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270
Chapter 7 Malformations of Cortical Development
ABC
DE F
Figure 7–24.
axial plane shows the presence of a small occipital encephalocele ( arrow ). Note the apparently normal size of the distal lateral ventricle and the lack of
sulcation on the same side. (B) Transvaginal median plane shows dysgenesis of the corpus callosum. The corpus callosum is shorter than usual, and the
genu and splenium are poorly developed ( small arrows ). Note the clear visualization of the intrathalamic adhesion due to dilation of the third ventricle
( large arrow ). (C) Paramedian plane shows lateral ventricle dilation and lissencephalic cortex. (D) Frontal coronal plane shows almost a complete lack
of sulcation. (E) Transcaudate coronal plane shows the dilated lateral ventricles and no sulci and gyri. ( F) Left eye cataract ( arrow ). (With permission
from Monteagudo A, 2001.
Implications for Screening, Including
Time of Earliest Recognition
WWS is a rare disease, and in the majority of cases, the
diagnosis will be possible only after delivery or in families
at risk. During routine second- and third-trimester examinations, the first sign of the disease usually will be moderate to severe ventriculomegaly with or without associated
anomalies. All patients with ventriculomegaly should be
specifically scanned for the presence of cephalocele, cerebellar, and brainstem anomalies and dysmorphology signs,
with particular attention to the eyes.
The presence of ventriculomegaly with abnormal
brain and echogenic lenses may be present as early as 15
postmenstrual weeks (
its rarity, WWS may remain undiagnosed in fetuses with
ventriculomegaly until after delivery.
Walker-Warburg syndrome (WWS) in a fetus at 34 postmenstrual weeks referred because of ventriculomegaly. (A) Transabdominal
142
)
examination with particular emphasis in the depiction of
the median plane for demonstration of the brainstem and
the vermis (see Chapter 2 ). MRI may be helpful in patients
in whom an optimal US evaluation is not possible
Figure 7–27 ).
(
19 , 148
Prognosis
Babies born with WWS have very poor tone (floppy baby)
due to the associated abnormal muscle development.
Muscle biopsy and molecular gene analysis can help with
diagnosis. The condition is usually lethal within the first
Figure 7–26 ). However, because of
150
few months of life, with almost all children dying by the
age of 3 years.
Obstetric Management
128
Following the prenatal diagnosis of WWS, termination of
Implications for Targeted Examination
In families at risk, the presence of any brain or eye anomaly
should be enough to reach a diagnosis. These findings
may present as early as 12 to 14 postmenstrual weeks.
143 , 144
As previously mentioned, fetuses with ventriculomegaly
must undergo a detailed multiplanar neurosonographic
pregnancy should be considered.
NEURONAL HETEROTOPIA
Synonyms
Heterotopic gray matter, heterotopia
Chapter 7 Malformations of Cortical Development
AB
CD
Figure 7–25. Neurosonographic transabdominal examination at 21 postmenstrual weeks consistent with recurrent WWS. In the previous pregnancy,
a fetus with suspected WWS was diagnosed at 26 weeks of pregnancy. (A) Axial transventricular plane shows mild ventricular dilation (12.6 mm).
(B) Coronal plane through the frontal horns shows dilation. (C) Median plane shows the abnormal shape of the kinked brainstem and lack of the anterior
protuberance of the pons ( arrows ). (D) The presence of retinal detachment is confirmatory of the diagnosis ( arrow ).
271
Definition
Neuronal heterotopia is characterized by the presence
of clusters of neurons in any abnormal location in their
pathway of migration from the periventricular germinal
matrix to the cortex ( Figure 7–28
nodular heterotopia (PNH), neurons remain in the subependymal region of the ventricle, where they appear
as a nodule at the surface of the ventricle. In nodular
ABC
Figure 7–26. Early development of ventriculomegaly at 15 postmenstrual weeks ( A ), with associated vermian anomaly ( arrow in B ) and cataract ( arrow
in C ). (Courtesy of Dr. Mordechai Tamarkin, Holon, Israel.)
