Original Paper Fetal Diagn Ther 2015;37:241–248 DOI: 10.1159/000366159
Received: May 5, 2014 Accepted after revision: July 25, 2014 Published online: October 29, 2014
Prenatal Imaging of Occipital Encephaloceles Gregor J. Kasprian a Michael J. Paldino b, d Amy R. Mehollin-Ray b, d Anil Shetty c, e Jennifer L. Williams b, d Wesley Lee c, e Chris I. Cassady b, d a
Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria; Departments of b Radiology and c Obstetrics and Gynecology, Baylor College of Medicine, d E.B. Singleton Department of Pediatric Radiology, Texas Children’s Hospital, and e Texas Children’s Pavilion for Women, Houston, Tex., USA
Abstract Introduction: This retrospective study aims to describe systematically the fetal cerebral MR morphology in cases with occipital meningoencephaloceles using standard and advanced fetal MRI techniques. Material and Methods: The 1.5-tesla MR examinations (T1- and T2-weighted imaging, echo planar imaging, EPI, diffusion-weighted imaging, DWI) of 14 fetuses with occipital/parietal meningoencephaloceles were retrospectively analyzed for the classification of anatomic characteristics. A diffusion tensor sequence was performed in 5 cases. Results: In 9/14 cases the occipital lobes were entirely or partially included in the encephalocele sac. Typical features of Chiari III malformation were seen in 6/14 cases. The displaced brain appeared grossly disorganized in 6/14. The brainstem displayed abnormal ‘kinking’/rotation (3/14), a z-shape (1/14) and/or a molar tooth-like configuration of the midbrain (3/14). Tractography revealed the presence and position of sensorimotor tracts in 5/5 and the corpus callosum in 3/5. DWI was helpful in the identification of a displaced brain (in 8/9). EPI visualized the anatomy of draining cerebral veins in 7/9 cases. Clinical (9/14) and MRI (7/14) follow-up data are presented. Discussion: Encephaloceles show a wide range of morphological heterogeneity. Fetal MRI serves as an accurate tool in the visualization of
© 2014 S. Karger AG, Basel 1015–3837/14/0373–0241$39.50/0 E-Mail [email protected] www.karger.com/fdt
brainstem, white matter pathway and cerebral venous involvement and facilitates the detection of specific underlying syndromes such as ciliopathies. © 2014 S. Karger AG, Basel
Introduction
Encephaloceles are congenital malformations of the central nervous system characterized by the protrusion of meninges and cerebral tissue through a bony defect of the skull. Although their true embryological etiology remains unclear [1], (meningo-)encephaloceles are currently classified as rare neural tube defects with a prevalence of 0.8–5 per 10,000 live births [2]. The sociodemographic characteristics of patients with encephaloceles share many commonalities with patients with spinal dysraphism and anencephaly [3]. In Europe and the USA, encephaloceles are most frequently located occipitally (2/3 cases); frontal, temporal and parietal locations are less common [3]. Associated cerebral and extracentral nervous system anomalies are found in a significant number of cases (20.5–60% depending on the examined patient cohort [2, 4]). When encephaloceles are detected prenatally, there is a need for detailed diagnostic assessment and characterization of a possible underlying syndrome [5]. The heterogeneity in their morphology and molecular pathology explains the variable outcome of fetuses with ocGregor Kasprian, MD Department of Biomedical Imaging and Image-Guided Therapy Medical University of Vienna, Währinger Gürtel 18–20 AT–1090 Vienna (Austria) E-Mail gregor.kasprian @ meduniwien.ac.at
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Key Words Diffusion tensor imaging · Joubert syndrome · Brain malformations · Ciliopathy · Fetal neurology
Material and Methods This study, which was compliant with the Health Insurance Portability and Accountability Act, was approved by the local institutional review board at Baylor College of Medicine. Patients were identified retrospectively from a search in the existing patient track record database of Texas Children’s hospital. Inclusion criteria included the following: (1) fetuses older than 18 gestational weeks (GW; gestational age was verified by biometry during the first sonographic examination and presented as postmenstrual age), (2) referral after abnormal ultrasound screening, (3) prenatal MR examinations between 2004 and 2013 and (4) cranial meningoceles or meningoencephaloceles in occipital or parietal location. Imaging Fetal MRI data were retrieved from 2 different 1.5-tesla MR systems. Examinations before the year 2011 were performed on a Philips Intera and those after 2011 on a Philips Ingenia MRI unit (Philips, Best, The Netherlands). On both systems, T2-weighted sequences were acquired in 3 orthogonal planes (TR/TE = 1,558/80 ms, resolution 1.09 × 1.1 × 4 mm, FOV = 280 mm). In 9 cases an axial echo planar sequence (echo planar imaging, EPI, TR/TE = 5,290/104 ms, resolution = 1.17 × 1.17 × 3 mm, FOV = 280) and in 10 cases an axial diffusion-weighted sequence (DWI, TR/TE = 2,007/84 ms, resolution = 2 × 2 × 5 mm, b-values of 0 and 700
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s/mm2) was available. In the most recent 5 cases, an axial diffusion tensor sequence (DTI, TR/TE = 2,189/60 ms, b-values of 0 and 700 s/mm2, resolution = 2 × 2 × 4 mm, 16 gradient-encoding directions, FOV = 230, scan time = 1 min 12 s) was also performed. Tractography was performed by a neuroradiologist with experience in fetal imaging (G.J.K.) using the provider-specific software (Philips Ingenia, version 4.1.2) and a deterministic approach with user-defined regions of interest and a linear tractography algorithm (thresholds: minimum angle change = 27°, minimum fractional anisotropy value = 0.1), as described elsewhere in further detail [11].
