Malformations

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Malformations

NEURAL TUBE DEFECTS: DYSRAPHIC DISORDERS

The following classification is based on present understanding of the development of the neural tube and axial skeleton (Figs 3.1–3.3).

DEFECTS OF NEURAL TUBE CLOSURE

ANENCEPHALY

MACROSCOPIC APPEARANCES

Anencephaly is characterized by replacement of most of the intracranial contents by a ragged, cavitated, vascular mass, the area cerebrovasculosa (Fig. 3.4). Remaining neural tissue usually includes the gasserian ganglia, distal parts of the cranial nerves, a variable amount of the medulla, and rarely, a few cerebellar folia.

The skull shows various abnormalities including:

image ANENCEPHALY

Spinal involvement varies from failure of fusion of the upper cervical vertebrae to craniorachischisis (Fig. 3.5).

Associated abnormalities are:

MYELOMENINGOCELE

Myelomeningocele (Figs 3.7, 3.8) is the herniation of spinal cord and meningeal tissue through a vertebral defect.

image MYELOMENINGOCELE

MICROSCOPIC APPEARANCES

Histologically, the epidermis overlying a myelomeningocele is atrophic (Fig. 3.9), lacking rete pegs and skin appendages, and often ulcerates. Beneath the epidermis there are fibrotic connective tissue, many dilated thin-walled vessels, and islands of glial tissue, which are sometimes accompanied by nerve cells and ependymal tissue.

HERNIATION OF NEURAL TUBE THROUGH AXIAL MESODERMAL DEFECTS

ENCEPHALOCELE

Encephalocele is herniation of brain tissue through a skull defect (Figs 3.10–3.16) and is usually (75%) occipital. Rarer examples are parietal or fronto-ethmoidal.

MACROSCOPIC APPEARANCES

Small encephaloceles contain jumbled fragments of CNS tissue, but many are voluminous and include considerable parts of the hemispheres with ventricular cavities and sometimes hindbrain. Herniation is usually asymmetric, often leaving the intracranial contents skewed.

The leptomeninges covering the herniated tissue have a persistent fetal vasculature, an exuberant plexus of thin-walled sinusoids. Both intracranial and extracranial brain may show cortical migration defects such as heterotopias and polymicrogyria. Associated lesions include hippocampal and commissural anomalies, agenesis of cranial nerve nuclei, and partial absence of the cerebellum.

image MECKEL SYNDROME

Occipital encephalocele may be associated with Meckel syndrome (also known as Meckel–Gruber syndrome) (Fig. 3.17). Other neuropathologic findings include midline and hindbrain anomalies. Protrusion of meninges alone is termed a cranial meningocele (Fig. 3.18).

OCCULT SPINA BIFIDA

Occult spina bifida is the mildest form of neural tube defect and probably reflects failure of tail bud development or of secondary neurulation.

MACROSCOPIC APPEARANCES

The cord may appear normal but often shows a distended central canal (hydromyelia) (Fig. 3.19), diastematomyelia (Fig. 3.20), or cord tethering (Fig. 3.21), all of which involve lower lumbar or sacral levels.

Although a closed lesion, occult spina bifida is often indicated by overlying tufts of hairy skin or lipomatous skin tags (Fig. 3.22). It may be associated with sacral, anorectal, and urogenital defects.

CHIARI TYPE I MALFORMATION

Chiari type I malformation is the herniation of a peg of cerebellar tonsil through the foramen magnum in the absence of an intracranial space-occupying lesion or preceding hydrocephalus (Figs 3.23–3.25).

image CHIARI TYPE I MALFORMATION

CHIARI TYPE II (ARNOLD–CHIARI)

MALFORMATION

Chiari type II malformation combines herniation of the cerebellar vermis with malformation and downward displacement of the brain stem (Figs 3.26–3.29). The degree of cerebellar herniation varies from slight (in fetuses) to extensive, at which point the choroid plexus and tonsils may be included. The cerebellar tail is bound by fibrous adhesions to the dorsal surface of the medulla or occasionally is situated within the fourth ventricle. Folia in the herniated cerebellar tissue show neuronal loss, absence of myelinated fibers, and gliosis.

Brain stem malformations include:

Other findings include:

CHIARI TYPE III MALFORMATION

Chiari type III malformation is the rare cerebello-encephalocele through an occipitocervical or high cervical bony defect (Fig. 3.30). Associated brain stem deformities and lumbar spina bifida are reminiscent of those associated with Chiari type II malformation.

image CHIARI TYPE II MALFORMATION

image PATHOGENESIS OF CHIARI TYPE II MALFORMATION

image Older theories attribute distortion of the cerebellum and brain stem to compression by hydrocephalic cerebral hemispheres or to traction from cord tethering, but these explanations cannot be sustained in the presence of an S-shaped brain stem deformity or the absence of spina bifida or hydrocephalus in a few cases.

image Disproportion between the growth of the posterior fossa and its contents is a more likely mechanism: the cerebellar weights and posterior fossa volumes are both reduced, and experimental administration of vitamin A to pregnant hamsters induces a shortened basichondrocranium and reduced posterior fossa volume, suggesting that the neurologic anomalies are secondary to skeletal defects.

image A small posterior fossa could compress the developing medulla causing abnormalities of the pontine and cervical flexures and force the cerebellum to grow into the spinal canal during its relatively late growth spurt. This theory is consistent with observations in second trimester human fetuses that show only slight cerebellar herniation in association with major medullary abnormality.

DISORDERS OF FOREBRAIN INDUCTION

Various interrelated hemispheric anomalies result from failures in outgrowth and separation of the forebrain vesicles and in the development of the commissures (Fig. 3.31). The hemispheric anomalies are associated with craniofacial anomalies (see Fig. 3.38).

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3.31 (a) Early development of the forebrain and outgrowth of the forebrain vesicles. Before closure of the neural tube in the third gestational week the signaling molecule Sonic hedgehog (Shh), in collaboration with another signaling molecule bone morphogenetic protein 7, induces the ventral midline cells in the forebrain primordium which grow slowly relative to the dorsolateral regions, so that rapid forebrain growth is constrained in the midline, resulting in an apparent cleavage into paired telencephalic vesicles. Shh also induces the optic primordium to divide into paired optic vesicles which grow out in the 4th to 5th week. Paired olfactory vesicles appear at 6 weeks, induced from olfactory placode by ingrowth of olfactory nerves. (b) Development of the midline structures. By 10 weeks’ gestation (1) the anlage of the anterior commissure (AC) appears in the ventral part of the lamina reuniens (LR) and the fornix (FO) appears in its dorsal part and grows dorsally with the hippocampal primordium (HP). In the floor of the interhemispheric fissure (1a) below the hemispheric sulcus (HS) the banks of a median groove, the sulcus medianus telencephali medii (SMTM) fuse into the massa commissuralis or commissural plate (MC), but the groove remains open below into the interhemispheric fissure. Soon after (2) the hippocampal commissure (HC) appears dorsal to the septal area (SA) and AC. By 12 (3, 3a) the corpus callosum (CC) is forming in the MC and then grows caudally with the growth of the hemisphere. Around 14 (4) as the hemisphere grows upwards and backwards a pocket forms in the SMTM below the CC. (5, 5a). As the CC grows and bends forwards and downwards into its genu (G) it covers the pocket in the SMTM, and finally the callosal fibers of the rostrum (R) grow through the MC so sealing the space which becomes the cavum septi pellucidi. LR lamina reuniens; LT lamina terminalis; CH optic chiasm; CP cortical plate; GM germinal matrix; IG Indusium griseum; MI massa intermedia; S splenium of callosum; SP septum pellucidum; PS hippocampal commissure (psalterium); TL temporal lobe.

