Developmental Neuropathology E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: International Society of Neuropathology Series
• Sprache: Englisch

Seitenzahl: 1689

Veröffentlichungsjahr: 2018

Beschreibung

A definitive, clinically oriented guide to the pathology of genetics of developmental neuropathology

Developmental neuropathology relates to the wide range of disorders affecting the developing brain or pre- and post-natal life, with emphasis on the genetic and molecular mechanisms involved. This book provides a practical guide to diagnosing and understanding these disorders affecting this vulnerable population and potentially stimulates further advances in this exciting area. It also addresses the controversies in inflicted head injury in infants.

The fourth major title to be approved by the International Society of Neuropathology (ISN), Developmental Neuropathology offers in-depth chapter coverage of brain development; chromosomal changes; malformations; secondary malformations and destructive pathologies; developmental vascular disorders; acquired metabolic and exogenous toxins; metabolic disorders; Rett syndrome and autism; and infectious diseases. The text provides:

• Clinical, disease-oriented approach to the pathology and genetics developmental neuropathology
• Fuses classical and contemporary investigative approaches
• Includes genetic and molecular biological pathogeneses
• Fully illustrated
• Approved and endorsed by International Society of Neuropathology

Developmental Neuropathology is the perfect book for practicing neuropathologists, pediatric pathologists, general pathologists, neurologists, and geneticists in deciphering the pathology and pathogenesis of these complex disorders affecting the nervous system of the embryo, fetus, and child.

Leseprobe

Developmental Neuropathology

SECOND EDITION

EDITED BY

HOMA ADLE-BIASSETTE

Université Paris Diderot, Paris

BRIAN N. HARDING

Children’s Hospital of Philadelphia, Philadelphia

JEFFREY A. GOLDEN

Ramzi S. Cotran Professor of Pathology, Boston

SERIES EDITORS

FRANÇOISE GRAY

Université Denis Diderot Paris 7, France

CATHERINE (KATY) KEOHANE

University College Cork, Ireland

This first published 2018© 2018 John Wiley & Sons Ltd

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Library of Congress Cataloging-in-Publication Data

Names: Adle-Biassette, Homa, editor. | Harding, Brian (Brian N.), editor. | Golden, Jeffrey A., 1961– editor.Title: Developmental neuropathology / [edited] by Homa Adle-Biassette, Brian Harding, Jeffrey A. Golden.Description: Second edition. | Hoboken, NJ : Wiley, 2018. | Includes bibliographical references and index. |Identifiers: LCCN 2017050347 (print) | LCCN 2017051636 (ebook) | ISBN 9781119013099 (pdf) | ISBN 9781119013105 (epub) | ISBN 9781119013082 (cloth)Subjects: | MESH: Central Nervous System Diseases–genetics | Central Nervous System Diseases–pathology | Genetic Diseases, Inborn–pathology | Nervous System Malformations–pathologyClassification: LCC RC347 (ebook) | LCC RC347 (print) | NLM WL 301 | DDC 616.8/047–dc23LC record available at https://lccn.loc.gov/2017050347

Cover design by: WileyCover images: Main image courtesy of Brian HardingSmaller images from top to bottom:1st one courtesy of Brian Harding; 2nd one courtesy of Jeff Golden;3rd one courtesy of Pr. Hans Goebel; 4th one courtesy of Pr. Annie Laquerrière;5th one courtesy of Jeff Golden

CONTENTS

List of Contributors

Introduction

Chapter 1: Central Nervous System Manifestations of Chromosomal Change

Introduction

The craniofacial complex

Genetic counseling and the neuropathologist

Autosomal trisomy

Other autosomal aneuploidies

Sex chromosome aneuploidy

Deletions

Duplications

Future perspective, conclusions

References

Chapter 2: Neural Tube Defects

Definition

Normal embryology

Epidemiology

Clinical features

Pathology

Genetics

Animal models and pathogenesis

Treatment, future directions and conclusions

References

Chapter 3: Midline Patterning Defects

Definition of the disorder, major synonyms and historical perspective

Embryology of forebrain patterning

Holoprosencephaly

Epidemiology

Atelencephaly and aprosencephaly

Agenesis of the corpus callosum

Septo-optic dysplasia

Other midline patterning defects

References

Chapter 4: Microcephaly

Definitions, major synonyms and historical perspective

Normal embryology

Epidemiology

Clinical features

Imaging

Genetics

Neuropathology

Differential diagnosis

Animal models and pathogenesis

Treatment, future perspectives, conclusions

References

Chapter 5: Hemimegalencephaly and Dysplastic Megalencephaly

Definition and synonyms

Epidemiology and genetics

Clinical features and differential diagnosis

Macroscopy

Histopathology

Immunohistochemistry

Pathogenesis

Experimental models

Future investigations and therapies

References

Chapter 6: Lissencephaly, Type I

Definition

Synonyms and historical annotations

Epidemiology

Embryology

Genetics

Clinical features

Macroscopy

Histopathology

Immunohistochemistry and ultrastructural findings

Differential diagnosis

Experimental models and pathogenesis

Future directions and therapy

References

Chapter 7: Lissencephaly, Type II (Cobblestone Lissencephaly)

Definition

Synonyms

Epidemiology

Genetics

Clinical features

Imaging

Embryology

Macroscopy

Histopathology

Differential diagnosis

Pathogenesis

Future directions and therapy

References

Chapter 8: Polymicrogyria

Definition

Epidemiology

Genetics

Clinical features

Macroscopy

Histopathology

Differential diagnosis

Experimental models

Pathogenesis

Future directions and therapy

References

Chapter 9: Cerebral Heterotopia

Definition, major synonyms and historical perspective

Normal embryology

Epidemiology

Clinical features

Macroscopy

Histopathology, immunohistochemistry and electron microscopy

Differential diagnosis

Genetics

Animal models

Pathogenesis

Treatment, future perspectives, and conclusions

References

Chapter 10: Hippocampal Sclerosis, Granule Cell Dispersion, and Cortical Dysplasia

Part 1: Hippocampal sclerosis and granule cell dispersion

Part 2: Cortical dysplasia

References

Chapter 11: Tuberous Sclerosis Complex

Definition

Synonyms and historical annotations

Epidemiology

Embryology

Genetics

Clinical features

Macroscopy

Histopathology

Immunohistochemistry findings

Ultrastructural findings

Differential diagnosis

Experimental models

Pathogenesis

Future directions and therapy

References

Chapter 12: Chiari Malformations

Definition, major synonyms and historical perspective

Embryology

Epidemiology

Clinical features

Macroscopy and histopathology

Differential diagnosis

Genetics

Experimental models

Pathogenesis

Future directions and therapy

References

Chapter 13: Dandy–Walker Malformation, Mega Cisterna Magna, and Blake's Pouch Cyst

Definitions

Synonyms and historical annotations

Clinical features

Neuroimaging

Epidemiology and genetics

Pathology

Embryology

Pathogenesis and etiology

Experimental models

Treatment

Future investigations

References

Chapter 14: Joubert Syndrome

Definition

Epidemiology

Clinical features

Neuroimaging

Neuropathology

Differential diagnosis

Genetics

Pathogenesis

Treatment

References

Chapter 15: Cerebellar Heterotopia and Dysplasia

Definitions

Cerebellar heterotopia of infancy

Cerebellar dysplasias associated with neurodevelopmental syndromes

Rhombencephalosynapsis

References

Chapter 16: Brainstem Malformations

Introduction

Olivary heterotopia

Dysplasias of the dentate and olivary nuclei

Dentato–olivary dysplasia with intractable seizures in infancy

Möbius syndrome

Pontine tegmental cap dysplasia

Pontocerebellar hypoplasia

Granule cell aplasia

References

Chapter 17: Spinal Cord Lesions

Introduction

Definitions, synonyms and epidemiology

Risk factors

Genetics

Clinical features

Imaging

Macroscopy

Histopathology

Differential diagnosis

Pathogenesis

Treatment

References

Chapter 18: Hydrocephalus

Definition, major synonyms and historical perspective

Normal embryology and pathways of CSF production, circulation and resorption

Epidemiology

Clinical features

Pathology and physiopathology

Genetics of congenital hydrocephalus (and pathogenesis)

