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Interrelationship of Genetics and Prenatal Injury in the Genesis of Malformations of Cortical Development
Maria Augusta Montenegro, MD;
Marilisa M. Guerreiro, MD, PhD;
Iscia Lopes-Cendes, MD, PhD;
Carlos A. M. Guerreiro, MD, PhD;
Fernando Cendes, MD, PhD
Arch Neurol. 2002;59:1147-1153.
ABSTRACT
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Context Although the causes of some malformations of cortical development (MCD)
have been established, others remain unclear. There are several lines of evidence
supporting the theory of a complex mechanism that involves genetic and environmental
factors.
Objective To investigate the interrelationship of genetics and prenatal injury
in the genesis of MCD.
Patients and Design A series of 76 consecutive patients with MCD and their families were
systematically questioned about their family histories of epilepsy or other
neurological impairment and the occurrence of prenatal events. Whenever possible,
magnetic resonance imaging was performed in other family members if MCD was
suspected or in the presence of any neurological impairment. Patients were
divided into 3 groups according to the type of MCD. Patients in group 1 had
focal cortical dysplasia, group 2 had heterotopias (periventricular or subcortical)
or agyria-pachygyria, and group 3 had polymicrogyria or schizencephaly. These
findings were also compared with a disease-control group of 40 consecutive
patients with epilepsy but without MCD.
Setting Neurology clinic of a university hospital.
Results Of the 76 patients with MCD, 21 (28%) had focal cortical dysplasia,
19 (25%) had heterotopias or agyria-pachygyria, and 36 (47%) had polymicrogyria
or schizencephaly. There were 39 men and 37 women, aged 2 to 52 years (mean
age, 13 years). In group 2, 6 patients (32%) had a family history of MCD,
mental retardation, or miscarriages, suggesting a genetic predisposition.
In group 3, family history of MCD was present in 5 patients (14%). Prenatal
events occurred in 28 patients with MCD (37%) and 2 controls (5%) and were
more frequent in patients with heterotopia or agyria-pachygyria and polymicrogyria
(P<.001). Conversely, epilepsy occurred in all
patients in group 1, in 17 patients (89%) in group 2, and in 17 patients (47%)
in group 3. In group 3, epilepsy was less frequent (P<.001)
and also more easily controlled (P = .005) than in
other forms of MCD.
Conclusions Our findings support the idea of a spectrum among the different types
of MCD. Focal cortical dysplasia (group 1) is associated with more frequent
and severe epilepsy and less important genetic and prenatal events, heterotopias
and agyria-pachygyria (group 2) are frequently associated with genetic predisposition,
and polymicrogyria and schizencephaly (group 3) are less frequently associated
with epilepsy but have a stronger association with genetic and detectable
prenatal events.
INTRODUCTION
THE MIGRATION of neuroblasts from the periventricular germinal matrix
to their final destination and their organization within the cortical mantle
may be disturbed by genetic or environmental factors.1-15
The interrelationship of genetics and prenatal events as contributors to malformations
of cortical development (MCD) has been reported previously. However, few studies
of large series are available.2, 4
The objective of this study was to investigate the occurrence of genetic
predisposition and prenatal events and the interaction between these factors
in a large series of patients with different types of MCD. We believe that
this study may clarify the complex mechanisms involved in normal and abnormal
cortical development.
PATIENTS AND METHODS
This study was conducted at the neurology clinic of a university hospital.
We evaluated 76 consecutive patients with a diagnosis of MCD confirmed by
high-resolution magnetic resonance imaging (MRI). All patients were examined
by at least 1 of us, and, whenever possible, an MRI was performed in other
family members if cortical maldevelopment was suspected. We systematically
investigated all patients and family members with any neurological disturbance,
even when symptoms were mild, such as speech delay in early childhood. All
patients signed an informed consent form approved by the ethics committee
of the University of Campinas, Campinas, Brazil.