Results
A total of 14 cases with parietal and/or occipital meningoencephaloceles were identified – except for 1 case, which appeared to be a meningocele only (table 1; fig. 1–4). The mean fetal age at imaging was 26 + 3 GW. Clinical follow-up data is available for 9 patients (table 2). All cases were detected by prior ultrasound screening examinations. Except for the case with a meningocele only (fig. 2, case 13), 13 cases showed a variable degree of brain displacement (table 1). Diffusion-weighted sequences were particularly helpful in the detection of herniated brain tissue, which visualized the displaced brain structures with similar diffusivity to the normal-appearing nondisplaced brain parenchyma in 8/9 cases (fig. 5, 6). An exact anatomical description of displaced brain structures was possible in all cases. In 9/13 cases the occipital lobes were entirely or at least partially included in the encephalocele sac. In further detail, the displaced brain regions included the following: (1) the occipital poles (3/13), (2) the entirety of the occipital lobe (bilaterally 2/13, unilaterally 1/13), (3) both the parietal and occipital lobes (bilaterally 1/13, unilaterally 2/13), (4) the parietal lobe only (1/13) and (5) parts of the brainstem, the cerebellum and the temporal and occipital lobes bilaterally (2/13; table 1). In 1 case, only parts of the frontal lobes, medulla and pons were identified intracranially. The neural tissue of the encephalocele was grossly disorganized in 9/14 (fig. 1, 3, 4) and showed polymicrogyria in 1/14 cases. Hemorrhagic components were found in 3/14 cases. In 6/14 cases histology of the surgically resected encephalocele was available and confirmed the presence of polymicrogyria in 1 case. In 4 cases, histology revealed the presence of neuroglial heterotopia as correlate for the gross ‘disorganization’ visible at prenatal MRI (table 2). The typical features of the so-called ‘Chiari III malformations’ [12] (crowding of the posterior fossa, Kasprian/Paldino/Mehollin-Ray/Shetty/ Williams/Lee/Cassady
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cipital and parietal meningoencephaloceles. As a group, half of them will be unable to live and function independently in society [4, 6]. As the presence of associated intracranial pathologies, including brain malformations, is predictive for the cognitive outcome [6], imaging plays an important role in the diagnostic workup of these conditions and often serves as the primary basis for prenatal counseling. Up to 80% of meningoencephaloceles can be detected by sonography during the first trimester [7] and, depending on the geographic region, almost all cases are identified after the second-trimester scan [8]. A detailed neurosonographic examination offers a depiction of the bony skull defect and the size and morphology of the herniated meningeal and brain tissue. However, due to the extreme divergence from normal brain anatomy in these cases, some morphological findings, such as the presence or absence of neuronal migration disorders (subependymal heterotopia [9], polymicrogyria and brainstem abnormalities [10]) or the position of developing white matter pathways, may be difficult to visualize by ultrasound. Currently, there are very few fetal MRI data available on this subject. Hence, this study aimed to systematically describe the fetal cerebral MR morphology in cases with occipital and parietal meningoencephaloceles using standard and advanced (diffusion-weighted imaging, DWI, diffusion tensor imaging, DTI and susceptibility-weighted imaging) fetal MRI techniques.
Table 1. Pre- and postnatal imaging characteristics of encephalocele cases Patient GW Location Extracranial at MRI structures
Skull shape
Brainstem
Exteriorized brain tissue
Corpus callosum
Added information by postnatal MRI/CT
Polymicrogyria
Not assessable Polymicrogyria confirmed
1
28+6
Low Pons, midbrain, Flat forehead Not assessable occipital cerebellum, occipital, temporal lobes
2
22+4
Occipital Occipital lobes
3
20+5
Occipital All supratentorial Flat forehead, Kinking/rotation Disorganized structures, midbrain Chiari III
4
24+3
Occipital Occipital lobes, temporal lobes, midbrain, pons, cerebellum
Flat forehead, Kinking/rotation Relatively organized, not Not assessable Chiari III normal
5
19+5
Occipital Occipital pole
Normal
Posteriorly displaced
Disorganized, Complete hemorrhage/calcification
6
25+5
Occipital Unilateral parietal and occipital lobe
Normal
Normal
Disorganized, Complete hemorrhage/calcification
7
28+5
Low Occipital pole occipital
Normal
Molar tooth sign, Meningocele medullary thickening
8
30+5
Occipital Occipital lobes
Normal, no eCSF
Normal
Disorganized, Not assessable hemorrhage/calcification
9
27
Parietal
Parietal lobe
Normal, no eCSF
Normal
Disorganized
Not assessable Added: exact extent of bony defect
10
18+6
Parietal
Unilateral parietal and occipital lobe
Chiari III
Normal
Disorganized
Not assessable Sinus tract, hemorrhagic transformation confirmed; added: normal corpus callosum
11
19+6
Occipital Occipital pole
Chiari III
Kinking, molar tooth-like midbrain
Disorganized
Not fully Added: bilateral assessable, polymicrogyria, dysplastic anterior there corpus callosum; confirmed: z-shaped brainstem, molar tooth-like midbrain
12
24+1
Low Occipital lobes occipital
Chiari III
Kinking, molar tooth-like midbrain
Disorganized
Complete
13
28+4
Occipital Meningocele
Normal
Normal
No brain tissue
Complete
14
27
Occipital Occipital pole
Chiari III
Normal
Disorganized
Not assessable
Flat forehead, Kinking/rotation Disorganized, Not assessable Chiari III hemorrhage/calcification Not assessable
Complete
Added: vascular anatomy clarified/confirmed, no calcification Molar tooth, polymicrogyria confirmed
Changed: no occipital lobes herniated, cerebellum displaced
‘lemon sign’, vermian displacement) were seen in 6/14 cases (table 1), whereas 4/14 cases showed no ‘lemon sign’ but isolated diminution of external CSF spaces. MRI was able to reveal an exact morphological description of the brainstem configuration, showing an abnormal morphology in 5/14 cases (3/14 showed an
abnormal ‘kinking’/rotation; fig. 1). An unequivocal molar tooth sign was seen in 1 case (fig. 2), whereas 2 other cases showed a molar tooth-like configuration of the midbrain (fig. 5, 6); in 1 of these (case 11, with a z-shaped brainstem) the final diagnosis of WalkerWarburg syndrome was established by gene sequenc-
Encephalocele Imaging
Fetal Diagn Ther 2015;37:241–248 DOI: 10.1159/000366159
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Chiari III configuration includes the following features: hypoplastic posterior fossa, vermian displacement and ‘lemon sign’ [19]. eCSF = External CSF spaces.