Animal models

Treatment, future perspective, conclusions

References

Chapter 19: Antenatal Disruptive Lesions

Definition, major synonyms and historical perspective

Normal embryology

Epidemiology

Clinical features, investigations and important differential diagnosis

Pathology

Genetics and pathogenesis

Animal models and pathogenesis

Treatment, future perspective, conclusions

References

Chapter 20: Hemorrhagic Lesions

Definition, major synonyms and historical perspective

Normal development

Epidemiology

Clinical features

Pathology

Pathogenesis and genetics

Animal models

Treatment, future perspective, conclusions

References

Chapter 21: White Matter Lesions in the Perinatal Period

Introduction

Definition, synonyms and historical annotations

Epidemiology

Genetics

Clinical features

Pathology

Experimental models

Pathogenesis

Future directions and therapy

References

Chapter 22: Gray Matter Lesions

Definition, major synonyms and historical perspective

Normal development

Epidemiology and risk factors

Clinical features

Pathology

Pathogenesis and genetics

Animal models

Treatment, future perspective, conclusions

References

Chapter 23: Pediatric Head Injury

Definition and historical perspective

Epidemiology

Clinical features

Pathology

Animal models

Conclusions

References

Chapter 24: Pediatric Vascular Malformations

Definition

Synonyms and historical annotations

Epidemiology

Embryology

Genetics

Clinical features

Pathology

Differential diagnosis

Experimental models

Future directions and therapy

Acknowledgments

References

Chapter 25: Sudden Infant Death Syndrome

Introduction

Definition

Synonyms and historical annotations

Clinical features

Epidemiology

Genetics

Pathology

Hypoxic–ischemic lesions in the brain

Pathogenesis

Future directions

Acknowledgments

References

Chapter 26: Kernicterus

Definition

Epidemiology

Genetics

Clinical features

Macroscopy

Histopathology

Biochemistry

Differential diagnosis

Experimental models

Future directions and therapy

References

Chapter 27: Lesions Induced by Toxins

Definition

Synonyms and historical aspects

Epidemiology

Embryology

Genetics

Clinical features

Imaging

Laboratory findings

Macroscopy

Histopathology

Differential diagnosis

Pathogenesis

Future directions and therapy

References

Chapter 28: Disorders of Carbohydrate Metabolism

Introduction

Lysosomal diseases

Polyglucosan disorders

Congenital disorders of glycosylation

References

Chapter 29: Sphingolipidoses and Related Disorders

Introduction

GM1 Gangliosidosis

GM2 gangliosidosis

Fabry disease

Gaucher disease

Metachromatic leukodystrophy

Multiple sulfatase deficiency

Globoid-cell leukodystrophy (Krabbe disease)

Niemann–Pick disease types A and B

Niemann–Pick type C disease

Farber disease

Sphingolipid activator protein deficiency

Sphingolipid biosynthesis deficiencies

References

Chapter 30: The Neuronal Ceroid Lipofuscinoses

Introduction

CLN1: palmitoyl-protein thioesterase 1 deficiency with granular osmiophilic deposits

CLN2: Classic late infantile NCL with tripeptidyl-peptidase I deficiency

CLN3: Juvenile NCL with mutations in the

CLN3

gene

Rare Forms of Neuronal Ceroid Lipofuscinoses

References

Chapter 31: Peroxisomal Disorders

Definition, major synonyms and historical perspective

Peroxisomal biogenesis disorders

Single protein deficiencies

Normal embryology

Epidemiology

Clinical features

Imaging

Pathology

Genetics and pathogenesis

Animal models and pathogenesis

Treatment, future perspective, conclusions

References

Chapter 32: Mitochondrial Disorders

Definition, major synonyms and historical perspective

Embryology

Epidemiology

Biochemistry

Clinical features

Neuropathology

Genetics

Pathogenesis

Animal models

Future perspectives and therapy

References

Chapter 33: Disorders of Amino Acid Metabolism and Canavan Disease

Introduction

Phenylketonuria

Nonketotic hyperglycinemia (glycine encephalopathy)

Homocystinuria and disorders of sulfur amino acids

Urea cycle disorders

Maple syrup urine disease

Propionic and methylmalonic acidemia

Canavan disease (spongy leukodystrophy)

References

Chapter 34: Pelizaeus–Merzbacher Disease

Definition

Historical annotation

Epidemiology, sex distribution

Genetics

Clinical features including appropriate investigations

Pathology

Experimental models

Pathogenesis

Hypomyelinating leukodystrophies

Future direction and therapy

References

Chapter 35: Cockayne Syndrome

Definition, major synonyms and historical perspective

Incidence and prevalence

Clinical features

Pathology

Genetics

Cellular and molecular biology

Pathogenesis

Animal models

Treatment, future perspective, conclusions

References

Chapter 36: Vanishing White Matter Disease

Definition

Synonyms and historical annotations

Epidemiology

Genetics

Clinical features

Pathologic findings

Differential diagnosis

Experimental models

Pathogenesis

Future directions and therapy

References

Chapter 37: Alexander Disease

Definition

Synonyms and historical annotations

Epidemiology

Genetics

Clinical features

Macroscopy

Histopathology

Immunohistochemistry and ultrastructural findings

Biochemistry

Differential diagnosis

Experimental models

Pathogenesis

Future directions and therapy

References

Chapter 38: Neuroaxonal Dystrophy/Neurodegeneration with Brain Iron Accumulation

Definition

Normal embryology

Epidemiology

Clinical features

Pathology

Genetics

Animal models

Treatment, future perspective, conclusions

References

Chapter 39: Spinal Muscular Atrophy

Definition and classification

Epidemiology

Genetics

Clinical features

Pathology

Differential diagnosis

Animal models

Pathogenesis

Management and future directions

Atypical forms of SMA

References

Chapter 40: Autism Spectrum Disorders

Definition, major synonyms and historical perspective

Epidemiology

Clinical features

Pathology

Treatment, future perspective, conclusions

References

Chapter 41: Intrauterine Infections

Introduction

Cytomegalovirus

Herpes simplex virus

Toxoplasmosis

Rubella

Varicella

Human immunodeficiency virus (HIV)

Enteroviruses

Parvovirus B19

Zika virus

Syphilis

Listeriosis

Tuberculosis

Other infections

Differential diagnosis

References

Chapter 42: Perinatal and Postnatal Infections

Introduction

Routes of infection

Host factors influencing an infection

Bacterial infections

Viral infections

Parasitic infections

Acknowledgments

References

Chapter 43: Rasmussen Encephalitis

Definition

Synonyms and historical annotations

Epidemiology

Genetics

Clinical features

Neuropathology

Differential diagnosis

Pathogenesis

Future directions and therapy

References

Index

EULA

List of Tables

Chapter 1

Table 1.1

Table 1.2

Table 1.3

Table 1.4

Table 1.5

Chapter 4

Table 4.1

Table 4.2

Table 4.3

Table 4.4

Chapter 6

Table 6.1

Chapter 7

Table 7.1

Chapter 8

Table 8.1

Chapter 10

Table 10.1

Table 10.2

Chapter 15

Table 15.1

Chapter 16

Table 16.1

Chapter 21

Table 21.1

Table 21.2

Chapter 28

Table 28.1

Table 28.2

Chapter 29

Table 29.1

Chapter 30

Table 30.1

Chapter 32

Table 32.1

Chapter 33

Table 33.1

Chapter 34

Table 34.1

Chapter 38

Table 38.1

Table 38.2

Chapter 39

Table 39.1

Chapter 40

Table 40.1

Table 40.2

Table 40.3

List of Illustrations

Chapter 1

Figure 1.1

Close view of cranial base, showing anterior and middle cranial fossae of patient with holoprosencephaly and trisomy 13. Note absence of ethmoid derivatives (crista galli, cribriform plates) and falx cerebri. In cases of ocular hypotelorism, the basisphenoid and sella turcica may be narrowed.

Figure 1.2

Two term infants with trisomy 13. (a) Superior view of calvaria (after reflection of scalp) altered by trigonocephaly and partial metopic craniosynostosis. (b) Basal view of deformed brain from patient with trigonocephaly; note absence of olfactory tracts (arhinencephaly), asymmetric optic nerves, and dysplastic cerebellar folia.

Figure 1.3

Infant with trisomy 13. (a) Basal view of brain with holoprosencephaly. (b) superior view of same brain. Note fusion of frontal lobes and lateral ventricles.

Figure 1.4

Coloboma is encountered frequently in patients with chromosomal abnormalities. Iridal colobomata are shown from a newborn infant with classic findings of trisomy 13.

Figure 1.5

Lateral view of brain of newborn infant with trisomy 21. Note mild blunting of frontal lobe and abnormally small superior temporal gyrus, common findings in this condition. The middle temporal gyrus is enlarged.

Figure 1.6

Median section of cerebellum and brainstem altered by Chiari malformation. Note small size of cerebellum and caudal herniation of the cerebellum and medulla, unrolled posterior medullary vellum, beaking of colliculi, and herniation of brainstem; the fourth ventricle is nearly obliterated.

