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320
Chapter 9 Intrauterine Infections Affecting the Brain
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115. Numazaki K, Fujikawa T. Intracranial calcification with congenital
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116. Desmond MM, Montgomery JR, Melnick JL, Cochran GG, Verniaud
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117. Balducci J, Rodis JF, Rosengren S, Vintzileos AM, Spivey G, Vosseller
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118. Paryani SG, Arvin AM. Intrauterine infection with varicella-zoster
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128. de Haan TR, van den Akker ES, Porcelijn L, Oepkes D, Kroes AC,
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129. Glenn OA, Bianco K, Barkovich AJ, Callen PW, Parer JT. Fetal cerebellar hemorrhage in parvovirus-associated non-immune hydrops
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147. Muñoz J, Coll O, Juncosa T, et al. Prevalence and vertical transmission of Trypanosoma cruzi infection among pregnant Latin
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Chapter 10
INTRAUTERINE INSULTS: FETAL STROKE AND DESTRUCTIVE PROCESSES
Ana Monteagudo ● Gianluigi Pilu ● Gustavo Malinger
●
Selim Buyukkurt
Ashwin Jadhav
KEY POINTS
1. Many congenital anomalies of the brain do not
derive from abnormal embryogenesis but are the
consequence of destructive processes that may
occur any time in gestation, particularly in the
third trimester.
2. Most of these destructive processes are the
consequence of vascular accidents, hemorrhage,
or occlusion. The etiology is often unknown,
but they may derive from a variety of obstetric
complications, such as placental insufficiency,
coagulation disorders, drug consumption, and
transplacental infections.
3. Disruptive lesions of the fetal brain are clinically
important because they may have severe
consequences, but they frequently escape early
detection.
4. Intracranial hemorrhage is probably the most
common and therefore the best known of all
intrauterine disruptions of the fetal brain. The
hemorrhage occurs usually into the lateral
ventricles, and the sonographic pictures change
with time. An echogenic collection is first seen,
and in the following days it develops into a
complex mass frequently complicated by severe
ventriculomegaly.
5. Prenatal stroke is considered the most important
determinant of cystic destruction of the cortex
that, depending on the time of occurrence and the
severity, may result in a spectrum of conditions,
including porencephaly (single or multiple cysts
replacing brain parenchyma), schizencephaly
(a gray matter–lined cleft in the cerebral mantle
connecting the cavity of lateral ventricles to
the subarachnoid space), and hydranencephaly
(complete destruction of the cerebral hemispheres).
6. Cerebellar lesions are discussed separately even
though they also deal with intracranial hemorrhage.
However, they deserve more focused attention.
Intrauterine insults may lead to brain ischemia (stroke),
which is a major contributor to the sonographic brain findings that we will discuss in this chapter. Prenatal stroke can
be the result of an arterial ischemic event, a venous thrombosis, or hemorrhage. The end-stage lesion is a cavity in
the brain tissue of variable size and location.
of the cavity is predictable and stable depending on the
vessel that was affected. 2 For example, stroke affecting the
middle cerebral artery (MCA) will result in porencephaly
and that affecting both internal carotid arteries (ICAs) in
hydranencephaly. There are several factors determining
the propensity of the immature brain to undergo dissolution and eventually cavitation: (1) the high water content
of the unmyelinated brain, (2) the relative paucity of myelinated fibers, and (3) deficient glial response. The first two
factors result in dissolution of the brain, and the latter is
responsible for the cavitation.
1
The location
PORENCEPHALY
Definition
Porencephaly is a collective term for a variety of cystic lesions
of the brain. Some of these cavities communicate with the
ventricular system, the subarachnoid space, or both. These
defects have many similarities in etiopathogenesis with
schizencephaly and hydranencephaly.
of an insult such as ischemic stroke, infection, hemorrhage, or trauma occurring between the second trimester
of pregnancy and the early postnatal period. This insult
results in focal or multifocal areas of brain necroses, which
subsequently undergo dissolution and cavity formation.
Synonyms
Perencephaly, porencephalia; schizencephaly, porencephalic cyst .