We used a semistructured questionnaire to ask patients and their families
about family history of epilepsy or other neurological impairment in first-degree,
second-degree, or third-degree relatives and the occurrence of any prenatal
event during the first 24 weeks of gestation. Significant prenatal events
included any abnormality reported by the mother or family during the first
24 weeks of gestation, such as a failed abortion attempt, drug addiction,
physical abuse, a fall with abdominal trauma, hypertension, fever, skin rash,
diabetes mellitus, exposure to x-rays, twin gestation, cytomegalovirus infection,
and tonic-clonic seizure. Vaginal bleeding was not included as a significant
prenatal event in this study because it is difficult to establish if the bleeding
had any repercussion that led to vascular injury, such as in placental anomalies,
or was already the result of a major malformation. In addition, we did not
include the use of over-the-counter medications as a risk factor because,
even though they are often used in the first 24 weeks of gestation, these
drugs have not been associated with the pathogenesis of MCD. Because the occurrence
of a prenatal event was retrospectively assessed, we directly interviewed
the patients' mothers and other available family members. In addition, we
reviewed the clinical files of all patients.
The diagnosis of MCD was established according to MRI findings. The
MRI was performed with a 2.0 T scanner (Elscint Prestige; Elscint Ltd, Haifa,
Israel), using our epilepsy protocol: (1) sagittal T1-weighted spin-echo,
6 mm thick (repetition time [TR], 430; echo time [TE], 12) for optimal orientation
of the subsequent images; (2) coronal T1 inversion recovery, 3 mm thick (flip
angle, 200°; TR, 2800-3000; TE, 14; inversion time [TI], 840; matrix,
130 x 256; field of view [FOV], 16 x 18 cm); (3) coronal T2-weighted
fast spin-echo, 3 to 4 mm thick, (flip angle, 120°; TR, 4800; TE, 129;
matrix, 252 x 320; FOV, 18 x 18 cm); (4) axial images parallel
to the long axis of the hippocampus; T1 gradient echo, 3 mm thick (flip angle,
70°; TR, 200; TE, 5; matrix, 180 x 232; FOV, 22 x 22 cm);
(5) axial T2 fast spin-echo, 4 mm thick (tip angle, 120°; TR, 6800; TE,
129; matrix, 252 x 328; FOV, 21 x 23 cm); and (6) volumetric (3-dimensional)
T1 gradient echo, acquired in the sagittal plane for multiplanar reconstruction,
1 to 1.5 mm thick (tip angle, 35°; TR, 22; TE, 9; matrix, 256 x
220; FOV, 23 x 25 cm). We performed multiplanar reconstruction and curvilinear
reformatting in all 3-dimensional MRIs.16
Patients were divided into 3 groups according to the MRI findings of
MCD. Patients in group 1 had focal cortical dysplasia, group 2 had heterotopias
(periventricular or subcortical) or agyria-pachygyria, and group 3 had polymicrogyria
or schizencephaly (Figure 1).
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Figure 1. A 2-dimensional curvilinear reconstruction
(A) shows a focal cortical dysplasia with thickening of the left postcentral
gyrus and blurring between gray and white matter (box; Table 1, patient 6). A coronal T1 image (B) shows diffuse subcortical
band heterotopia/double cortex (Table 2, patient 2). An axial T1 image (C) shows bilateral perisylvian
polymicrogyria (Table 3, patient
23). A curvilinear reconstruction of the same patient as in Figure 1C (D)
shows the extension of the polymicrogyria from the sylvian fissure until the
parieto-occipital regions.
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Table 1. Characteristics of Patients With Focal Cortical Dysplasia
(FCD; Group 1)*
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Table 2. Characteristics of Patients With Heterotopias or Agyria-Pachygyria
(Group 2)*
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Table 3. Characteristics of Patients With Polymicrogyria or Schizencephaly
(Group 3)*
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We also assessed a disease-control group and performed detailed interviews
about the occurrence of prenatal events and family history of any neurological
disturbance. The same semistructured questionnaire was used for patients with
MCD and controls. The disease-control group consisted of 40 consecutive patients
with epilepsy seen prospectively at our epilepsy clinic (26 women; age range,
6-54 years; mean age, 26.9 years) who underwent neuroimaging evaluation according
to our epilepsy protocol and whose MRI findings excluded the presence of MCD.
We excluded patients with major destructive lesions, such as porencephaly
or hemispheric atrophy.
We used the  2 test to analyze differences in the frequency
distribution of prenatal events, family history of epilepsy, family history
of neurological impairment, and occurrence of epilepsy and seizure control
among the different groups of patients with MCD and the control group, when
appropriate. A P value of less than .05 was considered
significant.
