Original Article
Hippocampal Abnormalities in Magnetic Resonance Imaging (MRI) of 15q Duplication Syndromes
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538669 jcn.sagepub.com
Susana Boronat, MD1,2, William A. Mehan, MD3, Elias A. Shaaya, BA1, Ronald L. Thibert, DO, MSPH1, and Paul Caruso, MD3
Abstract Patients with 15q duplication syndromes, including isodicentric chromosome 15 and interstitial duplications, usually present with autism spectrum disorder, intellectual disability, and frequently epilepsy. Neuroimaging studies in these patients are typically reported as normal, but nonspecific findings such as thinning of the corpus callosum and increased pericerebral spaces have been reported. A review of brain magnetic resonance imaging (MRI) studies of 11 individuals seen at the Massachusetts General Hospital Dup15q Center was performed. Hippocampus morphology was specifically reviewed, as a recent neuropathologic study has found frequent hippocampal heterotopias and dysplasias in these disorders. Two subjects had unilateral hippocampal sclerosis and 6 had bilateral hippocampal malformations. Hypoplasia of the corpus callosum was present in 2 subjects. Keywords CNV, duplication 15q11-q13, hippocampus, hippocampal malrotation, idic(15), neuroimaging, MR Received January 04, 2014. Received revised May 01, 2014. Accepted for publication May 14, 2014.
The 15q11-q13 region is prone to copy number variations, which may be due to the loss or gain of genes in this region. Part of the region is imprinted and its haploinsufficiency causes Angelman syndrome or Prader-Willi syndrome depending on parental origin. Maternal copy number gains of 15q11-q13, also known as 15q duplication syndromes (Dup15q), present with global developmental delay, intellectual disability, autism spectrum disorders, and epilepsy. The most frequent rearrangements are isodicentric chromosomes 15 (idic(15): 3 maternal copies) and interstitial duplications (interstitial dup(15): 2 maternal copies).1 Neuroimaging in patients with Dup15q is usually reported as normal2 or with nonspecific changes such as increase of pericerebral spaces and thinning of the corpus callosum.3 A recent pathological report of 9 cases indicates a high prevalence of heterotopia and dysplasias in the hippocampus.4 The aim of this article is to characterize the brain magnetic resonance imaging (MRI) findings in 11 subjects with Dup15q, including morphologic assessment of the hippocampus in coronal sequences.
Materials and Methods We retrospectively reviewed the medical records and MRI scans of 11 patients with genetically confirmed Dup15q seen at the Massachusetts General Hospital Dup15q Center between 2003 and 2012. Nine had idic(15) diagnosed by karyotype and 2 had interstitial dup(15) detected by fluorescent in situ hybridization. Epilepsy and
cognitive phenotypes were noted and epilepsy was considered refractory after failure of adequate trials of 2 tolerated, appropriately chosen, and used antiepileptic drugs, as defined by the International League Against Epilepsy.5 Ten subjects had 1 MRI and 1 subject had 2. Seven of the 11 had high-resolution coronal T2-weighted imaging sequences performed on a 3-Tesla unit. Three studies had lower resolution T2-weighted imaging, and 1 study had low-resolution coronal T1-weighted images. Hippocampal morphology was assessed and detailed separately at the level of the head, body, and tail. Other neuroimaging findings not related to the hippocampus were also noted. Two board-certified neuroradiologists reviewed all the images from the 12 available MRI studies and consensus was obtained for all examined criteria. Normal morphology of the hippocampus was defined by the following parameters based on the Duvernoy atlas of normal anatomy of the hippocampus6 and other literature about hippocampal morphology7-9: ovoid head with 3 or 2 internal digitations easily distinguished
1
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA Department of Pediatric Neurology, Vall d’Hebron Hospital, Universitat Auto`noma de Barcelona, Barcelona, Spain 3 Department of Neuroradiology, Massachusetts General Hospital, Boston, MA, USA 2
Corresponding Author: Susana Boronat, MD, Pediatric Epilepsy Program, Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114, USA. Email: [email protected]
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2
Journal of Child Neurology C5 to T1 in 1 subject who also had multiple small cysts in the pineal gland.
Discussion
Figure 1. In case 2, a T2-weighted image shows a normal hippocampus head with 3 internal digitations on the left (arrowhead). Abnormal hyperintensity and loss of volume is seen in the right hippocampal head, compatible with hippocampal sclerosis (arrow). (Figure 1), ovoid shape of the body and tail with major diameter horizontal, alveus and fimbria cranial to hippocampus, absence of T2 hyperintensity, collateral sulcus roughly horizontal at the body and tail level, hippocampal body located along the choroidal fissure and filling the lateral part of tip temporal horn, and collateral white matter (defined as the white matter between the collateral sulcus gray matter and hippocampus) located under the hippocampal body. The position of the fornices in the coronal plane was noted as symmetrical or asymmetrical.