Figure 1.7

Dandy–Walker malformation. (a) In situ demonstration of absent cerebellar vermis. (b) Horizontal section of cerebellum, with midline space representing absence of vermis.

Chapter 2

Figure 2.1

Events of neural tube closure in the human embryo and the main types of neural tube defects arising from disorders of neurulation. Closures 1 and 3 are sites of de novo initiation of fusion of the neural folds. Closure 2, which occurs at the forebrain–midbrain boundary in mouse embryos, is absent from human neurulation. Neural tube closure spreads between these sites with completion of closure at the rostral (or anterior), and caudal (or posterior) neuropores. The tail bud (green shaded region) contains a bi-potential neuromesodermal precursor cell population that gives rise to the sacral and caudal neural tube, through the process of secondary neurulation. These morphogenetic events occur sequentially between days 22 and 28 post-fertilization but, for purposes of clarity, have been projected onto a drawing of a late neurulation-stage embryo (reproduced with permission from

Lancet Neurology

12:799–810 [71]).

Figure 2.2

Craniorachischisis, as viewed from the back (a) and top of the head (b). Note the widely spaced pedicles of the vertebrae (arrows in a), and the area cerebrovasculosa (red arrow in b).

Figure 2.3

Anencephaly, as viewed from the front (a) and back (b). Note the area cerebrovasculosa (red arrow in b).

Figure 2.4

Myelocele (a) and myelomeningocele (b) as viewed from the back. In myelocele, the lumbosacral spinal cord is open and appears as a flat vascular lesion (a), whereas in myelomeningocele, the lesion comprises a fluctuant, cystic mass protruding through the dorsally open vertebrae (b).

Figure 2.5

Occipital encephalocele, as viewed from behind (a) and in a postmortem dissected specimen (b). The brain and meninges have partially herniated symmetrically through a defect in the occipital skull (a). Cut surface of a large surgical specimen (b) shows two attenuated occipital lobes that have herniated with their ventricular cavities (vc). The cortex varies in thickness and is partly fused (red arrow). Between brain and skin there is vascular meningeal tissue (red arrowhead) and a cystic space (yellow asterisk).

Figure 2.6

Anterior encephalocele. The large frontoethmoidal brain herniation has severely deformed the face, with compression of orbits and nose.

Figure 2.7

Hydromyelia and split cord (diplomyelia): (a) Hydromyelia, as observed in serial slices through the spinal cord. The expansion of the lumen is localised to the lumbar level of the cord (red arrow). (b) Split cord, observed in a haematoxylin and eosin-stained section. As the hemi-cords exist within a single dural sac, this defect is referred to as split cord malformation type II, according to the classification of Pang

et al

. [72]. Reproduced with permission of Oxford University Press.

Figure 2.8

Simplified summary of folate one-carbon metabolism. Cytosolic and mitochondrial reactions move one-carbon units around the pathways, generating purines and pyrimidines for DNA synthesis and methyl groups for methylation reactions (bold dotted arrows and white boxes) as the main outputs. MTHFR (5,10-methylene tetrahydrofolate reductase) and GCS (glycine cleavage system) are two enzyme systems (grey boxes) in which mutations have been identified to increase risk of neural tube defects. Note that dietary folate and folic acid enter at different steps in the pathways (light dotted arrows). DHF, dihydrofolate; Hcy, homocysteine; 5-MTHF, 5-methyl tetrahydrofolate; SAH, s-adenosyl homocysteine; SAM, s-adenosyl methionine; THF, tetrahydrofolate.

Figure 2.9

Mouse fetuses at embryonic day (E) 15.5 illustrating the appearance of (a) craniorachischisis in a

Celsr1

mutant and (b) exencephaly and open spina bifida in a

curly tail

(

Grhl3

) mutant. In craniorachischisis, the neural tube is open from midbrain to low spine (between the thin arrows in a). Exencephaly appears as an eversion of the cranial neuroepithelium which, in the

curly tail

fetus is restricted to the midbrain (thin arrow in b). The spina bifida affects the lumbosacral region (arrowhead in b). Note the presence of a curled tail in both fetuses (thick arrows in a and b).

Figure 2.10

Pathogenesis of craniorachischisis, as revealed by studies in the mouse. (a–d) Diagram of normal development in which the neural plate undergoes shaping prior to the onset of neural tube closure, at E8.5 Views from the left side (a, b) and top (c, d) of E7.5–8.0 (a, c) and E8.5 (b, d) embryos. Anterior is to the left, and posterior to the right. At E7.5–8.0, the retreating node (red), the site of origin of midline tissues including the notochord and neural tube floor plate, is prominent at the anterior end of the primitive streak. Anterior to the node, cells are moving medially and intercalating in the midline (red arrows in c). This process, termed ‘convergent extension’, leads to an increase in embryonic length relative to width by the stage of onset of neural tube closure. By E8.5, the primitive streak occupies only the caudal part of the embryo, with a well-defined neural plate anteriorly, flanked by five pairs of somites. The neural folds at the level of the third somite pair approach each other in the midline, to create the incipient Closure 1 site. (e–g) Scanning electron micrographs of neurulation stage embryos. The red line (e) passes through the Closure 1 site, and shows the plane of section in (f) and (g). Normal neural tube closure at this level involves midline bending to create a V-shaped neural plate (f) whereas this bending is disrupted in an embryo homozygous for the

loop-tail

(

Lp; Vangl2 gene

) mutation. A broadened midline, resulting from defective convergent extension, yields a U-shaped neural plate that cannot close owing to the wide spacing of the neural folds (g). Scale bar in (e) represents 0.25 mm (e) and 0.04 mm (f and f); cnf, caudal neural folds; hnf, hindbrain neural folds (modified from Greene

et al

. [73]).

Figure 2.11

Key developmental events in mouse cranial neurulation, each of which has been implicated in the development of exencephaly in mouse mutants. (a) Initial elevation of the cranial neural folds, and (b) dorsolateral inward bending of the neural fold tips, to achieve closure. See text for details (reproduced with permission from Copp and Greene [74].

Figure 2.12

Regulation of spinal neural tube closure by the influence of sonic hedgehog (Shh) and BMP diffusible proteins. Shh enhances midline bending (yellow triangles) but inhibits dorsolateral bending (red triangles). At upper spinal levels, Shh influence is strong and Noggin synthesis in the dorsal neural plate is inhibited. Bmp2 signalling from the adjacent surface ectoderm is unopposed by Noggin, and this inhibits dorsolateral bending. At low spinal levels, Shh influence during neurulation is less strong. Noggin expression is no longer inhibited and represses Bmp2 action, leading to dorsolateral bending (modified from Ybot-Gonzalez

et al.

[57]). Reproduced with kind courtesy of The Company of Biologists Ltd.

Chapter 3

Figure 3.1

The morphogen and holoprosencephaly (HPE) gene network in forebrain development (modified from Monuki [1]) Left, network diagram based on human and experimental model studies, with the four major HPE genes in red. Mutations in

FGF8

and

NODAL

have also been described in human HPE. Right, schematic of the developing forebrain (anterior oblique view) with midline morphogen sources indicated (purple, dorsal; green, rostral; dark blue, ventral). Reproduced with permission of Oxford University Press.

Figure 3.2

Alobar, semilobar and lobar holoprosencephaly. (a) Frontal view of a 20-week fetus with alobar holoprosencephaly, note there is no fissure separating the two hemispheres. (b) An adult with alobar holoprosencepahly showing continuity of the gray matter across the dorsal midline. This patient had minimal ventral abnormalities which is atypical for most cases of alobar holoprosencephaly. (c) Semilobar holoprosencephaly with a small cleft partially separating the dorsal–caudal cerebral hemispheres (caudal view, 19-week fetus). (d) Full-term child with semilobar holoprosencephaly. The diencephalic structures are fused and there appears to be a sagittal fissure, however, gray matter is seen crossing the midline and there is no corpus callosum. (e) 20-week fetus with lobar holoprosencepahly. The cerebral hemispheres appear separated in both anterior (top) and posterior (bottom) sections, although the diencephalon is fused (bottom section). (f) Coronal section from the same brain as (e) showing fusion across the midline in the frontal cortex only.

Figure 3.3

Middle interhemispheric variant of holoprosencephaly. A gray matter mass is fused across the midline of the dorsal forebrain, however the ventral structures including the myelinated optic tracts (arrowheads), appear normal. Coronal whole brain section (Luxol fast blue–hematoxylin and eosin).