). In periventricular
subcortical heterotopia, neuronal groups of neurons are
located in the white matter. Subcortical band heterotopia
results in the double cortex syndrome discussed under
lissencephaly.
Incidence/Prevalence
Clinically significant heterotopia is extremely rare; however,
affected children may have epilepsy, variable intellectual
272
A
Figure 7–27. MRI at 34 postmenstrual weeks of a fetus with WWS.
Axial ( A ) and coronal ( B ) sections show severe ventriculomegaly with
thin lissencephalic cortex and dysplastic cerebellum. (C) Sagittal plane
shows the characteristic Z shape of the brainstem and vermian dysgenesis. (Courtesy of Dr. Chen Hoffmann, Tel-Hashomer, Israel.)
deficits, other malformations, and genetic abnormalities
or develop normally.
Chapter 7 Malformations of Cortical Development
B
3
There are no data regarding its inci-
C
dence or prevalence. Periventricular nodular heterotopia
may be detected prenatally.
Pathogenesis
PNH is mainly caused by defects of the Filamin A ( FLNA )
gene. The specific roles of Filamin A and its association
with pathologic conditions are still to be fully under-
151
stood.
tion of cell stability, protrusion, and motility across various
biological systems.
Filamin homologues are implicated in the regula-
152
FLNA likely influences neuroblast
migration during cortical development in vertebrates, and
heterotopia in humans likely results from disruption of this
process.
153
Etiology
Periventricular heterotopia is a heterogeneous disease with
15 described phenotypes. Bilateral PNH is the most common subtype and was identified in a large series in 54%
(98 of 182) of the patients.
dominant disorder far more frequent in females who present normal intelligence to borderline mental retardation,
epilepsy of variable severity, and cardiovascular defects or
154
Bilateral PNH is an X-linked
coagulopathy. The disorder is generally associated with
prenatal lethality in males, although a few cases of males
with X-linked PNH due to germline and mosaic mutations
have been reported.
154
X-linked PNH has been demonstrated to be associated with mutations in the Filamin
A gene ( FLN1, FLNA, or ABP-280 ). FLN1 maps to Xq28
and codes for Filamin A, which binds to actin and a wide
range of cytoplasmic signaling proteins. Additional phenotypes include PNH with Ehlers-Danlos syndrome (EDS),
temporo-occipital PNH with hippocampal malformation
and cerebellar hypoplasia, PNH with frontoperisylvian or
temporo-occipital polymicrogyria, posterior PNH with
hydrocephaly, PNH with microcephaly (autosomal recessive due to mutations of the ARFGEF2 gene), PNH with
frontonasal dysplasia, PNH with limb abnormalities, PNH
with fragile X syndrome, PNH with ambiguous genitalia,
micronodular PH, unilateral PNH, and laminar ribbonlike
and linear PH.
PNH has also been reported in a few patients with a
chromosomal rearrangements in 5p15.1 and in 5p15.33
and as autosomal dominant disease affecting a father and
his son.
156
154
155
Pathology
The data regarding the neuropathologic findings in patients
with heterotopia are limited. In the largest published series
(24 patients), Meroni et al
of pathologies in nodular heterotopia. Patients in group 1
had clusters with large numbers of normal neurons in the
white matter, suggesting the existence of a possible mechanism of neuroblast overproliferation. The overlying cortex
was dysplastic but of normal thickness, suggesting that
the neurons are overproduced during corticogenesis.
The nodules observed in group 2 patients were smaller
than those observed in group 1, were always detected just
below the gray matter, and were associated with cortical
alterations that were particularly evident in the granular
and supragranular layers. This suggests that the impaired
neuronal migration occurred during the late phases of corticogenesis, in accordance with the inside-out mechanisms
of cortical development.
