brain stem structures (discussed later).

Shh plays a central role in the spatial and temporal expansion of neuronal and glial cells across cerebellar development. Expressed in the choroid plexus epithelium roof plate, Shh is released into the CSF and stimulates proliferation in the ventricular zone. When Shh signaling is impaired, proliferation of radial glial cells, as well as their ability to generate GABAergic interneuron progenitors, fails. During the phase of transit amplification, Shh secreted by the underlying Purkinje cells drives the rate of cell division in the overlying external granular layer. Later, Shh from the Purkinje cells drives the proliferation of a secondary population of inhibitory interneurons and glial cells in the future white matter of the cerebellum. Finally, Shh plays an important role in the patterning of folia in the cerebellar cortex.

Development of the cerebellar vermis ( Box 4.2 ). Understanding of normal vermian development is especially important because vermian anomalies are increasingly recognized for their impact on long-term outcome. Previous understanding was that the vermis was formed by fusion of the cerebellar hemispheres. It is now known that the entire cerebellum originates from a single cerebellar anlage, rather than by fusion of the hemispheres. The vermis develops from proliferative events in a distinct region of this primordium, at the rostral midline of the first rhombomere. Initially, vermian development lags behind that of the hemispheres, but then accelerates around the late first trimester. Vermis growth is in a craniocaudal direction ( Fig. 4.7 ); however, this is not primarily due to growth at the caudal leading edge. In fact, the caudal-most aspects of the posterior lobe of the vermis are among the earliest to develop. Rather, it is the delayed expansion of the neovermis below the primary fissure that pushes the inferior vermis caudalward; this is an important point in the terminology of vermian hypoplasia discussed later. In this regard, development of the vermis resembles that of the corpus callosum (see Chapter 2 ). The progressive complexity of cerebellar surface growth and foliation is demonstrated in Fig. 4.8 .

Box 4.2

Normal Development of the Vermis ( Figs. 4.7, 4.8, and 4.9 )

By 18–20 Weeks’ Gestation

• ◆
  

  Normal gestational age-appropriate rostrocaudal length as late as 24 weeks

  
  
• ◆
  

  Caudal edge covers the fourth ventricle and reaches the obex

  
  
• ◆
  

  Primary fissure is present between the anterior and posterior lobes of the vermis

  
  
• ◆
  

  Fastigium-declive line divides the vermis into anterior and posterior lobes with a 1 : 2 ratio.

Midline sagittal landmarks of the posterior fossa.

By 27–28 Weeks’ Gestation

• ◆
  

  Mature pattern of vermian lobules and fissures.

Normal mature vermis and its landmarks.

Growth of the cerebellar surface from 24 to 40 weeks. Drawings were made in the mid-sagittal plane. Note the extraordinary increase from 24 weeks to 40 weeks in cerebellar surface area, related primarily to increased foliation but also to increased overall cerebellar growth.

(Adapted from Rakic P, Sidman RL. Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans. J Comp Neurol . 1970;139:473–500.)

Overview

Cerebellar malformations are diverse and extensive, with onset in any of the major developmental events discussed earlier ( Box 4.3 ). Because the major components of the developing cerebellum are in place by 18 to 20 weeks’ gestation, most of the significant developmental lesions are now detectable during prenatal ultrasound screening, and the diagnosis confirmed by fetal or neonatal magnetic resonance imaging (MRI) testing. However, some lesions may be missed prenatally, and given their subtle or silent early postnatal clinical features, their diagnosis may be delayed. In addition, the prolonged phase of granule cell proliferation into late gestation and beyond, less severe forms of cerebellar hypoplasia may be missed by prenatal ultrasound. There is a lack of consensus about the diagnostic criteria and classification of posterior fossa malformations. Consistent attention to specific metrics and landmarks may lead to greater consistency in classification ( Box 4.4 ). Some view these malformations as a continuum ( Box 4.5 ) ranging from severe Dandy-Walker malformation (with an enlarged posterior fossa) ( Figs. 4.11 and 4.12 ; see Box 4.5 ), to mild Dandy-Walker malformation (with a normal posterior fossa), Blake pouch cyst with a normal vermis (see Figs. 4.13 to 4.15 ; Box 4.6 ), isolated vermian hypoplasia ( Fig. 4.16 ; Box 4.7 ), and mega cisterna magna with normal neural structures ( Fig. 4.26 ; Box 4.12 ). However, this is not a uniformly accepted notion. Box 4.4 shows helpful normal landmarks for delineation of this spectrum of anomalies.