RESULTS
DISEASE-CONTROL GROUP
Of 40 control subjects with epilepsy, 32 (80%) had temporal lobe epilepsy,
3 (8%) had frontal lobe epilepsy, and in 5 (13%) the localization was not
established. The cause of epilepsy according to MRI findings was hippocampal
sclerosis in 16 patients (40%), cavernous angioma in 3 (8%), low-grade tumor
in 3 (8%), gliosis in 2 (5%), and cysticercosis in 2 (5%); 14 patients had
normal findings on MRI. Family history of epilepsy was present in 13 patients
(33%), mental retardation in 1 patient (3%), and history of miscarriage in
1 patient (3%). Two patients (5%) had a history of prenatal events during
pregnancy. One reported fever in the first trimester of pregnancy, and the
other reported amniotic bands, with multiple finger amputation.
PATIENTS WITH MCD
We evaluated 76 patients, 39 men and 37 women, whose ages ranged from
2 to 52 years (mean age, 13.8 years). Twenty-one patients (28%) had focal
cortical dysplasia (52% men), 19 patients (25%) had heterotopias or agyria-pachygyria
(26% men), and 36 patients (47%) had polymicrogyria or schizencephaly (67%
men). Table 1, Table 2, and Table 3
present the characteristics of patients in each group. Figure 2 shows the frequency of prenatal events, epilepsy, family
history of neurological impairment, and family history of epilepsy, according
to each group.
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Figure 2. Frequency of epilepsy, prenatal
events, and family history of epilepsy or neurological impairment in each
group of patients with MCD and the disease-control group of patients with
epilepsy. Asterisk indicates statistical significance (P<.05).
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Patients in group 1 (Table 1;
focal cortical dysplasia) had a lower frequency of prenatal events (5 [24%])
and family history of neurological impairment (3 [14%]) than the other 2 groups
of patients with MCD and the disease-control group (P
= .002). None of the patients in group 1 had a family history of MCD.
In group 2 (heterotopias or agyria-pachygyria), 8 patients (42%) had
a history of a prenatal event that may have contributed to the pathogenesis
of MCD (Table 2; patients 1-4,
7, 8, 11, and 14). Six patients (32%) had familial occurrence of MCD, mental
retardation, or miscarriages, suggesting a genetic predisposition (Table 2; patients 1, 7, 9, and 11-13).
In group 3 (polymicrogyria or schizencephaly), 15 patients (42%) had
a history of a prenatal event (Table 3;
patients 1-15). Five patients (14%) had a family history of MCD in a first-degree
relative (Table 3; patients 1,
18, 19, 27, and 33), and 8 (22%) had a family history of mental retardation,
developmental delay, or miscarriage (Table
3; patients 5, 9-11, 20, 21, 31, and 32).
Family history of epilepsy was present in all groups of patients with
MCD and in the disease-control group, and no significant differences in the
frequency of a family history of epilepsy were detected among the groups (P = .18). Sixteen family members underwent MRI, and 5 (31%)
had MCD (group 2, patient 13; and group 3, patients 18, 19, 27, and 33).
Epilepsy occurred in all patients with focal cortical dysplasia, and
seizures were controlled with antiepileptic drugs in only 4 patients (19%).
In group 2 (heterotopias or agyria-pachygyria), 17 patients (89%) had epilepsy,
and only 1 (5%) had her seizures controlled with antiepileptic drugs. In group
3 (polymicrogyria or schizencephaly), 17 patients (47%) had epilepsy, and
9 of these (53%) were seizure-free after introduction of antiepileptic drugs.
The frequency of epilepsy was lower (P<.001) and
more easily controlled (P = .005) in group 3.
