03 -Disorders of Diverticulation and Cleavage

Sulcation and Cellular Migration Disorders of Diverticulation and Cleavage: Holoprosencephalies and Related Disorders AND RELATED DISORDERS During the fourth gestational week, the ne

Disorders of Diverticulation and Cleavage Sulcation and Cellular Migration

Disorders of Diverticulation and Cleavage:

Holoprosencephalies and Related Disorders

AND RELATED DISORDERS

During the fourth gestational week, the neural tube forms

three primary brain vesicles: the forebrain (prosencephalon),

midbrain (mesencephalon), and hindbrain

(rhombencephalon) During the fifth week the forebrain

further divides into two secondary vesicles: the

telencephalon and the diencephalon (see Fig 1-2) Anlage of

the telencephalon and diencephalon separate by day 32;

partial division of the telen cephalon into two cerebral

hemispheres

occurs by the end of the fifth fetal week

Complete or partial failure in division of the developing cerebrum (prosencephalon) into hemispheres and lobes results in the holoprosencephalies.1 In holoprosencephaly, there

is failure of lateral cleavage into distinct cerebral hemispheres and failure of transverse cleavage into diencephalon andtelencephalon

Prosencephalic abnormalities are directly related

to the mesenchymal tissue of the prechordal mesoderm This tissue is responsible for cleavage

of the telencephalon and development of the midline facial structures.3 The majority of patients with moderate or severe forms of holoprosencephaly also have facial anomalies As stated by DeMyer and paraphrased by Harwood-Nash, “The face predicts the brain.”4 Holoprosencephaly is classically divided into three types by degree of brain cleavage (Table 3-1):

1 Alobar holoprosencephaly (most severe)

2 Semilobar holoprosencephaly (moderately se- vere)

3 Lobar holoprosencephaly (mildest form)

In fact, these disorders form a continuum with no sharp division between the different types

Chapter 3 Disorders

of Diverticulation

38 PART ONE Brain Development and Congenital Malformations

Table 3-1 Holoprosencephalies

Finding Alobar Semilobar Labor

Alobar Holoprosencephaly

A "holoprosencephalic" appearance of the ventricular

system is normal in early fetal development At about 4

weeks of gestation, the primitive ventricles appear as a

single relatively undifferentiated cavity (see Fig 1-4) In

the most severe form of holoprosencephaly, alobar

holoprosencephaly, there is persistence of this primitive

central monoventricle

Pathology and imaging manifestations Alobar

holoprosencephaly is characterized by nearly complete

lack of ventricular and hemispheric cleavage The brain

is basically an undifferentiated holosphere with a central

monoventricle and fused thalami (Fig 3-1) Imaging

studies show a completely unsegmented rim of brain that

surrounds a largely undifferentiated central CSF-filled

cavity (Fig 3-2) There is no interhemispheric fissure,

falx cerebri, or corpus callosum (Figs 3-2, A, and 3-3, A

to C) A large posterior midline cyst is often present

(Fig 3-3, D and E)5 This should be distinguished from callosal agenesis with dorsal third ventricular

interhemispheric cyst (see Fig 2-26, A) Here, the

interhemispheric fissure is complete, the falx is present, and the frontal horns have a bicornuate appearance6 (Fig

3-3, F)

Associated abnormalities Severe craniofacial anomalies are seen in most cases of alobar holoprosencephaly These include cyclops with rudimentary displaced nose (ethmocephaly) and monkeylike head with defective nose and severe hypotelorism (cebocephaly).3 Reported extracranial abnormalities include polyclactyly, renal dysplasia, omphalocele, and hydrops.5 Most neonates with holoprosencephaly who die soon after birth have associated major congenital malformations Several chromosomal abnormalities have been reported with cyclopia or holoprosencephaly, most commonly trisomy13

Fig 3-1 Gross pathology of alobar hoIoprosencephaly A, Intact brain shows a completely

unsegmented holosphere B, Coronal cut section shows a central monoventricle (arrows) The

thalami are fused, the falx is absent, and there is no interhemispheric fissure (From archives of the Armed Forces Institute of Pathology.)

