Ultrasound Obstet Gynecol 2007; 29: 178–191 Published online 11 January 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.3906
Prenatal diagnosis of malformations of cortical development by dedicated neurosonography G. MALINGER*†‡, D. KIDRON‡§, L. SCHREIBER*‡¶, L. BEN-SIRA‡#, C. HOFFMANN‡, D. LEV*‡+ and T. LERMAN-SAGIE*‡◦ *Fetal Neurology Clinic, †Department of Obstetrics and Gynecology, ¶Department of Pathology, +Genetics Institute and ◦ Pediatric Neurology Unit, Wolfson Medical Center, Holon, §Department of Pathology, Sapir Medical Center, Kfar-Saba, #Pediatric Radiology Unit, Sourasky Medical Center, Tel Aviv and Neuroradiology Unit, Sheba Medical Center, Tel-Hashomer and ‡Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
K E Y W O R D S: cortical malformations; magnetic resonance imaging; migration disorders; prenatal diagnosis; ultrasound
ABSTRACT Objective Malformations of cortical development (MCD) are rarely diagnosed in utero. We describe and compare the ultrasonographic and pathology findings in a cohort of fetuses with MCD. Methods Fetuses with MCD were identified among all fetuses evaluated for suspected brain anomalies at the Fetal Neurology Clinic, and the ultrasonographic findings were compared with the results of the pathology examination. Results We suspected the presence of MCD by ultrasonography in 23 fetuses. The mean gestational age at the time of ultrasound diagnosis was 26.2 (range, 18–40) weeks. The ultrasonographic findings leading to the diagnosis of MCD were abnormally overdeveloped gyri and sulci for gestational age (n = 7), delay in sulcation (n = 5), abnormally thin cortex (n = 5) abnormally wide and broad sulci (n = 3), bulging into the lateral ventricle (n = 1), cortical cleft (n = 1), and multiple intraparenchymal echogenic nodules (n = 1). All fetuses had associated central nervous system (CNS) and/or non-CNS anomalies. Pathology examination (performed in 17 fetuses) confirmed MCD in 16. Conclusions Cortical malformations can be diagnosed in utero by ultrasonography based on the presence of specific deviations from the normal pattern of development. The identified cases may represent the more severe forms in the MCD spectrum. The pathology findings do not always conform to the current classification systems of MCD but help in differentiating between possible genetic and acquired etiologies and in some cases
provide a definitive syndromic diagnosis. Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
INTRODUCTION The human fetal brain undergoes an orderly developmental process. During the first 6 weeks of pregnancy dorsal and ventral induction gives the brain its external shape. In the following weeks complex sequential processes continue, including proliferation of neurons and glial cells, migration of these cells from the periventricular germinal zone, and neuronal organization1 . Genetic factors2,3 or prenatal injury of diverse etiology, including trauma, infections or exposure to teratogens4,5 produce a wide range of cortical malformations that may lead to neurological deficits and/or seizures. Different classification systems of malformations of cortical development (MCD), based on radiological or genetic criteria, have been proposed2,3 . The largest series include adult patients detected in epilepsy clinics6 and pediatric patients with neurological problems7 . Although the migration process reaches its peak at around 20 weeks’ gestation, there are only isolated case reports8 – 14 or small case series15 – 19 describing the prenatal ultrasonographic diagnosis of abnormal cortical development. This may be explained in some cases by the focal expression of the disorder, by the late appearance of significant morphological changes beyond the time of the recommended anatomic scan, by ultrasound evaluation of the brain frequently being limited to visualization of the lateral ventricles and cerebellum, and by incomplete knowledge of these entities and their ultrasonographic manifestations.
Correspondence to: Dr G. Malinger, Department of Gynecology & Obstetrics, E. Wolfson Medical Center, Holon 58100, Israel (e-mail:
[email protected]) Accepted: 1 November 2006
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
ORIGINAL PAPER
Malformations of cortical development According to some investigators, fetal magnetic resonance imaging (MRI) may have better diagnostic capabilities, particularly regarding MCD, in fetuses with ultrasonographically suspected brain anomalies19 – 21 , but confirmation of the prenatal ultrasonographic identification of MCD by histopathology is rarely available owing to the small number of late terminations and technical difficulties in preserving the fetal brain after abortion. We describe a large series of prenatal imaging and pathology findings in a cohort of fetuses with MCDs.