HOLOPROSENCEPHALY

Holoprosencephaly is expressed as variable degrees of failure in outgrowth and cleavage of the prosencephalic vesicles.

image HOLOPROSENCEPHALY

In its severest form holoprosencephaly results in stillbirth. Liveborn infants have facial dysmorphism, psychomotor retardation, spasticity, apneic attacks, and disturbed temperature regulation.

image ETIOLOGY OF HOLOPROSENCEPHALY

image Holoprosencephaly is a heterogeneous group of conditions.

image Etiologic factors include maternal diabetes mellitus, toxoplasmosis, syphilis, rubella, and fetal alcohol syndrome.

image Mechanical or chemical methods have been used to induce it experimentally.

image Genetic factors encompass autosomal recessive, autosomal dominant, and X-linked inheritance patterns. There are chromosomal aberrations in about 50% of cases. Trisomy 13 is most frequent (holoprosencephaly occurs in 70% of cases of trisomy 13). Others include trisomy 18 and triploidy.

image Holoprosencephaly is a feature of Smith–Lemli–Opitz syndrome.

image Forms of holoprosencephaly have been mapped to several chromosomal loci or involve mutations in particular genes:

ALOBAR HOLOPROSENCEPHALY

MACROSCOPIC APPEARANCES

Alobar holoprosencephaly (Figs 3.32–3.37) is the severest form and is characterized by:

The horseshoe-shaped dorsal surface of the holosphere continues posteriorly as a delicate membranous roof to the single ventricle, which attaches distally to the tentorium. A cavity is thus formed, which may be small or balloon into a dorsal cyst. In the floor of the ventricle are fused basal ganglia and thalami, from the lateral edges of which the hippocampus makes a continuous arch around the ventricle and attaches to the roof membrane. Corpus callosum and septum are absent. Holospheric white matter is minimal.

Craniofacial malformations are associated with alobar holoprosencephaly (Fig. 3.38). The face tends to predict the brain, particularly midfacial hypoplasia. The severest is cyclopia with fused orbits and eyes. Other anomalies include a proboscis (ethmocephaly), absent jaw (agnathia), fused ears (synotia, otocephaly), flat nose with a single nostril (cebocephaly), microphthalmia, hypotelorism, and occasionally hypertelorism.

Skeletal anomalies include a short narrow skull base, absent crista galli and lamina cribrosa, absent or shallow sella, and variable hypoplasia of nasal bones. The falx and sagittal sinus are also usually missing.

LOBAR HOLOPROSENCEPHALY

Despite near-normal brain size, normal lobe formation, and separated hemispheres, the cerebral cortex is continuous across the midline, at the frontal pole, or in the orbital region, or above the callosum (cingulosynapsis) (Fig. 3.40).

Olfactory bulbs and callosum may be absent or hypoplastic. Heterotopic gray matter may be found in the ventricular roof.

OLFACTORY APLASIA

This is characterized by absent olfactory bulbs, tracts, trigone, and anterior perforated substance and is associated with anomalous cortical convolutions and an absent gyrus rectus (Fig. 3.41). Olfactory aplasia is usually an incidental postmortem finding or associated with holoprosencephaly, callosal agenesis, septo-optic dysplasia, or Kallmann or Meckel syndrome. It is usually bilateral. Unilateral absence is exceptional.

ATELENCEPHALY AND APROSENCEPHALY

These rare syndromes manifest as microcephaly (Fig. 3.42) and show features common to both anencephaly and holoprosencephaly.

AGENESIS OF THE CORPUS CALLOSUM

Agenesis of the corpus callosum may be:

MACROSCOPIC AND MICROSCOPIC APPEARANCES

image AGENESIS OF THE CORPUS CALLOSUM

image ETIOLOGY OF AGENESIS OF THE CORPUS CALLOSUM

If the callosum is deficient, the cingulate gyrus is also deficient. A radiating gyral pattern forms the medial surface of the cerebral hemisphere. The lateral ventricles have a membranous roof with upturned pointed corners, and a large longitudinal myelinated fiber bundle (of Probst) is present laterally. The membranous roof of the (usually distended) third ventricle bulges into the interhemispheric fissure, displacing the fornices laterally from where the widely separated leaves of the septum incline laterally towards the Probst bundles (Figs 3.43–3.45). The occipital horns are often markedly dilated. The anterior commissure is variably present, the posterior commissure is always present, and the psalterium is never present.

Callosal anomalies are rarely associated with a midline mass (e.g. cyst, meningioma, hamartoma, lipoma) (Figs 3.46, 3.47). There is a high incidence of associated visceral and cerebral anomalies, especially hydrocephalus, and rhinencephalic and migration defects.

SEPTO-OPTIC DYSPLASIA

Septo-optic dysplasia (Fig. 3.48) is the clinical triad of:

The etiology is unknown, though there is a report of septo-optic dysplasia and semilobar holoprosencephaly following maternal first trimester alcohol abuse. One of the three prime features may occasionally be absent, notably the septal aplasia.

CAVUM SEPTI PELLUCIDI AND CAVUM VERGAE

Cavum septi pellucidi (Fig. 3.49) and cavum vergae are rostral and caudal cavities, respectively, bounded above by the corpus callosum and laterally by the two leaves of the septum pellucidum and the fornices. They are normally present in fetal life and usually obliterated by term. A cavum septi pellucidi is seen in 20% of brains at necropsy with or without a cavum vergae. Glial tissue lines the cavity, which may contain macrophages.

MALFORMATIONS OF CORTICAL DEVELOPMENT

Our current classification of this huge and diverse group of disorders combines descriptive morphology with genetic analysis; a given phenotype may result from several genetic, chromosomal or non-genetic causes while different mutations in a given gene result in different phenotypes. Figure 3.50 presents a simplified summary of our rapidly expanding understanding of the developmental biology of primordial cerebral cortex. New concepts of molecular pathogenesis obtained from animal models and human genetic disorders will revolutionize and modify our approach to this complex field.

AGYRIA AND PACHYGYRIA

A summary of normal gyral development is given in Figure 3.51. Agyria and pachygyria refer to an absence of gyri and sulci, or reduced numbers of broadened convolutions, respectively, associated both macroscopically and microscopically with a thickened cortical ribbon (Figs 3.52, 3.53 and see Fig. 3.57).

image THE SMOOTH BRAIN

Various synonyms are used in clinical radiologic and pathologic practice when referring to the macroscopic appearances of a smooth brain:

Various histologic patterns may be encountered in macroscopically smooth or poorly convoluted cortex:

MACROSCOPIC APPEARANCES

The skull vault is small, misshapen, and thickened. Brain weight is usually low, and very occasionally heavy. A markedly thickened cortical ribbon is associated with reduced white matter (see Fig. 3.52). Pachygyria is occasionally combined with polymicrogyria. The claustrum and extreme capsule are absent. Lateral ventricles are dilated and often associated with periventricular nodular heterotopia.

MICROSCOPIC APPEARANCES

The most characteristic histological appearance is a four-layer cortex (Fig. 3.54):

image Molecular layer.

image Thin, external neuronal layer.

image Sparsely cellular layer with a tangential myelin fiber plexus.

image A thick, inner neuronal layer (Fig. 3.54c), which splits in its deeper zone into columns of cells (lissencephaly type I).

image Posterior–anterior gradient of severity in LIS-I cases (Fig. 3.55).

image Anterior–posterior gradient of severity in DCX cases.

