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Introduction

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

There is considerable confusion in the literature regarding the terminology used when describing abnormalities of the cerebellum and of the vermis in particular. Terminology such as ‘closure of the fourth ventricle’, ‘craniocaudal growth of the vermis’ and ‘inferior vermian hypoplasia’, as well as the numbering (using Roman numerals) of the cerebellar lobules from anterior to posterior, has left us with the preconception and misconception that the vermis grows from superior to inferior, and that partial agenesis or hypoplasia always involves the inferior lobules. In light of recent advances in our understanding of the embryology of the cerebellum and cisterna magna, certain terminology and concepts can be demonstrated to be incorrect and should be abandoned.

This Editorial reviews the normal development of the cerebellum, describing and dispelling several misconceptions regarding both normal and abnormal cerebellar development, with specific reference to the cerebellar vermis. Examples of cerebellar and vermian anatomy at pathology, in-vitro and in-vivo fetal magnetic resonance imaging (MRI) and pre- and postnatal imaging are reviewed and correlated with cerebellar embryology, phylogeny, somatotopic mapping and functional MRI. The evidence indicates that the cerebellar vermis develops more in a ventral to dorsal direction than in a superior to inferior one and, therefore, that the concept of ‘inferior vermian hypoplasia’ is incorrect. Three possible categories of vermian anomaly are seen: it may not necessarily be the inferior vermis that is hypoplastic; it may not only be the inferior vermis that is hypoplastic; or it may not be vermian hypoplasia at all. The term ‘inferior vermian hypoplasia’ should only be used if it can be proved that only the inferior vermis is abnormal. There is no generic term which encompasses all the various etiologies that can cause a small vermis; thus, more appropriate terminology may be ‘vermian hypoplasia’ or ‘vermian dysplasia’, with ‘neovermian hypoplasia’ in cases in which the central lobules are proved to be abnormal.

Embryology of the posterior fossa

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

The neural tube

The neural tube develops, during the 3rd and 4th weeks of embryogenesis, as a longitudinal groove along the dorsal layer of the trilaminar germ cell disc[1]. This groove deepens until its edges meet and fuse over the top, forming a hollow tube, which closes off at the cranial and caudal ends on days 25 and 28, respectively. The cranial end of the neural tube differentiates into three distinct regions: the prosencephalon, caudal to this the mesencephalon, and even more caudally the rhombencephalon, each enclosing a brain vesicle containing amniotic fluid initially. The rhombencephalon segments into eight rhombomeres. The future cerebellum originates in the alar plate of the most rostral adjacent pair of these rhombomeres; namely, rhombomeres 1 and 2[2]. Several genes (Otx, Gbx, FGF, Hox)[3] play a role in the formation and function of the isthmic organizer at the junction of the mesencephalon and rhombomere 1, which in turn regulates cerebellar development through release of hormonal factors[4-6]. The more caudal rhombomere 2 gives rise to the germinal matrix of the ventricular zone, which forms the deep cerebellar nuclei (fastigial, globose, emboliform and dentate from medial to lateral) and the Purkinje cell layer. The more rostral rhombomere 1 gives rise to the germinal matrix of the rhombic lips. Initially, this forms the external granular layer of the cerebellum, which subsequently migrates deeper to form the internal granular layer, a process which is completed by approximately 2 years postnatally.

The cerebellar vermis per se is not formed through fusion of the adjacent developing cerebellar hemispheres but develops as a direct proliferation of the mesial primordium, starting in the 5th week of gestation[7, 8]. Experimental evidence shows us that granule cells arising from the lateral upper rhombic lip migrate medially into the posterior cerebellum, whereas granule cells arising in the medial upper rhombic lip are confined to an anterior cerebellar distribution (Figure S1)[8]. Therefore, as the primordia are separate, the development of the posterior vermis is not dependent on that of the anterior vermis. This is evident in the case of rhombencephalosynapsis, in which the posterior vermis and most inferior lobule (nodulus (X)) can be preserved in the absence of the anterior lobe of the vermis[9, 10]. Thus, vermian hypoplasia can be segmental, and normal development of the inferior vermis is not dependent on normal development of the superior vermis.

Key point: The vermis does not form through fusion of the cerebellar hemispheres, it develops from its own mesial primordium. Additionally, different parts of the vermis develop from different parts of the mesial primordium. Segmental vermian abnormalities can therefore exist.

The roof of the rhombencephalon

At around 8–10 weeks' gestation, a focal dilatation of the neural tube is seen in the dorsal aspect of the developing hindbrain; this is the rhombencephalic vesicle, the predecessor to the fourth ventricle. At this level in the brainstem, which is known as the open medulla, the two alar laminae do not touch in the midline dorsally, and the gap is bridged by a layer of tela choroidea[11] known as the area membranacea, which forms the roof of the rhombencephalic vesicle.

The hindbrain develops a kink, known as the dorsal pontine flexure, which causes a transverse crease to form in the area membranacea, dividing it into a more rostral anterior membranous area and a more caudal posterior membranous area (Figure 1). The cerebellum develops from the rhombic lips at the cranial end of the area membranacea and the vermis and cerebellum grow exophytically, inferiorly and laterally, to cover it. Due to its thinness, this layer of tela choroidea has not, until recently, been resoluble by in-vivo imaging, thus giving the false impression that the fourth ventricle is open to the developing subarachnoid space initially and then closes due to caudal growth of the overlying vermis[12]. This apparent developmental process is therefore often referred to in older literature as ‘closure’ of the fourth ventricle. This is typically complete by around 18 weeks' gestation, although physiological variation may give the appearance that the vermis is incomplete at the time of the initial mid-trimester assessment[13].

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Figure 1. (a) During formation of the dorsal pontine flexure (small arrow) a transverse crease (large arrow) forms in the roof of the rhombencephalic vesicle (image), dividing it into anterior (cranial) and posterior (caudal) membranous areas. (b) The vermis (arrowhead) develops from the rhombic lip at the superior margin of the anterior membranous area. Choroid plexus develops in the crease (arrow). Cavitation starts in the overlying meninx primitiva (double arrow) to form the subarachnoid space. (c) As the cerebellum grows inferiorly the posterior membranous area bulges out between the vermis (large arrow) and the nucleus gracilis (small arrow), forming Blake's pouch. The subarachnoid space remains trabeculated by pia-arachnoid septations (double arrow). (d) Blake's pouch fenestrates (dotted line) and the neck of Blake's pouch becomes the foramen of Magendie (dashed line). The choroid plexus (arrow) now appears to be in the cisterna magna. (All images reproduced, with permission of the American Institute of Ultrasound in Medicine, from Robinson and Goldstein[15].)