PATIENTS AND METHODS The study was conducted at the Fetal Neurology Clinic of Wolfson Medical Center. The MRI studies were performed at the Pediatric Radiology Unit of Sourasky Medical Center and at the Neuroradiology Unit of Sheba Medical Center. The pathology evaluations were performed at the Perinatal Pathology Unit of Sapir Medical Center and the Pathology Department of Wolfson Medical Center. Fetuses with MCD were identified among all fetuses evaluated for suspected brain anomalies at the Fetal Neurology Clinic during a 6-year period starting in January 2000. Cases of apparently isolated microcephaly and macrocephaly were not included. All the patients were evaluated using a transabdominal approach, and when the fetuses were in vertex presentation, the study was complemented by transvaginal ultrasound as previously described22,23 . Eighteen patients were referred for MRI and the results will be presented in a separate paper. MRI was used in order to confirm the ultrasonographic diagnosis before parental counseling and to try to obtain additional information. After counseling by the fetal neurology team regarding the diagnosis and its implications for child development and health, parents requesting termination of pregnancy were referred to one of the ad hoc ethics committees accredited by the Israeli Ministry of Health for approval. Termination of pregnancy was performed by intracardiac injection of potassium chloride followed by induction of labor. A complete autopsy was performed following signed parental consent.
RESULTS Ultrasonographic findings suggestive of MCD were identified in 23 fetuses (Table 1). Twenty-one were singletons and two were twins in which the other twin did not show brain malformations. Twenty-two patients were referred because of an unexpected abnormal finding during a routine ultrasound examination: mild bilateral or unilateral ventriculomegaly (n = 6), callosal anomalies (n = 4), multiple malformations (n = 4), arachnoid cysts (n = 2), small head circumference (n = 2), agenesis of the septum pellucidum (n = 1), multiple cardiac rhabdomyomas (n = 1), skeletal dysplasia (n = 1), and
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
179
intrauterine growth restriction (IUGR) (n = 1). One patient was studied because of a history of cortical malformation in two previous pregnancies24 . The findings in two of these patients (Table 1, Cases 7 and 21) have been previously reported25,26 . The mean gestational age at the time of referral was 26.2 (range, 18–40) weeks. On parental request 20 fetuses underwent termination of pregnancy at a mean gestational age of 27.9 (range, 20–40) weeks. An autopsy was performed in 17, while in the remaining three fetuses an autopsy was not performed because of termination of pregnancy by dilatation and evacuation or because of family refusal. Three families elected to continue pregnancy. Two of the newborns (Table 1, Cases 20 and 22) died shortly after birth, postnatal ultrasound confirming the diagnosis, although an autopsy was not obtained. The third child is 2 years old and suffers from severe mental retardation and epilepsy (Table 1, Case 21). During the study period one case of periventricular nodular heterotopia escaped detection by both ultrasound and MRI.
Ultrasonographic findings The main findings suggestive of MCD were the presence of prematurely appearing abnormal, overdeveloped sulci and gyri in seven fetuses (Figure 1); delayed appearance of landmark sulcation in five (Figure 2); an abnormally thin cortex in five (Figure 3); wide abnormal gyri in three (Figure 4); nodular bulging into the lateral ventricle in one (Figure 5); a cortical cleft in one (Figure 6); and multiple intraparenchymal echogenic nodules in one (Figure 7). In five fetuses, the periventricular zone was also abnormal owing to the presence of hyperechogenic lesions or irregular ventricular walls. The findings were bilateral in 18 and unilateral in five. In patients with bilateral MCD, the malformation was generalized in 13, involved only the frontal lobes in two, the parietal and occipital lobes in two and the occipital lobes in one. In patients with unilateral MCD, the whole hemisphere was involved in four and the frontal and parietal lobes in one (Table 1). Associated anomalies were identified in all fetuses (Table 1). Associated central nervous system (CNS) anomalies included: mild ventriculomegaly (n = 12) (bilateral (n = 7), unilateral (n = 3), 3rd ventricle dilatation (n = 2)); callosal anomalies (n = 10) (complete agenesis of the corpus callosum (n = 6), partial agenesis of the corpus callosum (n = 2), dysgenesis of the corpus callosum (n = 1), thick echogenic corpus callosum (n = 1)); vermian anomalies (n = 8) (dysgenesis (n = 3), agenesis (n = 3), Dandy–Walker malformation (n = 1), abnormal vermis echogenicity (n = 1)); microcephaly (n = 5); interhemispheric cysts (n = 5); large subarachnoid space (n = 5); periventricular pseudocysts (n = 4); cerebellar hypoplasia (n = 3); agenesis of the septum pellucidum (n = 2); abnormal brain stem (n = 2); and macrocephaly (n = 1). Abnormal fetal movements were observed in two patients.