Incidence
Perinatal arterial ischemic stroke (PAIS) is estimated to
occur in 1 in 2500 to 1 in 5000 term neonates. The perinatal
1
It is the outcome
1 – 3
322
Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
period spans from the 28th postmenstrual week of gestation
to a week after delivery; it is during this period that stroke
is more likely to occur when compared with any other time
during childhood. Porencephaly is the end result of a PAIS,
and the neonatal outcome is significant neurologic morbidities, such as hemiplegic cerebral palsy (CP).
4 , 5
Pathogenesis
Porencephaly can be the end-stage result of an ischemic
stroke following either an arterial or venous infarction or
an intraparenchymal hemorrhage. Areas affected by the
infarct undergo tissue necrosis and eventually resorption, leaving behind a cavity in the brain or porencephalic cyst. In “simple” porencephaly, the end result of a
venous medullary infarction, typically there is a single
cavity along the frontal, parietal, or temporal horns that
communicates with the ipsilateral ventricle. Often this
ventricle is dilated.
1
In preterm neonates, the parenchymal lesions associated with germinal matrix and intraventricular hemorrhages are the result of venous infarct
(see below). Eventually these infarcts undergo cystic
degeneration; small lesions are seen as periventricular
leukomalacia, and large lesions that connect with the
ventricles as porencephalic cysts. In most of these cases,
the cortical mantle is spared, and the cysts take the shape
of the area of the infarct.
1
In the arterial type or clastic porencephaly, there is
occlusion of an artery often on the left side of the brain;
typically, a cavity is seen along the path of the MCA,
which is the vessel most commonly involved. However, any
arteries, such as the anterior cerebral, posterior cerebral,
or anterior choroidal artery, can be affected.
above, arterial ischemic stroke occurs in the left hemisphere in ~55% of cases; bilaterally, in ~6%.
1
As eluded
6
Benders et al 6
theorize that this may be the result of the hemodynamic
differences from the patent ductus arteriosus or right-toleft intracardiac shunt involving the more direct route of
the left common carotid artery.
Thrombophilias, specifically factor V Leiden and
antiphospholipid antibodies, may play an important role
in the pathogenesis of perinatal stroke; however, at present
their role is not completely understood.
7
Etiology
The etiology of ischemic perinatal stroke that eventually may result in porencephaly has not been clearly
elucidated. However, there are multiple potential risk
factors both maternal and fetal/neonatal that have been
associated with this condition ( Table 10–1 ). In addition,
thrombotic events on the fetal side of the placenta may
potentially result in a thrombotic event due to the patency
of the foramen ovale and to the right-to-left direction of
the blood flow in the fetal system.
that in symptomatic cases of ischemic perinatal stroke, a
workup similar to that performed on neonates should be
done ( Table 10–2 ).
5
Porencephaly has also been described as the result of
several other types of intrauterine exposures or insults. A
more recent report
8
documents maternal carbon monox-
ide poisoning at 22 postmenstrual weeks resulting in the
5
It has been proposed
Table 10–1. POTENTIAL RISK FACTORS ASSOCIATED
WITH ISCHEMIC PERINATAL STROKE (IPS)
Maternal factors/conditions
Thrombotic disorders (see Table 10–2 )
Infertility and infertility treatment
Preeclampsia
Prolonged rupture of membrane (>24 h)
Chorioamnionitis
Maternal autoimmune conditions and autoantibodies
(platelet alloantigen-1)
Antiphospholipid syndrome
Fetal/neonatal disorders
Mutations in procollagen IVa1
Inherited thrombophilia
Twin-to-twin transfusion syndrome
Fetal/neonatal polycythemia
Congenital heart disease
Neonatal hypoglycemia (in preterm infants)
Persistent fetal circulation and extracorporeal membrane
oxygenation therapy
Intrauterine growth restriction
Fetal/neonatal infections and meningitis
Ethnicity and race (higher incidence in black infants
compared with non-Hispanic white infants)
Infant gender (higher incidence in boys)
Reproduced, with permission, from Raju TN, Nelson KB, Ferriero D, Lynch
JK; NICHD-NINDS Perinatal Stroke Workshop Participants . Ischemic perinatal stroke: Summary of a workshop sponsored by the National Institute
of Child Health and Human Development and the National Institute of
Neurological Disorders and Stroke. Pediatrics. 2007;120:609–616.
prenatal diagnosis of porencephaly. Another case report
described a patient who was treated with warfarin for a
prosthetic heart valve and at 22 postmenstrual weeks
suddenly had a surge on the prothrombin International
Normalized Ratio (INR) to double its previous values.