Other examples have 2, 3 or multiple layers (Figs 3.56, 3.57).

Variants may lack lamination or have a more complex horizontal organization.

Associated findings include olivary heterotopia (see Fig. 3.51), and hypoplastic pyramidal tracts. Less common associations are: dentate dysplasia, cerebellar heterotopia and granule cell ectopia.

image AGYRIA AND PACHYGYRIA

image Agyria and pachygyria are characterized clinically by the lissencephaly sequence of microcephaly, bitemporal hollowing, a small jaw, diminished spontaneous activity, profound mental and motor retardation, feeding problems, early hypotonia, late hypertonia, and epilepsy.

image These malformations occur either sporadically or as familial disorders.

image There are several associated syndromes including Miller–Dieker syndrome (the best known) in which >90% of patients with the syndrome have a visible or submicroscopic deletion in a critical 350 kb region of chromosome 17p13.3 (LIS-1) (Table 3.1).

image Other rarer autosomal recessive forms of agyria are characterized by slightly different dysmorphology, severe microcephaly, and a thick cortex with variable lamination.

image There is also overlap with laminar heterotopia.

Table 3.1

Genes and lissencephaly type I

Malformation Gene Locus
Lissencephaly (XL, AD)
X-linked lissencephaly with abnormal genitalia ARX Xp22.1
Isolated lissencephaly sequence (ILS) or subcortical band heterotopia (SBH) DCX Xq22.3-q23
ILS or SBH TUBA1A 12q13.12
ILS or SBH LIS1 17p13.3
Miller–Dieker syndrome LIS1 + YWHAE 17p13.3
Lissencephaly (AR)
Lissencephaly with cerebellar hypoplasia (LCH) RELN 7q22.1
LCH VLDLR 9p24.2

image PATHOGENESIS OF LISSENCEPHALY TYPE I

image CEREBRO-OCULAR DYSPLASIA SYNDROMES

image Walker–Warburg or HARD + E (hydrocephalus, agyria, retinal dysplasia plus encephalocele) syndrome is characterized by profound psychomotor retardation, hydrocephalus from birth, ocular anomalies (e.g. central corneal opacity, abnormalities of the iris, cataract, retinal detachment, retinal dysplasia), developmental defects, and death in infancy.

image Cerebro-ocular dysplasia–muscular dystrophy syndrome (COD–MD) produces similar manifestations to Walker–Warburg syndrome, plus electrophysiologic evidence of myopathy, and rising creatine phosphokinase (CPK) concentrations.

image Muscle–eye–brain disease is a further variant with a milder phenotype.

image In Fukuyama congenital muscular dystrophy cerebral malformations are less severe, and comprise microcephaly, extensive unlayered polymicrogyria, and small areas of type II lissencephaly. It is the commonest form of congenital muscular dystrophy in Japan.

CEREBRO-OCULAR DYSPLASIAS

Cerebro-ocular dysplasias show a distinct histologic form of cerebral cortical thickening and dysplasia (lissencephaly type II or cobblestone cortex). They occur in several rare overlapping autosomal recessive familial syndromes that combine complex cerebral and ocular malformations and muscular dystrophy. Six genetic defects (Table 3.2) have been reported, associated with proven or putative glycosyltransferases, and resulting in hypoglycosylation of α-dystroglycan, and a secondary reduction in laminin α-2.

MACROSCOPIC APPEARANCES

The Walker–Warburg syndrome is probably the best studied. An occipital meningocele or encephalocele is common. The cerebral hemispheres are usually enlarged, but occasionally small, and have a smooth surface that lacks convolutions and is covered by adherent thick white leptomeninges (Figs 3.58, 3.59). A cobblestone surface described on imaging is very occasionally observed. Fusion of the medial surfaces of the frontal lobes, olfactory aplasia or hypoplasia, thin optic nerves and optic chiasm, small flattened cerebellar hemispheres with a coarsely nodular surface, and a small or absent vermis are sometimes found. A massive hydrocephalus throughout the ventricular system and a thin corpus callosum are evident.

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3.59 Cerebro-ocular dysplasia (lissencephaly type II; Walker–Warburg syndrome) in a 6-week-old infant.
(a) The vertex of the brain is smooth and white, having no convolutions and very thickened leptomeninges. (b) Section at thalamic level compared with an age-matched normal control below, showing ventriculomegaly and a shallow interhemispheric fissure, beneath which the medial surfaces are fused. Although the cortex is abnormally thick, it is pale and difficult to distinguish from white matter. (c) Low power microscopy of the frontal lobe shows the irregularly thickened, unlaminated cortex and an archipelago of deeply placed islands of gray matter laterally. (d) The cortical ribbon on the medial parts of the frontal lobes is thin, undulating, and fused, reminiscent of polymicrogyria. (e) The typical histology of lissencephaly type II is of obliterated subarachnoid space and thickened disorganized cortex. (f) In places the thickened disorganized cortex is thrown into waves. (g) The hypoplastic midbrain, with the tectum above and nigra below, is surrounded by a thick collar of gliomesodermal tissue. There is a rest of neuroblasts dorsal to the aqueduct and the cerebral peduncles appear to be absent, but heterotopic bundles are situated dorsolaterally (arrows). (h) Horizontal section of the dysplastic cerebellum and pons below compared with a normal control above. The vermis is absent and normal folial structure is obliterated by extensive cortical dysplasia (see Fig. 3.100a,b).

MICROSCOPIC APPEARANCES

Mesodermal proliferation containing prominent glioneuronal heterotopia produces thickened leptomeninges and obliterates the subarachnoid space. A thickened and disorganized cortical ribbon is divided by centripetal fibrovascular septa into irregular neuronal clusters, which sometimes have a wave-like arrangement. The cortical ribbon is separated by a narrow hypocellular zone with thin-walled blood vessels from an inner layer or archipelago of gray matter islands. Cortex on the medial aspects of the hemispheres is often thin and undulating, reminiscent of polymicrogyria.

Cerebellar cortical dysplasia is associated with numerous heterotopias in the white matter, and dysplastic dentate nuclei. A hypoplastic brain stem is invested with a thick cuirass of fibrous and glial tissue, especially over the midbrain. The pyramidal tracts are absent or misdirected and the inferior olives dysplastic. Dystrophic muscle shows fiber degeneration and regeneration, fibrosis and inflammatory infiltrates.

image PATHOGENESIS OF CEREBRO-OCULAR DYSPLASIA

NEU–LAXOVA SYNDROME

This is a rare lethal autosomal recessive syndrome with a normal karyotype producing severe intrauterine growth retardation, microcephaly, grotesque facies, limb flexion deformities, and skin dysplasia (Fig. 3.60).

POLYMICROGYRIA

Polymicrogyria is characterized by a hyperconvoluted cortical ribbon of miniature, individually thin gyri, which are often fused together or piled on top of one another.