Results The clinical and MRI details of the subjects are listed in Table 1. There were 8 males and 3 females with a mean age of 7.2 years (range: 16 months to 17 years), all with intellectual disability and autistic spectrum disorder. Hippocampal abnormalities in idic(15) were more common in males (6/6) than females (1/3). Two had hippocampal sclerosis: 1 with interstitial dup(15) had right hippocampal sclerosis (Figure 1), but the underlying morphology of the hippocampus was well preserved and normal ovoid morphology and 3 internal digitations were easily seen at the head level. One with idic(15) had left hippocampal sclerosis. This hippocampus showed loss of internal digitations and the morphology of the body was abnormally globular (Figure 2). Both subjects with hippocampal sclerosis had refractory epilepsy. One subject with interstitial dup(15) and 2 with idic(15) had normal hippocampus bilaterally. Six subjects, all with idic(15), had bilateral hippocampal malformations that were asymmetric in 4 cases (left side more severely affected) (Figure 3). Four had the left fornix slightly inferior with respect to the right, whereas the rest had symmetric fornices. Other findings included hypoplasia of the corpus callosum in 2 subjects, nonspecific fluid-attenuated inversion recovery/ T2 hyperintensities in 2 subjects, and hydrosyrinx spanning
Most individuals with idic(15) and interstitial dup(15) have MRI or computed tomographic (CT) images that are reported to be normal whereas those with abnormalities reportedly show nonspecific findings such as thinning of the corpus callosum or increase in cerebrospinal fluid spaces.2,3,10 Hippocampal abnormalities might have been overlooked in previous literature since coronal acquisitions are not routinely performed or reviewed in detail. Our findings correlate with a neuropathologic study of 9 brains of patients with Dup15q— 7 cases of idic(15), 1 tricentric chromosome 15, and 1 interstitial triplication—in which heterotopia and/or dysplasia of the hippocampus were present in 89% of cases. No cases of interstitial dup(15) were studied in that report.4 Hippocampal morphology seems normal in our 2 interstitial dup(15) subjects, although 1 of them has a T1-weighted imaging study, which has less definition than T2 high-resolution studies. The brain MRI of the other interstitial dup(15) subject shows features of increased signal intensity on T2-weighted imaging and reduced hippocampal volume compatible with hippocampal sclerosis. Although disturbed internal architecture is a frequent finding in hippocampal sclerosis, our subject’s MRI shows 3 easily distinguishable internal digitations, consistent with normal hippocampal morphology. Hippocampal sclerosis is an acquired lesion, related to excitoxicity.11 Interestingly, this patient had focal status epilepticus at 14 years of age, 1 month prior to his first MRI findings of hippocampal sclerosis. The hippocampal findings were similar in an MRI performed 1 year later. Status epilepticus, frequently in the setting of febrile seizures, has been related to hippocampal sclerosis as it is often followed by extensive neuronal damage in the hippocampus due to excitotoxicity.11 Hippocampal sclerosis was also detected in 1 subject with idic(15). This 12-yearold boy has severe refractory epilepsy with onset at 20 months of age but no history of status epilepticus or febrile seizures. In contrast to the other subject with hippocampal sclerosis, this subject had blurring of the internal structures and a globular morphology of the left hippocampus. This suggests that an abnormal morphology likely predates the onset of hippocampal sclerosis. Moreover, some authors have proposed that preexisting hippocampal malformations may underlie some cases of febrile convulsions and subsequent hippocampal sclerosis.12 The frequency of hippocampal sclerosis in our cohort (18%) seems higher than hippocampal sclerosis in the setting of other focal epilepsies or after febrile status epilepticus. Hippocampal sclerosis was uncommon (2.5%) in a study of childhood nonsyndromic focal epilepsy—although 21% of subjects had hippocampal size anomalies13 that, according to the authors, may represent the milder end of hippocampal dysplasia. In the FEBSTAT study,14 a prospective study to determine the consequences of febrile status epilepticus in childhood, 11.5% had abnormal increased T2 signal
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Table 1. Magnetic Resonance Imaging (MRI) Findings in Patients With 15q Duplication Syndromes. Case Gender and age
HC head
HC body
HC tail
Bilateral: normal
Other MRI findings Epilepsy
Interstitial dup(15) cases 1
Male, 16 mo
Bilateral: normal
Bilateral: normal
2
Male, 15 y
Left: normal Right: smaller and T2 hyperintensity but internal digitations still visible (HS)
Left: normal Right: smaller and T2 hyperintensity (HS)
Bilateral: poorly defined internal digitations. More affected on left: temporal horn enlarged due to smaller left HC Bilateral: poorly defined internal digitations, more conspicuous on left than on right Bilateral: poorly defined internal digitations