At 26 postmenstrual weeks, an ultrasound (US) demonstrated a large intracranial echogenic lesion suggestive of a subdural hematoma, and at birth the magnetic
resonance imaging (MRI) revealed porencephalic cyst
and mild ipsilateral ventriculomegaly. A case report
10
documents a prenatally detected case of porencephaly at
28 weeks following inadvertent penetration of the fetal
skull during an amniocentesis unguided by continuous
US at 16 weeks. Initially, the head US was normal, but at
28 weeks a left-sided ventriculomegaly and an anechoic
mass in the area of the lateral ventricle were noted and
confirmed at birth by computed tomography (CT) and
MRI studies. Other reported events that have resulted
in porencephaly are chorionic villus sampling, cocaine,
vitamin A, and valproate use.
8
Porencephaly and other
cystic brain lesions are seen frequently in monozygotic
twins. 1 Familial cases of porencephaly have also been
described.
11 – 14
9
Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
323
Table 10–2. SCREENING FOR RISK FACTORS:
ACQUIRED OR INHERITED THROMBOTIC
DISORDER IN PEDIATRIC PATIENTS
WITH ISCHEMIC STROKE
Plasma/Protein Based DNA Based
Activated protein C resistance Factor V G1691A
Protein C activity/antigen Prothrombin G20210A
Free and total protein S antigen
Antithrombin activity/antigen
Lipoprotein (a)
Fasting homocysteine
Lupus anticoagulant/
antiphospholipid antibodies
Fibrinogen (Clauss)
Plasminogen
Factor VIIIC
Some experts make these recommendations for screening in pediatric
stroke cases
and their cost versus benefits are not known.
Reproduced, with permission, from Raju TN, Nelson KB, Ferriero D,
Lynch JK; NICHD-NINDS Perinatal Stroke Workshop Participants.
Ischemic perinatal stroke: Summary of a workshop sponsored by the
National Institute of Child Health and Human Development and the
National Institute of Neurological Disorders and Stroke. Pediatrics.
2007;120:609–616.
38
; however, no such recommendations exist for IPS cases,
5
Associated Anomalies
With the exception of ventriculomegaly, there are no typical associated anomalies in cases of porencephaly, but in
the arterial type or classic porencephaly, areas of polymicrogyria may border the cysts.
1
Risk of Recurrence
At present there are no data regarding the risk of recurrence of a perinatal stroke, but recurrent stroke is rare
among infants who have suffered a perinatal stroke.
risk of recurrence of stroke in children who have suffered
a perinatal stroke ranges from 3% to 30%.
15 , 16
Among fetuses/neonates who have suffered a perinatal arterial stroke and their mothers, there is a high
rate of thrombophilias when compared with the general
population. Simchen et al
7
found that 64% of infants with
perinatal arterial stroke had at least one thrombophilic
marker, and among the mothers, 68% were carriers of a
thrombophilia. In their study, factor V Leiden mutation,
protein C deficiency, and the presence of antiphospholipid
antibodies were significant factors for perinatal stroke.
The authors recommended that any child that has suffered a perinatal arterial stroke have both parents tested
for thrombophilias.
A mutation in collagen IV A1 ( COL4A1 ) gene has been
reported in a few families with an autosomal dominant
15
The
form of porencephaly in which the porencephalic cyst is
the result of a perinatal hemorrhage.
17
In cases of familial
autosomal dominant porencephaly (OMIM 175780), the
each baby has a 50% chance of receiving the affected
mutation.
Sonographic Diagnosis
The sonographic appearance of porencephaly is that of a
cystic lesion that communicates with the lateral ventricle
( Figure 10–1 ). The term porencephaly is derived from
the Latin word porus, meaning communication between
the ventricular and extracerebral space. The ipsilateral
ventricle is dilated. The porencephalic cyst never causes a
mass effect and is typically located along the distribution
of the middle cerebral artery or other arteries (see above).
This helps differentiate it from arachnoid and interhemispheric cysts.
18
Implications for Sonographic Screening
Porencephaly may be missed by antenatal sonography,
particularly in early gestation, because of two reasons.