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25
7
24
25
6
10
22
5
29
24
4
9
27
3
22
33
2
8
40
GA* (weeks)
1
Case
ACC
Mild ventriculomegaly (13 mm)
Multiple malformations
Atypical asymmetric ventricles
Multiple malformations
ACC
Mild ventriculomegaly (12–13 mm)
Mild ventriculomegaly (10 mm)
Suspected microcephaly S/P fetal reduction
Arachnoid cyst
Indication for referral
Table 1 Ultrasonographic findings
Abnormal overdeveloped gyri and sulci Mild ventriculomegly ACC Vermian dysgenesis Large extra axial spaces
Abnormal broad sulci Mild ventriculomegaly Large extra axial spaces Abnormal periventricular tissue
Abnormal overdeveloped gyri and sulci Partial ACC Vermian agenesis
Abnormal overdeveloped gyri and sulci Asymmetric ventriculomegaly Abnormal periventricular tissue Periventricular pseudocyst
Smooth cortex Ventriculomegaly Microcephaly ACC Dandy–Walker malformation
Abnormal overdeveloped gyri and sulci ACC Vermian hypoplasia
Smooth thin irregular cortex Mild ventriculomegaly Dysgenesis of corpus callosum Microcephaly Large subarachnoid spaces
Abnormal overdeveloped gyri and sulci ACC Cerebellar hypoplasia Abnormal general movements
Abnormal hyperechogenic gyri
Focal wide gyri Periventricular bulging Atypical asymmetric ventricles Interhemispheric cyst
Ultrasound CNS findings
Bilateral Generalized
Bilateral Parieto-occipital
Bilateral Generalized
Unilateral Generalized
Bilateral Generalized
Unilateral Generalized
Bilateral Generalized
Bilateral Generalized
Bilateral Frontal
Unilateral Left parieto-frontal
Laterality & location
Hemimegalencephaly
MCD
Complex MCD
Hemimegalencephaly
Lissencephaly
Hemimegalencephaly
Lissencephaly
Complex MCD
Possible ischemic insult Abnormal sulcation
Pachygyria
Main FNC diagnosis
No
No
TOP No autopsy
TOP Autopsy
TOP Autopsy
TOP Autopsy
TOP Autopsy
TOP Autopsy
TOP Autopsy
TOP Autopsy
TOP Autopsy
TOP Autopsy
Follow-up
(continued overleaf )
Dysplastic kidneys, megacystis Short bowed bones Hydrops fetalis
No
Hydrops fetalis Severe growth restriction Overriding sutures Skeletal dysplasia
No
No
Adducted thumbs
Abnormal cranial shape
No
Non-CNS findings
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25
26
23
24
29
12
13
14
15
16
31
18
11
17
GA* (weeks)
Case
Table 1 (Continued)
IUGR
Mild asymmetric ventriculomegaly
Skeletal dysplasia
Microcephaly; twins
Agenesis septum pellucidum
Familial history of agyria-pachygyria
Suspected interhemispheric cyst
Indication for referral
Delayed sulcation Periventricular cysts (3) left Periventricular echogenicity
Wide, abnormal gyri Mild asymmetric ventriculomegaly Macrocephaly Thick, echogenic corpus callosum 3rd ventricle dilatation Large extra axial spaces
Abnormal overdeveloped sulci and gyri Cerebellar hypoplasia Abnormal echogenicity of vermis
Thin cortex Microcephaly
Schizencephaly Agenesis septum pellucidum
Delayed sulcation (2–3 weeks) Abnormal periventricular tissue Large extra axial spaces
Abnormal overdeveloped gyri and sulci (right) Multiple periventricular cysts Abnormal hemispheric echogenicity Abnormal periventicular tissue Interhemispheric cyst
Ultrasound CNS findings
Bilateral Generalized
Bilateral Generalized
Bilateral Occipital
Bilateral Generalized
Bilateral Frontal
Bilateral Generalized
Unilateral Generalized
Laterality & location
Possible prenatal insult Lissencephaly
Pachygyria
MCD
Lissencephaly
Agyria
Hemimegalencephaly
Main FNC diagnosis
No
No
Lethal skeletal dysplasia
Left hypoplastic heart
No
Large echogenic kidneys Club foot Polyhydramnios Short femur
No
Non-CNS findings
TOP Autopsy
TOP Autopsy
TOP Autopsy
Delivered US confirmation Neonatal death
TOP Autopsy
TOP Autopsy
TOP No autopsy
Follow-up
Malformations of cortical development 181
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22
29
22
31
19
20
21
22
Periventricular bulging ACC Interhemispheric cyst Periventricular cyst
Delayed sulcation ACC, colpocephaly Interhemispheric cyst Dysgenesis of vermis
Ultrasound CNS findings
Cardiac rhabdomyomas
Varix of umbilical vein Large 3rd ventricle Polyhydramnios Twins
Ventriculomegaly
Parenchymal echogenic nodules Periventricular echogenic nodules
Smooth cortex Cerebellar hypoplasia Large extra axial spaces Incipient microcephaly
Delayed sulcation Agenesis septum pellucidum Abnormal general movements
Partial ACC Delayed sulcation Inferior vermian agenesis Ventriculomegaly Abnormal periventricular tissue Abnormal brain stem Interhemispheric cyst
ACC
ACC
Indication for referral
Bilateral Generalized
Bilateral Generalized
Bilateral Parieto-occipital
Bilateral Generalized
Unilateral Generalized
Bilateral Generalized
Laterality & location
Tuberous sclerosis
Lissencephaly
MCD
Suspected Walker–Warburg
Periventricular heterotopia
Lissencephaly
Main FNC diagnosis
Cardiac rhabdomyomas
Varix of umbilical vein
Hypotelorism
No
No
No
Non-CNS findings
TOP Autopsy
Delivered US confirmation Neonatal death
Delivered Epilepsy Mental retardation
Delivered Neonatal death
TOP Autopsy
TOP Autopsy
Follow-up
*At diagnosis. ACC, agenesis of the corpus callosum; CNS, central nervous system; FNC, fetal neurology clinic; GA, gestational age in weeks; IUGR, intrauterine growth restriction; MCD, malformation of cortical development; S/P, state post; TOP, termination of pregnancy; US, ultrasound.