Bilateral: globular shape, vertically oriented. More affected on left: temporal horn enlarged due to smaller left HC Bilateral: normal
Left: sulcus fimbriodentatus vertically oriented Lateral alveus and fimbria Right: normal Bilateral: normal
Idic(15) cases 3 Male, 18 mo
4
Male, 2 y
5
Female, 3 y
6
Male, 3 y 9 mo
Bilateral: poorly defined internal digitations
7
Male, 4 y
8
Male, 8 y
9
Male, 9 y
Bilateral: poorly defined internal digitations Bilateral: poorly defined internal digitations, more conspicuous on left than on right Left: smaller, abnormal T2 hyperintense signal and blurry internal digitations (HS) Right: normal
Left fornix slightly inferior with respect to the right Left: normal Left fornix slightly Right: smaller inferior with and T2 respect to the hyperintensity right (HS) Left: hypoplastic Right: normal
Bilateral: normal
Bilateral: Bilateral: globular hypoplastic shape. Lateral alveus and fimbria. No formation of sulcus fimbriodentatus
Left: globular. Poor definition of sulcus fimbriodentatus and HC sulcus Right: normal Left: Globular shape Smaller and T2 hyperintense (HS) Right: normal
Bilateral: normal
No
Yes, refractory
Hypoplasia of No corpus callosum
Yes, refractory
No Hypoplasia of posterior corpus callosum. Fluid-attenuated inversion recovery/T2 hyperintensities in bilateral frontal white matter Small pineal gland cysts Hydrosyrinx C5-T1 Yes, refractory
Bilateral: normal
Yes
Left: abnormally vertically oriented Right normal
No
Left: T2 hyperintense (HS) Right: normal
Yes, refractory
(continued)
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Journal of Child Neurology
Table 1. (continued) Case Gender and age
HC head
HC body
HC tail
Other MRI findings Epilepsy
10 Female, 15 y
Bilateral: normal
Bilateral: normal
Bilateral: normal
11 Female, 17 y
Bilateral: normal
Bilateral: normal
Bilateral: normal
Left fornix slightly Yes inferior with respect to the right Fluid-attenuated inversion recovery hyperintense foci in the bilateral frontal white matter Left fornix slightly Yes, refractory inferior with respect to the right
Abbreviations: HC, hippocampus; HS, hippocampal sclerosis; idic(15), isodicentric chromosome 15.
Figure 2. In case 9, hippocampal sclerosis findings of hyperintensity in T2-weighted image and loss of volume are seen on the left. An abnormal globular shape of the left hippocampal body suggests a preexisting malformation (arrow). Note the normal ovoid shape of the hippocampal body on the right (arrowhead).
in the hippocampus, and interestingly, developmental abnormalities of the temporal lobe were more common in the febrile status group (10.5%) than in the control population (2.1%). It may be extremely difficult to detect a subjacent hippocampal malformation once hippocampal sclerosis is present. As neither of our 2 subjects with hippocampal sclerosis had previous brain MRIs, we could not assess the presence of abnormal hippocampal morphology previous to the hippocampal sclerosis. Nonetheless, our MRI findings suggest that it was previously normal in the subject with interstitial dup(15) and abnormal in the 1 with idic(15). The hippocampal abnormalities found in the MRI studies of patients with Dup15q correlate with those in the neuropathologic
Figure 3. In case 3, bilateral globular shape is observed at the level of the hippocampal body (arrows) in T2-weighted image, more pronounced on the left, that shows a dilated temporal horn (arrowhead).
study,4 which reported frequent morphologic changes in patients with Dup15q who had 3 or more maternal copies of the region. These changes were heterotopic cells in the alveus with morphology of pyramidal neurons, although much smaller than neurons in the cornu Ammonis. Neurons with morphology of granule neurons of the dentate gyrus were detected in the CA4 sector and in the molecular layer of the dentate gyrus. Several types of dysplasia were found in the dentate gyrus, including hyperconvolution of the dentate gyrus, duplication of the granular layer distorting the molecular layer of the dentate gyrus and focal thinning, thickening or fragmentation of the granular layer. None of the Dup15q patients in that study had 2 maternal copies and we did not find morphologic abnormalities in our 2 patients with 2 maternal copies (ie, patients with interstitial dup(15)). This supports the idea that
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a greater number of maternal copies would be a risk factor for hippocampal malformations, although more studies are needed to support this hypothesis. Interestingly, the malformations coexisted with findings indicative of epilepsy-related brain damage in 2 patients in the neuropathologic report.4 These findings were neuronal loss without gliosis in the pyramidal layer in the CA1 sector in 1 patient and focal loss of the granular layer with gliosis in the other. Findings suggestive of acquired damage were also found in 2 of our patients, both with refractory epilepsy, who had hippocampal sclerosis. We did not find a correlation between the epileptic phenotype and the severity and bilateral involvement of the hippocampal malformation as 3 of 