MACROSCOPIC APPEARANCES

The macrogyric cerebral surface is irregular, and has been likened to cobblestones (Fig. 3.61). Sections of the cerebrum reveal heaped up or submerged gyri that widen the cortical ribbon (Figs 3.62, 3.63). Polymicrogyria (Figs 3.64–3.69) may be:

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3.66 Unilateral polymicrogyria in an asymmetrically small hemisphere.
Compare this with Fig. 3.67. (a) Coronal section. Compare the smaller hemisphere and abnormal cortical ribbon with the normal left side. (Courtesy of Dr M Carey, Birmingham.) (b) Microscopic section showing the branched and fused cortical ribbon and fingers of molecular layer.

image POLYMICROGYRIA

Polymicrogyria manifests with varying degrees of neurologic disability depending upon the extent of the lesion, and:

image ETIOLOGY OF POLYMICROGYRIA

Heterogeneous antecedents have been demonstrated.

MICROSCOPIC APPEARANCES

The cortical gray matter is abnormally thin and excessively folded, there is fusion of adjacent gyri, and abnormal cortical lamination. The commonest subtype is unlayered (or 2-layered including the marginal/molecular layer) polymicrogyria. A thin unlayered undulating band of gray matter is interrupted by branching ‘fingers’ of paucicellular tissue that has central blood vessels and radiates out from the overlying molecular layer. A complex pseudoglandular or map-like pattern of irregular neuronal clusters and cell-free zones is produced by the branching and fusing of the molecular layer.

A rarer subtype is four-layer polymicrogyria, which consists of a molecular layer and two layers of neurons sandwiching a paucicellular zone of myelinated fibers. The cortical ribbon is thin and undulating. Both types of polymicrogyria may coexist. Still rarer is an undulating 6-layered form.

Associated features include glioneuronal leptomeningeal heterotopia and nodular heterotopia. Polymicrogyria is sometimes combined with pachygyria.

image PATHOGENESIS OF POLYMICROGYRIA

image The topography, bilateral symmetry, frequency of middle cerebral artery distribution, juxtaposition to porencephaly, and clinical data suggest a hypoxic–ischemic pathogenesis or transient intrauterine perfusion failure.

image Clinical reports of antecedent catastrophic intrauterine events have led to an estimation that polymicrogyria develops in the fourth to fifth gestational months.

image There are direct observations of the disorder in fetuses of 17–22 weeks’ gestation, but ages of deceased co-twins suggest that the onset could be as early as the third to fourth month, implying interference with the later stages of neuronal migration.

image Initial studies with laminar markers have demonstrated normal laminar positioning, implying a failure of post-migrational organization.

image Rare X-linked, autosomal dominant and autosomal recessive inheritance is described.

image Autosomal recessive pseudo-TORCH syndrome with microcephaly, polymicrogyria and band-like calcification has been linked to mutation at 5q13 and defects in the OCLN gene.

CHONDRODYSPLASIAS

Cortical malformations are prominent features in some chondrodysplasias:

image In lethal thanatophoric dwarfism (Fig. 3.70), abnormally protuberant broad gyri in the temporal lobes show polymicrogyria, leptomeningeal glioneuronal heterotopia, and complete disorganization of Ammon’s horns.

image In short-rib polydactyly syndrome (Fig. 3.71), there is an extremely bizarre convolutional pattern of deep clefts and disorganized cerebral mantle.

DIFFUSE NEURONAL HETEROTOPIA

Diffuse neuronal heterotopia occurs in some epileptic patients (see Microdysgenesis, below) and is occasionally a principal finding in early myoclonic epilepsy. It is characterized by the presence of many haphazardly scattered neurons in gyral and central white matter and may be associated with other cerebral malformations (Fig. 3.72). Note that occasional neurons are a normal finding in the cerebral white matter, particularly in the anterior temporal region.

NODULAR HETEROTOPIA

Nodules of heterotopic neurons are most often situated in the wall of the lateral ventricle and bulge into its cavity, but are also found in gyral cores and the centrum semiovale. Heterotopias may be single or multiple, varying from small discrete neuronal clusters to large conglomerates, or may occur as irregular serpiginous bands (Figs 3.73, 3.74). Nodular heterotopias may be incidental findings, but in necropsy series are often associated with microcephaly or extensive CNS malformations, including megalencephaly.

Histologically, heterotopias vary from simple collections of neurons of random size and orientation to an arrangement resembling cortical lamination.

image NEURONAL HETEROTOPIA

image ETIOLOGY OF NEURONAL HETEROTOPIA

LAMINAR HETEROTOPIA

MACROSCOPIC APPEARANCES

The brain surface has a normal convolutional pattern, but in coronal slices there are bilateral, symmetric foci of heterotopic gray matter, arranged in extensive bands, wedges, or clustered nodules. These may be situated in most cortical regions except the striate or cingulate cortices, and the fusiform or medial temporal gyri (Fig. 3.75).

image LAMINAR HETEROTOPIA

Laminar heterotopias are situated just beneath and parallel to the cortex, but separated from it by a narrow layer of white matter. The deep gray nuclei are normal except for the incorporation of the claustrum into the heterotopia.

MICROSCOPIC APPEARANCES

In its outermost part, the heterotopic gray matter shows a haphazard arrangement of neurons and neuropil (Fig. 3.76). The intermediate part contains wide columns of cells separated by myelin fiber bundles. The innermost part fragments into islands surrounded by white matter. The cortex overlying the heterotopia has been reported as normal or pachygyric.

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3.76 Laminar heterotopia.
(a) The cortex overlying the laminar heterotopia in the patient depicted in Fig. 3.75b is qualitatively normal and correctly laminated. (b) Subcortical white matter clearly separates the cortex from the underlying heterotopia. (c) The superficial part of the heterotopia is a haphazardly arranged mass of neurons and neuropil. (d) More deeply, the heterotopia begins to break up into columns. (e) In its deepest part the heterotopia fragments into nodules. (f) Immunocytochemistry demonstrates similar staining for synaptophysin in both cortex and heterotopia (asterisk).

CORTICAL DYSPLASIA WITH HEMIMEGALENCEPHALY

MACROSCOPIC APPEARANCES

Total brain weight varies from well below to well above normal. One hemisphere is larger, but this is not always the pathologic one. All or part of the hemisphere shows greatly expanded firm convolutions with a finely pitted surface (Fig. 3.77). The cortical ribbon is irregularly thickened and poorly demarcated from underlying white matter. There is usually unilateral enlargement of the centrum semiovale, and occasionally enlargement of one olfactory tract or the basal ganglia.

MICROSCOPIC APPEARANCES

Architectural anomalies include:

image An abrupt transition from a normal to an abnormal widened cortex with loss of normal lamination (Fig. 3.78).

image In some cases, superficial undulations, lissencephaly, or four-layered cortex.

image Usually, poor demarcation of the cortex from the white matter.