COMMENT
The development of human cerebral cortex can be divided into 3 overlapping
stages: proliferation of stem cells into neuroblasts or glial cells, migration
from the periventricular germinal matrix toward the developing cortex, and
cortical organization within 6 layers associated with synaptogenesis and apoptosis.9, 17-19 This
is a dynamic process, and 1 or more stages may occur simultaneously during
several weeks. As a general rule, the proliferation stage ranges from the
5th or 6th until the 16th or 20th gestational week; migration from the 6th
or 7th until the 20th or 24th gestational week, and organization from the
16th until approximately the 24th gestational week.18
There is evidence that some migration and organization could take place even
during the third trimester of pregnancy.13, 20
Normal cortical development depends on many interacting components such
as trophic factors, cell-adhesion molecules, cell-cell contact-dependent signals,
and possibly other currently unrecognized factors.21
Its association with several genetically determined syndromes, such as neurofibromatosis
1, tuberous sclerosis, hypomelanosis of Ito, Walker-Warburg, Aicardi, Zellweger,
Miller-Diecker, and many others, and the occurrence of familial cases of MCD
(X-linked lissencephaly, subcortical-band heterotopia, schizencephaly, periventricular
nodular heterotopia, and congenital bilateral perisylvian syndrome) strongly
indicate a genetic component in the processes leading to different forms of
MCD.4, 9, 17, 22
More recently, mutations in a few genes, LIS-1 and DCX in lissencephaly and filamin 1 in periventricular nodular
heterotopia, have been shown to cause some forms of MCD.3, 5-9,22-23
The studies by des Portes et al10 and Gleeson
et al7-8 showed that some forms
of subcortical band heterotopia and agyria-pachygyria (or lissencephaly) represent
2 different extremes within the spectrum of the same disease, which has an
X-linked pattern of inheritance.
There are several reports indicating that harmful prenatal events are
likely to be involved in the pathogenesis of some MCD.2, 4, 13-15,20, 24-28
However, to our knowledge, no study has systematically evaluated the influence
of genetic or prenatal events in each of the 3 different stages of MCD.
The division of MCD into different groups is a major challenge because
many important aspects, such as association with a specific genetic syndrome
and pathological and neuroimaging findings, should be considered.25-26 In our study, the diagnosis of MCD
was based on well-established MRI findings, and the classification of patients
into 3 groups was consistent with imaging findings. Heterotopias (subcortical
or periventricular) and agyria-pachygyria (group 2) and polymicrogyria and
schizencephaly (group 3) were grouped together because there is strong evidence
that, in many cases, these lesions represent different ends within the spectrum
of the same disease.27
In group 1 (focal cortical dysplasia), the frequency of family history
of neurological impairment (3 patients [14%]) and the occurrence of a prenatal
event (5 patients [24%]) were significantly lower compared with the other
forms of MCD. In addition, none of these patients had a family history of
MCD. To our knowledge, there is no description of familial cases of focal
cortical dysplasia, other than those associated with specific syndromes, such
as tuberous sclerosis.
In group 2, 8 patients (42%) reported a prenatal event that might have
contributed to the pathogenesis of their cortical malformation, and 6 (32%)
had a family history of neurological disturbances, suggesting a central nervous
system lesion. However, 3 of these patients (16%) had a family history of
neurological impairment and a prenatal event. Although there are several reports
correlating prenatal events such as those reported by our patients and the
occurrence of MCD because of abnormal migration,18, 25
it is well established that the majority of patients with the so-called migration
disorders (bilateral periventricular nodular heterotopia, subcortical laminar
heterotopia, agyria-pachygyria, and lissencephaly) have mutations in specific
genes: LIS-1, DCX, and filamin
1.3, 7-8,10-12
We believe that MCD because of abnormal migration is mainly genetically determined,
either as a familial trait or a de novo mutation; however, prenatal events
could be acting in conjunction with the genetic predisposition to determine
the final phenotype.
In group 3 (polymicrogyria and schizencephaly), 15 patients (42%) reported
prenatal events, such as a failed abortion attempt, drug addiction, and abdominal
trauma due to a fall during the first trimester of pregnancy. All of those
factors could have induced a vascular injury, which may play an important
role as a contributor to the genesis of polymicrogyria and schizencephaly.26 The pathologic finding of a necrotic layer in patients
with layered polymicrogyria supports the traditional theory that, in many
cases, these abnormalities are a form of destructive lesion.27, 29
A family history of neurological impairment, suggesting a central nervous
system lesion, was also relatively common in this group (14 patients [39%]),
including 5 patients (14%) who had a first-degree relative with congenital
bilateral perisylvian syndrome. It is interesting to note that in this family
only 1 patient had a history of prenatal injury, and he had a more severe
phenotype.
Our data clearly show that prenatal events are very frequently linked
to MCD. One possible limitation of this finding is the fact that information
on the occurrence of prenatal events was ascertained retrospectively, and
precise recollection of events that may have occurred many years before is
difficult. Prenatal events, such as placental dysfunction, may be asymptomatic
in the mother, which could cause a substantial underestimation of the occurrence
of this kind of event. Although difficult to perform, a prospective study
on the association between prenatal events and MCD would be the best way to
address this issue.