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As the vermis grows caudally it invaginates into the rhombencephalic vesicle, and the posterior membranous area protrudes beneath the vermis into the overlying meninx primitiva[14, 15]. This evagination, first described in 1900, is known as Blake's pouch[11], and where Blake's pouch constricts to pass through the cerebellar vallecula (the normal space inferior to the vermis, superior to the nucleus gracilis and medial to the cerebellar hemispheres) it is known as Blake's metapore (Figure 1d). Even though Blake's pouch itself lies within the subarachnoid space of the developing cisterna magna, it is a direct extension of the fourth ventricle and therefore the fluid contained in Blake's pouch is intraventricular.

Normal linear echoes (the cisterna magna septa), which are typically seen in the fetal and neonatal cisterna magna and are most often described as bridging arachnoid septations[16], have recently been shown to represent the walls of Blake's pouch and the cisterna magna septa are a potential marker for normal development[15] (Figure 2a).

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Figure 2. (a) The cisterna magna septa (double arrows) are a normal structure thought to represent the walls of Blake's pouch. Cb, cerebellar hemispheres; Cp, choroid plexus in lateral ventricle. (Reproduced, with permission of the American Institute of Ultrasound in Medicine, from Robinson and Goldstein[15].) (b) On axial sonography, Blake's pouch can be seen within the developing subarachnoid space of the cisterna magna (double arrows). Blake's metapore (arrow) is visible between the developing cerebellar hemispheres. The walls of Blake's pouch are continuous with the walls of the fourth ventricle. The mesial portion of the future cisterna magna is derived from the ventricular system owing to fenestration of Blake's pouch. (Reproduced, with permission, from Robinson and Goldstein[15].) (c) Diagrammatic representation showing the brainstem (small arrow) and Blake's pouch (large arrow), within the meninx primitiva (double arrow) that will cavitate and form the true subarachnoid space of the cisterna magna.

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The cisterna magna

The future cisterna magna therefore forms in two compartments: a mesial compartment between the cisterna magna septa, which is derived from the rhombencephalic vesicle (Blake's pouch), and compartments lateral to the cisterna magna septa which develop through cavitation of the meninx primitiva overlying the surface of the brain, forming the subarachnoid space proper(Figures 2b and c).

Blake's pouch usually, but not always, fenestrates to a variable degree[11, 17] down to the obex (the inferior recess of the fourth ventricle), which leads to communication between the mesial ventricular-derived compartment and the true subarachnoid space of the cisterna magna. Fenestration and disappearance of Blake's pouch thus leaves an opening at Blake's metapore[15, 17, 18], which is known as the foramen of Magendie, allowing communication between the fourth ventricle and cisterna magna. Thus, the foramen of Magendie does not demarcate the true junction between the ventricular system and subarachnoid space of the cisterna magna.

A small communication beneath the vermis, between the fourth ventricle and the ‘cisterna magna’, often described in the literature on ultrasound[12, 15, 19-21] and sometimes seen on mid-sagittal images, therefore represents the normal Blake's metapore. Imaging the posterior fossa in the semicoronal plane will show this normal opening[12, 15, 21] (Figure 3), but can give a false appearance of a vermian defect[22] and, unfortunately, is often described wrongly as ‘Dandy–Walker variant’ (vide infra). This error can be avoided by making sure that the cavum septi pellucidi is included in the image, thus ensuring that the scan plane is truly axial or modified-axial.

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Figure 3. (a) Modified axial sonogram at 19 gestational weeks demonstrates a small gap inferior to the vermis and between the cerebellar hemispheres (arrow) which represents the foramen of Magendie. (b) Sagittal magnetic resonance image in same fetus at 21 weeks, after referral for ‘inferior vermian hypoplasia’, demonstrating small gap inferior to the vermis (arrow) in keeping with the foramen of Magendie. Follow-up imaging and outcome were normal. (Reproduced, with permission of Wolters Kluwer Health, from Robinson et al.[19].)

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Key point: A small gap between the vermis and the brainstem is normal and is known as Blake's metapore as it contains the neck of Blake's pouch. Once Blake's pouch fenestrates, the metapore is known as the foramen of Magendie.

Phylogeny of the cerebellum

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

‘Ontogeny recapitulates phylogeny’, or embryology repeats evolution. This important principle states that the development observed during embryology is like a ‘time-lapse photography’ rendition of the various steps taken during evolution; thus, structures that evolved first also develop first in the embryo, although the separate steps become somewhat merged.

The oldest part of the cerebellum, the archicerebellum, comprises the bilateral flocculi and the mesial nodulus (X), and is known as the flocculonodular lobe (Figure 4a and S2)[23]. Functionally, this lobe plus some of the adjacent uvula (IX) comprise the vestibulocerebellum, which has connections with the vestibular nuclei (which, although situated within the brainstem, are considered surrogate deep cerebellar nuclei) and semicircular canals, receives visual information from the superior colliculi, and is involved in balance, position and tone. These functions appear early in evolution, are shared among all vertebrates and phylogenetically are first seen in fish and amphibians; consequently they are the earliest to appear embryologically.

The next part of the cerebellum to appear is the paleocerebellum, which comprises the lobules of the anterior lobe of the vermis (lingula (I), centralis (II, III), culmen (IV, V)) and, importantly although often forgotten, but in fact supported by the literature[23, 24], the more caudal lobules of the posterior lobe of the vermis (pyramis (VIII)) and some of the adjacent uvula (IX)). The paleocerebellum plus adjacent paravermian tissue in the cerebellar hemispheres is known functionally as the spinocerebellum and, due to its connections with the spinocerebellar tracts and efferent connections via the deep cerebellar nuclei to the cerebral cortex, it is involved in proprioception and synergy of movement and locomotion. Phylogenetically this is first seen in higher amphibians and, in relative terms, is largest in reptiles and birds.