Dandy-Walker malformation.

Case 1 (A and B) shows marked elevation of the tentorium and torcular Herophili, marked vermian and hemispheric hypoplasia, and hydrocephalus. Note the striking posterior bulging of the occipital cranium. Case 2 (C and D) shows mild elevation of tentorium, torcular Herophili, with milder vermian hypoplasia, relative sparing of the cerebellar hemispheres, and normal lateral ventricles.

Development of the Dandy-Walker cyst.

Diagram showing dorsal view of the rhombencephalon.

Vermian hypoplasia.

MRI T2-weighted (A) Fetal MRI midline sagittal view showing primary fissure (white arrow) , normal anterior lobe, and hypoplastic posterior lobe. (B) Fetal MRI midline sagittal view showing vermian hypoplasia (black arrow) . (C) Neonatal MRI coronal view showing vermian hypoplasia/dysplasia (black arrow) .

Mega cisterna magna.

Fetal midline sagittal magnetic resonance imaging T2-weighted showing normal posterior parenchymal structures, including normal growth of the anterior and posterior lobes of the vermis and normal fourth ventricle and torcular Herophili with enlarged cisterna magna (double arrow) .

As with other regions of brain development, the earlier the onset of the disturbances in cerebellar development the more profound the subsequent deficits in development will be.

Arrested development of the anterior neural tube flexures (around 5 weeks p/c) is associated with the most fundamental malformations, leaving a kinked brain stem and usually major cerebellar dysgenesis ( Fig. 4.10 ). Patterning disorders of the hindbrain arise early, with abnormal positioning and function of the IsO (see Fig. 4.2 ). These lesions are currently not well characterized. Other patterning anomalies involve regional overgrowth or undergrowth of the brain stem and cerebellum (discussed later; Fig. 4.24 ). and are relatively rare. Developmental disorders of the fourth ventricle roof region include the Dandy-Walker malformation and Blake pouch cyst. The mesenchymal genes (e.g., Foxc1 ) play an important role in development of the fourth ventricular roof (see earlier) as well as in development of the meninges and skull. Therefore some authors group the developmental anomalies of the fourth ventricular roof and such lesions as mega cisterna magna (see Fig. 4.26 ) and arachnoid cysts (discussed later; Fig. 4.27 ) in the same spectrum. It has been proposed that the expression of Foxc1 dysfunction may be related to the extent of the gene deletion, which, in turn, determines the severity of the posterior fossa anomaly. These lesions are associated with cystic fluid collections in the posterior fossa, which increases the likelihood of their detection by prenatal ultrasound surveys, making them among the more common indications for prenatal neurological counseling. Disorders of cerebellar hemisphere and vermis development include conditions that arise from inadequate proliferation of cells in the posterior fossa neuroepithelial zones and of their subsequent trophic support (see Fig. 4.5A–D ). These disorders may result from primary disruption of proliferation in the ventricular zone, the rostral midline (vermis), and more lateral (hemispheric) rhombic lips, as well as migrational and organizational disturbances in the Purkinje cell and granule cell layers. Foxc1 has also been shown to play an important role in the normal differentiation and migration of the rhombic lip and roof plate derivatives. In addition, in Foxc1 deficient rodents there is significant expansion of the choroid plexus ; the resulting increase in CSF production may contribute to the cystic distention of the fourth ventricle and the development of the hydrocephalus, which often complicate Dandy-Walker malformation. Consequently, it has been suggested that defects in genes expressed solely by the cerebellar primordium result in vermian hypoplasia with or without hemispheric hypoplasia, whereas abnormal gene expression in the overlying mesenchyme results in lesions across the entire spectrum from Dandy-Walker malformation, vermian hypoplasia, and mega cisterna magna.