4 patients without epilepsy had a more severe manifestation of hippocampal malformations (bilateral malformations with involvement of head, body, and tail). Nonetheless, the 3 subjects were 18 months, 3 years, and 8 years of age, and the onset of epilepsy may be anytime throughout childhood—and even adolescence—in patients with idic(15).3 This fact precludes a correlation with the epileptic phenotype at this point. Inversion of the hippocampus is part of the normal gyration process as a result of the marked expansion of the neocortex and unequal growth of the hippocampal components, so incomplete hippocampal inversion9,15 has been frequently reported in association with developmental brain disorders and malformations such as agenesis of corpus callosum, lissencephaly, holoprosencephaly, polymicrogyria, heterotopias,15,16 and malformations of cortical development.17 Moreover, incomplete hippocampal inversion, often referred to as hippocampal malrotation,8,18 may be also found in normal individuals with a frequency as high as 10% to 19%.7,9 Another study,18 however, found an extremely low frequency in normal individuals— probably because of methodologic discrepancies. A higher prevalence of incomplete hippocampal inversion (25%-44%) has been reported in epileptic patients.7,19 Our subjects’ malformations share some similarities with incomplete hippocampal inversion such as abnormal globular shape, blurry internal structure of the hippocampus, and predominance on the left, although we have not detected other findings previously described in incomplete hippocampal inversion such as a clear vertical orientation of the ipsilateral collateral sulcus or location of the collateral white matter lateral to the hippocampus.8,9,18 Four subjects had the left fornix slightly inferior with respect to the right. Although a downwards displacement of the fornix was considered as part of the spectrum in the first description of hippocampal malrotation,8 a unilateral slight variation in position may be considered a normal variant, as it was seen in 58% of patients without seizures in 1 study18 and is present in the 3 subjects with normal hippocampus. Sudden unexpected death in epilepsy may be more frequent in subjects with idic(15) and triplication(15) than in other causes of epilepsy, as suggested by a pathologic report detailing sudden unexpected death in epilepsy in 6 of the 9 (66%) patients,4 including 4 children. The hippocampus is a main component of limbic circuits that modulate heart rate, blood pressure, and breathing, and hippocampal microdysgenesis
has been reported in sudden unexpected death in epilepsy, including in children.20 In a study of patients with sudden unexpected death in childhood,21 hippocampal or temporal anomalies were reported in 62% of cases, which are considered a cause of seizure-related autonomic and/or respiratory dysfunction leading to sudden death.22 Whether sudden unexpected death in epilepsy is more frequent in interstitial dup(15) is currently not known. Additional studies to further investigate a possible relation between hippocampal malformations in Dup15q and sudden unexpected death in epilepsy are needed. Two subjects have hypoplasia of the corpus callosum, which has been previously reported in 1 patient with idic(15).3 Other findings in our subjects, such as hyperintensities in T2/ fluid-attenuated inversion recovery, hydrosyrinx, or pineal cysts are nonspecific findings and have not been previously reported in Dup15q.
Conclusion Hippocampal malformations appear to be frequent findings in idic(15), and this is supported by a recent pathologic study. The severity of the malformation does not appear to correlate with the epileptic phenotype, as malformations may be present in individuals without epilepsy or with refractory epilepsy. Hippocampal sclerosis may be more frequent in Dup15q than in other epilepsy-causing syndromes, and our results suggest that hippocampal malformations may not be present or may be less severe in interstitial dup(15) than in idic(15). More neuroimaging studies are needed to better characterize the relationship between epilepsy, hippocampal malformations, and Dup15q. Acknowledgments We would like to thank the Dup15q Alliance for their support of this study. We would also like to thank all of the families who have visited the Dup15q Center at the Massachusetts General Hospital.
Author Contributions SB designed the project, reviewed the charts, and did the gathering and analysis of the data and drafting of the manuscript. EAS and RLT contributed to the drafting of the paper and revised the manuscript. WM and PC revised the brain magnetic resonance images. PC contributed to the drafting, supervised the study and revised the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: SB is supported by a BAE (beca de ampliacio´n de estudios) grant from the Carlos III Institute, Spain.
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Journal of Child Neurology
Ethical Approval This study was approved by the Institutional Review Board of the Massachusetts General Hospital (IRB Approval No. 2012P001128).
11. 12.