Color version available online
Fig. 1. Giant occipital encephalocele at 28 GW: DTI tractography
Fig. 2. Suboccipital meningocele and molar tooth sign (for further details, see tables 1, 2; patient 7).
Color version available online
displays abnormal corticocerebellar and spinal tract connectivity (green) and part of the corpus callosum (blue).
Fig. 3. Tractography depicts anisotropic
tissue characteristics (yellow) of the encephalocele at 22 GW and posterior distortion of the brainstem, which is confirmed by postnatal MRI (patient 2). Note the dysplastic appearance of the displaced brain tissue. At the age of 4 months, postnatal follow-up showed cortical blindness and reduced reaction to pain/sensory stimuli.
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tractography, whereas conventional sequences failed to visualize this structure unequivocally (fig. 3). In 3/5 cases massive fronto-occipitally oriented tracts connected the displaced extracranial with the intracranial brain tissue (fig. 1, 3). (2)EPI deoxyhemoglobin-sensitive sequences were the only sequences to visualize the detailed vascular anatomy of the draining cerebral veins in 7/9 cases (fig. 4). Kasprian/Paldino/Mehollin-Ray/Shetty/ Williams/Lee/Cassady
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ing. In none of the clinically followed cases did chromosomal microarray reveal positive results (table 2). In addition to conventional DWI, 2 other advanced fetal MR methods were helpful in a more detailed characterization of the encephalocele cases: (1)DTI-based tractography revealed the presence and position of sensorimotor tracts in 5/5 cases (fig. 1, 3). In 3/5 cases the corpus callosum could be identified by
quence depicts aberrant draining vein (postnatal MRI, lower row).
Postnatal MRI follow-up data were available in 7/14 cases. In 1/7 cases postnatal MRI confirmed the prenatal findings (confirmation of polymicrogyria) and in 4/7 additional morphological information was added (vascular anatomy – MRI, exclusion of calcification and extent of bony defect – CCT; fig. 6).
Discussion
Although postnatal MRI features of meningoencephaloceles have been systematically analyzed [12], prenatal MRI data of these defects are limited to rare case reports [13–22]. Due to the absence of systematically assessed imaging data, our confidence in predicting the neurological outcome in these cases is generally low. A mainly favorable outcome [23], in contrast to a major neurological disability or death, has been reported in more than half of the cases [4]. Therefore, this retrospective study aimed to describe the morphological features of occipital and parietal meningoencephaloceles using ‘standard’ fetal MR sequences and ‘advanced’ MRI techniques (DWI, EPI and DTI sequences). Encephalocele Imaging
Fetal Diagn Ther 2015;37:241–248 DOI: 10.1159/000366159
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Fig. 4. Parietooccipital encephalocele at 25 GW (patient 6). EPI se-
All examined cases had a bony skull defect with a varying degree of brain tissue displacement in common. In contradiction to the concept that some degenerative and dysplastic changes mainly occur during postnatal development, the externalized brain tissue of all prenatally examined cases displayed abnormal cortical folding (‘polymicrogyria’) patterns and/or degenerative changes such as calcification and hemorrhage (table 2; fig. 2, 4–6). Despite these common features, we also observed a remarkable morphological heterogeneity. First, there was diversity in the grade of involvement of certain brain structures and laterality of the displaced anatomical brain regions. Second, the appearance of the brainstem was found to be different. Third, the shape of the skull and width of external CSF spaces was variable (table 1). Fourth, the morphology of the corpus callosum was heterogeneous amongst the included cases. Pathological anatomical heterogeneity of this developmental pathology has been reported before. Obviously, the occipital lobes are found to be most frequently displaced, whereas the encephalocele rarely includes the pons and medulla [12]. In our series, the herniation of brainstem structures into the encephalocele sac was always associated with the displacement of a major portion of the forebrain (the entire occipital lobes and parts of the temporal lobes; fig. 1) and thus indicated the most severe expression of the encephalocele spectrum with generally very limited viability [24]. The commonly used terms ‘giant,’ ‘large’ or ‘massive’ encephalocele [25] exclusively refer to the size of the encephalocele sac and not to its content. With regard to the prognostic assessment of these extreme cases, a larger sample size will be needed to show whether brainstem displacement rather than size is the most important marker of lethality. Our experience supports the concept that the characterization of ‘atypical’ brainstem morphologies allows the classification of encephalocele cases (fig. 2, 5, 6), especially before 24 GW when associated malformations of cortical (forebrain) development have not yet fully found their morphological expression [26]. Due to the strength of fetal MRI in visualizing the brainstem and cerebellar anatomy, this imaging modality is especially helpful in accomplishing this task [21]. The brainstem was abnormally developed in more than one third of our patients. In cases with large herniation, the brainstem was bent posteriorly, leading to an atypical ‘kink’ between the midbrain and the diencephalon as well as between the medulla and the brainstem (fig. 1, 3). This configuration has to be discriminated from the ‘kinked’ and z-shaped configuration of the brainstem, which was found in 1 case
Fig. 5. Patient 11 with ‘kinking’ and a molar tooth-like configuration of the midbrain at 19 GW. DWI shows diffusion-restricted brain tissue within the encephalocele (arrowheads).