The final part of the cerebellum to appear is the neocerebellum (also known as the cerebrocerebellum or pontocerebellum), which comprises the most rostral lobules of the posterior vermis (between the primary and pre-pyramidal fissures) (i.e. declive (VI), folium (VIIa), tuber (VIIb)) plus the majority of the contiguous cerebellar hemispheres. Functionally, it is involved with motion intent, planning, precision, force and extent, and increasingly it is recognized to regulate cognitive and language functions[25]. Phylogenetically, this is seen in mammals only and it is largest in humans; it is therefore the latest to appear both in evolution and embryologically. It contributes the most to the transcerebellar diameter, and thus is one of the most widely used markers for normal cerebellar development in the fetus.

A similar pattern of development is seen in the deep cerebellar nuclei, among which the phylogenetically older nuclei, the fastigial nuclei, are the most medial within the white matter and connect primarily with the archicerebellum, followed by the globose and emboliform nuclei, which are more lateral and connect primarily with the paleocerebellum, and finally the dentate, the most lateral nuclei, which are connected primarily with the neocerebellum.

It therefore appears that, from an evolutionary and embryological perspective, rather than the anterior lobe developing first followed by the posterior lobe, the cerebellum actually develops with the most rostral and most caudal parts appearing together, initially adjacent to each other, with the more phylogenetically recent structures subsequently developing between these older structures, akin to the opening of a flower in which the outer petals are the first to appear and the inner ones appear later. Thus, the more anterior and posterior lobules and the associated medial deep cerebellar nuclei appear first, and the more central lobules, hemispheres and associated most lateral deep cerebellar nuclei appear last.

Key point: Phylogeny supports development of the vermis more in a ventrodorsal direction than in a craniocaudal direction.

Somatotopic mapping of the cerebellum

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

Further evidence in support of this pattern of development is seen when we look at the most recently proposed somatotopic map of the cerebellum (Figures 4b and S3)[26]. This reveals an initially confusing pattern in which, moving from superior to inferior, the posterior lobe appears inverted compared with the anterior lobe. However, when we look at the overall pattern of the anterior and posterior lobes as being a reflection on either side of the cerebellar ‘equator’, not only does it start to make sense, it also matches phylogeny.

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Figure 4. (a) Phylogenetic origins of the cerebellum. Phylogenetically, the archicerebellum is oldest and is only seen in fish and lower amphibians. The paleocerebellum is newer, is seen in higher amphibians and is larger in reptiles and birds. The neocerebellum is the most recent phylogenetically, is only found in mammals and is largest in humans. Note that the central lobules of the vermis are of neocerebellar origin. Superior (left) and inferior (right) views are shown. (Reproduced, with permission of Lippincott Williams & Wilkins, from Barr[23].) (b) Phylogenetically older functions which are common to more species map further away from the ‘equator’ than do newer functions which are seen in fewer species. A general correlation with evolutionary steps is seen, i.e. bipedality before manual dexterity before oromotor skills and associated cognitive and language skills, which developed last. cf Figure S2. (Reproduced, with permission from Macmillan Publishers Ltd, from Manni and Petrosini[26].)

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It follows that controls for the more basic or phylogenetically older functions of the lower limbs and trunk appear first and are represented in the areas closer to the brainstem and also closer to the midline, i.e. centralis (II, III), culmen (IV, V) and uvula (IX), whereas higher and phylogenetically newer functions, such as the fine motor control of the hands, mouth and lips and the associated cognitive functions of language, appear last and are represented more laterally and in the more central lobules of the vermis, i.e. declive (VI), folium (VIIa) and tuber (VIIb), and adjoining simplex, crus I and crus II of the ansiform lobes of the cerebellar hemispheres, respectively.

Key point: Somatotopic mapping supports development of the vermis more in a ventrodorsal direction than in a craniocaudal direction.

Functional magnetic resonance imaging of the cerebellum

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

The previously proposed cerebellar somatotopic map has in fact been confirmed by functional studies of the cerebellum by MRI (Figure S4)[27-31], i.e. the posterior lobe and anterior lobe appear as reflections of each other on either side of the cerebellar ‘equator.’

Key point: Functional MRI supports development of the vermis more in a ventrodorsal direction than in a craniocaudal direction.

Observation of the cerebellum in vitro and in vivo

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

There is direct observational evidence that this pattern of development is exactly what we see in the developing fetus in vivo. The flocculonodular lobe (X) is divided from the main part of the cerebellum by the posterolateral fissure, which, along with the primary fissure that divides the main anterior and posterior lobes, is the first to appear[32, 33]. The next fissures to appear are the secondary (or ‘post-pyramidal’), pre-pyramidal, pre-culmenate and pre-central fissures (Figure 5)[5, 19, 34, 35]. There is, however, a delay of approximately 6 weeks between what is resoluble histologically compared with in-vitro imaging[36], and also of approximately 2–3 weeks between in-vitro compared with in-vivo imaging. At best, by fetal MRI a single low-signal area is seen representing the white-matter core of each lobule; thus, at mid-trimester, typically only seven lobules can be seen because the lobules that mature later (declive (VI), folium (VIIa), tuber (VIIb)) are indistinguishable[19] and so only one structure representing these three lobules can be resolved between the primary and pre-pyramidal fissures (Figure 5a). Reimaging the same fetus later in gestation can demonstrate that this one structure develops into three separate lobules, bringing the total up to nine, which is the normal complement (Figure 5b). This may lead to misdiagnosis of vermian hypoplasia at earlier gestations[37] because the pyramis (VIII) and uvula (IX) can be misinterpreted as being the folium and tuber (lobules VIIa and VIIb) with the inferior-most lobules being considered erroneously to have not yet developed.

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Figure 5. (a) In midgestation only one lobule (declive) is seen between the primary and pre-pyramidal fissures. (b) In the same fetus later in gestation, the same single lobule can be resolved into three lobules (declive (VI), folium (VIIa), tuber (VIIb)). (Reproduced, with permission of Wolters Kluwer Health, from Robinson et al.[19].) (c) Sagittal three-dimensional ultrasound reconstruction just able to resolve three lobules (small arrow) below the primary fissure (large arrow). (d) Magnified inset of (b) with all fissures and lobules labeled. (Reproduced, with permission, from Robinson et al.[19].) (e) Gross adult specimen with all fissures and lobules labeled. (Adapted from Duvernoy[105].)

