Chapter 2. Neuronal Proliferation, Migration, Organization, and Myelination

Relative cell number



52



Unit I



HUMAN BRAIN DEVELOPMENT



3.0

Glial

2.0



1.0



Neuronal

and

radial glial



0 5 10



20

30

Prenatal



40

10

Birth

Age (wk)



20

30

Postnatal



40



50



Figure 2-1 Relative cell number in human forebrain as a function of

age. Total content of forebrain DNA is used to estimate relative cell

number. Note that the curve has two phases of rapid increase in cell

number. See text for details. (Adapted from Dobbing J, Sands J:

Quantitative growth and development of human brain, Arch Dis Child

48:757–767, 1973.)



the G1 phase of the cell cycle as the molecular ‘‘control

point’’ for these critical proliferative events.20,27

Rakic’s studies of monkey cortical development led

him to the conclusion that, in the earliest phases of proliferation, progenitor cells divide symmetrically into two



additional progenitor cells, and that ‘‘proliferative

units’’ of neuronal progenitor cells develop in this way

(see later and see also Table 2-1).16,25,26,28 This process

determines the number of proliferative units in the ventricular-subventricular zones. Later, at a time comparable to the second half of the second month of gestation

in the human, the number of these proliferative units

becomes stable as the progenitor cells begin to divide

asymmetrically (i.e., each division results in dissimilar

cells, one of which is a stem cell and the other a postmitotic neuronal cell). These asymmetrical divisions determine the size of each proliferative unit (see Table 2-1). As

the proliferative phase progresses, proportionately more

postmitotic neuronal cells and fewer stem cells are produced.19 Rakic concluded that the neurons of these proliferative units migrate together in a column to form the

neuronal columns of the cerebral cortex (Fig. 2-4).28

Other factors can become operative to determine the

complete functional organization of the cerebral cortex

(see later discussion of migration), but the general principle is the generation of neuronal units in the ventricular-subventricular zones with subsequent migration



Plexus tentorii



A. cerebelli superior

A. cerebri posterior



Plexus posterior



Plexus sagittalis



transve

Sinus



rs u s



Sin. rectus

A. choroidealis



Sin. petrosus

superior

Sin



Plexus

choroideus



. c a v e r n.



A. occipitalis

V. jugularis

interna



A. cerebri anterior



A. vertebralis

V. ophthalmica

Plexus maxillary

A. maxillaris interna

A. carotis interna



A. et V. cerebri media



A. centralis retinae



A. maxillaris externa



A. lingualis

Figure 2-2 Reconstruction of the perineural vascular territory of the brain (intracranial vasculature) of a stage 20 human embryo (%51 days,

%18 to 22 mm). The dural venous sinuses, the arachnoidal arterial and venous systems, and the pial plexus that characterize the adult brain are

already recognizable at this age. The wall of the cerebral cortex (cerebral vesicle) has been opened to demonstrate that, at this age, its intrinsic

vascularization has not started, but that of the choroid plexus is already under way. A, artery; cavern, cavernous; sin, sinus; V, vein. (From Streeter

GL: Contributions to Embryology, vol. 8. Carnegie Institute of Embryology, 1918.)



Chapter 2



Neuronal Proliferation, Migration, Organization, and Myelination



53



M

CP



Figure 2-3 Cerebral wall during cortical plate development. Schematic

drawing of the cerebral wall during

development of the mammalian cortical

plate (CP) to demonstrate the major

zones: ventricular (V), subventricular

(S), intermediate (I), and marginal (M).

(From Rakic P: Timing of major ontogenetic events in the visual cortex of the

rhesus monkey. In Buchwald NA, Brazier

MAB, editors: Brain Mechanisms in

Mental Retardation, New York: 1975,

Academic Press.)



M

CP

M



I



I



I

M

V



V



S

V



S



V



V



Figure 2-4 The relation between a small patch of the proliferative, ventricular zone (VZ) and its corresponding area within the cortical plate

(CP) in the developing cerebrum. Although the cerebral surface in primates expands and shifts during prenatal development, ontogenetic columns

(outlined by cylinders) may remain attached to the corresponding proliferative units by the grid of radial glial fibers. Neurons produced between E40

and E100 by a given proliferative unit migrate in succession along the same clonally related radial glial guides (RG) and stack up in reverse order of

arrival within the same ontogenetic column. Each migrating neuron (MN) first traverses the intermediate zone (IZ) and then the subplate (SP), which

contains subplate neurons and ‘‘waiting’’ afferents from the thalamic radiation (TR) and ipsilateral and contralateral corticocortical connections

(CC). After entering the cortical plate, each neuron bypasses earlier generated neurons and settles at the interface between the CP and marginal

zone (MZ). As a result, proliferative units 1 to 100 produce ontogenetic columns 1 to 100 in the same relative position to each other without a

lateral mismatch (e.g., between proliferative unit 3 and ontogenetic column 9, indicated by a dashed line). Thus, the specification of cytoarchitectonic areas and topographic maps depends on the spatial distribution of their ancestors in the proliferative units, whereas the laminar position

and phenotype of neurons within ontogenetic columns depend on the time of their origin. (From Rakic P: Specification of cerebral cortical areas,

Science 241:170-176, 1988.)