Two fetal cases with kinked brain stem with cerebellar hypoplasia.

(A) and (B) Midline sagittal T2-weighted fetal magnetic resonance imaging: kinked featureless brain stem with absent ventral pons (solid arrow) , severe cerebellar hypoplasia (dashed arrow) , markedly hypoplastic cerebrum, and microcephaly.

Pontine tegmental cap dysplasia.

Midline sagittal magnetic resonance imaging T2-weighted (A and C) and T1-weighted (B). All views show flat ventral pons, with dorsal cap (solid white arrows) projecting from the dorsal tegmentum into the fourth ventricle, and dysplastic vermis (broken white arrows) with apparent posterior lobe overgrowth in A and B.

Arachnoid cysts in the posterior fossa.

Fetal T2-weighted magnetic resonance imaging images from two cases of posterior fossa arachnoid cyst ( white arrows in A and B) showing displacement and distortion of vermis and effacement of the fourth ventricle.

The neurodevelopmental prognosis of rhombencephalic malformations is broad across the overall spectrum, as well as within the specific diagnostic categories.

Factors that influence outcome include the extent and topography of the lesion, associated supratentorial malformations or complications (e.g., hydrocephalus), and the presence of dysmorphic, genetic, or chromosomal syndromes. In addition, the more recent evidence for the importance of the vermis for normal cognitive-affective function has highlighted the role of vermian anomalies in the adverse outcome of rhombencephalic anomalies. As discussed earlier, the AMA of the fourth ventricular roof, which normally becomes incorporated into the developing vermis, contains a neuronal population, while the PMA contains ependymal tissue but no neurons. These features may underlie the fact that children with malformations involving the AMA (Dandy-Walker malformation, vermian hypoplasia) are at higher risk for neurodevelopmental impairment than are children with PMA lesions (isolated Blake pouch cyst, mega cisterna magna) who are usually developmentally normal. In addition, the integrity of cerebellar foliation, especially of the vermis, has important prognostic value.

Clinical features of rhombencephalic malformations differ in many respects from cerebellar lesions acquired later in life. Specifically, although hypotonia and motor delays are common, the classic motor signs, such as ataxia, intention tremor, nystagmus, and dysmetria, are less prominent overall. Conversely, the cognitive, affective, and behavioral consequences of early life cerebellar anomalies are now better appreciated and constitute a developmental form of the cerebellar cognitive-affective syndrome, seen in older individuals with cerebellar stroke or tumor. Recent studies suggest that the anatomical substrate for these nonmotor functions of the cerebellum is distinct closed-loop circuits, not only with the primary motor cortex, but also with many other higher cortical centers, such as the dorsolateral prefrontal cortex. The anatomical basis through which the cerebellum influences cortical activity is the ascending projections from the dentate nucleus.

Specific Developmental Anomalies of the Rhombencephalon

When formulating the diagnosis of a posterior fossa anomaly, it is helpful to consider the size and configuration of specific landmarks. These are outlined in Box 4.4.

The Dandy-Walker Malformation

Anatomical Abnormality.