Table 2. Clinical follow-up characteristics of 9 patients with encephaloceles Patient Age at follow-up
Seizures Shunt Respiratory Other clinical features
2
4 months
–
3
Death at 2 days
6
2 months
7
Death at 3 months
9
7 years
+
10
7 years
11
Pathology (autopsy/resected specimen)
Normal
Optic nerve hypoplasia, cortically Negative CMA blind, feeding difficulties, developmental delay
Apnea at day 2
Postnatal agonal breathing, acrocyanosis
Normal
Hearing loss, hemiplegia, delayed Negative CMA Oligo developmental milestones v9.1
Mild cortical dysplasia characterized by neuronal dropout, accentuation of the microcolumnar architecture and dyslamination
Respirator dependent
Panhypopituitarism, suspected Joubert-Boltshauser syndrome
Negative CMA Oligo v8.1
Microcephaly, vermian hypoplasia, dysplastic arcuate nucleus, disorganized spinal cord, occipitocervical encephalocele, polymicrogyria, cortical microdysgenesis
+
Normal
Speaks in fragmented sentences, abnormal gait
Negative CMA Oligo v8.1
Fairly well-organized brain tissue including a portion of hippocampal tissue, subarachnoid neuroglial heterotopia
–
+
Normal
Vision abnormalities, mild optic atrophy, no focal neurological findings
n.a.
Well-organized neural parenchyma, leptomeningeal fibrosis and leptomeningeal glioneuronal heterotopia
6 months
+
+
Global developmental delay, Frequent quadriplegia, persistent apneas, long-term hyperplastic primary vitreous respirator dependency
Negative CMA Oligo Subcutaneous tissue with nodules of v9.1; Walker-Warburg neuroglial tissue syndrome (whole exome sequencing)
12
2 years
+
+
Normal
Negative CMA Oligo v8.1
Subcutaneous tissue with dense collagenous tissue containing islands and trabeculae of heterotopic neuroglial and folia of immature cerebellar tissue
14
Intrapartum fetal demise
n.a.
n.a.
+
–
Genetics
+
Global developmental delay, retching, inconsistent tracking, no progress
n.a.
Negative MaterniT21 Autopsy refused results
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CMA = Chromosomal microarray; n.a. = not available.
with genetically proven Walker-Warburg syndrome (fig. 5, 6; tables 1, 2). Moreover, 1 of our presented cases (patient 7) displayed the characteristic molar tooth sign [26, 27] as a typical morphological feature of Joubert syndrome. The molar tooth sign consists of an abnormally deep cleft in the isthmus of the brainstem (pontomesencephalic junction), thickened and reoriented superior cerebellar peduncles and vermian hypoplasia [27] (fig. 2). The frequent association of occipital meningoencephaloceles with the Joubert syndrome and its related disorders, such as the Meckel-Gruber syndrome and cases of tectocerebellar dysraphism [28], has well been recognized by imaging studies [29] and genetic analyses [30]. As the Joubert and Walker-Warburg syndromes have a recurrence risk of 25% [31], their detection is important for further parental counseling. Fetal MRI nowadays does not only provide T2-weighted structural information – optimized high-resolution fetal DWI sequences allowed the detection of small volumes of herniated brain tissue within an encephalocele sac. This allows the discrimination between pure meningoceles and meningoencephaloceles (fig. 5, 6), which may be difficult by ultrasound [19] and further helps to identify rare cases of atretic encephaloceles [32]. DTI provides directional information on tissue water motion. This orientational information is used by the technique of tractography to visualize the local geometry of the examined structure in 3D. Due to the vastly altered intracranial anatomy of the forebrain in encephaloceles, the morphology of white matter tracts cannot be adequately assessed by conventional T2-weighted sequences. In cases of encephaloceles, DTI allowed the identification of the position of the sensory and motor tracts and the morphology of the corpus callosum in 3D (fig. 1, 3). Thus, callosal agenesis as a frequently associated pathology could be reliably excluded [33]. Moreover, DTI indirectly Encephalocele Imaging
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Fig. 6. Postnatal brain MRI of patient 11, confirming encephalocele of the occipital pole and the brainstem configuration and additionally showing bilateral polymicrogyria of the basal temporal lobes.