54



Unit I



HUMAN BRAIN DEVELOPMENT



pia



2'

1



2



2



1



2



vz



A



Early neural

progenitor



B



Radial glial

progenitor



Figure 2-5 Two types of neuronal progenitors. In A, as occurs especially early in neuronal proliferation, a single neural precursor (1) gives rise to

two identical precursors (2), that is, a symmetrical division. In B, as occurs especially later in neuronal proliferation, a radial neuronal progenitor

(radial glial progenitor or radial glial cell) (1) divides asymmetrically into dissimilar cells, that is, an identical radial progenitor (2) and a postmitotic

neuronal cell (20 ) that migrates along the fiber of its clonally related radial progenitor to ultimately reach the cerebral cortex.



of these groups. Rakic showed that the distinguishing

features of the kinetics of neuronal proliferation in primates versus species with smaller neocortices are a

longer cell-cycle duration and, particularly, a more prolonged developmental period of neuronal proliferation.19 Because of the latter, the total number of

proliferative units of neuronal cells generated is much

greater in the primate.

At least two types of neuronal progenitors are present in the

ventricular zone: (1) a short neural precursor that has a

ventricular endfoot and a leading process of variable

length and (2) the radial glial cell that spans the entire

cortical plate with contacts at both the ventricular and

pial surfaces (Fig. 2-5).23 The former progenitor

previously was considered the principal neuronal

precursor cell. An exciting advance in the understanding of neuronal proliferation was the identification

of the radial glial cell as another major neuronal progenitor

in the ventricular zone.22,23,23a,23b,29-38 Previously, the

major roles of this cell were considered to be, initially,

a glial guide for migrating neurons and, later, a

source of astrocytes (see later). However, more

recent studies based on immunocytochemical and

molecular techniques indicate that radial glial cells

give rise to many neurons generated in the ventricular

zone, particularly radially migrating excitatory projection cortical neurons. Thus, the term radial glial cell

(which I continue to use) may ultimately be replaced

by ‘‘radial glial progenitor’’ or ‘‘radial progenitor.’’

When the radial glial cell functions as a neuronal

progenitor, the clonally related neuron so generated

then migrates along the parent radial glial fiber (see

Fig. 2-5). These elegant proliferative events involving

the radial glial cell as neuronal progenitor are

modulated by several key signaling pathways involving

the Notch receptor, the ErbB receptor (through the

ligand neuregulin), and the fibroblast growth factor

receptor.28,38,39 Other critical molecular determinants

include beta-catenin, a protein that functions in the

decision of progenitors to proliferate or differentiate.40

Finally, of particular importance in the regulation of

radial glial production of neurons are calcium waves

propagating through connexin channels of the radial



glial cell.35 Calcium entry is critical in the regulation

of the cell cycle.

Subsequent to neurogenesis, radial cells produce

astrocytes and probably other glial cells (e.g., oligodendroglia).36 Additionally, more recent data indicate that

radial glial cells also give rise to cells that persist in the

subventricular zone of adult brain as stem cells capable

of producing neurons.36 The multiple functions of

radial glial cells are summarized in Table 2-2.

Disorders

Disorders of neuronal proliferation would be expected

to have a major impact on CNS function. Because of

difficulties in quantitating neuronal populations, however, proliferative disorders often are difficult to define

by conventional neuropathological examination. Even

when the disorder is so extreme that the brain is grossly

undersized (i.e., micrencephaly) or oversized (i.e.,

macrencephaly), defining the nature and severity of the

proliferative derangement is also difficult by conventional techniques. (Although theoretically there is the

possibility that the disorders relate to alterations in

later-occurring normal apoptotic events, I consider

these to be disorders of proliferation until evidence of

an apoptotic disorder is recorded.) In the following discussion, I focus on these two extremes of apparent proliferative disorders, but I emphasize that conclusions

about the nature of the disorders can be made only

cautiously.

Micrencephaly

Disorders apparently related to impaired neuronal

proliferation are categorized under the term primary

micrencephaly, to distinguish the disorder from micrencephalies secondary to destructive disease (Table 2-3).

TABLE 2-2



Functions of Radial Glial Cells



Progenitors for cortical neurons

Guides of neuronal migration

Progenitors for astrocytes and oligodendrocytes

Neural stem cells found in subventricular zone of adult brain



Chapter 2

TABLE 2-3



Disorders of Neuronal Proliferation:

Primary Micrencephaly*



Familial

Autosomal recessive (micrencephaly vera)

Autosomal dominant

X-linked recessive

Genetics unclear (ocular abnormalities)

Teratogenic

Irradiation

Metabolic-toxic (e.g., fetal alcohol syndrome, related to

cocaine, hyperphenylalaninemia)

Infection (rubella, cytomegalovirus)

Syndromic (Multiple Systemic Anomalies)

Chromosomal

Familial

Sporadic

Sporadic (Nonsyndromic)

*Excluded are cases of congenital microcephaly secondary principally

to destructive disease (hypoxia-ischemia, infection) developing

after the conclusion of cerebral neuronal proliferation.