26
26
18
23
GA* (weeks)
Case
Table 1 (Continued)
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Figure 1 (a) Transvaginal sonographic image in the sagittal plane showing abnormal sulcation and agenesis of the corpus callosum in a fetus with overdeveloped sulci and gyri at 27 weeks’ gestation (Case 3); (b) macroscopic specimen in a similar plane; (c) microscopic section showing white matter heterotopia (arrows; H & E stain, original magnification × 100); (d) microscopic section showing irregular cortical layering and polymicrogyria (arrow; H & E stain, original magnification × 100).
Figure 2 (a) Transvaginal sonographic image at 32 weeks’ gestation in the fontal coronal plane, showing poorly developed sulci and gyri in a fetus with delayed frontal sulcation due to possible prenatal insult (Case 17); (b) macroscopic specimen showing the normally developed occipital sulci (white arrow) in comparison with poorly developed frontal ones (black arrow).
Non-CNS anomalies were diagnosed in 10 fetuses and included a wide array of malformations (Table 1), some fetuses having more than one malformation. The skeletal system was affected in six, the urinary system was involved in two, one had hypoplastic
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
left heart syndrome and another had multiple cardiac rhabdomyomas. Hydrops fetalis and severe growth restriction were present in two, and polyhydramnios, a varix of the umbilical vein and hypotelorism in one fetus each.
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Figure 3 (a) Transvaginal ultrasound image in the axial plane, showing bilateral thin cortex without sulcation in a fetus with cobblestone lissencephaly at 24 weeks’ gestation (Case 4). Note the irregularity of the outer cortex/leptomeninges and the increased amount of cerebrospinal fluid surrounding the brain; (b) transvaginal ultrasound image in the parasagittal plane showing similar features and mild ventriculomegaly; (c) microscopic specimen of the cortex showing lissencephaly, disordered cortical layering and obliteration of the subarachnoid space. Note the lack of demarcation between the cortex (C) and leptomeninges (L). (H & E stain, original magnification × 100).
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
Malinger et al.
Figure 4 (a) Transvaginal ultrasound image (coronal plane) of a fetus at 40 weeks’ gestation with pachygyria and periventricular heterotopia, showing thick cortex without sulcation (arrowhead) and enlarged ventricle with an irregular ventricular wall (arrows) (Case 1); (b) fetal magnetic resonance image in a similar plane showing similar findings; (c) coronal section through the posterior aspect of the frontal horns showing marked hemispheric asymmetry, with pachygyria of the left hemisphere and periventricular nodules consistent with heterotopia.
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Figure 5 (a) Transvaginal ultrasound image in the frontal coronal plane showing a periventricular echogenic focus (heterotopia, arrow) in a fetus with polymicrogyria and agenesis of the corpus callosum at 22 weeks’ gestation (Case 19); (b) transvaginal ultrasound image in the parasagittal plane showing bulging into the lateral ventricle.
Pathology findings A complete autopsy was performed in 16 fetuses and only a macroscopic examination in one. Of these there were 12 females and five males, and the karyotype was normal in all 14 cases in which it was obtained. The brain weight was below that expected for the gestational age in only two fetuses. The pathology results are presented in Table 2. A wide range of cortical malformations was observed; usually more than one pathology was found in each fetus. These findings include: heterotopia (n = 14) (white matter (n = 8), cortical (n = 5), periventricular (n = 1)); polymicrogyria (n = 10) (focal (n = 7), multifocal (n = 3)); cortical dysplasia (n = 5); overdeveloped abnormal sulci (n = 6); neuronal bulging into the pia mater (n = 3); unlayered cortex (n = 3); gross hemisphere asymmetry (n = 2); pachygyria (n = 1); schizencephaly (n = 1); and multiple tubers (n = 1). Cortical calcifications and white matter gliosis were found in one patient each, suggesting an ischemic etiology. MCDs were confirmed in 15/16 fetuses, which were bilateral in 14 (in two patients the pathology examination
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
Figure 6 (a) Transvaginal ultrasound image in the coronal plane through the frontal lobes showing continuity between the lateral ventricles and the subarachnoid space in a fetus with schizencephaly at 26 weeks’ gestation (Case 13); (b) transvaginal ultrasound image in the sagittal plane showing frontal schizencephaly and an abnormally thin temporal lobe (arrows); (c) macroscopic specimen in a similar plane as in (a), demonstrating schizencephaly.