References 1. Webb T. Inv dup(15) supernumerary marker chromosomes. J Med Genet. 1994;31:585-594. 2. Cook EH Jr, Lindgren V, Leventhal BL, et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet. 1997;60:928-934. 3. Buoni S, Sorrentino L, Farnetani MA, et al. The syndrome of inv dup (15): clinical, electroencephalographic, and imaging findings. J Child Neurol. 2000;15:380-385. 4. Wegiel J, Schanen NC, Cook EH, et al. Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism. J Neuropathol Exp Neurol. 2012;71:382-397. 5. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51:1069-1077. 6. Duvernoy HM. The Human Hippocampus. 3rd ed. New York: Springer; 2005. 7. Bernasconi N, Kinay D, Andermann F, et al. Analysis of shape and positioning of the hippocampal formation: an MRI study in patients with partial epilepsy and healthy controls. Brain. 2005; 128:2442-2452. 8. Barsi P, Kene´z J, Solymosi D, et al. Hippocampal malrotation with normal corpus callosum: a new entity? Neuroradiology. 2000;42:339-345. 9. Bajic D, Wang C, Kumlien E, et al. Incomplete inversion of the hippocampus—a common developmental anomaly. Eur Radiol. 2008;18:138-142. 10. Battaglia A, Gurrieri F, Bertini E, et al. The inv dup(15) syndrome: a clinically recognizable syndrome with altered
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behavior, mental retardation, and epilepsy. Neurology. 1997; 48:1081-1086. Malmgren K, Thom M. Hippocampal sclerosis—origins and imaging. Epilepsia. 2012;53:19-33. Ferna´ndez G, Effenberger O, Vinz B, et al. Hippocampal malformation as a cause of familial febrile convulsions and subsequent hippocampal sclerosis. Neurology. 1998;50:909-917. Berg AT, Pardoe HR, Fulbright RK, et al. Hippocampal size anomalies in a community-based cohort with childhood-onset epilepsy. Neurology. 2011;76:1415-1421. Shinnar S, Bello JA, Chan S, et al. MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study. Neurology. 2012;79:871-877. Baker LL, Barkovich AJ. The large temporal horn: MR analysis in developmental brain anomalies versus hydrocephalus. Am J Neuroradiol. 1992;13:115-122. Sato N, Hatakeyama S, Shimizu N, et al. MR evaluation of the hippocampus in patients with congenital malformations of the brain. Am J Neuroradiol. 2001;22:389-393. Kuchukhidze G, Koppelstaetter F, Unterberger I, et al. Hippocampal abnormalities in malformations of cortical development: MRI study. Neurology. 2010;74:1575-1582. Gamss RP, Slasky SE, Bello JA, et al. Prevalence of hippocampal malrotation in a population without seizures. Am J Neuroradiol. 2009;30:1571-1573. Lehe´ricy S, Dormont D, Se´mah F, et al. Developmental abnormalities of the medial temporal lobe in patients with temporal lobe epilepsy. Am J Neuroradiol. 1995;16:617-626. Donner EJ, Smith CR, Snead OC 3rd. Sudden unexplained death in children with epilepsy. Neurology. 2001;57:430-434. Kinney HC, Chadwick AE, Crandall LA, et al. Sudden death, febrile seizures, and hippocampal and temporal lobe maldevelopment in toddlers: a new entity. Pediatr Dev Pathol. 2009;12:455-463. Frysinger RC, Harper RM. Cardiac and respiratory correlations with unit discharge in epileptic human temporal lobe. Epilepsia. 1990;31:162-171.
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Hippocampal Abnormalities in Magnetic Resonance Imaging (MRI) of 15q Duplication Syndromes
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538669 jcn.sagepub.com
Susana Boronat, MD1,2, William A. Mehan, MD3, Elias A. Shaaya, BA1, Ronald L. Thibert, DO, MSPH1, and Paul Caruso, MD3
Abstract Patients with 15q duplication syndromes, including isodicentric chromosome 15 and interstitial duplications, usually present with autism spectrum disorder, intellectual disability, and frequently epilepsy. Neuroimaging studies in these patients are typically reported as normal, but nonspecific findings such as thinning of the corpus callosum and increased pericerebral spaces have been reported. A review of brain magnetic resonance imaging (MRI) studies of 11 individuals seen at the Massachusetts General Hospital Dup15q Center was performed. Hippocampus morphology was specifically reviewed, as a recent neuropathologic study has found frequent hippocampal heterotopias and dysplasias in these disorders. Two subjects had unilateral hippocampal sclerosis and 6 had bilateral hippocampal malformations. Hypoplasia of the corpus callosum was present in 2 subjects. Keywords CNV, duplication 15q11-q13, hippocampus, hippocampal malrotation, idic(15), neuroimaging, MR Received January 04, 2014. Received revised May 01, 2014. Accepted for publication May 14, 2014.
The 15q11-q13 region is prone to copy number variations, which may be due to the loss or gain of genes in this region. Part of the region is imprinted and its haploinsufficiency causes Angelman syndrome or Prader-Willi syndrome depending on parental origin. Maternal copy number gains of 15q11-q13, also known as 15q duplication syndromes (Dup15q), present with global developmental delay, intellectual disability, autism spectrum disorders, and epilepsy. The most frequent rearrangements are isodicentric chromosomes 15 (idic(15): 3 maternal copies) and interstitial duplications (interstitial dup(15): 2 maternal copies).1 Neuroimaging in patients with Dup15q is usually reported as normal2 or with nonspecific changes such as increase of pericerebral spaces and thinning of the corpus callosum.3 A recent pathological report of 9 cases indicates a high prevalence of heterotopia and dysplasias in the hippocampus.4 The aim of this article is to characterize the brain magnetic resonance imaging (MRI) findings in 11 subjects with Dup15q, including morphologic assessment of the hippocampus in coronal sequences.