Neuronal Proliferation, Migration, Organization, and Myelination

TABLE 2-4



55



Radial Microbrain



Term newborns: death, birth–30 days

Brain weight 16–50 g (normal, 350 g)

No evidence for destructive process

Normal residual germinal matrix at term

Normal cortical lamination

Cortical neurons 30% of normal number

Cortical neuronal columns decreased in number

Neuronal complement of each column normal

Data from Evrard P, de Saint-Georges P, Kadhim HJ, Gadisseux J-F:

Pathology of prenatal encephalopathies. In French JH, Harel S,

Casaer P, editors: Child Neurology and Developmental Disabilities,

Baltimore: 1989, Paul H. Brookes.



proliferative events, which generates by symmetrical divisions of neuronal progenitors the total number of proliferative units, is based on the finding of a marked

reduction in number of cortical neuronal columns

but an apparent normal complement of the neurons

per column (i.e., normal size of columns) (Fig. 2-6).5



The latter relates to hypoxic-ischemic, infectious, metabolic, or other destructive events, occurring usually

following completion of cerebral neuronal proliferative

events near the end of the fourth month of gestation

(see Chapters 8, 9, 14, 15, 16, and 20). The primary

micrencephalies that have been shown most clearly to

be related to impaired neuronal proliferation include the

autosomal recessively inherited disorders, often categorized as micrencephaly vera. Thus, in the context of

this chapter, I discuss these conditions in most detail.

Micrencephaly Vera. Micrencephaly vera refers to a heterogeneous group of disorders that appear to have, as

the common denominator, small brain size because of a

derangement of proliferation (see Table 2-3). Thus, no

evidence of intrauterine destructive disease or of gross

derangement of other developmental events (e.g., neurulation, prosencephalic cleavage, neuronal migration)

exists, and the abnormal brain size is apparent as early

as the third trimester of gestation). The brain is generally well formed, although the gyrification pattern may

be simplified to a variable degree. As noted earlier, the

clearest examples of micrencephaly vera are the

autosomal recessively inherited micrencephalies, and I

use this term only for these examples of primary

micrencephaly. I first discuss radial microbrain, an informative but rare and particularly severe type of micrencephaly vera, and then the more common varieties of

micrencephaly vera.

Anatomical Abnormality: Radial Microbrain. Radial

microbrain is a rare disorder of particular interest

because it appears to provide the first clear example

of a disturbance in number of proliferative units.5,41

The major features of the seven cases studied carefully

by Evrard and colleagues5,41 are outlined in Table 2-4.

The extremely small brain has no marked gyral

abnormality, no evidence of a destructive process, and

no disturbance of cortical lamination. The conclusion

that the disturbance involves the early phase of



Figure 2-6 Radial microbrain. Brain of a full-term newborn with the

pathological picture of radial microbrain described in the text. Note the

normal cortical lamination (long arrows) and the normal residual germinative zone (both short arrows). From Evrard P, de Saint-Georges P,

Kadhim HJ, et al: Pathology of prenatal encephalopathies. In French JH,

Harel S, Casaer P, editors: Child Neurology and Developmental

Disabilities, Baltimore: 1989, Paul H. Brookes.)



56



Unit I



HUMAN BRAIN DEVELOPMENT



Timing and Clinical Aspects: Radial Microbrain.

The presumed timing of radial microbrain is no later

than the earliest phase of proliferative events in the

second month of gestation. The essential abnormality

involves the symmetrical divisions of progenitors to

form additional progenitors and thereby the number

of proliferative units. Later proliferative events that

determine the size of each column proceed normally,

as evidenced not only by the normal neuronal complement of each column but also by the presence of a

normal residual amount of germinal matrix at term

(see Fig. 2-6).

The clinical features are not entirely clear, because

this anomaly is rare. The reported cases have been fullterm newborns who died in the first month of life. The

distinction from anencephaly and aprosencephaly-atelencephaly is based on the presence of an intact

skull and dermal covering, in contrast to anencephaly,

and of a normal external appearance of cerebrum and

ventricles, observable by ultrasonography, in contrast

to aprosencephaly-atelencephaly. The disorder is

notably familial, probably of autosomal recessive

inheritance.

Anatomical Abnormality: Micrencephaly Vera. As

noted earlier, the designation micrencephaly vera

refers to a heterogeneous group of autosomal recessive disorders that appear to have, as the common

denominator, small brain size because of a derangement of proliferation (see Table 2-3). In recent years,

remarkable insights into the genetics and molecular bases of these disorders have been gained (see

later).