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Figure 7 (a) Transvaginal ultrasound image (coronal plane) of the frontal lobes showing multiple parenchymal echogenic nodules in a fetus with tuberous sclerosis at 28 weeks’ gestation (Case 23); (b) transvaginal ultrasound image in the sagittal plane, slightly lateral to the lateral ventricle, showing periventricular echogenic nodules (arrows); (c) macroscopic coronal section of the cerebral hemispheres showing compression and distortion of the lateral ventricles by subependymal nodules, and cerebral hemisphere asymmetry with several intraparenchymal nodules (arrow); (d) microscopic section showing an intraparenchymal nodule with giant balloon cells in a glial background (H & E stain, original magnification × 100).
showed bilateral involvement while ultrasonography suggested only unilateral involvement) and unilateral in one. In the bilateral cases the disorder was generalized in seven, generalized but asymmetric in two, multifocal with occipital predominance in one, and involved one lobe in two and two lobes in two. Unilateral MCD was limited to the frontal and parietal lobes. Ventriculomegaly was identified in six fetuses (bilateral (n = 4), unilateral (n = 2)). Associated cerebral anomalies were found in 14 and included: callosal anomalies (n = 8) (complete agenesis of the corpus callosum (n = 4), partial agenesis (n = 2), dysgenesis (n = 2)); microcephaly (n = 2); macrocephaly (n = 1); agenesis of the septum pellucidum (n = 1); periventricular cysts (n = 1); interhemispheric arachnoid cyst (n = 1) and large cavum septi pellucidi (n = 1). Cerebellar anomalies were found in nine fetuses, including vermian agenesis, hypogenesis or dysgenesis (n = 4); cerebellar cortical dysplasia (n = 4); hypoplasia
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
of the pyramidal tracts (n = 2); cerebellar heterotopia (n = 1); cerebellar hypoplasia (n = 1); and asymmetric cerebellar hemispheres (n = 1). There was a wide range of extra-CNS findings in 13 (out of 17) fetuses, including craniofacial anomalies (n = 7), hand and foot malformations (n = 4), skeletal dysplasia (n = 3), cardiac anomalies (n = 3), urinary tract anomalies (n = 2), retinal dysplasia (n = 2), lung hypoplasia (n = 2) and muscular anomalies (n = 2). Adrenal hypoplasias, organomegaly and intestinal malrotation were found in one patient each, and in four fetuses different types of neoplasm were found.
Correlation between ultrasound findings and pathology or postnatal examination Pathology examination of the brains of five out of seven fetuses with the ultrasonographic finding of an abnormal,
Ultrasound Obstet Gynecol 2007; 29: 178–191.
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
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5
32
26
4
7
29
3
27
35
2
6
40
Sex
Main diagnosis
2130 46XX Orofaciodigital syndrome
680 46XX Unclassified multiple malformation syndrome
620 Female Orofaciodigital syndrome
Periventricular heterotopia Unilateral ventriculomegaly Focal polymicrogyria Neuronal bulging into pia mater White matter gliosis Interhemispheric arachnoid cyst Focal polymicrogyria Focal white matter heterotopia
Other CNS findings
Abnormal overdeveloped sulci; left more than right ACC Colpocephaly Focal cerebellar dysplasia Focal polymicrogyria White matter heterotopia Bilateral Microcephaly Generalized Mild ventriculomegaly Short corpus callosum Focal polymicrogyria Focal white matter heterotopia Neuronal bulging into pia mater Cerebellar dysplasia Hypoplasia of pyramidal tracts Bilateral Abnormal overdeveloped sulci and gyri Left more than right Unlayered cortex, heterotopia Generalized ACC Vermian hypoplasia Multifocal polymicrogyria Bilateral Ventriculomegaly Generalized Thin unlayered cortex (bilateral) Microcephaly Focal cortical heterotopia Nodular laminar WM heterotopia Focal neuronal bulging into pia mater ACC Cerebellar hypoplasia Cerebellar white matter heterotopia Cerebellar dysplasia Hypoplasia of pyramidal tracts Bilateral Abnormal overdeveloped sulci and gyri Left more than right Asymmetric ventriculomegaly