Materials and Methods We retrospectively reviewed the medical records and MRI scans of 11 patients with genetically confirmed Dup15q seen at the Massachusetts General Hospital Dup15q Center between 2003 and 2012. Nine had idic(15) diagnosed by karyotype and 2 had interstitial dup(15) detected by fluorescent in situ hybridization. Epilepsy and
cognitive phenotypes were noted and epilepsy was considered refractory after failure of adequate trials of 2 tolerated, appropriately chosen, and used antiepileptic drugs, as defined by the International League Against Epilepsy.5 Ten subjects had 1 MRI and 1 subject had 2. Seven of the 11 had high-resolution coronal T2-weighted imaging sequences performed on a 3-Tesla unit. Three studies had lower resolution T2-weighted imaging, and 1 study had low-resolution coronal T1-weighted images. Hippocampal morphology was assessed and detailed separately at the level of the head, body, and tail. Other neuroimaging findings not related to the hippocampus were also noted. Two board-certified neuroradiologists reviewed all the images from the 12 available MRI studies and consensus was obtained for all examined criteria. Normal morphology of the hippocampus was defined by the following parameters based on the Duvernoy atlas of normal anatomy of the hippocampus6 and other literature about hippocampal morphology7-9: ovoid head with 3 or 2 internal digitations easily distinguished
1
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA Department of Pediatric Neurology, Vall d’Hebron Hospital, Universitat Auto`noma de Barcelona, Barcelona, Spain 3 Department of Neuroradiology, Massachusetts General Hospital, Boston, MA, USA 2
Corresponding Author: Susana Boronat, MD, Pediatric Epilepsy Program, Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114, USA. Email: [email protected]
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Journal of Child Neurology C5 to T1 in 1 subject who also had multiple small cysts in the pineal gland.
Discussion
Figure 1. In case 2, a T2-weighted image shows a normal hippocampus head with 3 internal digitations on the left (arrowhead). Abnormal hyperintensity and loss of volume is seen in the right hippocampal head, compatible with hippocampal sclerosis (arrow). (Figure 1), ovoid shape of the body and tail with major diameter horizontal, alveus and fimbria cranial to hippocampus, absence of T2 hyperintensity, collateral sulcus roughly horizontal at the body and tail level, hippocampal body located along the choroidal fissure and filling the lateral part of tip temporal horn, and collateral white matter (defined as the white matter between the collateral sulcus gray matter and hippocampus) located under the hippocampal body. The position of the fornices in the coronal plane was noted as symmetrical or asymmetrical.
Results The clinical and MRI details of the subjects are listed in Table 1. There were 8 males and 3 females with a mean age of 7.2 years (range: 16 months to 17 years), all with intellectual disability and autistic spectrum disorder. Hippocampal abnormalities in idic(15) were more common in males (6/6) than females (1/3). Two had hippocampal sclerosis: 1 with interstitial dup(15) had right hippocampal sclerosis (Figure 1), but the underlying morphology of the hippocampus was well preserved and normal ovoid morphology and 3 internal digitations were easily seen at the head level. One with idic(15) had left hippocampal sclerosis. This hippocampus showed loss of internal digitations and the morphology of the body was abnormally globular (Figure 2). Both subjects with hippocampal sclerosis had refractory epilepsy. One subject with interstitial dup(15) and 2 with idic(15) had normal hippocampus bilaterally. Six subjects, all with idic(15), had bilateral hippocampal malformations that were asymmetric in 4 cases (left side more severely affected) (Figure 3). Four had the left fornix slightly inferior with respect to the right, whereas the rest had symmetric fornices. Other findings included hypoplasia of the corpus callosum in 2 subjects, nonspecific fluid-attenuated inversion recovery/ T2 hyperintensities in 2 subjects, and hydrosyrinx spanning
Most individuals with idic(15) and interstitial dup(15) have MRI or computed tomographic (CT) images that are reported to be normal whereas those with abnormalities reportedly show nonspecific findings such as thinning of the corpus callosum or increase in cerebrospinal fluid spaces.2,3,10 Hippocampal abnormalities might have been overlooked in previous literature since coronal acquisitions are not routinely performed or reviewed in detail. Our findings correlate with a neuropathologic study of 9 brains of patients with Dup15q— 7 cases of idic(15), 1 tricentric chromosome 15, and 1 interstitial triplication—in which heterotopia and/or dysplasia of the hippocampus were present in 89% of cases. No cases of interstitial dup(15) were studied in that report.4 Hippocampal morphology seems normal in our 2 interstitial dup(15) subjects, although 1 of them has a T1-weighted imaging