Prenatal diagnosis of malformations of cortical development by dedicated neurosonography

Authors

  • G. Malinger,

    Corresponding author
    1. Fetal Neurology Clinic, Wolfson Medical Center, Holon, Israel
    2. Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, Israel
    3. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    • Department of Gynecology & Obstetrics, E. Wolfson Medical Center, Holon 58100, Israel
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  • D. Kidron,

    1. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    2. Department of Pathology, Sapir Medical Center, Kfar-Saba, Israel
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  • L. Schreiber,

    1. Fetal Neurology Clinic, Wolfson Medical Center, Holon, Israel
    2. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    3. Department of Pathology, Wolfson Medical Center, Holon, Israel
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  • L. Ben-Sira,

    1. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    2. Pediatric Radiology Unit, Sourasky Medical Center, Tel Aviv and Neuroradiology Unit, Sheba Medical Center, Tel-Hashomer, Israel
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  • C. Hoffmann,

    1. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • D. Lev,

    1. Fetal Neurology Clinic, Wolfson Medical Center, Holon, Israel
    2. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    3. Genetics Institute, Wolfson Medical Center, Holon, Israel
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  • T. Lerman-Sagie

    1. Fetal Neurology Clinic, Wolfson Medical Center, Holon, Israel
    2. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    3. Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel
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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.

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 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.

Table 1. Ultrasonographic findings
CaseGA* (weeks)Indication for referralUltrasound CNS findingsLaterality & locationMain FNC diagnosisNon-CNS findingsFollow-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.