Ventricles Monoventricle Rudimentary occipital horns Squared-off frontal horns

someanteroinferior

fusion

Fig 3-2 A and B, Axial noncontrast CT scans of alobar holoprosencephaly The

basal ganglia are fused (B, arrows), and a large CSF-filled monoventricle

fills most of the intracranial cavity The interhemispheric fissure and falx cerebri are absent

Fig 3-3 A to E, Imaging studies in alobar holoprosencephaly Coronal ultrasound (A) and Tl-weighted MR (B) scans show a central

horseshoe-shaped monovenricle (large arrows) with fused thalami centrally (open arrows)

There is no falx or interhemispheric fissure

The corpus callosum is absent C and D, Axial

T1-weighted MR scans show the fused thalami

(open arrows) and large central CSF-filled

ventricular cavity that is almost completely undifferentiated A dorsal interhemispheric cyst

is present (black arrows), also demonstrated on

the sagittal Tl-weighted scan (E, arrows) (A to

D, From archives of the Armed Forces Institute

of Pathology.)

40 PART ONE Brain Development and Congenital Malformations

Fig 3-3, cont’d F, Coronal gross specimen of callosal agenesis with an interhemispheric

cyst (large arrows) shown for comparison Note the bicornuate appearance of the lateral ventricles (small arrows) The thalami are completely separated and the interhemispheric

fissure is well developed (E, From archives of Armed Forces Institute of Pathology F,

Courtesy E Tessa Hedley-Whyte.)

Sernilobar Holoprosencephaly

Pathology and imaging Semilobar

holoprosencephaly is intermediate in severity There

is partial but interrupted attempt at brain

diverticulation A somewhat H-shaped monoventricle

with partially developed occipital and temporal horns

is common A rudimentary faIx cerebri and

incompletely formed interhemispheric fissure are

often seen, with partial or complete fusion of the

basal ganglia (Fig 3-4)

Associated abnormalities. In general, facial anomalies are either absent or are milder than those associated with alobar holoprosencephaly Facial le-sions commonly seen with various degrees of semilo-bar holoprosencephaly include hypotelorism, as well

as median and lateral cleft lip.3

Fig 3-4 Axial (A) T1- and (B) T2-weighted MR scans in an infant with severe semilobar

holoprosencephaly Primitive occipital horns are present (large black arrows) and a partial, rudimentary interhemispheric fissure is identified (small black arrows) The basal

ganglia are fused (B, open arrows)

Chapter 3 Disorders of Diverticulation and Cleavage, Sulcation and Cellular Migration 41

Lobar Holoprosencephaly

Pathology and imaging In this form of

holoprosencephaly there is nearly complete brain

cleavage The ventricles appear well lobulated

Absence of the septum pellucidum gives a

squared-off or boxlike configuration to the frontal

horns (Fig 3-5) Separation of the basal ganglia is

seen A nearly completely formed interhemispheric

fissure and falx cerebri are present, although their

most anteroinferior aspects may be absent and the

frontal lobes fused inferiorly across the midline (Figs

3-5 and 3-6) An azygous anterior cerebral artery may

be present (Fig 3-7)

Rarely, the inferior frontal lobes are separated and the posterior frontal or parietal regions are continuous across the midline, so-called middle interhemispheric fusion This variant of holoprosencephaly is associated with other abnormalities such as neuronal migration anomalies, callosal dysgenesis, and hypoplastic anterior falx cerebri.1

Associated abnormalities The optic vesicles and

olfactory bulbs may be hypoplastic Mild hypotelorism can be seen, but severe facial anomalies are rare

Fig 3-5. Holoprosencephaly intermediate between mild semilobar and lobar types is demonstrated A well-formed third ventricle is present, seen on the coronal T1-weighted MR

scan (A, Arrows) Complete separation of the

basal ganglia is present, but the interhemispheric fissure is only partially formed Fusion of the

frontal lobes is seen on coronal T1-weighted (B) and axial T2-weighted studies (C)

42 PART ONE Brain Development and Congenital Malformations

Septooptic Dysplasia

Pathology and imaging Septooptic dysplasia (d

Morsier syndrome) can be considered a very milc form of

lobar holoprosencephaly Absence or dysgen esis of the

septum pellucidurn in conjunction witf optic nerve

hypoplasia are the basic components (Fig 3-8, A) Imaging

studies in these patients typicaII3 show squared-off frontal

horns without a septum pel lucidum dividing the lateral

ventricles (Fig 3-8, B)