The anatomical studies of Evrard and colleagues5,41 provide insight into the fundamental disturbance in micrencephaly vera, at least in a prototypical

autosomal recessive variety (Table 2-5). The brain is

small (clearly more than several standard deviations

below the mean) but not so strikingly as in the tiny

radial microbrain. Simplification of gyral pattern

exists with no other external abnormality and no evidence of a destructive process. The number of cortical neuronal columns appears normal, but the

neuronal complement of each column, especially

the superficial cortical layers, is decreased markedly.

Additional evidence of disturbance of the later proliferative events that determine size of cortical neuronal



TABLE 2-5



Micrencephaly Vera: Autosomal

Recessive Type



No evidence for destructive process

No evidence for migrational defect

No apparent defect in number of cortical neuronal columns

Cortical neuronal columns with marked decrease in neurons

of layers II and III

No residual germinal matrix at 26 weeks of gestation (‘‘premature exhaustion’’ of matrix)

From Evrard P, de Saint-Georges P, Kadhim HJ, Gadisseux J-F:

Pathology of prenatal encephalopathies. In French JH, Harel S,

Casaer P, editors: Child Neurology and Developmental Disabilities,

Baltimore: 1989, Paul H. Brookes.



columns is the absence of residual germinal matrix in

the 26-week fetal brain studied by Evrard and colleagues (Fig. 2-7). The deficiency in neurons of the

superficial cortical layers may explain the simplification of gyral pattern (see the later discussion of gyral

development in migrational disorders).

Timing and Clinical Aspects: Micrencephaly Vera.

The presumed timing of the micrencephaly vera group

of disorders involves the period of later proliferative

events by asymmetrical divisions of neuronal progenitors, that is, onset at approximately 6 weeks in the

human, with later rapid progression until approximately

18 weeks (see earlier). The most severely undersized

brains are expected to have the earliest onsets and the

most marked deficiency of neurons in each cortical

column.

The clinical presentation of infants with the prototypical autosomal recessive forms of micrencephaly

vera is interesting in that, as newborns, most affected

infants do not show striking neurological deficits

or seizures. This presentation is in contrast to

that of other varieties of micrencephaly, that is,

intrauterine destructive disease or other developmental derangement (e.g., migrational defect). Rare autosomal recessive forms of micrencephaly with severe

neuronal migrational defects (i.e., microlissencephaly)

are more likely to be accompanied by neurological

deficits and seizures (see the later discussion of disorders of neuronal migration).

Magnetic resonance imaging (MRI) has been invaluable in the assessment of micrencephaly vera, especially

for evaluation of gyral development and the presence of associated migrational abnormalities.42 Most

commonly, gyral formation is variably simplified (Fig.

2-8), and the term microcephaly with simplified gyri is

often used.42-50 Simplification of the gyral pattern

often is not obvious. Rare cases are associated with

severe migrational disturbances, such as lissencephaly,

periventricular heterotopia, or posterior fossa deficits,

especially cerebellar hypoplasia.45,47,48,51-53

Etiology: Autosomal Recessive Micrencephaly. At

least six gene loci have been identified for autosomal

recessive primary micrencephaly, or micrencephaly

vera. Four of the genes have been identified (Table

2-6).46,54-59 Perhaps not unexpectedly, the genes play

key roles in mitosis. Microcephalin is crucial for cell cycle

control, chromosome condensation, and DNA repair.

CDK5RAP2 is a centrosomal protein involved in microtubular function necessary for formation of the mitotic

spindle. ASPM also is necessary for microtubular

function at the poles of the mitotic spindle, and

CENPT similarly is involved in formation of the mitotic

spindle.

Etiology: Other Disorders. The four major etiological

categories for primary micrencephaly, in addition to the

autosomal recessive group just discussed, are familial,

teratogenic, syndromic, and sporadic (see Table 2-3).

Familial syndromes are most critical to detect because of

implications for genetic counseling. In addition to the

autosomal recessive group (see earlier), these inherited

varieties include autosomal dominant and X-linked

recessive types, as well as familial types with ocular



A



B



Figure 2-7 Premature exhaustion of the germinal layer in microcephaly vera. A, Microcephaly vera, human fetal forebrain, 26 weeks of

gestation. B, Normal human fetal forebrain, 26 weeks, same cortical region for comparison. The germinal layer (arrowheads), cerebral cortex

(arrows), and intervening cerebral white matter are visible. In microcephaly vera (A), the germinal layer is exhausted at this age, and the white matter

is almost devoid of late migrating glial and neuronal cells. Cortical layers VI to IV are normal, whereas the two superficial layers are almost missing.

(From Evrard P, de Saint-Georges P, Kadhim HJ, et al: Pathology of prenatal encephalopathies. In French JH, Harel S, Casaer P, editors: Child

Neurology and Developmental Disabilities, Baltimore: 1989, Paul H. Brookes.)



A



B



Figure 2-8 Microcephaly with simplified gyri. In A, the sagittal T1-weighted magnetic resonance imaging (MRI) scan shows marked microcephaly.