Figure 3.4

Partial and complete agenesis of the corpus callosum. (a) A midsagittal section of the brain from a patient with complete agenesis of the corpus callosum. The medial gyri project to the midline without an intervening cingulate gyrus (arrows). This brain also shows a dilated and posteriorly rotated vermis (Dandy-Walker malformation). (b) A midsagittal section of a brain with partial agenesis of the corpus callosum. The partial corpus callosum present (black arrowheads) extends from the lamina terminalis posteriorly. The cingulate gyrus (partially obscured by the arrowheads) extends the length of the corpus callosum. Sulci extend from the dorsal surface of the brain to the third ventricle only posterior to the formed corpus callosum (white arrows). The cingulate gyrus and sulcus is found only where the corpus callosum is present (white arrowhead). (c) Section of a brain with agenesis of the corpus callosum (Luxol fast blue–hematoxylin and eosin). The lateral ventricle has taken on the batwing appearance and a bundle of Probst is present.

Figure 3.5

Septo-optic dysplasia. A coronal section through the brain of a child (two weeks postnatal, full term pregnancy) with septo-optic dysplasia. Note the smooth surface under the corpus callosum where the septum usually inserts. The fornix is free-floating in the ventricle.

Chapter 4

Figure 4.1

Overview of the different types of neural progenitors and their division modes during neurogenesis. (a) GW25 brain coronal section. (b) Diagram showing the different neural progenitors populating the VZ, i and oSVZ and generated neurons at mid neurogenesis. (c) Symmetric division of neural progenitors. (d) Asymmetric division of neural progenitors and their daughter cells.

Figure 4.2

T1-weighted images showing the typical features of MCPH1 (a) WDR62 (b) and ASPM (c) compared with an age-matched control (d).

Figure 4.3

(a) Microcephalia vera: termination of pregnancy for microcephaly at 35 weeks of gestation; brain weight: 251 g; third centile for term. All primary fissures, secondary and tertiary convolutions are present. (b) Microcephaly with harmonious simplified pattern. Termination of pregnancy for microcephaly at 31 weeks of gestation; brain weight (128 g) and external maturation correspond to 27 weeks of gestation. (c) Microcephaly with dysharmonious simplified gyration, with dysmorphic Sylvian fissure (arrow), presence of superior temporal fissure (normally present at 27 weeks of gestation), but with no pre- and post-central gyri (normally present at 25 weeks of gestation). Termination of pregnancy at 31 weeks of gestation; brain biometric data correspond to 24 weeks. (d) Marked frontal lobe hypoplasia (same case). (e) Agenesis of the corpus callosum (arrow) (same case). (f) Coronal section through the diencephalon, showing almost no fissures; brain weight: 88 g (< third centile for 22 weeks of gestation). Termination of pregnancy at 28 weeks for isolated microlissencephaly.

Figure 4.4

(a) Immature cortical plate with accumulation of granular neurons in layer II, other layers being hardly visible (×20). Termination of pregnancy at 26 weeks of gestation for microcephaly with simplified gyration and short corpus callosum. (b) Normal cortical plate in an age-matched control (×20). (c) Diffuse microcolumnar dysplasia of the cerebral cortex (×200). Termination of pregnancy at 23 weeks of gestation, brain measurements correspond to 20 weeks (recurrence of case depicted in d). (d) Marked neuron depletion (×250). Termination of pregnancy at 36 weeks of gestation for microcephaly with simplified gyration, brain measurements correspond to 32 weeks). (e) Small protrusions of external granular layer within layer I (×400), not to be confused with status verrucosus. Termination of pregnancy at 33 weeks of gestation for isolated microcephaly. (f) With focal frontal micropolygyria (arrow) (×10).

Figure 4.5

(a) Periventricular neuronal heterotopia (arrow) and premature regression of the ganglionic eminences (×200) (same case as in figure 4.1c). Termination of pregnancy at 31weeks of gestation. (b) Nodular neuronal heterotopia intermingled with the internal capsule (arrow) and the basal ganglia (×200). Termination of pregnancy at 19 weeks of gestation for severe microcephaly; brain weight: 14.3 g, less than third centile. (c) Numerous streaky neuronal heterotopia in the intermediate zone (×200). Termination of pregnancy at 30 weeks of gestation for microcephaly with simplified gyration; brain weight: 89 g, corresponding to 23 weeks of gestation. (d) Purkinje cell heterotopia (arrow) (×400). Termination of pregnancy at 35 weeks of gestation for microcephaly with simplified gyral pattern.

Chapter 5

Figure 5.1

Overview of the PI3K–AKT–MTOR intracellular signaling pathway, and genes linked to different dysplastic megalencephaly (DMEG) and hemimegalencephaly (HMEG) phenotypes. The PI3K–AKT–MTOR pathway regulates cell and tissue growth, in response to signals from receptor tyrosine kinase (RTK) binding by growth factors and other molecules [13]. Activation of PI3K, which has catalytic (p110) and regulatory (p85) subunits, leads to increased synthesis of PIP3, a potent signaling molecule that controls multiple downstream cascades. PTEN, a phosphatase, damps PI3K-AKT-MTOR signaling by degrading PIP3. Many enzymes in this pathway, such as AKT, have multiple isoforms encoded by different genes with tissue-specific expression, such as AKT3 in brain. Genes and mutation status linked to different DMEG or HMEG phenotypes and syndromes are indicated in boxes, and notable mouse models outside the boxes. EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; MCAP, megalencephaly capillary malformation syndrome; MEG, megalencephaly (usually DMEG); MPPH, megalencephaly polymicrogyria polydactyly hydrocephalus syndrome; PHTS,

PTEN

hamartoma tumor syndrome.

Figure 5.2

Neuroimaging of dysplastic megalencephaly and hemimegalencephaly caused by germline and somatic AKT3 activating mutations, respectively. (a) Axial magnetic resonance imaging (MRI) of a boy with a germline AKT3 mutation (p.R465T) shows generalized brain overgrowth, with bilateral cortical dysplasia resembling polymicrogyria (arrows). (b) Axial MRI of a girl with a functionally severe AKT3 mutation (p.E17K) in the mosaic state, causing left HMEG (3 arrows), plus limited right posterior cortical dysplasia (single arrow).

Figure 5.3

Macroscopic brain abnormalities and histopathology of dysplastic megalencephaly (DMEG) and hemimegalencephaly (HMEG): (a–d) DMEG in a child born at 37 gestational weeks who lived for 11 weeks. (a,b) Both hemispheres were large (brain weight 905 g, expected 506 ± 67 g) and exhibited abnormal gyral patterns. (c) In slices, the cortical gray matter appeared thick and dysplastic (pachygyria-like), and cerebral white matter was prematurely myelinated. (d) Histologic section through lateral temporal cortex, stained by immunohistochemistry for microtubule-associated protein 2 (MAP2), revealed thickening and dyslamination of the cortical ribbon, and numerous small periventricular heterotopia (arrows). (e–i) HMEG in a premature infant born at 34 gestational weeks who lived for 11 days: (e) The left hemisphere was larger, most notably in the occipital region (arrow). (f) The cortex was variably thickened, with abnormal configuration of sulci and gyri. (g) The left cerebellar hemisphere was larger. (h) Dysplasia involved the left hippocampus. (i) Leptomeningeal glioneuronal heterotopia. Scale bar: (d), 2 mm (adapted from Hevner [11]). Reproduced with permission of Elsevier.

Chapter 6

Figure 6.1

Schematic outline of early mouse cortical development. At E8.5, the wall of the neural tube consists of a pseudostratified neuropepithelium (band of blue cells). Cell processes maintain contact with both the inner (bottom of figure) and outer (top of figure) surfaces of the neural tube. However, the nucleus migrates according to the cell cycle with mitoses (M phase) occurring at the ventricular surface and S-phase at the pial surface. At E10, the first cells delaminate from the germinal neuroepithelium, which defines the ventricular zone and form the preplate. The preplate is composed of Cajal–Retzius neurons (light green cells) and subplate neuros (yellow cells). During the ensuing days, those ventricular zone cells which exit the cell cycle become neuroblasts (dark blue cells) and migrate from the ventricular zone along radial glia (red cells in the ventricular zone) to populate the definitive cortical plate. The neuroblasts that become layers II–VI split the preplate, leaving the subplate neurons adjacent to the ventricular zone while the Cajal-Retzius cells remain in contact with the pial surface. Cells accumulate from inside-to-out beginning with layer VI (purple cells) and ending with layer II neurons (pink cells).

Figure 6.2

External view of brain with lissencephaly. Note the complete absence of gyri and sulci at the surface.

Figure 6.3

Hemisection of brain from patient with lissencephaly. The cerebral cortical gray matter is markedly thickened and the white matter is diminished. Myelination in layer III can be seen (arrow). There is mild sparing of the temporal lobe where some evidence of gyral formation is present and the hippocampus is preserved.