Cytologic changes include:

image Neuronal cytomegaly (Fig. 3.79), notably in cortical regions, but also of heterotopic neurons in white matter, and occasionally in the hippocampus and basal ganglia. Some cells are larger than Betz cells, misaligned, and pleomorphic. These cells are often strongly immunopositive for αB-crystallin.

image Multilobed, vacuolated, or multiple nuclei outlined by a crescentic condensation of Nissl bodies.

image Central cytoplasmic clearing of Nissl bodies, abnormal dendritic arborization (as demonstrated by Golgi impregnation), and cytoskeletal abnormalities (i.e. formation of tangles immunopositive for various neurofilament epitopes, tau protein, and ubiquitin).

image Astrocytic dysplasia (Fig. 3.80), which varies from minimal to massive, evoking the appearance of a neoplasm, and is present in cerebral gray and white matter. Dysplastic cells have swollen glassy cytoplasm and round eccentric nucleolated nuclei. Associated findings are intense astrocytosis and calcification. Rarely Rosenthal fibers and cystic rarefaction in the white matter produce an appearance that may mimic Alexander’s disease.

image Large globular or ‘balloon’ cells of indeterminate phenotype, which may show immunohistochemical co-localization of glial fibrillary acidic protein (GFAP) and either vimentin or synaptophysin. Some of these cells are also immunopositive for αB-crystallin.

image DIFFERENTIAL DIAGNOSIS OF AN ASYMMETRICALLY ENLARGED HEMISPHERE (HEMIMEGALENCEPHALY)

Rarely, hemimegalencephaly is due to an excess of neurons without malformation.

image CORTICAL DYSPLASIA WITH HEMIMEGALENCEPHALY

image PATHOGENESIS OF HEMIMEGALENCEPHALY

FOCAL CORTICAL DYSPLASIA

Focal cortical dysplasia (FCD) is usually encountered in circumscribed surgical resections carried out for intractable focal epilepsy and commonly affects only a small part of one gyrus, which may be enlarged.

FCD is characterized by architectural and cytological abnormalities and classified into three main tiers (Table 3.3). Abnormalities of cortical lamination and organization are apparent, and depending on the variant dysmorphic neurons or balloon cells may be present. FCD type III is associated with various other pathologies.

Table 3.3

ILAE classification of focal cortical dysplasia (FCD)

image

ILAE, International League Against Epilepsy.

§Traumatic brain injury, glial scarring after prenatal or perinatal ischemic injury or bleeding, and inflammatory or infectious diseases, i.e. Rasmussen encephalitis, limbic encephalitis, bacterial or viral infections.

(Adapted from Blümcke I, Thom M, Aronica E et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158–74.)

Quantitative functional neuroimaging studies have shown that the dysplastic abnormalities are usually much more extensive than is evident by conventional imaging.

NODULAR CORTICAL DYSPLASIA

Nodular cortical dysplasia (Fig. 3.82) is the presence of superficial cortical nodules (brain warts) in otherwise normal cortex or occasionally in microcephalic brains with polymicrogyria. Nodules 1–5 mm in diameter are scattered over the cortical surface, most often the frontal lobe or near the operculum, on the crown of a gyrus, or in the bank of a sulcus. Histologically, cortical layers II and III protrude through a thin or absent molecular layer. Neurons of various sizes are grouped around a radial bundle of myelinated fibers and a central blood vessel.

STATUS VERRUCOSUS SIMPLEX OR STATUS PSEUDOVERRUCOSUS

This is a microscopic finding in the brains of fetuses from 10 to 28 weeks’ gestation (Fig. 3.83). The second cortical layer makes irregular protrusions into the molecular layer, while the external surface is smooth. Although considered by some to be a transient stage of normal development, its presence in some macerated brains and occasional association with polymicrogyria suggest that it may be a true malformation.

HIPPOCAMPAL ANOMALIES

A variety of hippocampal malformations is described including:

Duplication or dispersion of the dentate gyrus can also occur in cases of dysembryoplastic neuroepithelial tumor in the temporal lobe, microdysgenesis, and Sturge–Weber syndrome. In a personal case bilateral duplication of the dentate gyrus was associated with other migration defects and seizures from 6 of age (Fig. 3.84).

MICROCEPHALY

Microcephaly is a purely descriptive term for a small head, but is also in general use for a small brain, for which the term microencephaly is more appropriate. Brain weights two standard deviations below the mean are considered abnormal. By this definition microcephaly is common, but not invariable in malformed brains. Microcephaly plus associated malformations (Fig. 3.85) may be:

Microcephaly without associated malformations (Fig. 3.86) may be:

CHROMOSOMAL AND SINGLE GENE DEFECTS

The full range of chromosomal and single gene defects that are associated with CNS malformations is listed in Table 3.4.

TRISOMY 21 (DOWN SYNDROME)

Brain weights are usually about 1000 g. The cerebrum is brachycephalic and abnormally round and short with an almost vertical occipital contour. Other features include some reduction in secondary sulci, exposure of the insula, and a narrow superior temporal gyrus. The cerebellum and brain stem are small.

Microscopic anomalies are largely nonspecific. Neuronal density may be increased at birth, but declines markedly from birth onward. Abnormalities in dendritic arborization and decreased numbers of dendritic spines have been detected with Golgi’s method in neonates. Delayed myelination is also prominent in infants with congenital heart disease.

Middle-aged patients often develop clinical signs of dementia: their brains show changes of Alzheimer’s disease (see Chapter 31) thought to result from the presence of an extra copy of the amyloid-b precursor protein gene (on chromosome 21, at 21q21.3) and increased production of amyloid-β peptide.

FRAGILE X SYNDROME

This is the second most frequent genetic disorder (after Down syndrome) associated with developmental disability. It has an incidence of 1/1000 liveborn males and is the commonest familial form of mental retardation. The fragile X site at position Xq27 is induced in cells cultured at low folic acid and thymidine concentrations. The defect results from expansion of either of two (FRAXA and FRAXE) specific DNA triplet repeat regions in the FMR1 (fragile X mental retardation 1) gene. The size of the expansion correlates with the degree of mental retardation.

image Etiology of down syndrome

image Down syndrome is caused by trisomy of chromosome 21:

image The overall population frequency is 1/650–1000 live births.

image The incidence of trisomy 21 increases with advancing maternal age.

image Familial cases are usually due to translocations.

image Increased levels of the free radical scavenging enzyme Cu/Zn superoxide dismutase are evident in cell lines from both trisomy 21 patients and patients with Alzheimer disease.

image Down syndrome cells also show a reduced ability to repair the effects of X-ray damage. Defective DNA repair may contribute to the increased risk of acute leukemias in Down syndrome.

Trisomy 21 increases the risk of acute lymphoblastic and myeloblastic leukemias by 20-fold and that of acute megakaryocytic leukemia by over 200-fold.

Dysmorphologic features include macro-orchidism, a long face with prominent forehead, and large ears. Neuropathologic findings include microcephaly, neuronal heterotopias, and dendritic spine abnormalities.

ENVIRONMENTAL FACTORS

A list of teratogens that can cause CNS malformations is included in Table 3.5.

Table 3.5

Teratogens known or suspected in the production of CNS malformations

Teratogenic agent Malformations
Alcohol Microcephaly, occasional meningomyelocele and hydrocephaly
Carbamazepine Myelomeningocele
Cytomegalovirus Hydrocephalus, microcephaly, polymicrogyria, occasional cerebellar cortical dysplasia
Diabetes mellitus (maternal) Neural tube defects, increased incidence
Herpes simplex Microcephaly, hydranencephaly
Hyperthermia Neuronal heterotopias, microcephaly, ?neural tube defects
Methyl mercury Microcephaly, heterotopia
Phenylketonuria (maternal) Microcephaly
Phenytoin Microcephaly, holoprosencephaly
Retinoids Hydrocephaly, microcephaly, neuronal migration defects, cerebellar agenesis/hypoplasia
Rubella Microcephaly, occasional hydrocephalus and agenesis of the corpus callosum
Toxoplasmosis Necrotizing meningoencephalitis, hydrocephalus and calcification, occasional polymicrogyria and hydranencephaly
Valproic acid Myelomeningocele
Varicella-zoster Necrotizing encephalitis with polymicrogyria
Warfarin Microcephaly, hydrocephalus, Dandy–Walker cyst, agenesis of corpus callosum
X-irradiation Microcephaly, pachygyria, cerebellar cortical dysplasia, heterotopia

MATERNAL INFECTION

Rubella: CNS malformations are relatively common (affecting 10–20% of cases) following rubella infection during the first trimester and include chronic meningoencephalitis, microcephaly, and retarded myelination and cytoarchitectonic development (see also Chapter 12). Better known associated malformations are ocular defects (cataract, pigmentary retinopathy, microphthalmos) and sensorineural deafness.