In B, the axial T2-weighted MRI scan shows simplification of the gyral pattern. No other dysgenetic abnormalities are present, nor is any evidence of

destructive disease manifest. (Courtesy of Dr. Omar Khwaja.)



58



Unit I



TABLE 2-6



HUMAN BRAIN DEVELOPMENT



Autosomal Recessive Primary Micrencephaly (Micrencephaly Vera): Molecular Genetics



Locus



Gene/Protein



Function



MCPH 1

MCPH 3



Microcephalin

CDK5RAP2 (cyclin-dependent kinase-5 regulatory associated

protein-2)

ASPM (abnormal spindle in microcephaly)

CENPJ (centromere-associated protein J)



Cell cycle control

Mitotic spindle formation



MCPH 5

MCPH 6



Mitotic spindle formation

Mitotic spindle formation



MCPH, Autosomal recessive primary micrencephaly.



abnormalities and variable genetics.60-74 These ocular

abnormalities may include chorioretinopathy that can

be confused with the chorioretinitis of intrauterine

infection (see Chapter 20). One such disorder is Cohen

syndrome, which is inherited in an autosomal recessive

manner. Of the unusual cases of micrencephaly with

autosomal dominant inheritance, intellect subsequently is usually either spared or only mildly defective;

patients generally have no facial dysmorphism,

although digital anomalies and rare syndromic varieties

have been reported.71,74 X-linked recessive inheritance

of micrencephaly has been described, albeit less

commonly than autosomal recessive inheritance.

The best-documented teratogenic agent producing

micrencephaly is irradiation, such as by atomic bomb

or radiation therapy for tumor or ankylosing spondylitis, particularly before 18 weeks of gestation (see

Table 2-3).75-77 The most critical period in the

Nagasaki-Hiroshima experience was 8 to 15 weeks.77

Maternal alcoholism or cocaine abuse (see Chapter 24)

and maternal hyperphenylalaninemia have been associated with micrencephaly. Micrencephaly, usually

with mental retardation, occurs in as many as 75% to

90% of (nonphenylketonuric) children of women with

phenylketonuria; the risk for the fetus correlates

with the severity of the maternal hyperphenylalaninemia.78-88 With dietary treatment, the risk declines to

as low as 8% when phenylalanine levels are controlled

before conception and to 18% when control is

achieved by 10 weeks of pregnancy.89 When control

is not achieved until 20 to 30 weeks, the incidence of

microcephaly increases to 40%. Rarer intrauterine teratogens for micrencephaly include anticonvulsant

drugs (see Chapter 24), organic mercurials, and excessive ingestion of vitamin A or vitamin A analogues (see

Chapter 24).90 Finally, among intrauterine infections

that may cause micrencephaly (see Chapter 20), rubella

is the best candidate for an agent that may produce

micrencephaly through an impairment of proliferation

rather than principally through a destructive process.

Cytomegalovirus infection may also act in this way,

although disturbances of neuronal migration and

destructive lesions contribute to the condition.

Human immunodeficiency virus characteristically produces micrencephaly (without major destructive

lesions) after the neonatal period, although neonatal

cases have been reported (see Chapter 20).

Syndromic cases, that is, those with multiple associated systemic anomalies, may be related to chromosomal

disorders or monogenic (familial) defects, or they may

occur sporadically (see Table 2-3). In one consecutive sample of congenital microcephaly, syndromic



disorders accounted for only 6% of cases.91 The

nature of the proliferative disorder in this diverse

group is generally not known and is not discussed

further. Clinical details are available in standard

sources.73

Sporadic nonsyndromic cases, that is, those with no

related family history, identifiable teratogen, or recognizable syndrome, are the most common varieties of

micrencephaly vera (see Table 2-3).91,92 No associated

systemic or other neural malformations can be identified. The nature of the proliferative disturbance is

generally unknown.

Macrencephaly

Anatomical Abnormality. The designation macrencephaly signifies a large brain and is a feature of a heterogeneous group of disorders that have not been well

defined from the neuropathological standpoint.

Nevertheless, several entities clearly exist in which the

brain is generally well formed but is unusually large

(see Table 2-5). Genetic varieties, suggestive of a

derangement in the developmental program for neuronal proliferation, have been defined (see following

discussion). As with micrencephaly, however, the conclusion that we are dealing with proliferative disorders

can be made only tenuously until central neuronal

populations can be quantified more accurately. This

discussion excludes other rare disorders of macrocephaly, such as enlargement of the skull (craniometaphyseal dysplasia, hemoglobinopathy), subdural

hematoma or effusion (see Chapters 10, 21, 22), hydrocephalus (see Chapters 1, 11, 21), metabolic disorders

(see Chapter 15), or degenerative disorders (Alexander

disease, Canavan disease [see Chapter 16]).