In a study of the prenatal diagnosis of MCD, Malinger
et al 77 found that 12 out of 17 fetuses that underwent
necropsy demonstrated heterotopia of different types and
grades of severity, including 2 patients with cerebellar
white matter heterotopia (
157
described two different groups
157
Figure 7–28 ).
157
Associated Anomalies
In female fetuses, PNH may be isolated and diagnosed
incidentally or after the delivery of an affected child. Other
described phenotypes may present with microcephaly,
polymicrogyria, cerebellar hypoplasia, and ventriculomegaly.
AB C
Figure 7–28. Microscopic findings in three different patients with het-
erotopia. (A) Cortical heterotopia. (B) White matter laminar heterotopia.
(C) White matter nodular heterotopia.
2.0 mm
previously recognized in fetuses with multiple congenital
anomalies involving the CNS. In our series we found
heterotopia to be associated with agenesis of the corpus callosum, lissencephaly, and cobblestone complex
syndromes.
151
Probably heterotopia is more frequent than
77
Chapter 7 Malformations of Cortical Development
273
Non-CNS anomalies include aortic valvulopathy, patent ductus arteriosus, aortic aneurism, frontonasal dysplasia, limb abnormalities, and ambiguous genitalia.
151
Mental
retardation and epilepsy are common in these patients.
Risk of Recurrence
Genetic counseling is straightforward in familial cases with
a clear X-linked pattern of inheritance. The family should
be informed regarding prenatal or early lethality in boys
and a 50% recurrence risk in daughters. Although maternal transmission is much more likely, father-to-daughter
transmission is possible, implying that either parent can
transmit the mutation to a female proband. An affected
man with PNH caused by an FLN1 mutation would be
expected to transmit the mutation to all his daughters,
unless somatic mosaicism is present. If neither of the parents has epilepsy or cognitive impairment, the proband’s
mother should be studied first, in order to confirm the
mutation or the brain abnormality. If the mother is negative, and the proband is a female, the father should also
be studied, as germline and mosaic mutations have been
reported.
154
In autosomal recessive cases, the risk of recur-
rence is 25%.
Sonographic Diagnosis
The US prenatal diagnosis of PNH should be considered
when the lateral ventricle wall is variably irregular with
indentations of the periventricular heterotopic nodules
Figure 7–18 ). In cases where ventricle size is normal, it
(
can be difficult to detect the nodularity. We have found
a very small number of prenatal diagnosed cases, and all
of them presented with associated anomalies. Mitchell
158
et al
reported a female fetus referred for evaluation
at 23 postmenstrual weeks for suspected Dandy-Walker
malformation. Their US examination demonstrated the
presence of a megacisterna magna and bilateral periventricular nodules consistent with heterotopia. The diagnosis was confirmed by pre- and postnatal MRI. Garel
19
described a patient with progressive ventriculomegaly
initially detected at 22 weeks of gestation; at 30 weeks an
irregular, “bumpy” ventricular wall raised the suspicion of
PNH, which was confirmed by MRI. We reported on two
patients with abnormal irregular lateral ventricle walls
with associated malformations.
77
One patient was referred
at 40 postmenstrual weeks because of a large interhemispheric arachnoid cyst, and a transvaginal examination
showed the presence of focal abnormally wide gyri, atypical asymmetric lateral ventricles, and bulging of brain
). The second patient, referred at 22 postmenstrual
7–18
Figure
weeks because of ACC, showed a unilateral irregular
lateral ventricle wall with echogenic foci in the periventricular area. In both cases the diagnosis was confirmed
at necropsy. Others have also reported finding PNH at
neurosonography and confirmed by MRI during evaluation of fetuses with cerebral malformations, especially
agenesis of the corpus callosum.
159
Heterotopia may not
be recognized when the nodules are small or subcortical.
The differential diagnosis includes tumors (especially
tuberous sclerosis), hemorrhagic masses, and ventricular
irregularity associated with infections such as cytomegalovirus. In some cases a definitive diagnosis will not be
possible even after biopsy.