First, it is usually a unilateral lesion; this makes it difficult
to demonstrate when it occurs in the hemisphere proximal
to the transducer, being usually obscured by sound reverberation and artifacts.
late gestation.
1
19
Second, it usually occurs only in
Differential Diagnosis
The differential diagnosis of porencephaly includes all cystic brain lesions (see Chapter 9 ), but the most important
differential diagnosis is the arachnoid cysts and unilateral
schizencephaly. Arachnoid cysts are collections of cerebrospinal fluid (CSF). They are usually benign, congenital,
space-occupying lesions; unlike porencephaly they do not
communicate with the ventricles. The cyst wall is lined
with collagen and cells of the arachnoid matter. In the
arachnoid cyst, the CSF is located within the layers of the
arachnoid membrane, which may or may not communicate with the subarachnoid space. In unilateral schizencephaly, the cyst communicates with the subarachnoid
space, and the cavity is lined by gray matter; this is easily
seen during a fetal MRI. Cystic neoplasms are rare, and
these usually have mass effects with both solid and cyst
components.
Prognosis
Porencephaly is associated with significant morbidity and
mortality. Ischemic perinatal stroke resulting in porencephaly is the leading cause of cerebral palsy (CP), and
congenital hemiplegia is the most common type of CP.
Hemiparesis and motor deficits are seen in >80% of the
presumed perinatal ischemic stroke.
5 , 20
In addition, 50%
to 75% of survivors of perinatal ischemic stroke will have
neurologic deficits or epilepsy. Moreover, ~20% to 60% of
survivors will have deficits in language, vision, cognition,
and behavior. 5 Unfortunately, there are no clearcut figures. Most prenatally diagnosed cases tend to have a poor
outcome.
21 – 23
5 , 20
324
Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
A
C
Figure 10–1.
spaces representing infarcted areas, as well as the dilated ventricles. Coronal ( A ), sagittal ( B ), and axial ( C ) sections.
Porencephalic insult to the fetal brain imaged using three-dimensional (3D) transvaginal ultrasound (US). Observe the irregular anechoic
Advances in neuroimaging have facilitated outcome
prediction in cases of perinatal stroke, as described by
Kirton and deVeber.
20
Outcome prediction provides
B
the significant morbidities associated with porencephaly,
cesarean section should be performed for routine obstetric
indications.
important information for the family and allows patients
to be entered into appropriate clinical trials. For example,
lesion size and location are somewhat correlated with
SCHIZENCEPHALY
clinical outcomes. Poor motor outcomes can be predicted
by infarction lesions of the MCA, periventricular venous
lesions, or basal ganglia involvement, whereas isolated
subcortical lesions carry a low risk of language, cognitive
deficits, or epilepsy.
Obstetric Management
In cases where porencephaly is diagnosed early (earlier
than 24 weeks’ gestation), termination of pregnancy should
be offered to the patient; however, in the vast majority of
cases, porencephaly will be diagnosed only during the third
trimester; in these cases, management of the pregnancy
with porencephaly should include a thrombophilia workup
ideally of both parents, fetal MRI to further evaluate the
fetal brain, and consultations with a geneticist, neonatolo-
Definition
Schizencephaly is defined as a transcerebral, full-thickness,
gray matter–lined clefts or defects extending from the lat-
eral ventricles to the pial surface of the brain. The clefts of
schizencephaly can be unilateral or bilateral and open or
closed. In closed-lip schizencephaly (or type I), the lips of
the cleft touch or are fused with each other ( Figure 10–2 );
in contrast, in open-lip schizencephaly (or type II), the
walls of the clefts are widely separated, and the space is
filled with CSF, which is contiguous from the lateral ven-
tricles to the subarachnoid space ( Figure 10–2 ). Type II is
frequently seen with hydrocephaly. Although schizenceph-
aly can occur anywhere in the cerebral hemispheres, it is
more commonly seen in the perisylvian area.
gist, pediatric neurologist, and neurosurgeon. Given the
fact that porencephaly is a relatively rare condition, there
are no standard recommendations at this time regarding
the best route of delivery. It is our opinion that, given
Synonyms
True porencephaly; early fetal porencephaly .