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5 Thompson DN: Postnatal management and outcome for neural tube defects including spina bifida and encephalocoeles. Prenat Diagn 2009;29:412–419. 6 Lo BW, Kulkarni AV, Rutka JT, Jea A, Drake JM, Lamberti-Pasculli M, Dirks PB, Thabane L: Clinical predictors of developmental outcome in patients with cephaloceles. J Neurosurg Pediatr 2008;2:254–257. 7 Cameron M, Moran P: Prenatal screening and diagnosis of neural tube defects. Prenat Diagn 2009;29:402–411. 8 Boyd PA, Wellesley DG, De Walle HE, Tenconi R, Garcia-Minaur S, Zandwijken GR, Stoll C, Clementi M: Evaluation of the prenatal diagnosis of neural tube defects by fetal ultrasonographic examination in different centres across Europe. J Med Screen 2000;7:169–174. 9 Roelens FA, Barth PG, van der Harten JJ: Subependymal nodular heterotopia in patients with encephalocele. Eur J Paediatr Neurol 1999;3:59–63. 10 Glenn OA, Cuneo AA, Barkovich AJ, Hashemi Z, Bartha AI, Xu D: Malformations of cortical development: diagnostic accuracy of fetal MR imaging. Radiology 2012;263:843–855. 11 Kasprian G, Brugger PC, Weber M, Krssak M, Krampl E, Herold C, Prayer D: In utero tractography of fetal white matter development. Neuroimage 2008;43:213–224. 12 Castillo M, Quencer RM, Dominguez R: Chiari III malformation: imaging features. AJNR Am J Neuroradiol 1992;13:107–113. 13 Budorick NE, Pretorius DH, McGahan JP, Grafe MR, James HE, Slivka J: Cephalocele detection in utero: sonographic and clinical features. Ultrasound Obstet Gynecol 1995; 5: 77–85. 14 Lee R, Tai KS, Cheng PW, Lui WM, Chan FL: Chiari III malformation: antenatal MRI diagnosis. Clin Radiol 2002;57:759–761. 15 Smith AB, Gupta N, Otto C, Glenn OA: Diagnosis of Chiari III malformation by second trimester fetal MRI with postnatal MRI and CT correlation. Pediatr Radiol 2007;37:1035– 1038.
Received: May 5, 2014 Accepted after revision: July 25, 2014 Published online: October 29, 2014
Prenatal Imaging of Occipital Encephaloceles Gregor J. Kasprian a Michael J. Paldino b, d Amy R. Mehollin-Ray b, d Anil Shetty c, e Jennifer L. Williams b, d Wesley Lee c, e Chris I. Cassady b, d a
Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria; Departments of b Radiology and c Obstetrics and Gynecology, Baylor College of Medicine, d E.B. Singleton Department of Pediatric Radiology, Texas Children’s Hospital, and e Texas Children’s Pavilion for Women, Houston, Tex., USA
Abstract Introduction: This retrospective study aims to describe systematically the fetal cerebral MR morphology in cases with occipital meningoencephaloceles using standard and advanced fetal MRI techniques. Material and Methods: The 1.5-tesla MR examinations (T1- and T2-weighted imaging, echo planar imaging, EPI, diffusion-weighted imaging, DWI) of 14 fetuses with occipital/parietal meningoencephaloceles were retrospectively analyzed for the classification of anatomic characteristics. A diffusion tensor sequence was performed in 5 cases. Results: In 9/14 cases the occipital lobes were entirely or partially included in the encephalocele sac. Typical features of Chiari III malformation were seen in 6/14 cases. The displaced brain appeared grossly disorganized in 6/14. The brainstem displayed abnormal ‘kinking’/rotation (3/14), a z-shape (1/14) and/or a molar tooth-like configuration of the midbrain (3/14). Tractography revealed the presence and position of sensorimotor tracts in 5/5 and the corpus callosum in 3/5. DWI was helpful in the identification of a displaced brain (in 8/9). EPI visualized the anatomy of draining cerebral veins in 7/9 cases. Clinical (9/14) and MRI (7/14) follow-up data are presented. Discussion: Encephaloceles show a wide range of morphological heterogeneity. Fetal MRI serves as an accurate tool in the visualization of
© 2014 S. Karger AG, Basel 1015–3837/14/0373–0241$39.50/0 E-Mail [email protected] www.karger.com/fdt
brainstem, white matter pathway and cerebral venous involvement and facilitates the detection of specific underlying syndromes such as ciliopathies. © 2014 S. Karger AG, Basel
Introduction
Encephaloceles are congenital malformations of the central nervous system characterized by the protrusion of meninges and cerebral tissue through a bony defect of the skull. Although their true embryological etiology remains unclear [1], (meningo-)encephaloceles are currently classified as rare neural tube defects with a prevalence of 0.8–5 per 10,000 live births [2]. The sociodemographic characteristics of patients with encephaloceles share many commonalities with patients with spinal dysraphism and anencephaly [3]. In Europe and the USA, encephaloceles are most frequently located occipitally (2/3 cases); frontal, temporal and parietal locations are less common [3]. Associated cerebral and extracentral nervous system anomalies are found in a significant number of cases (20.5–60% depending on the examined patient cohort [2, 4]). When encephaloceles are detected prenatally, there is a need for detailed diagnostic assessment and characterization of a possible underlying syndrome [5]. The heterogeneity in their morphology and molecular pathology explains the variable outcome of fetuses with ocGregor Kasprian, MD Department of Biomedical Imaging and Image-Guided Therapy Medical University of Vienna, Währinger Gürtel 18–20 AT–1090 Vienna (Austria) E-Mail gregor.kasprian @ meduniwien.ac.at
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Key Words Diffusion tensor imaging · Joubert syndrome · Brain malformations · Ciliopathy · Fetal neurology
Material and Methods This study, which was compliant with the Health Insurance Portability and Accountability Act, was approved by the local institutional review board at Baylor College of Medicine. Patients were identified retrospectively from a search in the existing patient track record database of Texas Children’s hospital. Inclusion criteria included the following: (1) fetuses older than 18 gestational weeks (GW; gestational age was verified by biometry during the first sonographic examination and presented as postmenstrual age), (2) referral after abnormal ultrasound screening, (3) prenatal MR examinations between 2004 and 2013 and (4) cranial meningoceles or meningoencephaloceles in occipital or parietal location. Imaging Fetal MRI data were retrieved from 2 different 1.5-tesla MR systems. Examinations before the year 2011 were performed on a Philips Intera and those after 2011 on a Philips Ingenia MRI unit (Philips, Best, The Netherlands). On both systems, T2-weighted sequences were acquired in 3 orthogonal planes (TR/TE = 1,558/80 ms, resolution 1.09 × 1.1 × 4 mm, FOV = 280 mm). In 9 cases an axial echo planar sequence (echo planar imaging, EPI, TR/TE = 5,290/104 ms, resolution = 1.17 × 1.17 × 3 mm, FOV = 280) and in 10 cases an axial diffusion-weighted sequence (DWI, TR/TE = 2,007/84 ms, resolution = 2 × 2 × 5 mm, b-values of 0 and 700
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s/mm2) was available. In the most recent 5 cases, an axial diffusion tensor sequence (DTI, TR/TE = 2,189/60 ms, b-values of 0 and 700 s/mm2, resolution = 2 × 2 × 4 mm, 16 gradient-encoding directions, FOV = 230, scan time = 1 min 12 s) was also performed. Tractography was performed by a neuroradiologist with experience in fetal imaging (G.J.K.) using the provider-specific software (Philips Ingenia, version 4.1.2) and a deterministic approach with user-defined regions of interest and a linear tractography algorithm (thresholds: minimum angle change = 27°, minimum fractional anisotropy value = 0.1), as described elsewhere in further detail [11].