Timing and Clinical Aspects. Although neuronal

proliferation in the cerebrum is an event that occurs

principally during the third and fourth months of

gestation, this time period may be prolonged in disorders of excessive proliferation. Alternatively, abnormal

proliferation may occur at the appropriate time during

development but at an excessive rate. Additionally, a

later-occurring defect of normal apoptosis or programmed cell death (see later section on organization)

perhaps could lead to macrencephaly. The issues of

mechanism are unresolved and await development of

suitable experimental models for elucidation.

The clinical syndrome in the several types of macrencephaly (Table 2-7) varies from no apparent

neurological deficit (e.g., autosomal dominant, isolated

macrencephaly) to severe recalcitrant seizures and

mental retardation (e.g., autosomal recessive, isolated



Chapter 2

TABLE 2-7



Disorders of Neuronal Proliferation:

Macrencephaly



Isolated Macrencephaly

Familial

Autosomal dominant (relation to ‘‘benign enlargement of

extracerebral spaces’’ or ‘‘external hydrocephalus’’)

Autosomal recessive

Sporadic

Associated Disturbance of Growth

Achondroplasia

Beckwith syndrome

Cerebral gigantism

Fragile X syndrome (see ‘‘Chromosomal Disorders’’ below)

Marshall-Smith syndrome

Thanatophoric dysplasia

Weaver syndrome

Neurocutaneous Syndromes

Multiple hemangiomatosis

Lipomas, hemangiomas, lymphangiomas, pseudopapilledema (Bannayan-Riley-Ruvalcaba)

Asymmetrical hypertrophy, hemangiomata, varicosities

(Klippel-Trenaunay-Weber)

Asymmetrical hypertrophy, telangiectatic lesions, flame

nevus of the face (cutis marmorata telangiectatica

congenita)

Neurofibromatosis,* tuberous sclerosis,{ Sturge-Weber

syndrome{

Epidermal nevus syndrome (see ‘‘Unilateral

Macrencephaly’’ below)

Chromosomal Disorders

Fragile X syndrome (relative macrencephaly)

Klinefelter syndrome

Unilateral Macrencephaly (Hemimegalencephaly)

Isolated

Syndromic: epidermal nevus syndrome, Proteus syndrome

(most common)

*Neurocutaneous disorder of cellular proliferation causing macrencephaly and affecting primarily nonneuronal elements (i.e., glia).

{

Neurocutaneous disorders of cellular proliferation but not usually

associated with neonatal macrencephaly.



A



Neuronal Proliferation, Migration, Organization, and Myelination



59



macrencephaly, or unilateral macrencephaly). In other

types of the disorder, extraneural features may dominate the clinical presentation (e.g., associated growth

disorders and certain neurocutaneous syndromes).

Some of these individual clinical aspects are mentioned

briefly in the following discussion.

Familial, Isolated Macrencephaly. Perhaps the most

common variety of macrencephaly occurs in the familial setting and in the absence of any other extraneural

findings. For this group, I use the term familial, isolated

macrencephaly. Two genetic types can be recognized:

autosomal dominant and autosomal recessive; the

former is much more common.

In familial, isolated macrencephaly of the autosomal

dominant type, the head is usually large at birth (>90th

percentile in %50%) and continues to grow postnatally

at a relatively rapid rate.93,94 Neurological deficits are

rarely striking, and development and ultimate level of

intelligence are in the normal range in approximately

50% to 60% of cases. Mental retardation is present in

only approximately 10%. The genetic component of

this syndrome is overlooked frequently until the head

circumference of the parents is measured. The diagnosis of fetal macrocephaly of this type was made in the

34th week of pregnancy in a woman with benign

macrocephaly.95

Related to autosomal dominant macrencephaly is a

syndrome of macrocephaly, categorized under several

names: benign enlargement of extracerebral spaces, benign

subdural effusions of infancy, and idiopathic external hydrocephalus.94,96-102 The clinical features described in the

previous paragraph are present, and brain imaging studies show prominent extracerebral subarachnoid

spaces and a large brain (Fig. 2-9). The cisterna

magna especially may be prominent. In some cases,

subdural and subarachnoid fluid appears to be present;

the distinction is best made by MRI scan.96 Head

growth in the first year is rapid, and infants not overtly

macrocephalic at birth attain rates of head growth at

the 97th percentile or slightly higher. Accelerating



B



Figure 2-9 ‘‘Benign’’ macrocephaly. A, Coronal sonogram demonstrates mild ventricular enlargement and moderate extra-axial fluid over the

convexities (arrowheads). B, Axial computed tomography scan shows similar findings. (From Babcock DS, Han BK, Dine MS: Sonographic findings in

infants with macrocrania, AJNR Am J Neuroradiol 9:307-313, 1988.)