Cytomegalovirus: More than 5% of neonates infected with cytomegalovirus have a rapidly fatal systemic disorder, with brain involvement reported in 10–80% of cases (see also Chapter 12). Clinical features are microcephaly, mental retardation, epilepsy, diplegia, chorioretinitis, and intracerebral calcification. Neuropathologic findings include:

Other findings that are sometimes seen are porencephaly or hydranencephaly, polymicrogyria and cerebellar cortical dysplasia, and perivascular calcifications (see Fig. 3.69a).

Typical viral inclusions are often sparse (see Fig. 3.69b); the virus is more readily identified by immunocytochemistry or in situ hybridization.

Other viruses: Herpes simplex infection can cause chorioretinitis, microcephaly, hydranencephaly, and microphthalmia (see also Chapter 12).

Varicella–zoster infection in the first or second trimester rarely causes a characteristic embryopathy involving the skin, muscle, eye, and brain (see also Chapter 12). Some necropsy studies report necrotizing encephalitis, and polymicrogyria (see Fig. 3.69c,d).

Other organisms: Intrauterine toxoplasmosis produces necrotizing meningoencephalitis, hydrocephalus, and widespread calcification, sometimes with polymicrogyria and hydranencephaly (see also Chapter 18).

MEGALENCEPHALY

Megalencephaly is defined as a brain weight at least 2.5 standard deviations above the mean for age and sex (Fig. 3.87). Primary megalencephaly may be:

There is a male:female ratio of 2:1, and most patients are mentally retarded and have some sort of neurologic disorder. One-third has cytoarchitectonic or neuronal abnormalities, and one-third has macroscopic malformations (Fig. 3.88). Megalencephaly with olivary heterotopia is occasionally observed in autistic subjects. Secondary megalencephaly is associated with:

MALFORMATIONS OF THE CEREBELLUM

The classification of cerebellar malformations follows developmental principles (Fig. 3.89).

image

3.89 Development of the hind brain.
In the 4th week of gestation, the neural tube closes and segments, so that the rhombencephalon becomes temporarily the largest part of the brain. Differential growth in the rhombencephalon during the 5th week results in formation of the pontine flexure, widening the neural tube at this point and thinning its roof which becomes transversely creased as the plica choroidea; these give rise to the choroid plexus. The pouch-like evagination caudal to it forms a membranous roof to the fourth ventricle which perforates, forming the foramen of Magendie, by 12 weeks. The roof rostral to the plica is later incorporated into the developing vermis. Also anterior to the plica, the lateral parts of the alar plates undergo intense neuroblastic proliferation, enlarging into the rhombic lips, the paired primordia of the cerebellum which gradually extend dorsomedially to meet the roof of the fourth ventricle and then fuse together in the midline during the 3 rd month. Cerebellar growth which has been intraventricular now becomes extraventricular and various subdivisions appear: first the posterolateral or flocculonodular fissure at 9 demarcating the vestibular or archicerebellum from the rest, then at 12 the primary fissure separating anterior from posterior lobes, the spino- or paleo-cerebellum from the ponto- or neo-cerebellum. This last, phylogenetically youngest, part of the cerebellum predominant in mammals, forms its various fissures 4–8 after those of the vermis and flocculonodular lobes. The neurons of the cerebellar cortex and deep nuclei as well as the pontine and arcuate nuclei and inferior olivary nuclei all derive from the alar plates: ventral migrations into the pontine gray and olivary ribbons, and lateral migration into the rhombic lips. The latter has two divergent pathways, inwards through the cerebellar plate for Purkinje cells and deep nuclei, and outwards guided over the surface of the developing cerebellum by pial basal lamina to form the external granular layer (EGL). The rapidly proliferating EGL first appears in week 9, covers the whole cerebellar surface by 14 weeks, and persists until the third postnatal month, disappearing by the end of the first year. From the EGL arise the neurons and glia of the molecular layer, and by inward growth across the molecular layer the internal granule cells.

CEREBELLAR AGENESIS

Total absence of the cerebellum is rare, as the flocculus or nodulus often remains. The nuclei pontis and inferior olives are hypoplastic or dysplastic in association with the cerebellar agenesis.

Partial or total cerebellar agenesis is a feature of large occipital encephaloceles.

Cerebellar agenesis may be unsuspected in life or associated with mental handicap.

Rare examples of total or partial agenesis variably associated with pontine hypoplasia have been associated with amniocentesis and possible intrauterine inference with the vascular supply (Fig. 3.90).

image DIFFERENTIAL DIAGNOSIS OF PALEOCEREBELLAR MALFORMATIONS INVOLVING THE VERMIS

image Dandy–Walker syndrome.

image Joubert syndrome.

image Tectocerebellar dysraphia with occipital encephalocele in which partial or total vermal agenesis, a severe deformation of the midbrain tectum, and a cerebello-encephalocele coexist.

image Rhombencephalosynapsis, a cerebellar hypoplasia consisting of fused hemispheres and dentate nuclei, absent vermis and paleocerebellar roof nuclei, dysplastic olives, and other midline anomalies (Fig. 3.91).

image Walker–Warburg syndrome.

DANDY–WALKER SYNDROME

This is a combination of vermal agenesis, a cystically dilated fourth ventricle, and an enlarged posterior fossa, and is usually accompanied by hydrocephalus (Figs 3.92, 3.93). Many systemic and CNS malformations are associated with Dandy–Walker syndrome (Table 3.6).

Table 3.6

Malformations associated with Dandy–Walker syndrome

CNS

Microcephaly

Callosal agenesis

Polymicrogyria and pachygyria

Aqueduct stenosis

Infundibular hamartoma

Occipital meningocele

Hindbrain abnormalities

 Cerebellar hypoplasia

 Cerebellar heterotopias

 Cerebellar cortical dysplasia

 Dentate dysplasia

 Olivary dysplasia and heterotopia

 Anomalies of pyramidal tract decussation

Systemic

Klippel–Feil syndrome

Cornelia de Lange syndrome

Cleft palate

Polycystic kidneys

Spina bifida

Polydactyly and syndactyly

image

image

image

image

3.92 Dandy–Walker malformation.
This is the same case as in Fig. 3.73c,d and Fig. 3.88. (a) The vermis is absent and there is a widely dilated fourth ventricle with smooth white lateral walls and a roof membrane reinforced by thickened meninges. (b,c) Horizontal slices through the brain stem and cerebellum show the remaining superior part of the vermis, the ridged surface of the ventricle with granular ependymal lining, and asymmetry of the cerebellar hemispheres and dentate nuclei. (d) The right dentate nucleus is fragmented in the smaller right hemisphere.

image DANDY–WALKER SYNDROME

image PATHOGENESIS OF DANDY–WALKER SYNDROME

JOUBERT SYNDROME

This is a familial syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and mental retardation, associated with agenesis of the vermis.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The characteristic radiologic ‘molar tooth’ and ‘umbrella’ signs are readily demonstrated on horizontal section of the hindbrain (Fig. 3.94a,b). There is almost complete absence of the vermis, numerous heterotopias in the cerebellar white matter, a dysplastic segmented dentate nucleus, absent roof nuclei, C-shaped dysplasia of the olives, and anomalies of the pyramidal tracts, cranial nerve nuclei, and midbrain tegmentum (Fig. 3.94c). Occipital meningocele, cystic kidneys, and retinal dysplasia are also reported.