24
Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
325
Unilateral
Closed
AB
Open
CD
Figure 10–2. Graphic representations of the four types of schizenceph-
aly. ( A ) Unilateral closed lip. ( B ) Bilateral closed lip. (C ) Unilateral open
lip. ( D) Bilateral open lip.
Bilateral
Incidence
Schizencephaly is a rare brain abnormality that was first
described by Yakovlev and Wadsworth in 1946.
publication of the birth prevalence of schizencephaly in
south-eastern Hungary found it to be present in 0.54 per
10,000 live births;
26
this is in contrast with a study from the
California Birth Defects Monitoring Program that found a
prevalence of 1.54 per 100,000 (0.15 per 10,000). 27 A major
difference between the studies was that the California
study included patients up to 1 year of age, whereas in
the Hungarian study, the average age at confirmation was
28.7 months; as a result, the California study may have
underreported mild cases.
26
In the majority of patients,
schizencephaly is sporadic, but familial schizencephaly has
been reported. 24
25
A recent
Pathogenesis
There are two main theories regarding the pathogenesis of
schizencephaly. The first is that of a failure of induction of
neuronal migration; the second is that of vascular disruption and hypoxia-ischemia at critical points during the
neuronal development (acquired). These processes usually
occur before the 24th week of the pregnancy.
26 , 28
Etiology
The etiology of schizencephaly is heterogeneous and is
not clear at present. Etiologies reported in the literature
include viral teratogenicity as the result of in utero exposure to cytomegalovirus (CMV), warfarin exposure, alcohol abuse, cocaine use, trauma during the first and second
trimesters, syndromic associations, association with the
EMX2 gene, maternal and/or infant thrombophilia, and
alloimmune thrombocytopenia (hemorrhage).
27
Associated Anomalies
Curry et al 27 reported on 63 cases of schizencephaly from
the California Birth Defects Monitoring Program; 43 cases
had schizencephaly and central nervous system (CNS)
anomalies only. The more common CNS anomalies present were hypoplastic or absent corpus callosum, absence of
the septum pellucidum, hydrocephaly, gyral malformations
(including heterotopias and polymicrogyria), and optic
nerve hypoplasia. Rarely seen CNS anomalies included
fusion of the thalami, accompanying porencephaly, arachnoid cyst, and cerebellar malformations. There were
20 cases that in addition to the associated CNS anomalies
had non-CNS anomalies, such as amniotic band disruptive
sequence, arthrogryposis, death of a monozygotic twin,
septo-optic dysplasia, gastroschisis, cleft lip and/or palate,
Aicardi syndrome, meningocele, 8p+, VATER association (vertebral defects, imperforate anus, tracheoesophageal fistula, radial and renal dysplasia), craniosynostosis,
microphthalmia, cataracts, and hydronephrosis. In a more
recent study by Szabo et al,
26
~50% of the cases of schizencephaly had associated agenesis of the septum pellucidum;
however, none of the patients had optic nerve hypoplasia
or endocrinological abnormalities, which are typically seen
in septo-optic dysplasia. In ~20% there was polymicrogyria
contralateral to the cleft and agenesis or dysgenesis of the
corpus callosum; there was also one case each of crossed
cerebellar diaschisis and intracerebral calcification in the
absence of any intrauterine infections.
Risk of Recurrence
The risk of recurrence is uncertain at this time, as most
cases are sporadic; familial cases of schizencephaly have
been described. Some patients with schizencephaly have
been found to have mutations in the EMX2 gene (OMIM
269160).
Diagnosis
The sonographic diagnosis is that of bilateral or unilateral
wedge like defects or clefts in the cerebral cortex extending from the lateral ventricles to the subarachnoid space
( Figure 10–3 ). The cavum septi pellucidi and the corpus
callosum may be absent; there may be optic nerve hypoplasia. The thalami typically are not fused. The ventricles may
be dilated. The circle of Willis is normal.
Fetal MRI is helpful in identifying the gray matter.