Results
A total of 14 cases with parietal and/or occipital meningoencephaloceles were identified – except for 1 case, which appeared to be a meningocele only (table 1; fig. 1–4). The mean fetal age at imaging was 26 + 3 GW. Clinical follow-up data is available for 9 patients (table 2). All cases were detected by prior ultrasound screening examinations. Except for the case with a meningocele only (fig. 2, case 13), 13 cases showed a variable degree of brain displacement (table 1). Diffusion-weighted sequences were particularly helpful in the detection of herniated brain tissue, which visualized the displaced brain structures with similar diffusivity to the normal-appearing nondisplaced brain parenchyma in 8/9 cases (fig. 5, 6). An exact anatomical description of displaced brain structures was possible in all cases. In 9/13 cases the occipital lobes were entirely or at least partially included in the encephalocele sac. In further detail, the displaced brain regions included the following: (1) the occipital poles (3/13), (2) the entirety of the occipital lobe (bilaterally 2/13, unilaterally 1/13), (3) both the parietal and occipital lobes (bilaterally 1/13, unilaterally 2/13), (4) the parietal lobe only (1/13) and (5) parts of the brainstem, the cerebellum and the temporal and occipital lobes bilaterally (2/13; table 1). In 1 case, only parts of the frontal lobes, medulla and pons were identified intracranially. The neural tissue of the encephalocele was grossly disorganized in 9/14 (fig. 1, 3, 4) and showed polymicrogyria in 1/14 cases. Hemorrhagic components were found in 3/14 cases. In 6/14 cases histology of the surgically resected encephalocele was available and confirmed the presence of polymicrogyria in 1 case. In 4 cases, histology revealed the presence of neuroglial heterotopia as correlate for the gross ‘disorganization’ visible at prenatal MRI (table 2). The typical features of the so-called ‘Chiari III malformations’ [12] (crowding of the posterior fossa, Kasprian/Paldino/Mehollin-Ray/Shetty/ Williams/Lee/Cassady
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cipital and parietal meningoencephaloceles. As a group, half of them will be unable to live and function independently in society [4, 6]. As the presence of associated intracranial pathologies, including brain malformations, is predictive for the cognitive outcome [6], imaging plays an important role in the diagnostic workup of these conditions and often serves as the primary basis for prenatal counseling. Up to 80% of meningoencephaloceles can be detected by sonography during the first trimester [7] and, depending on the geographic region, almost all cases are identified after the second-trimester scan [8]. A detailed neurosonographic examination offers a depiction of the bony skull defect and the size and morphology of the herniated meningeal and brain tissue. However, due to the extreme divergence from normal brain anatomy in these cases, some morphological findings, such as the presence or absence of neuronal migration disorders (subependymal heterotopia [9], polymicrogyria and brainstem abnormalities [10]) or the position of developing white matter pathways, may be difficult to visualize by ultrasound. Currently, there are very few fetal MRI data available on this subject. Hence, this study aimed to systematically describe the fetal cerebral MR morphology in cases with occipital and parietal meningoencephaloceles using standard and advanced (diffusion-weighted imaging, DWI, diffusion tensor imaging, DTI and susceptibility-weighted imaging) fetal MRI techniques.