PONTONEOCEREBELLAR HYPOPLASIA (PNCH)

PNCH is a severe neocerebellar hypoplasia with relatively well-preserved paleocerebellum, and a peculiar segmentation of the dentate nucleus (Figs 3.95, 3.96).

MACROSCOPIC APPEARANCES

There is often severe microcephaly, but the hindbrain is disproportionately small and is usually 3% or less of total brain weight. The extremely small cerebellar hemispheres are virtually smooth or reduced to a few coarse convolutions (Figs 3.95, 3.96), while the vermis and flocculonodular lobes are almost normal in size. The pons is narrow and the olivary bulges are poorly defined.

image PONTONEOCEREBELLAR HYPOPLASIA

image PATHOGENESIS OF PONTONEOCEREBELLAR HYPOPLASIA

MICROSCOPIC APPEARANCES

The hypoplastic cerebellar hemispheres (Figs 3.95, 3.96) may show normal zones interposed with others where Purkinje and granule cells are completely lacking and replaced by tenuous gliotic tissue. There is only minimal, poorly myelinated, central white matter. The dentate nuclei are disorganized, lacking an undulating ribbon, hilum or amiculum (i.e. a surrounding sheath of myelinated fibers), and the reduced neuronal population is clustered into small neuropil islands embedded in a meshwork of myelin fibers. The vermis, archicerebellum, and roof nuclei are normal.

The superior and middle cerebellar peduncles are thin and poorly myelinated, but the inferior peduncles are preserved. The shallow basis pontis has few transverse fibers and markedly hypoplastic nuclei pontis. The inferior olives are hypoplastic or dysplastic, and the arcuate nuclei are absent.

CEREBELLAR HYPOPLASIA IN OTHER CONTEXTS

Various combinations of neocerebellar and paleocerebellar hypoplasia, rudimentary segmented dentate nucleus, large heterotopias in cerebellar white matter, and olivary dysplasia have been reported (Fig. 3.97a).

Cerebellar hypoplasia may accompany anterior horn cell degeneration resembling Werdnig–Hoffmann disease (Fig. 3.97b), and clinically classified as PCH type 1. The hemispheres and vermis are equally involved and associated with severe secondary cortical atrophy in the inferior parts of the hemispheres and dentate and olivary dysplasia. Most cases are sporadic, but autosomal recessive inheritance has been recorded. These are genetically distinct from SMA.

GRANULE CELL APLASIA

This is a developmental disorder affecting mainly the cerebellar granule cells.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain is usually small, but its convolutional pattern and histology are normal. The brain stem looks relatively normal, but the cerebellum is very small. The cerebellum retains individual folia, but they are shrunken and sclerotic (Fig. 3.98).

Microscopically, the folia are short and show a narrow molecular layer above a crowded row of Purkinje cells. The internal granular layer is absent. Purkinje cells are often misplaced into the molecular layer. An abnormal dendritic arborization and spiked expansions of terminal dendrites are common. There are few distinct pericellular baskets, but Purkinje axonal swellings (‘torpedoes’) are numerous.

Ectopic granule cell somata can be found at any level within the molecular layer. Fibrillary gliosis extends through the cortex and white matter. Dentate and olivary neurons are preserved within a gliotic neuropil.

CEREBELLAR HETEROTOPIAS

Heterotopic gray matter within the cerebellar white matter is quite frequent and often an incidental finding in infants (perhaps present in over 50%). It is more common in the hemispheres, varying from a few cells to large islands of gray matter in which there are clusters of large cells surrounded by neuropil or islands of heterotopic cortex (Fig. 3.99).

Heterotopias are notably associated with trisomy 13, cerebellar hypoplasias, brain stem dysplasias, and other migration disorders.

CEREBELLAR CORTICAL DYSPLASIA

Small foci of dysplastic cerebellar cortex in the flocculonodular lobes and tonsils and adjacent to the cerebellar peduncles are found in a minority of normal infants. In other parts of the cerebellum, cortical disorganization can be considered to be abnormal (Fig. 3.100). It occurs either alone or with many other malformations, but in the cerebro-ocular dysplasias it is particularly extensive and replaces most of the normal cerebellar cortex. Macroscopically, the branched folia are replaced by a smooth or irregularly fissured surface.

image

image

image

image

image

3.100 Cerebellar cortical dysplasia.
(a) In association with cerebro-ocular dysplasia (lissencephaly type II), the whole of the external surface of the cerebellum is bumpy and lacks folia. Compare with the normal control below. (b) Microscopically, the dysplastic cerebellar cortex comprises extensively fused cortical ribbons. This is the same case as shown in Fig. 3.59 h. (c) A more restricted example of cerebellar cortical dysplasia limited to part of the superior surface in one hemisphere. (d) Low magnification cresyl violet-stained section of the specimen shown in (c). (e) Histologically, the cortical layers are fused, but their normal relationships to each other are maintained.

Microscopically, the folia are scrambled together with an apparent fusing of apposed molecular layers. However, the cortical layers remain in correct order.

image PATHOGENESIS OF CEREBELLAR CORTICAL DYSPLASIA

BRAIN STEM MALFORMATIONS

OLIVARY HETEROTOPIA

One or more heterotopic fragments of inferior olivary nucleus can be found anywhere along the migration route taken before the end of the third gestational month by their neuroblastic precursors from the rhombic lip to the ventral medulla:

These small groups of typical olivary neurons and neuropil can be folded and ensheathed by myelinated fibers rather like the normal nucleus, but the residual main nucleus may be dysplastic (Fig. 3.101). Associations include:

OLIVARY AND DENTATE DYSPLASIAS

Malformations of the inferior olive and dentate nucleus are often combined (Figs 3.102–3.104), probably because of their common origin from the rhombic lip.

Inferior olivary dysplasia has various forms including:

The appearance of dentate dysplasia may be:

image DENTATO-OLIVARY DYSPLASIA

image PATHOGENESIS OF DENTATO-OLIVARY DYSPLASIA

MÖBIUS SYNDROME

Congenital facial diplegia with bilateral abducens palsies produces an expressionless face with internal strabismus in the neonate. The third and fourth cranial nerves and some lower cranial nerves including the twelfth may also be affected. Skeletal abnormalities, absent muscles, and mental retardation are also described, and it may be associated with Poland’s anomaly (absent pectoralis muscle and symbrachydactyly). Möbius syndrome may include:

MALFORMATIONS OF THE SPINAL CORD

Malformations of the spinal cord associated with dysraphic states, are described on p. 60. The other principal abnormalities of the spinal cord are syringomyelia and syringobulbia.

SYRINGOMYELIA

Syringomyelia is tubular cavitation of the spinal cord, which may extend over many segments and sometimes occurs in association with hindbrain cavities (i.e. syringobulbia) (Fig. 3.107).

image SYRINGOMYELIA

SYRINGOBULBIA

Syringobulbia describes the presence of slit-like cavities in the medulla that may occur alone or in association with syringomyelia (Fig. 3.107c).

ARTHROGRYPOSIS MULTIPLEX CONGENITA

This is a clinical syndrome of multiple congenital contractures and results from the many causes of fetal hypokinesia (Table 3.7).