In open-lip schizencephaly, the gray matter is seen lining
the walls of the clefts. In addition, it can help in identifying areas of polymicrogyria and heterotopias, which are
common in cases of schizencephaly.
the following postnatal MRI findings in schizencephaly:
(1) a defect that extends from the pial surface to the ventricle; (2) the walls of the defect are lined with gray matter;
(3) the ventricle may be tented, thus pointing to the defect;
(4) absent cavum septi pellucidi in as many as 75% of cases
of schizencephaly; (5) the corpus callosum is focally thinned
29
30
Oh et al 30 described
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Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
or may be absent; (6) polymicrogyria and heterotopias are
common; and (7) a roofing membrane covering the defect
is infrequent ( Figures 10–4 , 10–5 , and 10–6 ). Threedimensional (3D) US helps to better define the defect,
and pictures are comparable to MRI ( Figures 10–7 , 10–8 ,
and 10–9 ).
Implications for Sonographic Screening
Schizencephaly occurs very early in gestation. It is therefore likely that the cerebral clefts associated with the
type II variety can be recognized by the midtrimester.
Absence of the corpus callosum and ventriculomegaly are
also frequently present, and this would facilitate the diagnosis. An exception could be represented by cases with
unilateral clefts involving the cerebral hemisphere proximal to the transducer that is commonly not seen during
standard examinations.
19
Most cases thus far have been
recognized only in late gestation.
Differential Diagnosis
The main differential diagnoses include holoprosencephaly, hydrocephaly, hydranencephaly, porencephaly, and
arachnoid cysts (see Chapter 9 ). In holoprosencephaly,
there is absence of the midline structures, fused thalami,
and facial abnormalities (alobar and semilobar type); however, in schizencephaly, although the cavum septi pellucidi
and corpus callosum may be absent, there are large cortical
abnormalities, and typically the thalami are not fused. In
hydrocephaly, the dilated lateral ventricles do not communicate with the subarachnoid space. In cases of hydranencephaly, the cerebral hemispheres may be completely
or almost completely absent, and CSF fills the space. In
porencephaly, although it may have a similar appearance,
the porencephalic cavities are not lined by gray matter;
this can be diagnosed by using MRI. Arachnoid cysts are
not symmetrical and do not communicate with the lateral
ventricles.
Prognosis
The clinical symptoms correlate with the degree and
severity of the cleft coupled with the severity of the
cortical abnormalities. 24 Clinically, schizencephaly is
typically characterized by a triad of abnormalities of
neuronal migration, namely, motor disorder, such as
hemi- or tetraparesis; intellectual impairment; and sei-
31
Epilepsy is usually seen in children with unilat-
zures.
eral closed schizencephaly, and microcephaly, spastic
quadriplegia, and mental retardation in children with
bilateral open clefts.
1
In a recent study by Szabo et al, 26
A
Figure 10–3. Tomographic images of bilateral open-lip schizencephaly detected at 21 postmenstrual weeks. ( A ) Coronal section.
Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
327
B
C
Figure 10–3. (continued) ( B) Sagittal section. ( C ) Axial (horizontal section).
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Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
I
II
III
IV
III
A
III
IV
III
II
I
I
IV
II
IIIB
IV
Figure 10–4. Serial magnetic resonance imaging (MRI) of bilateral open-lip schizencephaly. The arrows point to the clefts. ( A ) Axial plane.
( B ) Coronal plane.
Chapter 10 Intrauterine Insults: Fetal Stroke and Destructive Processes
Figure 10–5. Comparison of US ( left ) and MRI ( right ) of a right-sided, open-lip schizencephaly. The arrows point to the cleft.
329
of 10 children with schizencephaly, 7 exhibited unilateral
schizencephaly, and 3 had bilateral. Of the seven children with unilateral schizencephaly, six had contralateral
spastic hemiplegia, and one had spastic tetraplegia; five
of the seven had delayed development and intellectual
disability, and two of the seven had seizures. Of the three
children with bilateral schizencephaly, two had spastic
tetraplegia, and the other had generalized hypotonia; all
three had delayed developmental and intellectual disability, and one had seizures.
Obstetric Management
Schizencephaly is a rare heterogeneous disease; if diagnosed early (earlier than 24 postmenstrual weeks), termination of pregnancy should be offered to the patient;
Figure 10–6. Comparative US ( upper row ) and MRI ( lower row ) of a unilateral, right-sided, open-lip schizencephaly. Sagittal, coronal, and axial planes,
respectively (same case as in Figures 10–7 and 10–8 ).