Table 1. Pre- and postnatal imaging characteristics of encephalocele cases Patient GW Location Extracranial at MRI structures
Skull shape
Brainstem
Exteriorized brain tissue
Corpus callosum
Added information by postnatal MRI/CT
Polymicrogyria
Not assessable Polymicrogyria confirmed
1
28+6
Low Pons, midbrain, Flat forehead Not assessable occipital cerebellum, occipital, temporal lobes
2
22+4
Occipital Occipital lobes
3
20+5
Occipital All supratentorial Flat forehead, Kinking/rotation Disorganized structures, midbrain Chiari III
4
24+3
Occipital Occipital lobes, temporal lobes, midbrain, pons, cerebellum
Flat forehead, Kinking/rotation Relatively organized, not Not assessable Chiari III normal
5
19+5
Occipital Occipital pole
Normal
Posteriorly displaced
Disorganized, Complete hemorrhage/calcification
6
25+5
Occipital Unilateral parietal and occipital lobe
Normal
Normal
Disorganized, Complete hemorrhage/calcification
7
28+5
Low Occipital pole occipital
Normal
Molar tooth sign, Meningocele medullary thickening
8
30+5
Occipital Occipital lobes
Normal, no eCSF
Normal
Disorganized, Not assessable hemorrhage/calcification
9
27
Parietal
Parietal lobe
Normal, no eCSF
Normal
Disorganized
Not assessable Added: exact extent of bony defect
10
18+6
Parietal
Unilateral parietal and occipital lobe
Chiari III
Normal
Disorganized
Not assessable Sinus tract, hemorrhagic transformation confirmed; added: normal corpus callosum
11
19+6
Occipital Occipital pole
Chiari III
Kinking, molar tooth-like midbrain
Disorganized
Not fully Added: bilateral assessable, polymicrogyria, dysplastic anterior there corpus callosum; confirmed: z-shaped brainstem, molar tooth-like midbrain
12
24+1
Low Occipital lobes occipital
Chiari III
Kinking, molar tooth-like midbrain
Disorganized
Complete
13
28+4
Occipital Meningocele
Normal
Normal
No brain tissue
Complete
14
27
Occipital Occipital pole
Chiari III
Normal
Disorganized
Not assessable
Flat forehead, Kinking/rotation Disorganized, Not assessable Chiari III hemorrhage/calcification Not assessable
Complete
Added: vascular anatomy clarified/confirmed, no calcification Molar tooth, polymicrogyria confirmed
Changed: no occipital lobes herniated, cerebellum displaced
‘lemon sign’, vermian displacement) were seen in 6/14 cases (table 1), whereas 4/14 cases showed no ‘lemon sign’ but isolated diminution of external CSF spaces. MRI was able to reveal an exact morphological description of the brainstem configuration, showing an abnormal morphology in 5/14 cases (3/14 showed an
abnormal ‘kinking’/rotation; fig. 1). An unequivocal molar tooth sign was seen in 1 case (fig. 2), whereas 2 other cases showed a molar tooth-like configuration of the midbrain (fig. 5, 6); in 1 of these (case 11, with a z-shaped brainstem) the final diagnosis of WalkerWarburg syndrome was established by gene sequenc-
Encephalocele Imaging
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Chiari III configuration includes the following features: hypoplastic posterior fossa, vermian displacement and ‘lemon sign’ [19]. eCSF = External CSF spaces.
Color version available online
Fig. 1. Giant occipital encephalocele at 28 GW: DTI tractography
Fig. 2. Suboccipital meningocele and molar tooth sign (for further details, see tables 1, 2; patient 7).
Color version available online
displays abnormal corticocerebellar and spinal tract connectivity (green) and part of the corpus callosum (blue).
Fig. 3. Tractography depicts anisotropic
tissue characteristics (yellow) of the encephalocele at 22 GW and posterior distortion of the brainstem, which is confirmed by postnatal MRI (patient 2). Note the dysplastic appearance of the displaced brain tissue. At the age of 4 months, postnatal follow-up showed cortical blindness and reduced reaction to pain/sensory stimuli.
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tractography, whereas conventional sequences failed to visualize this structure unequivocally (fig. 3). In 3/5 cases massive fronto-occipitally oriented tracts connected the displaced extracranial with the intracranial brain tissue (fig. 1, 3). (2)EPI deoxyhemoglobin-sensitive sequences were the only sequences to visualize the detailed vascular anatomy of the draining cerebral veins in 7/9 cases (fig. 4). Kasprian/Paldino/Mehollin-Ray/Shetty/ Williams/Lee/Cassady
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ing. In none of the clinically followed cases did chromosomal microarray reveal positive results (table 2). In addition to conventional DWI, 2 other advanced fetal MR methods were helpful in a more detailed characterization of the encephalocele cases: (1)DTI-based tractography revealed the presence and position of sensorimotor tracts in 5/5 cases (fig. 1, 3). In 3/5 cases the corpus callosum could be identified by
quence depicts aberrant draining vein (postnatal MRI, lower row).
Postnatal MRI follow-up data were available in 7/14 cases. In 1/7 cases postnatal MRI confirmed the prenatal findings (confirmation of polymicrogyria) and in 4/7 additional morphological information was added (vascular anatomy – MRI, exclusion of calcification and extent of bony defect – CCT; fig. 6).
Discussion
Although postnatal MRI features of meningoencephaloceles have been systematically analyzed [12], prenatal MRI data of these defects are limited to rare case reports [13–22]. Due to the absence of systematically assessed imaging data, our confidence in predicting the neurological outcome in these cases is generally low. A mainly favorable outcome [23], in contrast to a major neurological disability or death, has been reported in more than half of the cases [4]. Therefore, this retrospective study aimed to describe the morphological features of occipital and parietal meningoencephaloceles using ‘standard’ fetal MR sequences and ‘advanced’ MRI techniques (DWI, EPI and DTI sequences). Encephalocele Imaging
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Fig. 4. Parietooccipital encephalocele at 25 GW (patient 6). EPI se-
All examined cases had a bony skull defect with a varying degree of brain tissue displacement in common. In contradiction to the concept that some degenerative and dysplastic changes mainly occur during postnatal development, the externalized brain tissue of all prenatally examined cases displayed abnormal cortical folding (‘polymicrogyria’) patterns and/or degenerative changes such as calcification and hemorrhage (table 2; fig. 2, 4–6). Despite these common features, we also observed a remarkable morphological heterogeneity. First, there was diversity in the grade of involvement of certain brain structures and laterality of the displaced anatomical brain regions. Second, the appearance of the brainstem was found to be different. Third, the shape of the skull and width of external CSF spaces was variable (table 1). Fourth, the morphology of the corpus callosum was heterogeneous amongst the included cases. Pathological anatomical heterogeneity of this developmental pathology has been reported before. Obviously, the occipital lobes are found to be most frequently displaced, whereas the encephalocele rarely includes the pons and medulla [12]. In our series, the herniation of brainstem structures into the encephalocele sac was always associated with the displacement of a major portion of the forebrain (the entire occipital lobes and parts of the temporal lobes; fig. 1) and thus indicated the most severe expression of the encephalocele spectrum with generally very limited viability [24]. The commonly used terms ‘giant,’ ‘large’ or ‘massive’ encephalocele [25] exclusively refer to the size of the encephalocele sac and not to its content. With regard to the prognostic assessment of these extreme cases, a larger sample size will be needed to show whether brainstem displacement rather than size is the most important marker of lethality. Our experience supports the concept that the characterization of ‘atypical’ brainstem morphologies allows the classification of encephalocele cases (fig. 2, 5, 6), especially before 24 GW when associated malformations of cortical (forebrain) development have not yet fully found their morphological expression [26]. Due to the strength of fetal MRI in visualizing the brainstem and cerebellar anatomy, this imaging modality is especially helpful in accomplishing this task [21]. The brainstem was abnormally developed in more than one third of our patients. In cases with large herniation, the brainstem was bent posteriorly, leading to an atypical ‘kink’ between the midbrain and the diencephalon as well as between the medulla and the brainstem (fig. 1, 3). This configuration has to be discriminated from the ‘kinked’ and z-shaped configuration of the brainstem, which was found in 1 case
Fig. 5. Patient 11 with ‘kinking’ and a molar tooth-like configuration of the midbrain at 19 GW. DWI shows diffusion-restricted brain tissue within the encephalocele (arrowheads).