Figure 6.4

Neurofilament stained section from patient with lissencephaly and schematic of normal cortical laminar organization and that found in lissencephaly. Neurofilament staining highlights the few cells in layer I, the numerous large and disorganized pyramidal neurons in layer II, the relatively hypocellular layer III which becomes myelinated (see Figure 6.3.), and the thick layer IV composed of medium and small neurons. The schematic highlights the normal organization of the cortex in contrast to that found in classical lisssencephaly. Note the apparent reversal of layers with the exception of Cajal–Retzius neurons in layer I (green).

Figure 6.5

Summary of the LIS1 and RELN signaling pathways for neural migration. Extracellular Reln binds to one of three receptor complexes: cadherin-related neural receptor (Cnr), VldlR/ApoER2, or 3β1 integrin. Receptor stimulation causes activation of mDab1, which, via c-Abl or other pathways, can activate Cdk5/p35. Cdk5 can phosporylate many intracellular targets including regulators of the actin cytoskeleton and Nudel. Phosphorylated Nudel forms a complex with Lis1, mNudE, Dynein and microtubules. This complex is required for nuclear positioning and cell migration.

Dcx

is also believed to modulate microtubule function. Adapted from Wynshaw-Boris and Gambello [59].

Chapter 7

Figure 7.1

A hypothesized scheme for the pathogenesis of type II lissencephaly. In normal development, cells migrate out and populate the cortical plate in an inside to outside fashion. In type II lissencephaly, the initial migration to the cortical plate may be normal, but subsequent cells migrate past the cortical plate and into the leptomeninges.

Figure 7.2

Histopathological features of type II lissencephaly. (a) Normal cortex at 20 weeks of gestation. Note the well defined and uniform molecular layer (black arrowhead) and the well defined thickness of the cortical plate (white line). (b) Twenty-week fetus with Walker–Warburg syndrome. The cortex is markedly thickened (white line, compare to a). It shows marked disorganization with large blood vessels (black arrow) buried deep in the parenchyma. There is a well-defined white matter but the irregular border with the cortex blurs the gray–white junction. (c) Four-month-old child with Walker–Warburg syndrome. The cortex shows no clear laminar structure with undulating vessels in the parenchyma and irregular arrangement of neurons around these vessels. Although not well appreciated on this section, areas of polymicrogyria-like cortex can be found.

Figure 7.3

Section of 21-week fetus with Walker–Warburg syndrome. (a) Compare with Figure 7.1; an apparent cortical plate (CPa) exists below a line of what was likely the original pial–glial limitans (horizontal white arrow at right). There are numerous areas where an apparent breach of the pial–glial limitans has occurred (see vertical white arrows as examples). The subsequent cells migrate past this into the leptomeninges forming a second and highly disorganized cortical region (CPb). (b) Vimentin-labeled radial glia extend past CPa into the area of CPb, possibly providing a migratory route for neurons. The disorganized cortex is again appreciated, as in Figure 7.2.

Figure 7.4

Cerebellum from a patient with Walker–Warburg syndrome, showing the marked disorganization of both granular neurons and Purkinje cells.

Figure 7.5

The glycosylation that occurs on α-dystroglycan in response to the enzymes affected in various congenital disorders of glycosylation (reproduced from Willer

et al

. [52]).

Chapter 8

Figure 8.1

Polymicrogyria. (a) The external surface of the brain exhibits a fine bumpy appearance often likened to morocco leather or cobblestones. (b) Section of the brain demonstrates the hyperconvoluted cortex with a festooned surface. The abnormal cortex is markedly thickened on gross appearance; however, this is an illusion created by the extensively folded microgyria; in fact, the cortex in polymicrogyria is thinned.

Figure 8.2

Acquired polymicrogyria in varicella zoster embryopathy. The polymicrogyric cortex shows complex folding, fusion and branching.

Figure 8.3

Schematic diagram of polymicrogyria. The upper image shows the normal development of gyri and sulci with leptomeningeal vessels (red), the pial–glial limitans (lavender) and a cartoon of the laminated cortex. In polymicrogyria (lower image), there is fusion across the pial–glial limitans with entrapment of blood vessels and thinning of the cortex.

Chapter 9

Figure 9.1

Leptomeningeal heterotopia. (a) Focal leptomeningeal heterotopia in a nine-month-old infant demonstrating the “eruption” of cortical neurons and marginal zone tissue through the pial–glial barrier and into the overlying leptomeninges (hematoxylin and eosin, H&E). (b) Immunohistochemistry for NeuN shows mature pyramidal neurons present within a leptomeningeal heterotopia. Synaptic connections appear to exist between these heterotopic neurons and those within the underlying brain (diaminobenzidine reaction). (c) Immunohistochemistry for glial fibrillary acidic protein shows a disorganized collection of enlarged reactive astrocytes within a leptomeningeal heterotopia. Focal discontinuity of the normally uniform layer of subpial astrocytes that form the glia limitans is associated with the lesion (alkaline phosphatase reaction). (d) Diffuse leptomeningeal heterotopia overlying the brainstem in a fetal case of lissencephaly. The lesion contained classic confluent eruptions of glioneuronal tissue into the leptomeninges with encasement of cranial nerves and large vessels (H&E).

Figure 9.2

Macroscopic appearance of subcortical-band heterotopia demonstrating the classic features of a well-delineated band of gray matter located in the centrum semiovale. Note the presence of well-myelinated white matter superficial and deep to the heterotopic gray matter, and the lack of involvement of intragyral white matter. The overlying cortex in this case had a normal appearance, but can be pachygyric in others. Subcortical-band heterotopia may appear as a solid band of heterotopic tissue or as numerous islands of radially oriented gray matter separated by white matter, as in this case. (Courtesy of Joe Gleeson, UC San Diego.)

Figure 9.3

Periventricular heterotopia. (a) Macroscopic appearance of periventricular heterotopia, consisting of multiple confluent nodules lining the lateral ventricles and distorting the ventricular surface. (b) Macroscopic appearance of nodular heterotopia in a diffuse distribution. Note the presence of nodules in periventricular and subcortical locations, as well as the involvement of normal gray matter structures. Such florid cases can make identification of normal gray matter and the distinction of periventricular compared with subcortical-band heterotopia difficult. (Courtesy of Phil Boyer, UT Southwestern.) (c) Microscopic appearance demonstrating multiple discrete nodules of gray matter separated by strands of myelinated white matter (hematoxylin and eosin/Luxol fast blue).

Chapter 10

Figure 10.1

Hippocampal sclerosis. (a) Postmortem from a patient with sudden death in epilepsy who had not undergone magnetic resonance imaging during life; bilateral hippocampal sclerosis was confirmed at postmortem. (b) A surgical resection of the hippocampus in a patient with temporal lobe epilepsy, sliced coronally, showing visible atrophy of CA1 sector (arrowed). (c) and (d) MAP2 staining can aid in the confirmation of hippocampal sclerosis with preservation of neurons and dendrites in the intact CA1 and CA4 of a normal hippocampus (c) compared with reduction of labeling in these regions in hippocampal sclerosis (d). (e) GFAP confirmed intense labeling in CA1 and CA4 compared with the subiculum in hippocampal sclerosis. (f, g, h, i) Mossy fiber sprouting in the molecular layer is a common finding and can be confirmed with zinc transporter 3 (ZnT3) immunolabeling (f); mossy fiber sprouting also shown in higher magnification in (g) Timms stain, (h) dynorphin immunohistochemistry and (i) ZnT3. Original magnification (b, c, d, e, f) ×1; (g, h, i) ×20.

Figure 10.2

Granule cell dispersion. (a, b) Shown at higher magnification with haemotoxylin and eosin stain (a) and cresyl violet (b), with increased separation of the cells, intervening neuropil, and elongated and fusiform appearing neurons. (c–f) NeuN showing a relatively compact and normal granule cell layer in hippocampal sclerosis (c) contrasting with regions showing clusters of dispersed cells in the molecular layer, or a focal bilaminar pattern (d), poor definition of the basal cell layer in addition to the outer layer (e), and “migration” of single neurons into the molecular layer (f). Original magnification: ×20. (g) Low-power view of entire dentate gyrus with dispersion of the granule cells imparting a bilaminar pattern (NeuN).