Associated abnormalities Two anatomic subsets of

septooptic dysplasia have been identified One is associated

with schizencephaly In this group the ventricles are normal,

a remnant of the septum pellucidum is present, and the

white matter of the optic radiations appears normal The

clinical symptoms in this group are seizures and visual

symptoms The second group does not have associated

schizenceph

Fig 3-6 Mild lobar holoprosencephaly is demonstrated on coronal (A and B) and axial (C) Tl-weighted scans Note the relatively well-formed falx cerebri and interhemispheric fissure

(large black arrows) The basal ganglia are separated by the third ventricle (open arrow) A small area of persistent fusion in the anteroinferior frontal lobe region is seen (small black

aly, exhibits diffuse white matter hypoplasia wit ventriculomegaly, has complete absence of the sel turn, and typically presents clinically with symptom of hypothalamic-pituitary dysfunction 7

Dysplasia or absence of the septum pellucidurn i also associated with other brain anomalies, includin aqueductal stenosis, Chiari 11 malformation, cephak celes, callosal agenesis, porencephaly, and hydraner cephaly.'

Arhinencephaly Pathology and imaging In arhinencephaly the o

factory bulbs and tracts are absent (Fig 3-9, A) Coro nal

MR scans show olfactory sulci but no olfacto bulbs or tracts (Fig 3-9, B)

Associated abnormalities Arhinencephaly is ac tually

a spectrum of disorders Although isolated o factory aplasia can occur, it is usually part of a com plex cerebral and somatic malformation syndrome Most, although not all, cases of holoprosencephal are associated with absent olfactory bulbs and tracts Olfactory aplasia also occurs in some genetic condi tions such as Kallmann's syndrome (anosmia, hypo gonadism, and mental retardation).9

Chapter 3 Disorders of Diverticulation and Cleavage, Sulcation and Cellular Migration 43

Fig 3-7 Lobar holoprosencephaly with azygous anterior cerebral artery (ACA)

A, Axial T2-weighted scan shows minimal fusion of the frontal lobe cortex

(large arrows) The azygous ACA is indicated by the small arrows B, MR

angiograrn shows the azygous ACA (open arrows) (Courtesy Joel Cureù.)

Fig 3-8 Gross coronal gross pathology specimen (A) and coronal Tl-weighted

MR scan (B) show characteristic findings of septooptic dysplasia The absent

septum pellucidum with a squared-off appearance to the frontal horns is

indicated by the small black arrows The optic nerves (open arrows) are mildly

hypoplastic (A, Courtesy J Townsend.)

44 PART ONE Brain Development and Congenital Malformations

1

Fig 3-9 A, Gross pathologic specimen of arhinencephaly The olfactory bulbs are absent

B, Coronal Tl-weighted MR scan in a patient with arhinencephaly shows absence of the

olfactory bulbs in their usual position below the olfactory sulci (arrows) (A, Courtesy

Rubinstein Collection, Armed Forces Institute of Pathology.)

SULCATION AND CELLULAR MIGRATION

Beginning with the seventh gestational week, neuronal

and glial precursors are generated in the germinal matrix

that lines the lateral and third ventricles These young

neurons then migrate along the radial glial fibers that

extend from the ventricle to brain surface There is a direct

correspondence between the site of cell proliferation

within the germinal zone and location within the cerebral

cortex.2 Disruption in the normal process of neuronal

generation and cellular migration results in a spectrum of

brain malformations.10 These are divided into several

types, depending on the timing and severity of the arrest of

neuronal migration.2

Lissfincephaly

Etiology and pathology The developing brain of a 16

or 17 week fetus normally has a smooth, "agyric"

appearance with shallow sylvian fissures and almost-no

surface sulcation (Fig 3-10, A to C) Lissencephaly, or

"smooth brain," refers to brains with absent or poor

sulcation (Fig 3-10, D) Lissencephaly can be complete

(synonymous with agyria) or incomplete, where a few

shallow sulci are present In the latter case, it is

synonymous with agyria-pachygyria, or nonlissencephalic

cortical dysplasia (see subsequent discussion).Intrauterine infections can also result in a smooth lissencephalic-appearing brain (see Chapter 16)