140Arachnoid cystFocal wide gyriUnilateralPachygyriaNoTOP
Periventricular bulgingLeft parieto-frontal  Autopsy
Atypical asymmetric ventricles 
Interhemispheric cyst 
233Suspected microcephalyAbnormal hyperechogenic gyriBilateralPossible ischemic insultAbnormal cranial shapeTOP
  S/P fetal reduction FrontalAbnormal sulcation Autopsy
327Mild ventriculomegaly (10 mm)Abnormal overdeveloped gyri and sulciBilateralComplex MCDAdducted thumbsTOP
ACCGeneralized  Autopsy
Cerebellar hypoplasia 
Abnormal general movements 
424Mild ventriculomegaly (12–13 mm)Smooth thin irregular cortexBilateralLissencephalyNoTOP
Mild ventriculomegalyGeneralized  Autopsy
Dysgenesis of corpus callosum 
Microcephaly 
Large subarachnoid spaces 
522ACCAbnormal overdeveloped gyri and sulciUnilateralHemimegalencephalyNoTOP
ACCGeneralized  Autopsy
Vermian hypoplasia 
625Multiple malformationsSmooth cortexBilateralLissencephalyHydrops fetalisTOP
VentriculomegalyGeneralized Severe growth restrictionAutopsy
Microcephaly  Overriding sutures 
ACC  Skeletal dysplasia 
Dandy–Walker malformation 
725Atypical asymmetric ventriclesAbnormal overdeveloped gyri and sulciUnilateralHemimegalencephalyNoTOP
Asymmetric ventriculomegalyGeneralized  Autopsy
Abnormal periventricular tissue 
Periventricular pseudocyst 
822Multiple malformationsAbnormal overdeveloped gyri and sulciBilateralComplex MCDDysplastic kidneys, megacystisTOP
Partial ACCGeneralized Short bowed bonesAutopsy
Vermian agenesis  Hydrops fetalis 
929Mild ventriculomegaly (13 mm)Abnormal broad sulciBilateralMCDNoTOP
Mild ventriculomegalyParieto-occipital  Autopsy
Large extra axial spaces 
Abnormal periventricular tissue 
1024ACCAbnormal overdeveloped gyri and sulciBilateralHemimegalencephalyNoTOP
Mild ventriculomeglyGeneralized  No autopsy
ACC 
Vermian dysgenesis 
Large extra axial spaces 
1118Suspected interhemispheric cystAbnormal overdeveloped gyri and sulci (right)UnilateralHemimegalencephalyNoTOP
Multiple periventricular cystsGeneralized  No autopsy
Abnormal hemispheric echogenicity 
Abnormal periventicular tissue 
Interhemispheric cyst 
1225Familial history of agyria-pachygyriaDelayed sulcation (2–3 weeks)BilateralAgyriaLarge echogenic kidneysTOP
Abnormal periventricular tissueGeneralized Club footAutopsy
Large extra axial spaces  Polyhydramnios 
   Short femur 
1326Agenesis septum pellucidumSchizencephalyBilateral NoTOP
Agenesis septum pellucidumFrontal  Autopsy
1423Microcephaly; twinsThin cortexBilateralLissencephalyLeft hypoplastic heartDelivered
MicrocephalyGeneralized  US confirmation
    Neonatal death
1524Skeletal dysplasiaAbnormal overdeveloped sulci and gyriBilateralMCDLethal skeletal dysplasiaTOP
Cerebellar hypoplasiaOccipital  Autopsy
Abnormal echogenicity of vermis 
1629Mild asymmetric ventriculomegalyWide, abnormal gyriBilateralPachygyriaNoTOP
Mild asymmetric ventriculomegalyGeneralized  Autopsy
Macrocephaly 
Thick, echogenic corpus callosum 3rd ventricle dilatation 
Large extra axial spaces 
1731IUGRDelayed sulcationBilateralPossible prenatal insultNoTOP
Periventricular cysts (3) leftGeneralizedLissencephaly Autopsy
Periventricular echogenicity 
1826ACCDelayed sulcationBilateralLissencephalyNoTOP
ACC, colpocephalyGeneralized  Autopsy
Interhemispheric cyst 
Dysgenesis of vermis 
1922ACCPeriventricular bulgingUnilateralPeriventricular heterotopiaNoTOP
ACCGeneralized  Autopsy
Interhemispheric cyst 
Periventricular cyst 
2029Partial ACCDelayed sulcationBilateralSuspected Walker–WarburgNoDelivered
Inferior vermian agenesis Generalized  Neonatal death
Ventriculomegaly  
Abnormal periventricular tissue 
Abnormal brain stem  
Interhemispheric cyst  
2122VentriculomegalyDelayed sulcationBilateralMCDHypotelorismDelivered
Agenesis septum pellucidumParieto-occipital  Epilepsy
Abnormal general movements   Mental retardation
2231Varix of umbilical veinSmooth cortexBilateralLissencephalyVarix of umbilical veinDelivered
Large 3rd ventricleCerebellar hypoplasiaGeneralized  US confirmation
PolyhydramniosLarge extra axial spaces   Neonatal death
TwinsIncipient microcephaly 
2326Cardiac rhabdomyomasParenchymal echogenic nodulesBilateralTuberous sclerosisCardiac rhabdomyomasTOP
Periventricular echogenic nodulesGeneralized  Autopsy

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.

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).

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) trans- vaginal 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 demar- cation between the cortex (C) and leptomeninges (L). (H & E stain, original magnification ×100).

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.

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.

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 schizence- phaly at 26 weeks' gestation (Case 13); (b) transvaginal ultra- sound 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.

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).

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.

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 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.

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.

Table 2. Pathological findings
CaseGA at TOP (weeks)Weight (g)SexMain diagnosisLaterality & locationOther CNS findingsNon-CNS findingsNeoplasms
  1. 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.