Figure 10.3

Focal cortical dysplasia type IIA. (a) With region of cortex showing scattered dysmorphic neurons on hematoxylin and eosin (H&E) stain; (inset) these neurons are highlighted with neurofilament immunohistochemistry. (b) FCDIIB on macroscopic examination shows regions of poor definition between the white and gray matter, and ‘thickening’ (arrow) compared with adjacent slice on the right side, with normal cortex. (c) Balloon cells in FCDIIB on H&E with dysmorphic neuron shown at higher magnification (inset) with coarse Nissl substance. (d) The abnormalities of lamination can be appreciated on NeuN staining, which, in this case, shows a transition from laminated cortex to the right of the arrows compared with a dyslaminar cortex to the left of the arrows in the region of dysplasia. (e) Neurons in FCDIIB from case shown in (d) at higher magnification on NeuN, with dysmorphic and hypertrophic neurons mingled with normal-appearing and -sized neurons. (f) Neurofilament immunohistochemistry (nonphosphorylated, as shown here, as well as phosphorylated neurofilament) highlight the dysmorphic and hypertrophic pyramidal neuronal cells, as well as thick dendrites and axons. (g) Myelin basic protein immunohistochemistry shows paucity of axon labeling in the white matter in the zone of FCDIIB compared with (inset) normal white matter myelination. (h, i, j) Balloon cells. Immunohistochemsitry for intermediate filaments such as nestin shown here (h), as well as vimentin, GFAP and GFAP-delta, highlight balloon-cell populations, which can also show focal membranous labeling with stem-cell markers as CD34 (i) and strong expression of gap junction proteins (connexin 43) (j), among others. Original magnification: (a) ×10, (c, e, f, g, h) ×20, (d) ×2.5, (i, j) ×40.

Figure 10.4

Focal cortical dysplasia type IIIA and IIIB. (a) FCDIIIA (dysplasia adjacent to hippocampal sclerosis in temporal lobe epilepsy) with clustering of neurons in the most superficial aspect of layer II and loss of neurons from the deeper parts of layer II and layer III pyramidal cells. (b) FCDIIIA architectural abnormalities are always accompanied by gliosis of the superficial cortex on GFAP in the regions of cell loss. (c, d) FCDIIIB is cortical dysplasia adjacent to low-grade glioneuronal tumors. In this case, apparent abnormal lamination in NeuN (c) was a result of infiltrating CD34-positive tumor cells at the margins of a ganglioglioma, highlighted in (d) with CD34 labelling. (e) Clustering of small layer II neurons in FCDIIIA shown at high magnification through a thick section and abnormal orientation compared with (f) normal temporal lobe cortex. Original magnification: (a, b) ×10 and (c, d) ×2.5, (e, f) ×40; all figures are NeuN apart from those indicated.

Figure 10.5

Focal cortical dysplasia type IIIC. (a, b, c, d) Occipital lobe resections (a) for an adult with Sturge–Weber syndrome seen in (b) on coronal slicing. Abnormal leptomeningeal vessels with calcification and atrophy of the underlying cortex on haemotoxylin and eosin (c). Dyslamination and cortical thinning, as well as some mineralization, extended beyond the boundaries of the vascular anomaly and into adjacent gyri a shown with NeuN (d), amounting to FCD IIIC (FCD adjacent to a vascular malformation). Original magnifications in (c) and (d) ×10.

Figure 10.6

Focal cortical dysplasia type IIID. (a) Cortical resection in an adult with epilepsy with a known hypoxic ischemic cortical damage occurring in the perinatal period. (b) Coronal slices confirm a “ulegyric” pattern of atrophy to some gyri. (c) High field magnetic resonance imaging (MRI) with a 9.4T MRI shows the lamination of the cortex in more detail than conventional MRI, as well as regions with disrupted lamination (arrow). (d) Neuronal markers as MAP2 can highlight the abnormal cortex adjacent to the main lesion/infarct; in this case, illustrating the thick cortical layer with a corrugated interface between gray and white matter – the so-called

etat criblé

, or post-ischemic marbled cortex. (e) GFAP stain also highlights patchy islands of gliosis in the cortex at this region and islands of gray matter. (f, g) NeuN showing a regions of more normal laminar cortex in the margins (f) compared with abnormal regions harboring FCDIIID in (g). Original magnifications (d, e) ×1 and (f, g) ×2.5.

Chapter 11

Figure 11.1

Subependymal giant cell astrocytoma. Coronal post-contrast T1-weighted magnetic resonance image demonstrates a large exophytic mass with avid enhancement in the right lateral ventricle near the foramen of Monro. Images courtesy of Dr. Noriko Salamon, Department of Radiological Sciences, UCLA Medical Center, California.

Figure 11.2

Multiple cortical tubers and subependymal nodules. Axial magnetic resonance imaging demonstrates multiple areas of subcortical hypointensity on T1-weighted image (a) and corresponding hyperintensity on T2/fluid attenuated inversion recovery sequences (b) including bilateral posterior parietal lobes (arrows). Multiple small subependymal nodules are also present (arrowheads). Images courtesy of Dr. Whitney B Pope, Department of Radiological Sciences, UCLA Medical Center, California.

Figure 11.3

Cortical tuber and subependymal nodules. (a) Coronal section of right cerebral hemisphere from an autopsy of a patient with tuberous sclerosis showing blurring of the cortical–white matter junction (arrow) indicative of a tuber. (b) Multiple subependymal nodules with calcification are seen in both lateral ventricles (arrowheads), of the same patient.

Figure 11.4

Cortical tuber. (a) Neuronal disorganization can be appreciated at low magnification. (b) Highlighted with NeuN immunohistochemistry. (c) Enlarged cells with abundant glassy eosinophilic cytoplasm, “balloon cells” (arrow), admixed with bizarre dysmorphic appearing neurons (arrowheads), which show variable staining with NeuN (d).

Figure 11.5

Cortical tuber from a young child with tuberous sclerosis and infantile spasms. (a) Numerous balloon cells with eccentric nuclei, coarse chromatin, occasional prominent nucleoli, and eosinophilic cytoplasm that are variably positive for glial fibrillary acidic protein (b). Dysmorphic neurons with abnormal processes highlighted by neurofilament staining (arrows, c) and membranous halo of synaptophysin immunoreactivity (d).

Figure 11.6

Cortical tuber. Dysmorphic, markedly enlarged neurons, with abnormally dispersed Nissl substance and bizarre ramified processes.

Figure 11.7

Cortical tuber from a young child with tuberous sclerosis, intractable epilepsy and developmental delay. (a,b) Balloon cells with vacuolated cytoplasm, focally in small clusters (a).

Figure 11.8

Surgically resected SEGA. (a) SEGAs are well demarcated from adjacent brain (arrows) and are composed of large cells and often perivascular pseudorosettes (inset). (b) The polygonal cells resemble gemistocytic astrocytes, as well as ganglion cells with their coarse chromatin, prominent nucleoli, and glassy eosinophilic cytoplasm. (c) Calcifications, prominent in this case can also be seen. (d) The tumour cells are variably positive for glial fibrilaary acidic protein.

Figure 11.9

Tuberous sclerosis mouse model. Coronal haemotoxylin and eosin stained section of brain from a tuberous sclerosis mouse model demonstrating megalencephaly (a) and neuronal disorganization, highlighted with NeuN immunohistochemistry (c), compared with a control mouse (b, d).

Chapter 12

Figure 12.1

Midline section of adult with a Chiari type I malformation. Note that the cerebellar vermis is completely intact and the fourth ventricle has a normal morphology. The cerebellar tonsils extend down over the cervical spinal cord.

Figure 12.2

A Chiari type II malformation in a 20-week fetus with a lumbosacral myelomeningocele. (a) Dorsal view with the midline cerebellar vermis extending down over much of the cervical cord (arrow). The fused inferior colliculus can also be appreciated from this view. (b) Lateral view from the same case with the cerebellar vermis (arrow) lifted up exposing the underlying cord. The elongated fourth ventricle, abnormal medulla and pons are not as obvious.

Figure 12.3

A newborn child with a Chiari type III malformation. Note the cervical/low occipital origin of the encephalocele, which contained cerebellum (courtesy of Dr. R Hakim).

Chapter 13

Figure 13.1

Classic examples of Dandy–Walker malformation (DWM). (a, b) Case of Dandy and Blackfan [8], drawings by Brödel. The girl was well until she had meningitis and seizures at 4 postnatal months, then had progressive hydrocephalus and death at 13 months. Ventral view (a) shows the distended fourth ventricle cyst, and laterally splayed hemispheres. Sagittal view (b) shows the hypoplastic, upwardly rotated cerebellum. The cyst displaced tentorium superiorly, and contained choroid plexus. (c, d) DWM in a four-year-old girl [40]. Midsagittal slice (c) of the brainstem and cerebellum reveals upward rotation of the vermis, and splayed hemispheres. Histology (d) reveals flayed appearance of the nodulus (labeled “N”), separated through white matter, with cerebellar cortex in anterior cyst wall.