160
We studied two patients
with asymmetric ventriculomegaly and hyperechogenic
cortex who were postnatally diagnosed as suffering from
nodular heterotopia; one of them developed epilepsy
by the age of 8 months, but the definitive diagnosis was
reached only at the age of 5 years
161
( Figure 7–29 ).
ABC
Figure 7–29. Periventricular nodular heterotopia initially evaluated due to fetal asymmetric ventriculomegaly and suspected white matter echogenic-
ity. The girl developed complex partial seizures by the age of 2 years. The MRI was performed at the age of 5 years following the first episode of generalized seizures. T2 axial (A), T1 axial ( B ), and T1 coronal ( C ) images demonstrate periventricular heterotopia surrounding and protruding into the occipital
horn and associated abnormal overlying cortex.
274
Chapter 7 Malformations of Cortical Development
MRI Diagnosis
Fetal MRI was used to confirm US diagnosis in three of the
fetuses previously mentioned.
an MRI diagnosis of PNH was obtained in patients referred
for suspected CNS anomalies, including ventriculomegaly,
mega cisterna magna,
163
Implications for Screening, Including
Time of Earliest Recognition
According to isolated case reports, PNH may be diagnosed
as early as 22 postmenstrual weeks, but most cases, especially
if isolated, will remain undiagnosed during pregnancy.
Implications for Targeted Examination
Visualization of the smoothness of the walls of the lateral
ventricles and the periventricular zone is an integral part of
the detailed neurosonographic examination. Axial planes
alone may fail to depict subtle nodules, and we prefer to
obtain coronal and parasagittal images of both ventricles
Figure 7–30 ).
(
Tuberous sclerosis (TS), periventricular hemorrhage (PVH), and irregularity associated with infections
should be considered in the differential diagnosis. TS is
usually associated with the visualization of intracardial
19 , 77 , 158
In other reported cases,
and thick corpus callosum.
162
164
rhabdomyomas, and the nodules are not only periventricu-
77
lar.
PVH occurs mainly around or at the caudate nuclei;
the lesions evolve with time and are frequently associated
with intraventricular bleeding and clots. In some cases,
MRI with expert interpretation can be of help, along with
evaluation of the remaining members of the family for
subtle signs of TS.
Prognosis
In families at risk, the identification of PNH is difficult
to counsel due to the wide phenotypic and functional
variations of the disease. Bilateral PNH in males is almost
invariable lethal.
Obstetric Management
Multispecialty counseling may be helpful, but limitations
in the establishment of a prognosis make decisions difficult.
Schizencephaly
Synonyms
None
A
IHC
CD
Figure 7–30. Histologically confirmed periventricular nodular heterotopia with agenesis of the corpus callosum in a female fetus at 22 postmenstrual
weeks of gestation. Transvaginal technique. (A) Modified axial plane shows parallel colpocephalic lateral ventricles. Note the increase in echogenicity at
the periventricular zone ( arrows ). (B) Frontal coronal plane shows a single hyperechogenic nodule. (C) Median plane fails to show the corpus callosum
that has been replaced by large intrahemispheric cysts (IHC). (D) Paramedian plane at the level of the lateral ventricle shows the irregular ventricular
wall with nodules protruding into the ventricle ( arrows ).
B
Chapter 7 Malformations of Cortical Development
275
Definition
Schizencephaly is a cerebral disorder characterized by the
presence of a cleft of the cerebrum lined by abnormal gray
matter and connecting the meningeal surface with the
lateral ventricle (see Chapter 10 ). In closed-lip or type I
schizencephaly, the walls of the defect are in contact, and
a gray matter column is visible traversing the white matter between the cortex and ventricle, often with a dimple
at the ventricle surface, but there is no communication
between the ventricles and the subarachnoid space. Openlip or type II schizencephaly refers to a wide open defect in
which the gray matter – lined lips of the cleft are separated,
allowing communication.