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Key point: Direct observation, both in vitro and in vivo, supports development of the vermis more in a ventrodorsal direction than in a craniocaudal direction.

In many cases of ‘inferior vermian hypoplasia’ we have no evidence that it is actually the inferior lobules that are deficient, because often we cannot distinguish the inferior vermian lobules from the other lobules of the vermis by antenatal imaging. Some of the vermian lobules do have distinguishing features based on the sub-lobules and folia; for example, the lingula (I), centralis (II, III), culmen (IV, V), folium (VIIa), tuber (VIIb), uvula (IX) and nodulus (X) each have one primary division, the culmen (IV, V) has two anterior and three posterior secondary divisions, the declive (VI) has one primary and several secondary divisions, and the pyramis (VIII) has one primary and one secondary division. Therefore, most of the lobules are essentially identical[4]. A unique feature of the declive (VI), folium (VIIa) and tuber (VIIb), which makes them difficult to distinguish on early imaging, is that all three are united to the arbor vitae by a single white-matter core, whereas all the other named lobules have their own individual white-matter cores (Figure 5d). One reason for making such a distinction from the other lobules by giving them separate names is likely the fact that the folium (VIIa) and tuber (VIIb) are in direct contiguity laterally with crus I and crus II of the ansiform lobes, which form the majority of the cerebellar hemispheres (Figure S5).

Key point: Features that distinguish the different vermian lobules either do not exist or are simply non-resoluble at the time of imaging; therefore, in ‘inferior vermian hypoplasia’ it may not be possible to prove that it is the inferior lobules that are deficient; in fact, it may not be ‘inferior’ vermian hypoplasia at all.

Biometric measurement of the cerebellum

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

Biometric measurement of the cerebellum also supports the aforementioned model for cerebellar development. Growth of the vermian craniocaudal diameter has been confirmed both ultrasonographically and by MRI[38-45], but, importantly, so has relative growth of both the superior and the inferior lobes which grow symmetrically on either side of the primary fissure without any significant change in ratio with gestational age[19]. If the inferior vermis grew later, linear growth of both lobes would not be seen and there would be a change in the ratio of the anterior and posterior lobes throughout gestation.

Key point: Biometric measurement supports development of the vermis more in a ventrodorsal direction than in a craniocaudal direction.

Pathology of the posterior fossa

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

The Dandy–Walker continuum

Classic Dandy–Walker malformation was described initially in infants with hydrocephalus and was thought to be the sequela of atresia of the foramina of Luschka and Magendie[46-48]; however, current theories suggest that it is a more global developmental defect affecting the roof of the rhombencephalon[7, 15] and leading to variable degrees of vermian hypoplasia and variable fenestration of the fourth ventricular outlet foramina, with variable associated anomalies (Figure 6)[49]. The term ‘Dandy–Walker variant’ was introduced to describe those patients with vermian hypoplasia but without the other features of the classic triad (namely, elevation of the torcula and enlarged posterior fossa) (Table 1).

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Figure 6. (a) In Dandy–Walker continuum, the vermis is elevated and abnormally lobulated (small arrow), with enlargement of the fourth ventricle (image) and Blake's pouch. The elongated nodulus (X) and displaced germinal matrix can be seen in the superior margin of Blake's pouch (double arrow). (b) Diagrammatic representation showing the small vermis (small arrow), enlarged Blake's pouch (double arrow) and fourth ventricle (image). (Reproduced, with permission of the American Institute of Ultrasound in Medicine, from Robinson and Goldstein[15].) (c) Histological specimen showing abnormal vermis (small arrow) and choroid plexus (double arrow) displaced into the inferior wall of Blake's pouch, which remains intact. The fastigial recess is abnormally formed (image) and the germinal matrix (large arrow) is displaced from its normal position just below the fastigial recess into the superior margin of Blake's pouch.

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Table 1. Categorization of ‘cystic’ posterior fossa malformations
FindingsVermisCisterna magnaseptaChoroid plexuspositionDiagnosis
Rotation/elevationHypoplasia
  1. Compiled and adapted from Robinson et al.[19], Garel[37], Guibaud and des Portes[57], Bonnevie and Brodal[78] and Volpe et al.[97]. a.k.a., also known as.

Enlarged Blake's pouch, enlarged posterior fossa, elevated torcula, (often hydrocephalus)Yes: > 40–45°Yes: variable, may be severeInvisible: apposed to side walls of cisterna magnaInferior margin of Blake's pouchVermian hypoplasia, a.k.a. Dandy–Walker malformation
Enlarged Blake's pouch, normal-sized posterior fossa, normal torculaYes: usually 30–45°Yes: variable to intermediateInvisible: apposed to side walls of cisterna magnaInferior margin of Blake's pouchVermian hypoplasia, a.k.a. Dandy–Walker variant or ‘inferior vermian hypoplasia’
Enlarged Blake's pouch, normal-sized posterior fossa, normal torculaYes: mild to moderate (usually < 30°)No: may be misdiagnosed as ‘inferior vermian hypoplasia’Visible: bowed laterallySuperior margin of Blake's pouchBlake's pouch cyst, a.k.a. persistent Blake's pouch
Enlarged Blake's pouch, enlarged posterior fossaNoNoVisible: bowed laterallySuperior margin of Blake's pouchMega cisterna magna (may represent mega Blake's pouch)
True cyst that does not communicate with the fourth ventricle (not Blake's pouch)NoNo: may have extrinsic compressionNormal, but may be distorted by mass effectSuperior margin of Blake's pouchPosterior fossa arachnoid cyst

Current theories suggest that the spectrum of findings with respect to the posterior fossa ‘cyst’ in the Dandy–Walker continuum might result from two potential processes: either arrest of vermian development so it does not cover the fourth ventricle, or failure of adequate fenestration of the fourth ventricular outflow foramina, leading to an enlarged Blake's pouch with secondary elevation and compression of the vermis. In classic Dandy–Walker malformation these two processes are thought to occur together.