60



Unit I



HUMAN BRAIN DEVELOPMENT



head growth ceases by approximately 1 year, and over

the next several years extracerebral spaces become

smaller, although the brain is clearly larger than average. Because of the large brain size, if the infant is first

evaluated after the second year of life, isolated macrencephaly will be observed. Because as many as 90% of

these infants have a parent with a large head, the

genetic features are similar to those of autosomal dominant isolated macrencephaly. The similarity of the

clinical features and genetics suggests that these may

represent different forms of the same fundamental disorder. Those unusual patients with isolated macrencephaly that conforms to autosomal recessive inheritance

are more likely to exhibit definite mental retardation,

epilepsy, and motor deficits.90

Sporadic, Isolated Macrencephaly. Isolated macrencephaly with no evidence of a familial disorder by history

and after measurement of parental head circumference occurs only slightly less often than the autosomal

dominant disorder described previously.93,103,104 The

clinical course is similar.

Associated Disturbance of Growth. Macrencephaly

may be associated with generalized disorders of growth,

such as achondroplasia, Beckwith syndrome, cerebral

gigantism (Sotos syndrome), fragile X syndrome,

Marshall-Smith syndrome, thanatophoric dysplasia,

and Weaver syndrome (see Table 2-7).73,93,105-108

Except in Beckwith syndrome, which is complicated

by neonatal hypoglycemia, neurological features in

the neonatal period are unusual. The precise neuropathological correlates for the macrencephaly in these

disorders remain to be defined. The gene mutated or

deleted in Sotos syndrome, NSD1, encodes a nuclear

receptor binding protein that may be involved in

proliferative events.

Neurocutaneous Syndromes. Several of the neurocutaneous disorders are associated with evidence of

excessive cellular proliferation within the CNS,

sometimes with overt macrencephaly, and evidence of

excessive proliferation of mesodermal structures (see

Table 2-7). Macrencephaly occurs most consistently

in this context in the multiple hemangiomatosis

syndromes.73,109-115

In neurofibromatosis, an autosomal dominant disorder, the principal proliferative abnormality involves

glia, particularly astrocytes. (Thus, the onset of the proliferative disorder in this disease primarily occurs after

the time period of neuronal proliferative events.)

Approximately 40% of infants exhibit more than five

´-au-lait spots larger than 5 mm at birth.116-122

cafe

Approximately 40% to 50% of such infants have

macrocephaly, usually after the neonatal period.123,124

Consistent with the predominantly glial rather than

neuronal involvement in the disorder, the megalencephaly relates primarily to increases in cerebral white

matter volume, primarily in frontal and parietal areas.125

Relative macrocephaly with generalized glial tumors

has been documented by prenatal ultrasound.126

Hemimegalencephaly with neonatal seizures and



associated neuronal migrational defects also have

been observed.127,128 Of the glial tumors that are the

hallmark of this disease, optic nerve glioma and plexiform neuroma of the eyelid have been observed in the

newborn, albeit rarely.117,122 The gene for this disorder,

located on chromosome 17, NF1, has been shown to

encode a protein involved in the negative regulation of

a key signal transduction pathway, the Ras pathway,

which transmits mitogenic signals to the nucleus.120-122,129,130 Thus, loss of the neurofibromatosis

protein, neurofibromin, leads to increased mitogenic

signaling and thereby to the proliferative abnormalities

characteristic of the disorder.

In Sturge-Weber disease, a sporadic disorder, the principal abnormality affects leptomeningeal blood vessels.

Thus, the time of onset is probably coincident with that

for neuronal proliferation. Data suggest that the fundamental defect in this disorder is a failure of development

of superficial cortical veins that diverts blood to the

developing leptomeninges, with the formation of abnormal vascular channels as a consequence.131 Abnormalities of fibronectin in cerebral vessels may play a role in

the genesis of the vascular abnormality.132 The characteristic facial port-wine stain is described in Chapter 3;

the overall incidence of clinical manifestations of SturgeWeber disease (glaucoma or seizures) is 2% to 8% in

patients with unilateral facial lesions and 24% in patients

with bilateral facial lesions.131,133,134 Identification of

the newborn with intracranial involvement is difficult.

Seizures and cerebral calcification (identified by computed tomography [CT]) have been noted only

occasionally in newborns (Fig. 2-10).42,135-138 Cerebral

calcifications most commonly appear after 6 months of

age and often considerably later.114,131,139-141 MRI

appears to be the most useful imaging study in the

first year42,114,131,134,140-143; the principal findings are

cerebral cortical and white matter changes in the

region of the leptomeningeal angiomatosis, angiomatous alteration of overlying calvaria, and atypically

located, congested deep cerebral veins.114,140,142

Gadolinium-enhanced MRI is the gold standard for

demonstration of the leptomeningeal vascular lesion

(Fig. 2-11).42,114,131,140-142 The choroid plexus is

enlarged on the side of the leptomeningeal lesion, presumably because of the diversion of venous blood into

the deep venous system, as a consequence of the lack of

superficial cortical venous drainage (see earlier discussion). On single photon emission tomographic studies,

decreased cortical perfusion may be observed in the

region of the vascular lesion.131,141,144,145 MRI perfusion

studies also may be useful in detecting perfusion

deficits.146 Infants with Sturge-Weber syndrome who

have bilateral cerebral disease have a much poorer

outcome (8% with average intelligence) than those

with unilateral cerebral disease (45% with average

intelligence).134,138,144,145,147,148

In tuberous sclerosis, the principal proliferative abnormality affects both neurons and glia. The neuropathological and molecular aspects of these disorders

indicate that tuberous sclerosis also reflects abnormal

migration and differentiation (see later).149-151 The critical neonatal cutaneous feature is a depigmented, ash