165
Incidence/Prevalence
In a population-based study of affected patients diagnosed
before 1 year of age, Curry et al
of 1.54 per 100,000. In about two-thirds of the patients
the disease was isolated, and the remaining one-third had
associated anomalies . In a pediatric population with MCD,
only 5% had schizencephaly.
166
reported a prevalence
167
Pathogenesis
The developmental mechanism of schizencephaly is still
not clear. The observed structural changes have been
assumed to be a true malformation of cortical development by some authors;
168
however, similar lesions can
result from arterial or venous circulatory disturbances,
infections, or even maternal trauma. In any case, schizencephaly results from an early arrest of growth of parts of
the hemispheric wall with quantitatively (if not qualitatively) normal growth or even overgrowth of the spared tissue occurring before or close after migration starts.
169
The
possibility of a disruptive process in some of the patients is
highlighted by the fact that in over half of the patients with
a non-CNS abnormality, it was found to be secondary to
vascular disruption.
Barkovich et al
166
3
classified schizencephaly and polymicrogyria under the polymicrogyria/schizencephaly complex, as they are frequently observed together. 3
It has been postulated that in some patients, schizencephaly may be the result of a mutation in the homeobox
2 gene ( EMX2 ), which plays a role in the patterning of the
developing neocortex.
with schizencephaly failed to detect any pathogenic
mutation.
171
170
But a recent study of 37 patients
Etiology
The etiology of schizencephaly is heterogeneous with
well-documented cases of multiple occurrences within a
family, but patients with schizencephaly have also been
found following intrauterine viral infections, exposure
to teratogens, or maternal trauma.
been found to be associated with some well-defined syndromes.
166
Common associations are absence of the sep-
tum pellucidum and septo-optic dysplasia.
166
Schizencephaly has
168 , 172
Pathology
Transmantle gray matter connection from brain surface to ventricle surface characterizes this malformation
Figure 7–31 ). The abnormality may be unilateral or bilat-
(
eral, and there may or may not be communication (closed
or open lip) between the ventricles and subarachnoid space.
When open, the walls of the defect are lined by gray matter.
Schizencephaly is always accompanied by polymicrogyria
Figure 7–31 ). Pachygyria or heterotopia may be also found
(
in some patients. Glial scarring is usually absent.
Associated Anomalies
CNS anomalies are very common in these patients. Packard
et al, in a series of 47 patients, found that 43 (91%) had associated cerebral developmental anomalies, most commonly
absence of the septum pellucidum (45%) (
7–32 ) and focal cortical dysplasia (40%).
Figures 7–31 and
173
Other anomalies
commonly observed are dysgenesis of the corpus callosum,
mega cisterna magna, hydrocephaly, gyral malformations,
and optic nerve hypoplasia.
166 , 172
Non-CNS anomalies have
been described, but in most cases they seem to occur
sporadically. Arthrogryposis and ectrodactyly have been
reported in more than isolated cases.
166
Risk of Recurrence
In the vast majority of cases this is a sporadic condition
but some autosomal dominant and recessive cases have
been reported.
Sonographic Diagnosis
The prenatal US diagnosis of schizencephaly is possible but
depends on the extent of cleft separation and on the presence of associated malformations ( Figure 7–32
). Closed-lip
and open-lip variants with a very small gap may escape
detection. In some patients the occipital median sulci in
the visual cortex area may be erroneously suspected as a
closed-lip defect.
The first prenatal diagnosis was performed in 1986 by
Klingensmith and Cioffi-Ragan in a fetus at 31 postmenstrual weeks that presented with severe bilateral clefts.
174
Following this report, at least 17 fetuses with schizencephaly have been diagnosed at a mean gestational age of 29.3
postmenstrual weeks (range 21–28 weeks).
77 , 175 – 183
These
fetuses were diagnosed during routine US examinations
(4), following the visualization of enlarged lateral ventricles
or unspecified suspicion of brain anomalies (9), following
the diagnosis of septo-optic dysplasia (2), the inhalation of
organic solvents (1), and due to lack of fetal movements
(1). All the clefts were type II (open lip), 12 were bilateral
and 5 unilateral.