140375046XYPeriventricular heterotopia with PMGUnilateralPeriventricular heterotopiaNoNo
 Left frontoparietalUnilateral ventriculomegaly  
 Focal polymicrogyria  
Neuronal bulging into pia mater  
White matter gliosis  
Interhemispheric arachnoid cyst  
235203046XYMultiple nodular cortical heterotopia with PMGBilateralFocal polymicrogyriaBroad flat nasal bridgeNo
 GeneralizedFocal white matter heterotopiaSloping forehead 
  Brachycephaly 
3291340MaleCortical dysplasia unclassifiedBilateralAbnormal overdeveloped sulci; left more than rightNoNo
 Frontoparietal   
 ACC  
Colpocephaly  
Focal cerebellar dysplasia  
Focal polymicrogyria  
White matter heterotopia  
42679046XXCobblestone lissencephalyBilateralMicrocephalyRetinal dysplasiaNo
    Walker–Warburg syndromeGeneralizedMild ventriculomegalyMuscular dystrophy 
 Short corpus callosumRenal dysplasia 
Focal polymicrogyriaSubendocardial hypertrophy 
Focal white matter heterotopia  
Neuronal bulging into pia mater  
Cerebellar dysplasia  
Hypoplasia of pyramidal tracts  
522620FemaleOrofaciodigital syndromeBilateralAbnormal overdeveloped sulci and gyriPreaxial polydactylyNo
 Left more than rightUnlayered cortex, heterotopiaSyndactyly 
GeneralizedACCCleft lip 
 Vermian hypoplasiaHypertelorism 
Multifocal polymicrogyria  
62768046XXUnclassified multiple malformation syndromeBilateralVentriculomegalyIUGRNo
 GeneralizedThin unlayered cortex (bilateral)Hydrops fetalis 
 MicrocephalySkeletal dysplasia 
Focal cortical heterotopia (unclassified) 
Nodular laminar WM heterotopiaBrachydactyly 
Focal neuronal bulging into pia materFacial dysmorphism 
ACCLung hypoplasia 
Cerebellar hypoplasiaAdrenal hypoplasia 
Cerebellar white matter heterotopiaAtrophy of skeletal muscle 
Cerebellar dysplasia  
Hypoplasia of pyramidal tracts  
732213046XXOrofaciodigital syndromeBilateralAbnormal overdeveloped sulci and gyriRetinal dyplasiaBasaloid follicular hamartomas of skin
 Left more than rightAsymmetric ventriculomegalyIntestinal malrotation 
GeneralizedCortical heterotopiaFour-leaflet pulmonary valveNeuromuscular hamartomas: gastrointestinal muscularis, mesentery, spleen
 Focal polymicrogyriaPreaxial polydactyly 
Focal white matter heterotopiaSyndactyly 
Thin CCAsymmetric skull (base) 
Focal cerebellar heterotopiasCleft lip 
822850MaleUnclassified multiple malformation syndromeBilateralAbnormal overdeveloped sulci and gyriMDK, megacystisAdrenal neuroblastoma
 GeneralizedLaminar WM heterotopiaShort bowed bones 
 Multifocal polymicrogyriaHypoplastic lungs 
Partial ACCHydrops fetalis 
Vermian agenesisCleft lip 
935230046XXUnclassified multiple malformation syndromeBilateralMild ventriculomegalyNoChondromatous hamartoma of lung bilateral peripheral
 Parieto-occipitalAbnormal broad sulci  
 Laminar WM heterotopia  
Multifocal polymicrogyria  
Dysplastic corpus callosum  
Cerebellar dysplasia  
Vermian dysplasia  
1226104046XXNormal cortex Large CSPOrganomegaly (liver, adrenals, kidney, tongue)No
 Milky CSF  
Large choroid plexus cellsClub foot 
 Postaxial polydactyly 
1326113946XXSchizencephalyBilateralAgenesis septum pellucidumNoNo
 FrontalAsymmetric cerebral hemispheres  
 Abnormal overdeveloped gyri  
Focal polymicrogyria parietotemporal  
Neuronal heterotopia  
152454446XXAbnormal sulci and gyriBilateralFocal cortical dysplasiaThanatophoric dysplasiaNo
 Occipitotemporal   
1631197046XXNo histologyBilateralMacrocephalyFrontal bossingNo
 GeneralizedMRI findings similar to US findingsNasal depression 
1732139046XXmp fetal ischemiaBilateralMultiple cortical nodular heterotopiasPlacental floor fibrin thrombiNo
 GeneralizedFocal bilateral PMG, discontinuous cortexIntervillous thrombi 
 Periventricular germinal matrix cysts  
182667246XXLissencephalyBilateralACCFacial dysmorphismNo
 GeneralizedUnlayered cerebral cortex  
 Mild ventriculomegaly  
Hypoplastic vermis  
192355046XYHeterotopia with PMGBilateralACCNoNo
 Frontal   
2328136046XXTuberous sclerosisBilateralIntraparenchymal andNoCardiac rhabdomyomata
 Multifocalperiventricular tubers  

MCDs were confirmed in 15/16 fetuses, which were bilateral in 14 (in two patients the pathology examination 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 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, 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.

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 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 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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