The essential anatomical criteria for the diagnosis of Dandy-Walker malformation include (1) complete or partial agenesis of the cerebellar vermis; (2) cystic dilation of the fourth ventricle; and (3) enlargement of the posterior fossa with elevation of the tentorium, torcular Herophili, and lateral venous sinuses (see Fig. 4.11 and Box 4.5 ). Although 85% of children with Dandy-Walker malformations will develop hydrocephalus by the age of 1 year (see later), this is a complication and not a diagnostic criterion. Associated central nervous system (CNS) abnormalities occur in as many as 70% of cases—the most important clinical examples being agenesis of the corpus callosum and disorders of neuronal migration (see Box 4.5 ). The Dandy-Walker malformation is a fundamental defect in development of the rhombencephalic roof and vermis (see Figs. 4.11 and 4.12 ). Abnormal rhombencephalic roof formation results from disturbances in both the AMA and PMA (see Fig. 4.12 ). The often-massive cystic enlargement of the fourth ventricle in Dandy-Walker malformations results from a combination of failed incorporation of the AMA into the developing vermis, as well as a delay or failure in foraminal development in the PMA. Consequently, the redundant AMA billows out, possibly driven by CSF pulsations, leading to cyst formation and expansion of the posterior fossa. During development of the fourth ventricular roof, the foramen of Magendie usually opens before the foramina of Luschka. The disturbance in Dandy-Walker malformation appears to be primarily a delay or total failure of the PMA to form the foramen of Magendie (see Normal Development earlier), allowing a buildup of CSF and the development of cystic dilation of the fourth ventricle. Despite the subsequent opening of the foramina of Luschka (which are usually patent in Dandy-Walker malformation), cystic dilation of the fourth ventricle persists and CSF flow is impaired. As discussed earlier, rodent models of Foxc1 deficiency demonstrate significant expansion of the choroid plexus, which may contribute not only to the cystic distention of the fourth ventricle but also to the development of hydrocephalus. Neuropathological studies of the Dandy-Walker malformation have shown that all vermian lobules are present but hypo/dysplastic, especially inferiorly, and that vermis development appears arrested at about the 12-week p/c level. The superior-to-inferior gradient of increasing hypo/dysplasia of the vermis may result from the waning influence of the IsO with increasing distance. The anomalous structures in the Dandy-Walker malformation are of rhombic lip origin, with largely normal development of the primary ventricular neuroepithelium derivatives, such as the Purkinje cells and deep cerebellar nuclei.

Timing.

The timing of the development of the Dandy-Walker malformation is not entirely clear. However, the major time period of foramina development is the second and third months of gestation, that is, the peak time period of midline prosencephalic development (see Chapter 2 ). This time period also overlaps that of neuronal migration ( Chapter 6 ). Thus agenesis of the corpus callosum and defects of neuronal migration are not unexpected as important accompaniments to the Dandy-Walker malformation (see Box 4.5 ).

Clinical Aspects.

The postnatal clinical spectrum of the Dandy-Walker malformation is difficult to define decisively from published writings because of inconsistent diagnostic criteria and inclusion of additional conditions. For example, in one series ( n = 50) of fetal cases, karyotype (when available) was abnormal in 46%. Moreover, the Dandy-Walker malformation is a feature of many syndromes, including Rubinstein-Taybi, Meckel-Gruber, Coffin-Siris, Ellis-van Creveld, and Smith-Lemli-Optiz, among a number of others, many of which are autosomal recessive traits. Nevertheless, certain clinical aspects are consistent.

The dominant clinical feature in early infancy is the occurrence of hydrocephalus, with a striking occipital prominence to the cranium and a large cystic dilation of the fourth ventricle, enlarging the posterior fossa (see Fig. 4.11 ; Box 4.5 ). However, pronounced hydrocephalus in the neonatal period is present in only a minority of cases. Nevertheless, because of widespread prenatal and neonatal ultrasonography, more cases now are identified in utero and in the neonatal period, despite the absence of a rapidly enlarging head and overt signs of increased intracranial pressure. By 3 months, approximately 75% of cases exhibit hydrocephalus, and ultimately 90% or more have hydrocephalus. Indeed, in some cases of Dandy-Walker malformation, hydrocephalus may not develop until adulthood.

Other important clinical features include the accompanying anomalies of CNS and extraneural structures (see Box 4.5 ). Systemic anomalies are present in approximately 30% to 40% of cases, and include serious cardiac and urinary tract defects.

Prognosis.

Prognosis of the Dandy-Walker malformation is highly variable and related to the severity both of the malformation and the presence of associated cerebral and extracerebral anomalies, as well as the degree of hydrocephalus ( Table 4.1 ). The degree of vermian hypo/dysplasia appears to play an important role in the long-term neurological outcome. Specifically, if anomalous brain development is confined to the posterior fossa, then the primary prognostic factor is lobulation of the vermis, with size of the cystic lesion and posterior fossa being largely irrelevant. Disturbances in vermis lobulation appear to be correlated with the intellectual impairment seen in about half of Dandy-Walker malformation cases.

TABLE 4.1

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