Figure 13.2

The Dandy–Walker malformation (DWM) spectrum of cystic fourth ventricle malformations includes mega-cisterna magna (MCM), Blake's pouch cyst (BPC), and DWM. In a previous nosology, the “Dandy–Walker complex” was proposed to include MCM, BPC, DWM, and cerebellar vermis hypoplasia (CVH) [1], but genetic links between CVH and DWM are few [13]. Diagrams represent sagittal magnetic resonance images (anterior left, superior up). Key: brainstem, gray; vermis, medium blue; hemisphere, lavender; tela choroidea or cyst membrane, light green; ependyma, dark green; choroid plexus, red; torcula, dark blue; pia, yellow; arachnoid, light blue; dura, orange; bone, brown. Arachnoid trabeculae (not shown) traverse the subarachnoid space and contact the pial surface, including tela choroidea.

Figure 13.3

Magnetic resonance images of Dandy–Walker malformation. The vermis (v) is small with reduced folia, and is rotated far upward (a) so the fourth ventricle (4v) communicates widely with a large posterior fossa cyst (cy) (a, b). Cerebellar hemispheres (he) are moderately splayed (a, b), and appear less prominent in sagittal view (a). The posterior fossa is enlarged, and the torcula (t) is elevated.

Figure 13.4

Dandy–Walker malformation in 27 weeks of gestation fetus. (a) Cerebellum and brainstem, posterior view into the fourth ventricle. Immersed under water, the delicate cyst membranes are visible surrounding the cerebellum. The small vermis is rotated upward, and the hemispheres are splayed apart. (b) Cyst membrane, interior down (hematoxylin and eosin). Note trilaminar appearance of flattened ependyma, disorganized neuronal and glial elements, and leptomeninges. Scale bar: 100 µm.

Figure 13.5

Prominent cisterna magna in an 18-day-old infant, born prematurely at 34 weeks of gestation. Transcranial ultrasound indicated mega-cisterna magna, possible Dandy–Walker malformation. Additional studies were diagnostic of Smith–Lemli–Opitz syndrome with microcephaly. (a) Cerebellum and brainstem, posterior view into the fourth ventricle. A thin, gray, glistening, translucent membrane (tela choroidea) covered the posterior fourth ventricle (arrows). The brain was photographed in air so the membrane appears partially collapsed. (b) The vermis appeared hypoplastic. Enlargement of the retrocerebellar space reflected cerebellar hypoplasia without cystic dilatation of the fourth ventricle, so the pathologic diagnosis was prominent cisterna magna (tela choroidea collapsed during slicing).

Figure 13.6

Multifactorial pathogenesis of Dandy–Walker malformation (DWM) and related disorders. The continuum of mega-cisterna magna– Blake's pouch cyst –DWM malformations is a product of diverse etiologies, pathogenesis, and modifying factors. Important factors in fourth ventricular cyst expansion include timing, severity, and duration of foraminal occlusion. Cerebellar dysgenesis in DWM may be caused by a combination of direct effects of factors such as mutations and teratogens, as well as indirect effects of altered meningeal signaling and cyst expansion and pressure. In some cases, isolated cerebellar vermis hypoplasia may be caused by the same underlying etiology; for example, mutations in genes that are also linked to DWM (e.g.,

FOXC1

mutations).

Chapter 14

Figure 14.1

Neuroimaging of Joubert syndrome: the molar tooth sign. (a) Sagittal plane: the vermis is very small, but found in a normal position (yellow arrowheads). The cerebellar tissue filling the posterior fossa behind the vermis is hemisphere tissue, since the imaging plane was not perfectly parallel to midline. The fourth ventricle (white asterisk) is enlarged. (b) Axial image shows thick and long superior cerebellar peduncles (yellow arrowheads), forming the roots of the so-called “molar tooth” sign. The basis pontis and ventral midbrain form the tooth crown (blue arrowheads). Note the fluid-filled midline space (black asterisk), resembling a Dandy–Walker type cyst.

Figure 14.2

Macroscopic features of the brainstem and cerebellum in Joubert syndrome. The patient was 13 months old at death, and had

TCTN2

mutations (subject 4 [17]). (a) Ventral view (anterior up) shows pyramids separated by a deep cleft (blue arrowheads), with little or no decussation. (b) Inferior view (dorsal up) shows enlarged cerebellar hemispheres wrapping almost circumferentially around the medulla. The fourth ventricle (white asterisk) was enlarged and communicated with a fluid-filled space covered by a thin membrane, reminiscent of a Dandy–Walker cyst. (c) Transverse slice at the level of the upper pons shows only a tiny rudiment of vermis in the anterior midline; almost all of the cerebellar tissue is hemispheres. The fourth ventricle exhibits a “bat-wing” or “inverted umbrella” appearance. Inset shows a superior view (dorsal up), with enlarged superior cerebellar peduncles (yellow arrowheads) connecting to the midbrain.

Figure 14.3

Histologic anomalies in the Joubert syndrome brainstem and cerebellum. (a) The dentate nuclei of the cerebellum, rather than forming a ribbon, are broken up into small islands. Neurofilament immunohistochemistry. (b) Cross section through the cervicomedullary junction of a patient with posterior medullary protuberance [17,18]. The dorsal region (normal location of dorsal column nuclei) is extremely disorganized (blue arrowheads), and no posterior median sulcus is present. Boxed area is the normal location of the pyramidal decussation, where very few crossing fibers were seen. Myelin basic protein immunohistochemistry. (c) Sagittal section (anterior left) through brainstem and cerebellum of a fetus at 22 weeks of gestation with Joubert syndrome and posterior medullary protuberance (arrow). The corticospinal tracts (asterisk) was tightly bundled and did not decussate or shift to dorsolateral funiculi. Calretinin immunohistochemistry (adapted from Juric-Sekhar

et al

. [17]).

Chapter 15

Figure 15.1

Cerebellar dysplasia/heterotopia. (a) Low-magnification view showing a localized area of disorganized cerebellar cytoarchitecture just lateral to the nodulus of the vermis. (b) Immature-appearing granular cell collections arranged in perivascular configuration. (c) Poorly organized mixed cell rest composed of mature neurons and immature granular cell collections. (d) Mixed cell rest with perivascular granular cells separated from Purkinje-like neurons (bottom of figure) by a cell poor molecular-like layer (“heterotopia” of Brun). (e) Large disorganized mixed cell rest (“heterotaxia” of Brun) in the floculus of a full-term infant (photograph contributed by Dr. Lucy B. Rorke, Children's Hospital of Philadelphia). (f) Dysplasia of dentate nucleus in a full-term infant with trisomy 18. The structure is fragmented into several islands of gray matter.

Figure 15.2

Nodular cerebellar heterotopia. (a) Nodular collection of mature neurons within the cerebellar white matter (hematoxylin and eosin). (b) Synaptophysin immunostained section of a heterotopic collection of mature neurons. (c) Glial fibrillary acidic protein immunostained section revealing astrocyte-like cells at the periphery of a heterotopic collection of mature neurons in the deep cerebellar white matter. Glial fibrillary acidic protein immunoreactive cell processes extend toward the center of the lesion.

Figure 15.3

Rhombencephalosynapsis. (a) Gross section at the pontomedullary junction showing the midline location of the dentate nuclei (arrow), and small, diamond-shaped fourth ventricle (arrowhead). A vermis is not present. (b) Synaptophysin immunostained histologic section at the same level shown in (a). The closely apposed dentate nuclei form the shape of an inverted “U” (arrow) above the small fourth ventricle (arrowhead). (c) Gross section at the mid-medullary level showing the closely apposed dentate nuclei (arrow). The vermis is absent. A nodulus-like structure (fused paramedian lobule?) fills the fourth ventricle (arrowhead). (d) Synaptophysin immunostained whole mount preparation corresponding to (c). The dentate nuclei (arrow) are closely apposed but more completely formed than in (b).

Chapter 16

Figure 16.1

Olivary heterotopia. (a) Small islands of olivary tissue stranded along their line of migration in the medullary tegmentum (arrows) (luxol fast blue–cresyl violet). (b) In the medial tegmentum on the left side, there is a small S-shaped ectopic island of olivary tissue (arrow) (luxol fast blue–cresyl violet).

Figure 16.2

Dentato-olivary dysplasia with intractable seizure in infancy. (a) Characteristic globose shaped dentate (arrow). (b) Same at higher magnification is composed of meandering islands of grey matter. (c) Coarse C-shaped inferior olive (arrows) (luxol fast blue–cresyl violet).

Figure 16.3

Möbius syndrome. Old scars in the (a) medullary and (b) pontine tegmentum (luxol fast blue–cresyl violet).

Figure 16.4

Pontine tegmental cap dysplasia. Horizontal section at level of fourth ventricle and pons. The cap is an aberrant white tract extending across the floor of the fourth ventricle. Note the disorganized tegmentum, through which myelinated fibers run towards the cap.