Table 2. Clinical follow-up characteristics of 9 patients with encephaloceles Patient Age at follow-up
Seizures Shunt Respiratory Other clinical features
2
4 months
–
3
Death at 2 days
6
2 months
7
Death at 3 months
9
7 years
+
10
7 years
11
Pathology (autopsy/resected specimen)
Normal
Optic nerve hypoplasia, cortically Negative CMA blind, feeding difficulties, developmental delay
Apnea at day 2
Postnatal agonal breathing, acrocyanosis
Normal
Hearing loss, hemiplegia, delayed Negative CMA Oligo developmental milestones v9.1
Mild cortical dysplasia characterized by neuronal dropout, accentuation of the microcolumnar architecture and dyslamination
Respirator dependent
Panhypopituitarism, suspected Joubert-Boltshauser syndrome
Negative CMA Oligo v8.1
Microcephaly, vermian hypoplasia, dysplastic arcuate nucleus, disorganized spinal cord, occipitocervical encephalocele, polymicrogyria, cortical microdysgenesis
+
Normal
Speaks in fragmented sentences, abnormal gait
Negative CMA Oligo v8.1
Fairly well-organized brain tissue including a portion of hippocampal tissue, subarachnoid neuroglial heterotopia
–
+
Normal
Vision abnormalities, mild optic atrophy, no focal neurological findings
n.a.
Well-organized neural parenchyma, leptomeningeal fibrosis and leptomeningeal glioneuronal heterotopia
6 months
+
+
Global developmental delay, Frequent quadriplegia, persistent apneas, long-term hyperplastic primary vitreous respirator dependency
Negative CMA Oligo Subcutaneous tissue with nodules of v9.1; Walker-Warburg neuroglial tissue syndrome (whole exome sequencing)
12
2 years
+
+
Normal
Negative CMA Oligo v8.1
Subcutaneous tissue with dense collagenous tissue containing islands and trabeculae of heterotopic neuroglial and folia of immature cerebellar tissue
14
Intrapartum fetal demise
n.a.
n.a.
+
–
Genetics
+
Global developmental delay, retching, inconsistent tracking, no progress
n.a.
Negative MaterniT21 Autopsy refused results
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CMA = Chromosomal microarray; n.a. = not available.
with genetically proven Walker-Warburg syndrome (fig. 5, 6; tables 1, 2). Moreover, 1 of our presented cases (patient 7) displayed the characteristic molar tooth sign [26, 27] as a typical morphological feature of Joubert syndrome. The molar tooth sign consists of an abnormally deep cleft in the isthmus of the brainstem (pontomesencephalic junction), thickened and reoriented superior cerebellar peduncles and vermian hypoplasia [27] (fig. 2). The frequent association of occipital meningoencephaloceles with the Joubert syndrome and its related disorders, such as the Meckel-Gruber syndrome and cases of tectocerebellar dysraphism [28], has well been recognized by imaging studies [29] and genetic analyses [30]. As the Joubert and Walker-Warburg syndromes have a recurrence risk of 25% [31], their detection is important for further parental counseling. Fetal MRI nowadays does not only provide T2-weighted structural information – optimized high-resolution fetal DWI sequences allowed the detection of small volumes of herniated brain tissue within an encephalocele sac. This allows the discrimination between pure meningoceles and meningoencephaloceles (fig. 5, 6), which may be difficult by ultrasound [19] and further helps to identify rare cases of atretic encephaloceles [32]. DTI provides directional information on tissue water motion. This orientational information is used by the technique of tractography to visualize the local geometry of the examined structure in 3D. Due to the vastly altered intracranial anatomy of the forebrain in encephaloceles, the morphology of white matter tracts cannot be adequately assessed by conventional T2-weighted sequences. In cases of encephaloceles, DTI allowed the identification of the position of the sensory and motor tracts and the morphology of the corpus callosum in 3D (fig. 1, 3). Thus, callosal agenesis as a frequently associated pathology could be reliably excluded [33]. Moreover, DTI indirectly Encephalocele Imaging
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Fig. 6. Postnatal brain MRI of patient 11, confirming encephalocele of the occipital pole and the brainstem configuration and additionally showing bilateral polymicrogyria of the basal temporal lobes.
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