Imaging findings Imaging studies in childre

with so-called type I lissencephaly show colpocephaly and a thickened cortex with broad, flat gyri smooth gray-white matter interface, and straight oblique or shallow sylvian fissures, giving

a figure eigh appearanc11 (Fig 3-11) If intrauterine infection has resulted in lissencephaly, parenchymal calcification can be present as well (Fig 3-12) A second type of lissencephaly, type

II, has been described as an agyric, severely disorganized unlayered cortex10 with poor corticomedullary demarcation.12 MR studies in patients with type II lissencephaly show thickened cortex that has a polymicrogyric appearance associated with hypomyelination of the underlying white matter A third type of lissencephaly, the cerebrocerebellar type, occurs without a figure eight configuration and has microcephaly, moderately thick cortices, enlarged ventricles, and hypoplastic cerebellum andbrain stem11

Fig 3-11 Contrast-enhanced axial CT scan of

lissencephaly The sylvian fissures are shallow

(arrows), giving the brain a figure eight appearance

The virtual absence of surface sulcation is characteristic for lissencephaly

Chapter 3 Disorders of Diverticulation and Cleavage, Sulcation and Cellular Migration 45

Fig 3-10 A to C, Sixteen week aborted

fetus The brain normally has a smooth, agyric appearance at the this stage of

development D,Coronal gross pathology section of an agyric (lissencephalic) brain Note virtually complete adsence of sulcation and gyration (Courtesy Rubinstein Collection, Armed Force Institude of Pathology

46 PART ONE Brain Development and Congenital Malformations

Fig 3-12 Axial noncontrast CT scans through the midventricular (A) and basal ganglionic (B) levels in a newborn with intrauterine TORCH Note the small,

agyric brain with shallow sylvian fissures (A, open arrows) and figure eight

appearance Dystrophic calcification in the basal ganglia and subcortical white

matter (black arrows) is also present

Associated abnormalities Miller-Dieker

syndrome is associated with type I lissencephaly

Type II lissencephaly is associated with

Walker-Warburg syndrome These patients have

ocular malformations, cephaloceles, and profound

congenital hypotonia13 (Fig 3-13; see Fig 2-18, A to

C) Fukuyama's congenital muscular dystrophy

(cerebro-oculo-muscular syndrome) is probably part

of this spectrum as well.10, 11 Fukuyama's congenital

muscular dystrophy may also have migrational

malformations (pachygyria/polymicrogyria) and

delayed myelination.14

Nonlissencephalic Cortical Dysplasias

The agyria-pachygyria complex has recently been

reclassified into a more general category,

nonlissencephalic cortical dysplasia, because the

terms pachygyria and polymicrogyria actually are

histologic descriptions and can be difficult to

distinguish on MR examination.15 The cortical

dysplasias can be either diffuse or focal, unilateral or

bilateral

Pathology and imaging Gross pathologic and

imaging appearance in the nonlissencephalic cortical

dysplasias varies from a diffusely thickened,

abnormal cortex that has an irregular, "bumpy" gyral

(polymicrogyria) and relative paucity of underlying white matter (Figs 3-14 and 3-15) to more focal areas

of thickened, flattened cortex (pachygyria) (Figs 3-16 and 3-17) Approximately one quarter of patients with nonlissencephalic cortical dysplasias

Fig 3-13 A For legend, see next page

Chapter 3 Disorders of Diverticulation and Cleavage, Sulcation and Cellular Migration 47

Fig 3-13, cont'd Sagittal (A) and coronal (B)

Tl-weighted MR scans in a patient with

Walker-Warburg syndrome, sphenoethmoidal

cephalocele (large arrows), and lissencephaly The right

hemisphere has a disorganized appearance, with

thickened, nearly agyric cortex (small arrows) and poor

gray-white matter demarcation (Courtesy Joel Cureù.)

Fig 3-14 Gross pathology specimen, lateral view,

demonstrating foci of multiple small, “bumpy” gyri along the sylvian fissure characteristic of

polymicrogyria (arrows)

Fig 3-15 Axial T2-weighted scan demonstrating

polymicrogyria (arrows) with a relative paucity of

underlying white matter

Fig 3-16 Gross pathology specimen of nonlissencephalic cortical dysplasia Some comparatively more normal sulcation and gyration is present in the frontal lobes, but both sylvian fissures are shallow and the parietooccipital cortex is almost completely agyric (Courtesy YakovIev Collection, Armed Forces Institute of Pathology.)