Several interesting facts have been described in histopathological studies of Dandy–Walker fetuses[50, 51]. Rather than the inferior vermian lobules being absent, typically all of the lobules were actually present and the overall features resembled those of an arrested 12-week fetus. Reduced arborization of the lobules and weak neurofilament protein expression was seen throughout the vermis, including both the inferior lobe and the superior lobe, although the inferior lobules were more severely affected. Also, the nodulus (X) appeared elongated, overriding the uvula (IX) and in one case the pyramis (VIII), with abnormal caudal displacement of the germinal matrix, as if it were drawn out by the distention of the fourth ventricle (superior margin of Blake's pouch) (Figure S6). These effects appeared to be mechanical. It was also noted that the Purkinje cells and deep cerebellar nuclei (which arise from the periventricular germinal matrix) were normal: the abnormality affected the germinal matrix of the rhombic lips only, i.e. the abnormality was confined to derivatives of rhombomere 1. Compared to normal there is also an apparent gradient of increasing severity of abnormality in a superior to inferior direction, possibly due to genetic and concentration gradients within the molecular milieu of the developing vermis due to increasing distance from the isthmic organizer.

Key point: It may be that it is not only the inferior vermis that is abnormal since in the Dandy–Walker continuum there appears to be a rostrocaudal gradient of severity of abnormality and the superior vermis is also abnormal. Genetic gradients may account for this.

Inferior vermian hypoplasia

The term ‘inferior vermian hypoplasia’ is growing in usage, apparently as an alternative to the nomenclature ‘Dandy–Walker variant’[52-56], and has evolved as a result of terminology such as ‘closure of the 4th ventricle’, ‘craniocaudal growth of the vermis’, ‘craniocaudal diameter’ and ‘fusion’ of the cerebellar hemispheres as well as the numbering of the cerebellar lobules from superior to inferior. We are currently saddled with the preconception that the vermis grows in a superior-to-inferior direction and that, due to craniocaudal development of the vermis, partial agenesis involves its inferior part[57]. Consequently, when development appears incomplete, as indeed it always appears before 18 weeks, we have a misconception that it must be the inferior vermis that is deficient. However, even in a normal vermis there is always an inferior gap early in gestation, and yet the inferior lobules (flocculonodular (X), uvula (IX), pyramis (VIII)) are the ones that we expect to develop first. This has been shown on in-vitro imaging, when the posterolateral, pre- and post-pyramidal fissures (and therefore the lobules either side of them, i.e. flocculonodular (X), uvula (IX), pyramis (VIII)) can be seen as early as 16 weeks' gestation, whereas the declive (VI), folium (VIIa) and tuber (VIIb) are not distinguishable from each other (Figure S7)[33]. Thus, the inferior gap seen in every fetus this early in gestation cannot be due to deficiency of the inferior lobules; it must be due to the overall smaller size of the vermis, in particular the relative lack of development of the declive (VI), folium (VIIa) and tuber (VIIb). Therefore when truly deficient it may be due to a deficiency generally or focally in any part of the vermis, because the vermis will not extend as far inferiorly as it should.

Conceptually, when the budding flower is not fully open, is it that the outside petals are missing, or is it that the inner petals have failed to grow and push the outer petals into their normal position? In view of the ontological appearance of the cerebellar structures, it is more likely that, in cases of arrested development, the flocculonodular lobe (X) and lobules closer to the brainstem (lingula, centralis (II, III), culmen (IV, V), nodulus (X), uvula (IX), pyramis (VIII)) would be present, and the ‘neo’-vermian lobules (declive (VI), folium (VIIa), tuber (VIIb)) and contiguous cerebellar hemispheres (lobus simplex and ansiform) would fail to develop. Hence, in this situation the term ‘neovermian hypoplasia’ may be more appropriate. A clinical example of this may be seen in idiopathic autism, in which selective volume loss in the neovermian lobules can be observed[58, 59], but the archicerebellar lobules are normal (Figure S8).

The opposite may also occur if a destructive episode damages the lobules which are developing at that time, allowing the lobules that appear later to develop normally, i.e. the ‘archi’-vermian lobules and adjacent cerebellum would be deficient, but the ‘neo’-vermis and hemispheres would be normal. A clinical example of this may be seen in fetal alcohol syndrome, when the archicerebellar lobules may be affected due to depletion of the Purkinje cells which exist at the time of the toxic alcohol level[60-62], but without affecting subsequent development; therefore, the archicerebellar lobules are selectively damaged, but the neocerebellar lobules are normal (Figure S9).

Thus, depending on the nature and timing of the insult, a completely different clinical picture would be expected, tending towards either ataxia, hypotonia, balance and visual disturbance (vestibulocerebellum, spinocerebellum), or alternatively a disturbance of executive functions, memory, language and cognition (neocerebellum) which have been shown to localize to the tuber (VIIb) and contiguous ansiform lobes[28, 63-67].

Key point: ‘Inferior vermian hypoplasia’ may actually be due to hypoplasia of other vermian lobules, for example the neovermian lobules, leading to overall reduction in craniocaudal growth. This may explain why in certain cases of ‘inferior vermian hypoplasia’ we may see only cognitive defects.

Isolated ‘inferior vermian hypoplasia’ vs Blake's pouch cyst

The term ‘isolated inferior vermian hypoplasia’ has been used to describe that subset within ‘inferior vermian hypoplasia’ in which there are no known underlying or associated abnormalities[68-70] and this group generally has a better outcome[71-76].

Unfortunately, it is likely that, until very recently, due to the subtleties of distinguishing between ‘inferior vermian hypoplasia’ and Blake's pouch cyst (vide infra), in the literature these two groups of patients, with differing outcomes, have been included together. The problem lies in our poor ability even by modern antenatal imaging techniques, except perhaps in expert hands, to distinguish an isolated persistent Blake's pouch from true vermian hypoplasia, because both have an enlarged Blake's pouch and both have a rotated vermis, and the difference in definition is based purely on the appearance of the vermis[77]. Thus, the essential task is to ensure that the vermis is normal. However, to achieve this we need to be sure that we evaluate all of the vermis, and not just the inferior part.