Bilateral Generalized
Unilateral Left frontoparietal
Laterality & location
Cortical dysplasia unclassified Bilateral Frontoparietal
790 46XX Cobblestone lissencephaly Walker–Warburg syndrome
1340 Male
2030 46XY Multiple nodular cortical heterotopia with PMG
3750 46XY Periventricular heterotopia with PMG
GA at TOP Weight (weeks) (g)
1
Case
Table 2 Pathological findings
Retinal dyplasia Intestinal malrotation
IUGR Hydrops fetalis Skeletal dysplasia (unclassified) Brachydactyly Facial dysmorphism Lung hypoplasia Adrenal hypoplasia Atrophy of skeletal muscle
Preaxial polydactyly Syndactyly Cleft lip Hypertelorism
Retinal dysplasia Muscular dystrophy Renal dysplasia Subendocardial hypertrophy
Broad flat nasal bridge Sloping forehead Brachycephaly No
No
Non-CNS findings
(continued overleaf )
Basaloid follicular hamartomas of skin
No
No
No
No
No
No
Neoplasms
Malformations of cortical development 187
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35
26
26
24
31
32
26
23
28
9
12
13
15
16
17
18
19
23
1360
550
672
1390
1970
544
1139
1040
2300
850
Weight (g)
46XX
46XY
46XX
46XX
46XX
46XX
46XX
46XX
46XX
Male
Sex
Tuberous sclerosis
Heterotopia with PMG
Lissencephaly
mp fetal ischemia
No histology
Abnormal sulci and gyri
Schizencephaly
Normal cortex
Unclassified multiple malformation syndrome
Unclassified multiple malformation syndrome
Main diagnosis
Bilateral Frontal Bilateral Multifocal
Bilateral Generalized
Bilateral Occipitotemporal Bilateral Generalized Bilateral Generalized
Bilateral Frontal
Bilateral Parieto-occipital
Bilateral Generalized
Generalized
Laterality & location
Intraparenchymal and periventricular tubers
Macrocephaly MRI findings similar to US findings Multiple cortical nodular heterotopias Focal bilateral PMG, discontinuous cortex Periventricular germinal matrix cysts ACC Unlayered cerebral cortex Mild ventriculomegaly Hypoplastic vermis ACC
Agenesis septum pellucidum Asymmetric cerebral hemispheres Abnormal overdeveloped gyri Focal polymicrogyria parietotemporal Neuronal heterotopia Focal cortical dysplasia
Cortical heterotopia Focal polymicrogyria Focal white matter heterotopia Thin CC Focal cerebellar heterotopias Abnormal overdeveloped sulci and gyri Laminar WM heterotopia Multifocal polymicrogyria Partial ACC Vermian agenesis Mild ventriculomegaly Abnormal broad sulci Laminar WM heterotopia Multifocal polymicrogyria Dysplastic corpus callosum Cerebellar dysplasia Vermian dysplasia Large CSP Milky CSF Large choroid plexus cells
Other CNS findings
No
No
Facial dysmorphism
Frontal bossing Nasal depression Placental floor fibrin thrombi Intervillous thrombi
Thanatophoric dysplasia
Organomegaly (liver, adrenals, kidney, tongue) Club foot Postaxial polydactyly No
Four-leaflet pulmonary valve Preaxial polydactyly Syndactyly Asymmetric skull (base) Cleft lip MDK, megacystis Short bowed bones Hypoplastic lungs Hydrops fetalis Cleft lip No
Non-CNS findings
Cardiac rhabdomyomata
No
No
No
No
No
No
No
Chondromatous hamartoma of lung bilateral peripheral
Adrenal neuroblastoma
Neuromuscular hamartomas: gastrointestinal muscularis, mesentery, spleen
Neoplasms
ACC, agenesis of the corpus callosum; CC, corpus callosum; CNS, central nervous system; CSF, cerebrospinal fluid; CSP, cavum septi pellucidi; GA, gestational age; IUGR, intrauterine growth restriction; MDK, multicystic dysplastic kidney; mp, most probably; MRI, magnetic resonance imaging; PMG, polymicrogyria; TOP, termination of pregnancy; US, ultrasound; WM, white matter.