Figure 16.5

Pontocerebellar hypoplasia, type 2 (PCH2). (a) In PCH2, there is a tiny cerebellum with plate-like hemispheres. (b) The folia show variable depletion of Purkinje and granule cells (hematoxylin and eosin). (c) The dentate nucleus is formed of disconnected islands (microtubule-associated protein 2). (d) In another case with severe hypoplasia of the cerebellar hemispheres, there is evidence of segmental cortical loss, fragmented dentate nucleus and dysplastic olives. (a,b,c, Courtesy of Dr. Eleonora Aronica. d, From Ellison

et al

. [78]).

Figure 16.6

Granule cell aplasia. (a) Atrophic cerebellar folia showing massive depletion of the internal granular layer. There is also some Purkinje cell fall out and ectopic granule cells are present in the molecular layer. (hematoxylin and eosin). (b) Neurofilament immunostain of cerebellar cortex. There are numerous Purkinje cell dendritic expansions or cactus bodies, and some axonal torpedoes.

Chapter 17

Figure 17.1

(a) Dilatation of the central canal in hydromyelia, with no structural anomalies of the spinal cord; termination of pregnancy at 19 weeks of gestation for lumbosacral myelomeningocele (hematoxylin and eosin, H&E, ×40). (b) At higher magnification, note an intact ependymal lining (H&E, ×200). (c) Dimyelia associated with open neural tube defect, each cord having its own set of roots; termination of pregnancy at 23 weeks of gestation for myelomeningocele (H&E, ×10). (d) At higher magnification, both spinal cords are separated by an incomplete fibrocartilaginous septum (H&E, ×40).

Figure 17.2

(a) Diastematomyelia with two hemicords contained in a single dural sac (hematoxylin and eosin, H&E, ×10). (b) Hemimegamyelia with overgrowth of the left hemicord, displacing the ascending tracts (arrow); termination of pregnancy at 35 weeks of gestation for total hemimegalencephaly (Luxol fast blue stain, ×40). (c) Atresia–forking of the central canal, at the level of the pyramidal decussation; termination of pregnancy at 23 weeks of gestation for Roberts syndrome (H&E, ×40). (d) These consist of three small channels lined by normal ependyma (H&E, ×100).

Figure 17.3

(a) Diplomyelia, one of the two hemicords being assessory; termination of pregnancy at 23 weeks of gestation for myelomeningocele (hematoxylin and eosin, H&E, ×10). (b) Duplication of the central canal in the same case (Luxol fast blue stain, ×100). (c) Marked depletion of the anterior horns; termination of pregnancy at 17 weeks of gestation for recurrent cerebro-oculofacioskeletal syndrome (Luxol fast blue stain, ×40). (d) Numerous pyknotic motor neurons (arrow); termination of pregnancy at 27 weeks of gestation for lethal multiple pterygium syndrome (H&E, ×200).

Figure 17.4

(a) Symmetric hypoplasia of the ascending tracts (arrow); termination of pregnancy at 31 weeks of gestation for partial trisomy 1 (hematoxylin and eosin, H&E, ×40). (b) Age-matched control case (H&E, ×20). (c) Abnormally shaped pyramidal tracts associated with asymmetrical ascending tracts; termination of pregnancy at 25 weeks of gestation for caudal regression syndrome (H&E, ×10). (d) Fragmentation of the pyramidal tracts into several bundles in the same case (H&E, ×20). (e) Unilateral agenesis of the pyramidal tracts (arrow); termination of pregnancy at 32 weeks of gestation for arthrogryposis multiplex congenita (Luxol fast blue stain, ×20). (f) Glomeruloid proliferative vasculopathy (arrow), with hemorrhage and calcifications (black triangle), hydromyelia and dilatation of the subarachnoid spaces; termination of pregnancy at 25 weeks of gestation for Fowler syndrome (hematoxylin eosin saffron stain, ×20).

Chapter 18

Figure 18.1

Brain computed tomography (a) and T1 weighted MRI (b, c) of three patients with X-linked hydrocephalus. (The cases from which images b and c were taken have been confirmed genetically to have mutations in the

L1CAM

gene. Courtesy of Dr. M Yamasaki, Department of Neurosurgery, Osaka National Hospital, Japan.) (a) An axial plane image of a boy taken on the day of birth, demonstrating extensive hydrocephalus with marked thinning of the cerebral mantle. (b) An axial image of another boy taken at 18 months of life, following a shunt operation, showing marked decompression of the ventricular system and thin white matter. (c) A sagittal image of a four-year-old boy discloses hypoplasia of the corpus callosum, hypoplasia of the anterior portion of the cerebellar vermis, and an abnormally large interthalamic structure.

Figure 18.2

The brain of an eight-week-old boy with marked hydrocephalus. (a) A coronal section of the cerebral hemispheres, demonstrating enlargement of the lateral and third ventricles. (b) Section through the thalamus and hippocampus showing marked volume loss of the white matter (arrows) around the inferior horn of the lateral ventricle. Note that the cortical ribbon of the inferior gyri of the temporal lobe is thin (Luxol fast blue stain).

Figure 18.3

Histopathological features of aqueductal stenosis. (a) Section through the inferior colliculus of the midbrain. The aqueduct is not visible. (b) Light micrograph of the mid-sagittal portion of the section depicted in (a), showing marked narrowing of the qaqueductal lumen. Note that there is no gliosis or inflammatory cell infiltration in the surrounding tissue (Luxol fast blue stain). (c) Light micrograph of another case with aqueductal atresia, showing a small tubule and nearby scattered small ependymal canals (forking) in the midline of the midbrain tegmentum (hematoxylin and eosin). (d,e) Atresia and forking at the level of the medulla in a seven-month-old child presenting with arthrogryposis, who died suddenly.

Figure 18.4

L1CAM

mutation in fetus aged 24 postovulatory weeks [38], presenting all the cardinal signs. (a) Section through the medulla showing agenesis of the pyramids. (b) Note the presence of hydrocephalus, corpus callosum agenesis, atrophy of the germinal zone, and fusion of the thalami. Reproduced with permission of Taylor and Francis.

Chapter 19

Figure 19.1

Hydranencephaly, 22 weeks of gestation. Twin, with co-twin deceased at 17 weeks. (a) Diaphenous bubble-like hemispheres photographed in water, vertex view. (b) When removed from water the membranes collapse showing the shape; demarcated areas of destruction involving internal carotid artery territory and surrounded by ridged polymicrogyric cortex. Reproduced with permission from Ellison

et al

. [15] and Elsevier.

Figure 19.2

Porencephaly (a) A full-thickness defect in the occipital lobe communicating with the ventricle. Note the radial pattern of the surrounding convolutions, the cortex extending over the edge of the defect into the cleft; (b) bilateral porencephaly in 32-weeks of gestation twin (co-twin deceased at 19 weeks of gestation). Macrophages and disorganized immature neural tissue fill the center of the defects, which are fringed by polymicrogyria. Reproduced with permission from Ellison

et al

. [15] and Elsevier.

Figure 19.3

Multicystic encephalopathy. (a) Vertex view of cystic convolutions. (b) Coronal section. A “spider's web” of fine gliovascular bands replaces deep cortex, white matter and basal ganglia.

Chapter 20

Figure 20.1

(a) Scattergram showing the maximum thickness of the ganglionic eminence (GE) over the head of the caudate nucleus as a function of gestational age (weeks). The third order polynomial regression curve shows that germinal tissue in this region is maximal from around 20

–

26 weeks, and involutes shortly before or around full-term gestation [10,18]. (b) Scattergram showing the incidence of intraventricular hemorrhage (IVH) as a function of gestational age (in weeks) at the time of birth. The data were compiled from four large, prospective cranial ultrasound studies of premature infants conducted in the early to mid-1990s [24,39,82,83]. The second order polynomial regression curve shows that the risk of IVH becomes low after around 31 weeks of gestation.

Figure 20.2

(a) Sonogram in the coronal plane through the anterior fontanel showing the brain of a 28-weeks of gestation premature infant imaged at one day of age. There is a large, echogenic (bright; arrow), unilateral intraventricular hematoma. (b) Axial T2-weighted magnetic resonance image from a premature infant born at 30 weeks of gestation and imaged at 34 weeks. Three separate foci of residual hemosiderin at sites of periventricular hemorrhage are evident (dark areas; arrows).

Figure 20.3

Photograph showing the medial surface of a hemisphere from a premature infant who was born alive at 22 weeks and died immediately after birth. Extensive subarachnoid hemorrhage is evident on the brain surface.

Figure 20.4