One suggested useful landmark for differentiating between Blake's pouch cyst and vermian hypoplasia is the position of the choroid plexus: if it is in its normal position on the inferior surface of the vermis (superior margin of the cyst), this is compatible with Blake's pouch cyst, because it indicates that the anterior membranous area formed normally; if it is on the inferior margin of the cyst, this indicates that the anterior membranous area formed abnormally (Figure 6c)[18, 78, 79], warranting further evaluation of the vermis. This landmark is, however, extremely difficult to see.

It is often impossible to tell prenatally whether vermian hypoplasia is isolated since associated abnormalities, for example genetic or chromosomal ones, may be undetectable[80]. In one study, 50% of Dandy–Walker and ‘inferior vermian hypoplasia’ patients had abnormal outcome even if the abnormality appeared to be isolated[81]. In another study, postnatal imaging and follow-up findings were normal in six out of 19 cases of ‘isolated inferior vermian hypoplasia’, and the 13 with postnatal confirmation of hypoplasia had good overall outcome, with only mild developmental delays in a subset of infants[68].

Key point: The position of the choroid plexus may be useful to distinguish true vermian hypoplasia from Blake's pouch cyst, which have different outcomes.

Blake's pouch cyst (or ‘persistent Blake's pouch’)

In Blake's pouch cyst (Figure 7) there is thought to be inadequate fenestration of both Blake's pouch and the foramina of Luschka, leading to imbalance of cerebrospinal fluid (CSF) egress into the subarachnoid space of the cisterna magna, with consequent dilatation of the fourth ventricle[18]. Although the pouch communicates freely with the fourth ventricle, there is a failure of communication between the pouch and the perimedullary subarachnoid spaces[17, 82].

image

Figure 7. (a) In persistent Blake's pouch, the vermis is elevated away from the brainstem but the major landmarks of the primary fissure (small arrow) and fastigial recess (large arrow) appear normal and the lobulation appears normal. (Reproduced, with permission from Taylor and Francis Group LLC Books, from Robinson and Blaser[106].) Diagrammatic representation showing Blake's pouch (double arrow) elevating a normal vermis (small arrow). (Reproduced, with permission of the American Institute of Ultrasound in Medicine, from Robinson and Goldstein[15].) (c) Pathological specimen of the same fetus with Blake's pouch collapsed (double arrow) and vermian lobulation apparently normal (arrow). (Reproduced, with permission, from Robinson and Blaser[106].)

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In most of the lower species, including dogs, Blake's pouch is a normal persistent structure, yet in these species the vermis grows even more caudally than it does in humans, thereby obliterating the mesial portion of Blake's metapore and dividing it into two lateral metapores[11]. However, other than in humans, the foramina of Luschka are also larger and therefore the normal non-fenestration of Blake's pouch does not impede CSF egress. In contrast, in humans, with smaller foramina of Luschka, non-fenestration of Blake's pouch causes it to enlarge and elevate/rotate the vermis away from the brainstem, but, because this causes a gap between the inferior vermis and the brainstem, this can lead to the false-positive diagnosis of ‘inferior vermian hypoplasia’. This theory of Blake's pouch cyst explains why historically there has been poor correlation of ultrasound and autopsy findings in apparent cystic malformations of the posterior fossa[83], because postmortem the cyst deflates and the vermis derotates back into a normal position. This same scenario is seen in children and adults with Blake's pouch cyst, in whom there is no intrinsic vermian hypoplasia. CSF shunting or third ventriculostomy to decompress the ventricular system results in a return to normal appearance and clinical normality of these patients once the hydrocephalus has resolved[84, 85].

Isolated elevation/rotation of the vermis due to a persistent Blake's pouch does not necessarily indicate an adverse outcome[12, 15, 68, 79, 86-89]. In one study, one third of cases of Blake's pouch cyst or mega cisterna magna underwent spontaneous resolution in utero and 90% of survivors with no associated anomalies had normal developmental outcome at 1–5 years once the initial referral misdiagnosis of vermian hypoplasia had been excluded[81]. In another large retrospective study of 19 cases of Blake's pouch cyst, associated anomalies were seen in eight. There were two neonatal deaths and eight terminations. Of nine survivors, one had trisomy 21, and the other eight were neurodevelopmentally normal, although obstructive hydrocephalus was seen in one[77].

It has also been suggested in several cases in the literature that persistent Blake's pouch phenotype can be ‘acquired’ if the balance of CSF egress is upset by the presence of fetal intraventricular hemorrhage[81, 89] or fetal infection[90, 91], which result in tetraventricular dilatation and enlargement of the ‘cisterna magna’ (i.e. enlargement of Blake's pouch contained within the cisterna magna), presumably through resultant debris within the ventricular system causing obstruction of the fenestrations in both the foramina of Luschka and Blake's pouch, in much the same way as can be demonstrated postnatally[92, 93] (Figure S10). However, it is important to recognize that, depending on the nature and timing of the insult, injury to the developing brain itself can also result from endotoxins, free radicals and inflammatory cytokines[94-96].

Mega cisterna magna may in fact represent mega Blake's pouch but with better CSF egress such that the vermis is not elevated.

Key point: Blake's pouch cyst can give the appearance of ‘inferior vermian hypoplasia’ when there is no intrinsic abnormality of the vermis at all. Evidence suggests that in-utero infection or intraventricular hemorrhage may cause this appearance.

Conclusions

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

The vermis appears to grow in a craniocaudal direction, thus giving rise to the preconception that when it is incomplete the deficiency must affect the inferior vermis; however, evidence indicates that the vermis and cerebellum develop more in a ventral-to-dorsal direction, with the more phylogenetically recent structures developing in-between the older structures, akin to the opening of a flower. Deficiency generally or focally in any part of the vermis, or enlargement of Blake's pouch leading to elevation of an intrinsically normal vermis, can both give the appearance of ‘inferior vermian hypoplasia’ and can be difficult to differentiate. The term ‘inferior vermian hypoplasia’ is incorrect because it is not necessarily the inferior vermis that is abnormal, it may not only be the inferior vermis that is abnormal, or the vermis may not be abnormal at all. The term should be abandoned in favor of simply vermian hypoplasia or vermian dysplasia unless it can be proved that it is the inferior vermis that is deficient, and recognizing the fact that the etiology may be due to hypoplasia, atrophy, destruction or disruption (Table S1). The part of the vermis affected depends on the nature and the timing of the insult, which can selectively damage structures existing at the time of the insult, or selectively damage those which develop after the insult; this concept thus governs the resulting constellation of clinical findings. In certain cases it may even be more appropriate to use the term ‘neovermian hypoplasia’ in recognition of the fact that the declive (VI), folium (VIIa) and tuber (VIIb) may be the only lobules affected.