22
GA at TOP (weeks)
8
Case
Table 2 (Continued)
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Malformations of cortical development overdeveloped cortex was performed, the macroscopic examination showing an excellent correlation with the ultrasonographic findings in all fetuses. The microscopic examination showed the presence of MCD in the macroscopically abnormal zones in five fetuses but also revealed further involvement of the other hemisphere that did not appear abnormal either by ultrasound or macroscopically. The underlying pathologies in this group included white matter heterotopia and polymicrogyria (n = 4) and bilateral temporal focal cortical dysplasia (n = 1). The pathology examination enabled a syndromic diagnosis to be made in two fetuses that was not suspected by ultrasonography, which suggested a diagnosis of hemimegalencephaly. The autopsy demonstrated gross hemispheric asymmetry, but MCD involved both hemispheres and was associated with midline cleft lip, dysmorphic facial features, preaxial polydactyly and syndactyly. The findings were consistent with orofaciodigital syndrome27 . In the other two patients in which an autopsy was not obtained, the findings were confirmed before termination of pregnancy by the use of MRI, but a definitive diagnosis was not possible. An autopsy was obtained in three of the five fetuses in which ultrasonography demonstrated immature sulcation. In one fetus the microscopic examination showed the presence of heterotopia and polymicrogyria associated with placental thrombi, suggesting an ischemic etiology; in the second there was thickening and unlayering of the cortical ribbon; and in the last no cortical abnormalities were found, but the fetus was clearly syndromatic with multiple organ involvement. The correlation between the pathology examination and ultrasound was good in the three autopsied fetuses, which showed an abnormally thin cortex by ultrasound scan. In the first the diagnosis was cobblestone lissencephaly, the second demonstrated a thin unlayered cortex accompanied by focal cortical heterotopia, laminar white matter heterotopia and focal neuronal bulging into the pia mater, and the third showed bilateral frontal polymicrogyria, white matter heterotopia and calcifications, confirming an ischemic insult probably at the time of selective reduction of an abnormal twin. The remaining two patients from this group were delivered and postnatal ultrasound demonstrated similar abnormalities. The ultrasonographic visualization of wide abnormal gyri in two autopsied fetuses correlated with pachygyria and polymicrogyria. In the third fetus macroscopic examination confirmed the diagnosis but microscopic examination was not possible because of maceration. The ultrasonographic finding of periventricular bulging into the lateral ventricle with irregular ventricular shape, which raised the suspicion of periventricular nodular heterotopia, was not confirmed by pathological examination, but white matter heterotopia and polymicrogyria were found. Pathological examination confirmed the ultrasonographic diagnoses of bilateral cortical clefts as schizencephaly with polymicrogyria, and intraparenchymal and periventricular nodules as tuberous sclerosis.
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DISCUSSION MCDs consist of aberrations in cellular proliferation, differentiation and migration, and cortical organization. Insults to the developing brain may either be acquired or be due to genetic factors4,5 . The timing and the location of the insult will determine the pattern and the severity of the cortical malformation1 . Different classifications combining clinical information, imaging features, pathology findings and genetic data have been proposed1 – 3 . The major groups of MCD consist of microcephalies, megalencephalies, lissencephaly/subcortical band heterotopia spectrum, cobblestone complex, heterotopia, polymicrogyria and schizencephaly. These malformations have been well characterized in children and adults and in many of them specific genes involved in cell migration have been identified2,3 . Although the vast expansion of our knowledge regarding brain malformations stems from MRI, ultrasound is more widely available, inexpensive, does not require sedation and can be performed at the bedside. Therefore it is still the most commonly utilized modality in the prenatal22 and neonatal28 diagnosis of brain anomalies. However, the literature on the diagnosis of MCD by postnatal ultrasonography is sparse. Pellicer et al.29 are the only group to have reported a series of (17) neonates who were diagnosed by ultrasound as having cortical malformations. The authors described the ultrasound patterns that led to the diagnosis of MCD: lissencephaly was diagnosed by the presence of a smooth brain surface with poor sulcation and rudimentary Sylvian fissures; schizencephaly by breaks along the ventricular wall and a communication between the ventricular lumen and the subarachnoid space; hemimegalencephaly by a unilaterally enlarged and abnormal hemisphere; and subependymal heterotopia by an irregular ventricular wall or periventricular hyperechogenic nodules. An excellent correlation was found between the ultrasonographic and MRI findings. There are no similar studies describing the prenatal ultrasonographic diagnosis of these entities in a large cohort. Only small case series or case reports describing the in-utero identification of single malformations have been published8 – 19 . In our study, the ultrasonographic findings that suggested the diagnosis of MCD were: the presence of abnormal sulci and gyri, overdeveloped in relation to gestational age; a smooth and thin cortex; delayed appearance of landmark sulcation; small abnormal gyri; cortical clefting; irregular ventricular margins; intraparenchymal echogenic nodules; and an enlarged hemisphere. Abnormal overdeveloped sulci were found in seven of our fetuses during the second trimester. This ultrasonographic finding has been described in pathology specimens of fetuses aborted during the second trimester before cortical organization had occurred, thus reflecting abnormal migration. It has been associated with agenesis of the corpus callosum and the presence of mature neurons in the germinal matrix, probably reflecting the future development of periventricular heterotopia30 ; a similar finding has been described in