We are well aware that MRI does not always detect focal cortical dysplasia
and that it may be associated with other types of lesions. On the other hand,
it is not known if people without epilepsy may have focal cortical dysplasia
that cannot be detected with MRI. This is quite possible, judging from the
fact that other types of MCD may not be associated with epilepsy. We believe
that a disease-control group with epilepsy helped to differentiate factors
that could be related to the seizure disorder itself and not necessarily to
MCD. For example, family history of epilepsy was not significantly different
among groups, but family histories of neurological impairment and prenatal
events were significantly less frequent in the disease-control group. If the
control group consisted of healthy subjects, there would also be a significant
difference for family history of epilepsy.
Epilepsy due to MCD probably depends on many factors such as size, localization,
and type of MCD lesion. The frequency of epilepsy was significantly lower
and the disease was more easily controlled in group 3. These findings are
in agreement with previous studies in which epilepsy was present in 57% to
87% of patients with polymicrogyria or schizencephaly.30-34
In these studies, the epileptic spectrum was wide, and most patients had their
seizures controlled with antiepileptic drugs.
In conclusion, we believe that environmental factors, such as prenatal
events, may act in conjunction with genetic predisposition to determine the
variable phenotypes seen in the different forms of MCD. Our findings support
the idea of a clinical spectrum among the different types of MCD. Focal cortical
dysplasia (group 1) is associated with more frequent and severe epilepsy and
less important genetic and prenatal events, heterotopias and agyria-pachygyria
(group 2) are frequently associated with genetic predisposition, and polymicrogyria
and schizencephaly (group 3) are less frequently associated with epilepsy
but have a stronger association with genetic and detectable prenatal events.
AUTHOR INFORMATION
Accepted for publication January 21, 2002.
Author contributions: Study concept and design (Drs Montenegro, M. Guerreiro, Lopes-Cendes, C. Guerreiro, and
Cendes); acquisition of data (Drs Montenegro, M.
Guerreiro, C. Guerreiro, and Cendes); analysis and interpretation of
data (Drs Montenegro, M. Guerreiro, Lopes-Cendes, C. Guerreiro,
and Cendes); drafting of the manuscript (Drs Montenegro,
M. Guerreiro, Lopes-Cendes, C. Guerreiro, and Cendes); critical revision
of the manuscript for important intellectual content (Drs
Montenegro, M. Guerreiro, Lopes-Cendes, C. Guerreiro, and Cendes);
statistical expertise (Drs Montenegro and Cendes);
study supervision (Drs M. Guerreiro, Lopes-Cendes, C. Guerreiro,
and Cendes).
This study was supported by grants 00/03502-7 (Dr Montenegro) and 97/07584-3
from the Fundação de Amparo à Pesquisa do Estado de São
Paulo, São Paulo, Brazil.
Corresponding author and reprints: Marilisa M. Guerreiro, MD, PhD,
Department of Neurology, University of Campinas, PO Box 6111, 13083-970 Campinas,
São Paulo, Brazil (e-mail: mmg{at}fcm.unicamp.br).
From the Departments of Neurology (Drs Montenegro, M. Guerreiro, C.
Guerreiro, and Cendes) and Medical Genetics (Dr Lopes-Cendes), University
of Campinas, Campinas, Brazil.
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Stromal-Derived Factor-1 (CXCL12) Regulates Laminar Position of Cajal-Retzius Cells in Normal and Dysplastic Brains.
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Epileptic Features of Patients With Unilateral and Bilateral Schizencephaly
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Intrapartum Complications Associated With Malformations of Cortical Development
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Prenatal Diagnosis of Polymicrogyria by Fetal Magnetic Resonance Imaging in Monochorionic Cotwin Death
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Fetal Schizencephaly: Pre- and Postnatal Imaging with a Review of the Clinical Manifestations
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RadioGraphics 2005;25:647-657.
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Severe Epilepsy and Pachygyria Associated With Peculiar Facial Traits Characterize Fryns-Aftimos Syndrome
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Excitatory and Inhibitory Postsynaptic Currents in a Rat Model of Epileptogenic Microgyria
Jacobs and Prince
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Mutation screening in a cohort of patients with lissencephaly and subcortical band heterotopia
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Neuroimaging in Spasticity and Movement Disorders
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