study, which has less definition than T2 high-resolution studies. The brain MRI of the other interstitial dup(15) subject shows features of increased signal intensity on T2-weighted imaging and reduced hippocampal volume compatible with hippocampal sclerosis. Although disturbed internal architecture is a frequent finding in hippocampal sclerosis, our subject’s MRI shows 3 easily distinguishable internal digitations, consistent with normal hippocampal morphology. Hippocampal sclerosis is an acquired lesion, related to excitoxicity.11 Interestingly, this patient had focal status epilepticus at 14 years of age, 1 month prior to his first MRI findings of hippocampal sclerosis. The hippocampal findings were similar in an MRI performed 1 year later. Status epilepticus, frequently in the setting of febrile seizures, has been related to hippocampal sclerosis as it is often followed by extensive neuronal damage in the hippocampus due to excitotoxicity.11 Hippocampal sclerosis was also detected in 1 subject with idic(15). This 12-yearold boy has severe refractory epilepsy with onset at 20 months of age but no history of status epilepticus or febrile seizures. In contrast to the other subject with hippocampal sclerosis, this subject had blurring of the internal structures and a globular morphology of the left hippocampus. This suggests that an abnormal morphology likely predates the onset of hippocampal sclerosis. Moreover, some authors have proposed that preexisting hippocampal malformations may underlie some cases of febrile convulsions and subsequent hippocampal sclerosis.12 The frequency of hippocampal sclerosis in our cohort (18%) seems higher than hippocampal sclerosis in the setting of other focal epilepsies or after febrile status epilepticus. Hippocampal sclerosis was uncommon (2.5%) in a study of childhood nonsyndromic focal epilepsy—although 21% of subjects had hippocampal size anomalies13 that, according to the authors, may represent the milder end of hippocampal dysplasia. In the FEBSTAT study,14 a prospective study to determine the consequences of febrile status epilepticus in childhood, 11.5% had abnormal increased T2 signal
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Table 1. Magnetic Resonance Imaging (MRI) Findings in Patients With 15q Duplication Syndromes. Case Gender and age
HC head
HC body
HC tail
Bilateral: normal
Other MRI findings Epilepsy
Interstitial dup(15) cases 1
Male, 16 mo
Bilateral: normal
Bilateral: normal
2
Male, 15 y
Left: normal Right: smaller and T2 hyperintensity but internal digitations still visible (HS)
Left: normal Right: smaller and T2 hyperintensity (HS)
Bilateral: poorly defined internal digitations. More affected on left: temporal horn enlarged due to smaller left HC Bilateral: poorly defined internal digitations, more conspicuous on left than on right Bilateral: poorly defined internal digitations
Bilateral: globular shape, vertically oriented. More affected on left: temporal horn enlarged due to smaller left HC Bilateral: normal
Left: sulcus fimbriodentatus vertically oriented Lateral alveus and fimbria Right: normal Bilateral: normal
Idic(15) cases 3 Male, 18 mo
4
Male, 2 y
5
Female, 3 y
6
Male, 3 y 9 mo
Bilateral: poorly defined internal digitations
7
Male, 4 y
8
Male, 8 y
9
Male, 9 y
Bilateral: poorly defined internal digitations Bilateral: poorly defined internal digitations, more conspicuous on left than on right Left: smaller, abnormal T2 hyperintense signal and blurry internal digitations (HS) Right: normal
Left fornix slightly inferior with respect to the right Left: normal Left fornix slightly Right: smaller inferior with and T2 respect to the hyperintensity right (HS) Left: hypoplastic Right: normal
Bilateral: normal
Bilateral: Bilateral: globular hypoplastic shape. Lateral alveus and fimbria. No formation of sulcus fimbriodentatus
Left: globular. Poor definition of sulcus fimbriodentatus and HC sulcus Right: normal Left: Globular shape Smaller and T2 hyperintense (HS) Right: normal
Bilateral: normal
No
Yes, refractory
Hypoplasia of No corpus callosum
Yes, refractory
No Hypoplasia of posterior corpus callosum. Fluid-attenuated inversion recovery/T2 hyperintensities in bilateral frontal white matter Small pineal gland cysts Hydrosyrinx C5-T1 Yes, refractory
Bilateral: normal
Yes
Left: abnormally vertically oriented Right normal
No
Left: T2 hyperintense (HS) Right: normal
Yes, refractory
(continued)
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Journal of Child Neurology
Table 1. (continued) Case Gender and age
HC head
HC body
HC tail
Other MRI findings Epilepsy
10 Female, 15 y
Bilateral: normal
Bilateral: normal
Bilateral: normal
11 Female, 17 y
Bilateral: normal
Bilateral: normal
Bilateral: normal
Left fornix slightly Yes inferior with respect to the right Fluid-attenuated inversion recovery hyperintense foci in the bilateral frontal white matter Left fornix slightly Yes, refractory inferior with respect to the right
Abbreviations: HC, hippocampus; HS, hippocampal sclerosis; idic(15), isodicentric chromosome 15.