Chapter 2



61



Neuronal Proliferation, Migration, Organization, and Myelination



Figure 2-10 Sturge-Weber disease, computed tomography (CT) scan. This infant exhibited seizures on the fifth day of life. The CT scan was

obtained at the age of 4 months. Left, Conventional CT scan. Right, Contrast-enhanced CT scan. Note marked atrophy and calcification in the left

frontal region and, to a lesser extent, in the left parietal region. Only scant contrast enhancement is apparent. (From Kitihara T, Maki U: A case of

Sturge-Weber disease with epilepsy and intracranial calcification at the neonatal period, Eur Neurol 17:8-12, 1978.)



leaf–shaped macule. Seizures may occur in the neonatal

period.149,152-155 Cardiac tumors (rhabdomyomata) are

characteristic and uncommonly may lead to neurological

features by causing cardiac failure, arrhythmias, or cerebral emboli (personal cases). Cardiac rhabdomyomata

have been identified in affected fetuses and are usually

the first clue to prenatal diagnosis.156,157 The diagnosis



A



of tuberous sclerosis is established in 80% to 95% of

fetuses with cardiac rhabdomyomata.158,159 The

natural history of these tumors is favorable—virtually

all regress at least partially.159 Subependymal nodules,

the most common cerebral lesion detected in utero,

have been identified as early as 21 weeks.160 Indeed,

I consider the most useful constellation of features for



B



Figure 2-11 Sturge-Weber disease, gadolinium-enhanced magnetic resonance imaging (MRI) scan. A, Axial MRI scan before administration of

gadolinium in an infant with a port-wine stain shows no definite abnormality. B, The scan after gadolinium enhancement shows diffuse leptomeningeal enhancement in the right occipital and temporal regions. The findings are characteristic of Sturge-Weber disease. (Courtesy of Dr. Omar

Khwaja.)



62



Unit I



HUMAN BRAIN DEVELOPMENT



Figure 2-12 Tuberous sclerosis, computed tomography

scan. This infant exhibited generalized seizures and depigmented macules at 4 weeks of age. Note, A, the striking

cortical tuberous change in the left occipital region and, B,

the small subependymal nodules (arrowheads) near the

heads of both caudate nuclei.



A



B



the diagnosis of tuberous sclerosis in the neonatal period to

consist of the depigmented macule, cardiac rhabdomyoma, subependymal nodule, and cortical tuber. In

one large series, approximately 90% of newborns

studied by MRI exhibited the latter two cerebral

lesions.157 Neuropathological features include both

the characteristic subependymal and cerebral corticalsubcortical collections of abnormal neurons and

glia (i.e., subependymal nodules and cortical tubers)

and heterotopic collections of similar cells in the

cerebral white matter, often arranged in radial

bands.161-166 The cells are often bizarre, large, and

poorly differentiated, exhibiting features of both

neurons and astrocytes. Subependymal giant cell astrocytoma has been reported in newborns with tuberous

sclerosis157,167-169 but more typically it appears in

older children. Both CT scanning and ultrasonography

can be useful in diagnosis (Figs. 2-12 and

2-13).42,152,153,170,171 However, MRI has proven of

particular value in the neonatal period and demonstrates

the subependymal collections, the cortical tubers, and



Figure 2-13 Tuberous sclerosis, ultrasound scan. This infant exhibited depigmented macules with myoclonic seizures at 3 weeks of age.

The parasagittal ultrasound scan shows an echogenic subependymal

nodule (arrowhead) that was also seen on a computed tomography

scan.



the white matter lesions especially well (Fig.

2-14).42,157,165,166,168,172-174 Because of the unmyelinated cerebral white matter in the newborn, the cortical

tubers (hypointense on T1-weighted images, hyperintense on T2-weighted images) have signal characteristics

opposite those exhibited by older children with the

disorder.42,166

The tuberous sclerosis phenotype is associated with

dysfunction of genes on either chromosome 9 or chromosome 16.130,175-177 The disorder, although autosomal dominant, is associated with a high spontaneous

mutation rate. Overall, approximately 80% of cases are

sporadic.150,151 The genes, TSC1 on chromosome

9 and TSC2 on chromosome 16, encode the respective



Figure 2-14 Tuberous sclerosis, magnetic resonance imaging

(MRI) scan. This 11-day-old infant was identified in utero with a cardiac

rhabdomyoma. On this axial T1-weighted MRI, note the multiple cortical

tubers (thick arrow), subependymal nodules (thin arrow), and radial

cerebral white matter lesion (double arrow). (Courtesy of Dr. Omar

Khwaja.)