Acknowledgments

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information

I would like to thank the following: Dr Ants Toi, Department of Medical Imaging, Mt. Sinai Hospital, Toronto, for the images in Figures 3a and 5c; Dr Susan Blaser, Department of Radiology, Hospital for Sick Children, Toronto, for the images in Figures 3b, 5a, 5b, 6a and 7a; Dr Ruth Goldstein, Department of Radiology, University of California, San Francisco, for the images in Figures 2a and 2b; and Dr William Halliday, Department of Pathology, Hospital for Sick Children, Toronto, for the images in Figures 6c and 7c.

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  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information
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SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article:

Table S1 Associations with cerebellar hypoplasia (updated and adapted from Alkan et al.[69], Guibaud et al.[80], Murray et al.[98], Osenbach and Menezes[99], Boddaert et al.[100], Winter et al.[101], Poretti et al.[102], Limperopoulos et al.[103], Lehman et al.[104])

Figure S1 The more inferior parts of the cerebellum and vermis derive their granule cells from the more lateral upper rhombic lip germinal matrix, whereas cells originating in the mesial germinal matrix are confined to an anterior cerebellar distribution. (Reproduced with permission from Elsevier, from Sgaier et al.[8].)

Figure S2 Functional origins of the cerebellum. The vestibulocerebellum (blue) includes the flocculonodular lobe (X) and adjacent uvula (IX), the spinocerebellum (green) includes the anterior lobe and the pyramis (VIII) and contiguous medial hemispheres and the neocerebellum (yellow) includes the declive (VI), folium (VIIa) and tuber (VIIb) and the majority of the cerebellar hemispheres. (Adapted from Duvernoy[105].)

Figure S3 Somatotopic map of the cerebellum. This appears incompatible with a craniocaudal development pattern, but entirely compatible with a ventrodorsal one. The anterior lobe is a reflection of the posterior lobe on either side of the cerebellar ‘equator’. Feet are represented at the cranial and caudal extents, upper limbs inside that, and mouth inside that (centrally). (Reproduced, with permission from Macmillan Publishers Ltd, from Manni and Petrosini[26].)

Figure S4 Functional magnetic resonance imaging of the cerebellum demonstrates a pattern in which phylogenetically older functions map further away from the ‘equator’ than do newer functions. This pattern replicates the previously proposed somatotopic map. (Reproduced, with permission from Elsevier, from Grodd et al.[27].)

Figure S5 Diagram of the cerebellum demonstrating both the naming system and the corresponding numbering system for all of the vermian lobules, plus their corresponding cerebellar lobules and fissures. Lobule VI is also known as the declive (not labeled). (Reproduced, with permission from Macmillan Publishers Ltd, from Manni and Petrosini[26].)

Figure S6 (a) Dandy–Walker (DW) fetus demonstrating that all of the vermian lobules are present and abnormal and the nodulus (X) is elongated and distorted (arrow). (b) Normal fetus for comparison. (c) Histological specimen from DW fetus again showing distortion of the nodulus (X). (d) Normal fetus for comparison. (e) DW fetus: the germinal matrix (arrow) appears to have been pulled inferiorly by the superior margin of Blake's pouch. (f) Normal position of the germinal matrix (arrow) below the fastigial recess. (g) Neurofilament protein expression in DW fetus shows marked reduction in the inferior vermis (arrow); however, there is also reduction in the superior vermis (double arrow) and a gradient of increasing severity of abnormality in a superior to inferior direction. (h) Normal neurofilament protein expression for comparison. (All images reproduced, with permission from Sage Publications, from Russo and Fallet-Bianco[51].)

Figure S7 In this specimen at 16 weeks' gestation the pre-pyramidal and post-pyramidal (secondary) fissures can be seen; thus, the pyramis (VIII) and uvula (IX) are present even though there is a gap separating the inferior vermis from the brainstem. (Reproduced, with permission from Lippincott Williams & Wilkins, from Chong et al.[33].)

Figure S8 In idiopathic autism, the affected lobules (numbered in red) are those that are phylogenetically newer (neocerebellum (yellow)) and appear later during embryogenesis. The vestibulocerebellum (blue) and spinocerebellum (green) are spared. (Adapted from Duvernoy[105].)

Figure S9 In fetal alcohol syndrome, the affected lobules (numbered in red) are those that are phylogenetically older (vestibulocerebellum (blue), spinocerebellum (green)) and appear earlier during embryogenesis, therefore suffering depleted Purkinje cells during exposure to toxic alcohol levels. The neovermian lobules (yellow) are spared. (Adapted from Duvernoy[105].)

Figure S10 (a) Sagittal half-Fourier acquisition single-shot turbo spin-echo (HASTE) magnetic resonance image (MRI) in a fetus with sonographically diagnosed intraventricular hemorrhage. The cerebellar vermis (arrow) is elevated but appears normal otherwise, with normal landmarks and biometry. There is no ‘inferior vermian hypoplasia’. (b) Axial HASTE image in the same fetus, demonstrating unilateral low signal in the caudothalamic groove (arrow). (c) Parasagittal oblique diffusion-weighted image in the same fetus, demonstrating restricted diffusion (arrow), which was also corroborated on the apparent diffusion coefficient map, in keeping with germinal matrix hemorrhage. (d) Coronal MRI in a different 30-week-gestation neonate, showing blood within Blake's pouch (image) in continuity with the fourth ventricle, but the subarachnoid space of the cisterna magna has normal fluid signal (arrows). (e) Sagittal MRI in the same neonate, showing blood within Blake's pouch (image) and an elevated and compressed vermis (arrow), giving a vermian hypoplasia phenotype.