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thanatophoric dysplasia31 . Righini et al.32 also reported the fetal MRI finding of ‘cortical-rim abnormal profile with apparent irregular infolding’; the postnatal MRI diagnosis was polymicrogyria, although the typical MRI features had not yet developed. The pathology diagnoses in our cases were heterotopia and polymicrogyria in four, and thanatophoric dysplasia in one. In five out of the seven fetuses with this finding there were associated callosal anomalies, and in six of the seven cerebellar anomalies were present. Thus the identification of overdeveloped sulci during the second trimester probably reflects the association of both polymicrogyria and heterotopia, and may represent a transient phenomenon occurring as part of the maturation process of abnormal cortex. In thanatophoric dysplasia a similar abnormal sulcation pattern has been described previously and found to be associated with MCD confirmed by microscopic findings31 . While immature sulcation was assumed to reflect pachygyria it was found to be less specific and was seen both in a fetus with polymicrogyria and heterotopia confirmed by pathology and in fetuses with pachygyria. Pachygyria/lissencephaly can present with different ultrasonographic patterns – immature sulcation, a thin and smooth cortex or wide and thick gyri. Further collaborative studies of a larger number of patients are needed in order to determine whether a specific pattern can predict the exact type of lissencephaly. Our impression is that, in the fetus, a thin and smooth cortex reflects cobblestone lissencephaly, while immature sulcation or the presence of wide and thick gyri is suggestive of lissencephaly/band heterotopia sequence. Microscopic examination failed to demonstrate the presence of any cortical pathology in one fetus (Tables 1 and 2, Case 12) in which ultrasound, MRI and the macroscopic findings all demonstrated abnormal sulcation. This is difficult to explain since two previously delivered siblings died shortly after birth and were diagnosed as suffering from an unknown syndrome that included a simplified gyral pattern as shown by MRI24 . A possible explanation may be the early interruption of pregnancy, before the end of the organization process. We believe that some fetuses with more subtle forms of MCD and without associated anomalies may have escaped prenatal detection since most of the fetuses were referred by the treating physician because of the presence of other brain anomalies (e.g. ventriculomegaly, agenesis of the corpus callosum, cerebellar dysgenesis) or extra-CNS malformations. In this context we recommend that fetuses with even minor CNS anomalies, and probably also those with non-CNS anomalies, should undergo either a detailed neurosonographic examination or fetal brain MRI, both performed by well trained physicians. The most recent revised classification of MCD is based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected2 . This new classification enables the inclusion of patients who show the coexistence of more than one MCD. Thus if a patient has both heterotopia, which is classified as belonging to
Copyright 2007 ISUOG. Published by John Wiley & Sons, Ltd.
cell migration abnormalities, and polymicrogyria, which belongs to the organization abnormalities, they should be included in the cell migration abnormalities that occur earlier. Even though this is a second revision it is clear that the classification is not final, and that it will continue to be modified as our knowledge advances and new malformations are described. Wieck et al.33 recently described patients with the association of polymicrogyria and periventricular heterotopia; many of their patients also demonstrated callosal and cerebellar anomalies, and Parrini et al.34 demonstrated that in many cases periventricular heterotopia is not isolated and is associated with other brain malformations, including hippocampal malformation and cerebellar hypoplasia, bilateral fronto-perisylvian or temporo-parieto-occipital polymicrogyria, hydrocephalus and microcephaly. In some cases periventricular heterotopia was associated with non-neurological defects. These two studies are consistent with our findings. The pathology examination revealed the frequent coexistence of different MCDs, usually polymicrogyria with either laminar or nodular heterotopia. In the majority of our patients these findings were associated with callosal and cerebellar anomalies. These two recent studies combined with our observations suggest that the current classification scheme should be extended to include patients with different associations of cerebral and cerebellar malformations and those with specific multiple malformation syndromes (e.g. velocardiofacial, orofaciodigital, frontonasal dysplasia). It seems possible that there are more such syndromes combining severe malformations and multiple MCDs but that they may be not diagnosed in the clinical setting since they may be lethal in utero or shortly after birth. Dedicated neurosonography enables the diagnosis of such cases and provides new insights into understanding the complexity of MCDs. It should be emphasized that in our study many of the MCDs were not depicted by either ultrasound or MRI and were only demonstrated by the microscopic pathology examination. This observation may suggest the limitations of classifications based on neuroimaging. It may also be one of many reasons that explain the frequent occurrence of mental retardation with an apparently normal MRI. In conclusion, MCDs may be depicted by ultrasound starting at midgestation, and can present with different sulcal and gyral patterns that may be associated with specific diagnoses. The importance of the pathological examination should be highlighted since autopsy provides additional, unsuspected information and in some cases even enables one to reach specific diagnoses and provide accurate parental counseling.
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