Table 3.7

Causes of fetal hypokinesia

Neurogenic

Muscle fiber type predominance or disproportion

Dysgenesis of motor nuclei of spinal cord and brain stem

Dysgenesis of central nervous system: abnormal chromosome 18

Arthrogryposis with trisomy 21

Dysgenesis of motor nuclei of brain stem and cord in Pierre–Robin syndrome

Dysgenesis of motor nuclei of brain stem and cord in Möbius syndrome

Dysgenesis of spinal cord and prune belly syndrome

Craniocarpotarsal (Freeman–Sheldon) syndrome

Arhinencephaly, encephalocele; Meckel syndrome, dysgenesis of anterior horns

Anencephaly with dysgenesis of anterior horn neurons

Microcephaly alone and with Marden–Walker and Bowen–Conradi syndromes

Arnold–Chiari syndrome

Caudal regression syndrome

Arthrogryposis and Potter sequence

Cerebrohepatorenal (Zellweger) syndrome

X-linked spinal muscular atrophy

Type 1 spinal muscular atrophy

Congenital infection (secondary)

Posterior column and peripheral neuropathy

Myopathic

Congenital muscular dystrophy

Congenital myotonic dystrophy

Central core disease

Nemaline myopathy

Myopathy with increased glycogen

Muscle fibrosis in congenital torticollis

Maternal autoimmune myasthenia gravis

Congenital myasthenic syndrome

DYSGENETIC SYNDROMES

Malformations occur in several dysgenetic syndromes (phakomatoses) including:

STURGE–WEBER SYNDROME

This syndrome is a neurocutaneous syndrome consisting of:

The pathogenesis is unknown. Occasional cases are familial.

image STURGE–WEBER SYNDROME

TUBEROUS SCLEROSIS (BOURNEVILLE’S DISEASE)

Tuberous sclerosis is characterized by CNS malformations, cutaneous lesions, and ocular abnormalities. It causes epilepsy from a few months of age, and mental deficiency (see also Chapter 35).

Tuberous sclerosis is inherited as an autosomal dominant trait with high penetrance, and a prevalence among children 0–5 of age of 1:10 000.

MACROSCOPIC APPEARANCES

The cortical tubers are firm, pale, flat or rounded, dimpled nodules projecting from the cortical surface, their diameter varying from a few millimeters to several centimeters (Fig. 3.110). Up to 40 may be scattered over a single brain. In brain sections, the tubers greatly expand the gyri, blurring the gray–white matter junction.

Subependymal nodules occur singly or in rows (candle gutterings). They are firm or calcified hard protrusions in the wall of the lateral ventricles, particularly near the sulcus terminalis, and less often the third and fourth ventricles or aqueduct. Nodules at the foramen of Monro may obstruct the flow of cerebrospinal fluid, causing hydrocephalus.

image TUBEROUS SCLEROSIS (TSC)

image In the CNS, TSC produces cortical tubers (cerebral and cerebellar), subependymal nodules, and subependymal giant cell astrocytoma.

image Neurologic manifestations include seizures beginning in the first few months, mental retardation, various behavioral problems, and raised intracranial pressure.

image Cutaneous lesions in TSC include hypomelanic macules (seen in 90% of patients), facial angiofibromas or adenoma sebaceum (over the cheeks, nose, lower lip, and chin), periungual or subungual fibromas (more often on toes than on fingers), shagreen patches or fibrous hamartomas (of dorsal surfaces, forehead, or scalp), poliosis, and leukotrichia.

image TSC involves the eyes in 50% of cases, producing a variety of lesions including retinal giant cell astrocytoma, hypopigmented iris spot, white eyelashes, and eyelid and conjunctival hamartomas.

image TSC commonly involves the heart. Single or multiple cardiac rhabdomyomas may produce fetal hydrops, obstruction to flow, myocardial dysfunction, cardiac arrhythmias, and sudden death.

image TSC causes renal lesions, principally multiple angiomyolipomas and renal cysts.

image ETIOLOGY OF TUBEROUS SCLEROSIS COMPLEX (TSC)

image There is locus heterogeneity with disease-determining genes mapped to chromosome 9q34 (TSC1 gene; product – hamartin) and 16p13.3 (TSC2 gene; product – tuberin).

image Allelic loss (i.e. loss of heterozygosity) for 16p13.3 has been demonstrated in hamartomas, a cortical tuber, and a giant cell astrocytoma from tuberous sclerosis patients. This is consistent with the hypothesis that TSC2 acts as a tumor suppressor gene.

image TSC1 and 2 gene products are strategically important in cell growth and turnover (Fig. 3.111).

image

3.111 Interactions of the TSC1–TSC2 complex with multiple cellular pathways.
The TSC1–TSC2 protein complex integrates cues from growth factors, the cell cycle, and nutrients to regulate the activity of mTOR, p70S6 kinase (S6K), 4E-BP1, and ribosomal S6 (S6) proteins. Additional proteins known to interact with either TSC1 or TSC2 are shown: rabaptin-5, 14-3-3, estrogen receptor α, calmodulin, p27, SMAD2 and SMAD3 (the human isoform homologues of Drosophila mothers against decapentaplegic), protein associated with Myc (PAM), cyclin-dependent kinase 1 (CDK1), and cyclin A and B. TSC1 and TSC2 have additional roles besides the modulation of mTOR. For example, Rheb–GTP inhibits B-Raf kinase in a rapamycin-independent manner, indicating that mTOR is not involved in this process. Multiple kinases phosphorylate and inactivate TSC2 and thereby activate Rheb and mTOR: mitogen-activated protein kinase–activated protein kinase 2 (MAPKAPK2), p90 ribosomal S6 kinase 1 (RSK1), and extracellular-related kinase 2 (ERK2). TSC1 is phosphorylated during the G2 and M phases of the cell cycle by CDK1, and phosphorylation-deficient TSC1 mutants result in enhanced inhibition of p70S6K, suggesting that the phosphorylation of TSC1 inhibits the activity of the TSC1–TSC2 complex. The activity of TSC1 and TSC2 can also be enhanced by phosphorylation. Under conditions of energy deprivation, TSC2 is phosphorylated and activated by AMP kinase (AMPK), and the phosphorylation of TSC1 by glycogen synthase kinase 3β (GSK3β) increases the stability of the TSC1–TSC2 complex. (From Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006; 355(13):1345–1356.)

MICROSCOPIC APPEARANCES

Cortical tubers show effacement of the hexalaminar cortex by collections of large bizarre cells with stout processes, peripheral vacuolation, prominent nucleoli, and sometimes multiple nuclei. These cells have a variable immunophenotype that suggests they are atypical astrocytes, atypical neurons, or of indeterminate origin. Clusters of abnormal cells are also found in the deep white matter. Neurofibrillary tangles, argentophilic globules, and granulovacuolar degeneration may also be evident. There is impressive fibrillary gliosis, both beneath the pia and in myelin-depleted gyral cores. Tubers calcify readily. Occasional cerebellar tubers consist of disorganized calcified cortex, abnormal astrocytes, and Purkinje cells.

Subependymal nodules comprise elongated or swollen glial cells and their processes, giant or multinucleated cells, and calcium deposits. Progression to subependymal giant cell astrocytoma (SEGA) is documented. While in clinicopathological terms the SEGA is neoplastic, not hamartomatous, there is considerable histologic overlap between subependymal nodule and SEGA.

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