Association with cerebral vascular occlusion and vaso-
constrictive substances (cocaine) has been described.
184
MRI Diagnosis
The MRI diagnosis of fetal schizencephaly has been
reported following US demonstration of diverse fetal
276
Chapter 7 Malformations of Cortical Development
A
C
Figure 7–31. Macroscopic brain findings at 26 postmenstrual weeks in a fetus with schizencephaly. (A, B) Lateral and superior views of the brain dem-
onstrate focal polymicrogyria ( arrows ). (C) Inferior view of the brain showing the communication between the frontal cortex and the lateral ventricles;
the arrow points to the right lateral ventricle. (D) Associated agenesis of the septi pellucidi.
malformations.
77 , 178 , 179 , 182
MRI is indicated when the US
D
depicts an abnormal sulcal pattern and rises the suspicion
of schizencephaly or in patients with agenesis of the CSP
to search for the presence of closed lip or small open lip
defects that may remain undiagnosed after US examina-
179
( Figure 7–33 ). Although large lesions are readily
tion
detected, the smaller closed ones can be missed by MRI.
Implications for Sonographic Screening, Including
Earliest Recognition
B
Implications for Targeted Examination
The majority of the affected patients in postnatal series
and in prenatal descriptions present with ventriculomegaly
and/or agenesis of the CSP. Multiplanar neurosonographic
examination may be helpful to investigate the brain parenchyma in search of abnormal continuity between the
arachnoid space and the lateral ventricles (
Figure 7–32 ).
When the US examination is limited, or there is a suspicion of a closed-lip defect, MRI may help in the diagnosis
but may also miss small closed lesions.
Schizencephaly has been diagnosed occasionally during
routine sonographic examinations; careful examination
of both hemispheres conducted at the three axial planes
as recommended in the basic evaluation of the brain will
depict at least some fetuses with large open-lip schizencephaly. The earliest diagnosis of a cortical cleft has
been reported at 21 postmenstrual weeks in a fetus with
osteogenesis imperfecta.
181
Successive “slicing” of a 3D US
volume using the transgraphic display may be of help to
localize and diagnose the pathology.
Prognosis
Patients with schizencephaly commonly have delayed psychomotor development (57–80%), cerebral palsy (80–85%),
and epilepsy (34–65%).
or unilateral but large, the prognosis is significantly worse.
Patients with small unilateral schizencephaly may have
a good developmental prognosis, particularly when the
motor cortex is not involved.
172 , 185 , 186
When the clefts are bilateral
187
Chapter 7 Malformations of Cortical Development
LV
AC E
277
BD F
Figure 7–32. Transabdominal axial (A, B) and transvaginal coronal (C, D) and sagittal (E, F) US images in the same fetus as in Figure 7–30 . Although
the agenesis of the septi pellucidi may be suspected in B ( arrow ), these axial planes may be misinterpreted as normal. Note the apparent presence of the
septi pellucidi in A ( arrow ) and the normal size of the lateral ventricle (LV). The diagnosis is evident in the coronal and axial planes. The corpus callosum
is present and apparently normal ( arrows in E).
ABC
Figure 7–33. T2-weighted MRI at 28 postmenstrual weeks shows bilateral schizencephaly with multiple clefts lined by abnormal gray matter. (A) The
axial section demonstrates the presence of an open lip ( arrowhead ) and a closed lip ( arrow ). Coronal ( B ) and sagittal ( C ) planes show open-lip defects
lined with gray matter.
278
Chapter 7 Malformations of Cortical Development
Obstetric Management
Because all prenatally diagnosed cases tend to have bilateral or large unilateral clefts and a very poor prognosis, we believe that termination of pregnancy should be
offered when legally possible, particularly when associated
anomalies have been found. When unilateral closed-lip
schizencephaly is diagnosed, it is difficult to give a straightforward recommendation, and the management should be
individualized.
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