Supporting Information

  1. Top of page
  2. Introduction
  3. Embryology of the posterior fossa
  4. Phylogeny of the cerebellum
  5. Somatotopic mapping of the cerebellum
  6. Functional magnetic resonance imaging of the cerebellum
  7. Observation of the cerebellum in vitro and in vivo
  8. Biometric measurement of the cerebellum
  9. Pathology of the posterior fossa
  10. Conclusions
  11. Acknowledgments
  12. REFERENCES
  13. Supporting Information
FilenameFormatSizeDescription
uog13296-sup-0001-TableS1.docxWord 2007 document20KTable S1 Associations with cerebellar hypoplasia (updated and adapted from Alkan et al.[69], Guibaud et al.[80], Murray et al.[98], Osenbach and Menezes[99], Boddaert et al.[100], Winter et al.[101], Poretti et al.[102], Limperopoulos et al.[103], Lehman et al.[104])
uog13296-sup-0002-FigureS1.tifWord 2007 document3688KFigure S1 The more inferior parts of the cerebellum and vermis derive their granule cells from the more lateral upper rhombic lip germinal matrix, whereas cells originating in the mesial germinal matrix are confined to an anterior cerebellar distribution. (Reproduced with permission from Elsevier, from Sgaier et al.[8].)
uog13296-sup-0003-FigureS2.tifWord 2007 document6849KFigure S2 Functional origins of the cerebellum. The vestibulocerebellum (blue) includes the flocculonodular lobe (X) and adjacent uvula (IX), the spinocerebellum (green) includes the anterior lobe and the pyramis (VIII) and contiguous medial hemispheres and the neocerebellum (yellow) includes the declive (VI), folium (VIIa) and tuber (VIIb) and the majority of the cerebellar hemispheres. (Adapted from Duvernoy[105].)
uog13296-sup-0004-FigureS3.tifWord 2007 document4384KFigure S3 Somatotopic map of the cerebellum. This appears incompatible with a craniocaudal development pattern, but entirely compatible with a ventrodorsal one. The anterior lobe is a reflection of the posterior lobe on either side of the cerebellar ‘equator’. Feet are represented at the cranial and caudal extents, upper limbs inside that, and mouth inside that (centrally). (Reproduced, with permission from Macmillan Publishers Ltd, from Manni and Petrosini[26].)
uog13296-sup-0005-FigureS4.tifWord 2007 document5523KFigure S4 Functional magnetic resonance imaging of the cerebellum demonstrates a pattern in which phylogenetically older functions map further away from the ‘equator’ than do newer functions. This pattern replicates the previously proposed somatotopic map. (Reproduced, with permission from Elsevier, from Grodd et al.[27].)
uog13296-sup-0006-FigureS5.tifWord 2007 document4893KFigure S5 Diagram of the cerebellum demonstrating both the naming system and the corresponding numbering system for all of the vermian lobules, plus their corresponding cerebellar lobules and fissures. Lobule VI is also known as the declive (not labeled). (Reproduced, with permission from Macmillan Publishers Ltd, from Manni and Petrosini[26].)
uog13296-sup-0007-FigureS6.docxWord 2007 document1137KFigure S6 (a) Dandy–Walker (DW) fetus demonstrating that all of the vermian lobules are present and abnormal and the nodulus (X) is elongated and distorted (arrow). (b) Normal fetus for comparison. (c) Histological specimen from DW fetus again showing distortion of the nodulus (X). (d) Normal fetus for comparison. (e) DW fetus: the germinal matrix (arrow) appears to have been pulled inferiorly by the superior margin of Blake's pouch. (f) Normal position of the germinal matrix (arrow) below the fastigial recess. (g) Neurofilament protein expression in DW fetus shows marked reduction in the inferior vermis (arrow); however, there is also reduction in the superior vermis (double arrow) and a gradient of increasing severity of abnormality in a superior to inferior direction. (h) Normal neurofilament protein expression for comparison. (All images reproduced, with permission from Sage Publications, from Russo and Fallet-Bianco[51].)
uog13296-sup-0008-FigureS7.tifWord 2007 document2204KFigure S7 In this specimen at 16 weeks' gestation the pre-pyramidal and post-pyramidal (secondary) fissures can be seen; thus, the pyramis (VIII) and uvula (IX) are present even though there is a gap separating the inferior vermis from the brainstem. (Reproduced, with permission from Lippincott Williams & Wilkins, from Chong et al.[33].)
uog13296-sup-0009-FigureS8.tifWord 2007 document6802KFigure S8 In idiopathic autism, the affected lobules (numbered in red) are those that are phylogenetically newer (neocerebellum (yellow)) and appear later during embryogenesis. The vestibulocerebellum (blue) and spinocerebellum (green) are spared. (Adapted from Duvernoy[105].)
uog13296-sup-0010-FigureS9.tifWord 2007 document6805KFigure S9 In fetal alcohol syndrome, the affected lobules (numbered in red) are those that are phylogenetically older (vestibulocerebellum (blue), spinocerebellum (green)) and appear earlier during embryogenesis, therefore suffering depleted Purkinje cells during exposure to toxic alcohol levels. The neovermian lobules (yellow) are spared. (Adapted from Duvernoy[105].)
uog13296-sup-0011-FigureS10.docxWord 2007 document435KFigure S10 (a) Sagittal half-Fourier acquisition single-shot turbo spin-echo (HASTE) magnetic resonance image (MRI) in a fetus with sonographically diagnosed intraventricular hemorrhage. The cerebellar vermis (arrow) is elevated but appears normal otherwise, with normal landmarks and biometry. There is no ‘inferior vermian hypoplasia’. (b) Axial HASTE image in the same fetus, demonstrating unilateral low signal in the caudothalamic groove (arrow). (c) Parasagittal oblique diffusion-weighted image in the same fetus, demonstrating restricted diffusion (arrow), which was also corroborated on the apparent diffusion coefficient map, in keeping with germinal matrix hemorrhage. (d) Coronal MRI in a different 30-week-gestation neonate, showing blood within Blake's pouch (image) in continuity with the fourth ventricle, but the subarachnoid space of the cisterna magna has normal fluid signal (arrows). (e) Sagittal MRI in the same neonate, showing blood within Blake's pouch (image) and an elevated and compressed vermis (arrow), giving a vermian hypoplasia phenotype.

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