Figure 2. In case 9, hippocampal sclerosis findings of hyperintensity in T2-weighted image and loss of volume are seen on the left. An abnormal globular shape of the left hippocampal body suggests a preexisting malformation (arrow). Note the normal ovoid shape of the hippocampal body on the right (arrowhead).
in the hippocampus, and interestingly, developmental abnormalities of the temporal lobe were more common in the febrile status group (10.5%) than in the control population (2.1%). It may be extremely difficult to detect a subjacent hippocampal malformation once hippocampal sclerosis is present. As neither of our 2 subjects with hippocampal sclerosis had previous brain MRIs, we could not assess the presence of abnormal hippocampal morphology previous to the hippocampal sclerosis. Nonetheless, our MRI findings suggest that it was previously normal in the subject with interstitial dup(15) and abnormal in the 1 with idic(15). The hippocampal abnormalities found in the MRI studies of patients with Dup15q correlate with those in the neuropathologic
Figure 3. In case 3, bilateral globular shape is observed at the level of the hippocampal body (arrows) in T2-weighted image, more pronounced on the left, that shows a dilated temporal horn (arrowhead).
study,4 which reported frequent morphologic changes in patients with Dup15q who had 3 or more maternal copies of the region. These changes were heterotopic cells in the alveus with morphology of pyramidal neurons, although much smaller than neurons in the cornu Ammonis. Neurons with morphology of granule neurons of the dentate gyrus were detected in the CA4 sector and in the molecular layer of the dentate gyrus. Several types of dysplasia were found in the dentate gyrus, including hyperconvolution of the dentate gyrus, duplication of the granular layer distorting the molecular layer of the dentate gyrus and focal thinning, thickening or fragmentation of the granular layer. None of the Dup15q patients in that study had 2 maternal copies and we did not find morphologic abnormalities in our 2 patients with 2 maternal copies (ie, patients with interstitial dup(15)). This supports the idea that
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Boronat et al
5
a greater number of maternal copies would be a risk factor for hippocampal malformations, although more studies are needed to support this hypothesis. Interestingly, the malformations coexisted with findings indicative of epilepsy-related brain damage in 2 patients in the neuropathologic report.4 These findings were neuronal loss without gliosis in the pyramidal layer in the CA1 sector in 1 patient and focal loss of the granular layer with gliosis in the other. Findings suggestive of acquired damage were also found in 2 of our patients, both with refractory epilepsy, who had hippocampal sclerosis. We did not find a correlation between the epileptic phenotype and the severity and bilateral involvement of the hippocampal malformation as 3 of 4 patients without epilepsy had a more severe manifestation of hippocampal malformations (bilateral malformations with involvement of head, body, and tail). Nonetheless, the 3 subjects were 18 months, 3 years, and 8 years of age, and the onset of epilepsy may be anytime throughout childhood—and even adolescence—in patients with idic(15).3 This fact precludes a correlation with the epileptic phenotype at this point. Inversion of the hippocampus is part of the normal gyration process as a result of the marked expansion of the neocortex and unequal growth of the hippocampal components, so incomplete hippocampal inversion9,15 has been frequently reported in association with developmental brain disorders and malformations such as agenesis of corpus callosum, lissencephaly, holoprosencephaly, polymicrogyria, heterotopias,15,16 and malformations of cortical development.17 Moreover, incomplete hippocampal inversion, often referred to as hippocampal malrotation,8,18 may be also found in normal individuals with a frequency as high as 10% to 19%.7,9 Another study,18 however, found an extremely low frequency in normal individuals— probably because of methodologic discrepancies. A higher prevalence of incomplete hippocampal inversion (25%-44%) has been reported in epileptic patients.7,19 Our subjects’ malformations share some similarities with incomplete hippocampal inversion such as abnormal globular shape, blurry internal structure of the hippocampus, and predominance on the left, although we have not detected other findings previously described in incomplete hippocampal inversion such as a clear vertical orientation of the ipsilateral collateral sulcus or location of the collateral white matter lateral to the hippocampus.8,9,18 Four subjects had the left fornix slightly inferior with respect to the right. Although a downwards displacement of the fornix was considered as part of the spectrum in the first description of hippocampal malrotation,8 a unilateral slight variation in position may be considered a normal variant, as it was seen in 58% of patients without seizures in 1 study18 and is present in the 3 subjects with normal hippocampus. Sudden unexpected death in epilepsy may be more frequent in subjects with idic(15) and triplication(15) than in other causes of epilepsy, as suggested by a pathologic report detailing sudden unexpected death in epilepsy in 6 of the 9 (66%) patients,4 including 4 children. The hippocampus is a main component of limbic circuits that modulate heart rate, blood pressure, and breathing, and hippocampal microdysgenesis
has been reported in sudden unexpected death in epilepsy, including in children.20 In a study of patients with sudden unexpected death in childhood,21 hippocampal or temporal anomalies were reported in 62% of cases, which are considered a cause of seizure-related autonomic and/or respiratory dysfunction leading to sudden death.22 Whether sudden unexpected death in epilepsy is more frequent in interstitial dup(15) is currently not known. Additional studies to further investigate a possible relation between hippocampal malformations in Dup15q and sudden unexpected death in epilepsy are needed. Two subjects have hypoplasia of the corpus callosum, which has been previously reported in 1 patient with idic(15).3 Other findings in our subjects, such as hyperintensities in T2/ fluid-attenuated inversion recovery, hydrosyrinx, or pineal cysts are nonspecific findings and have not been previously reported in Dup15q.
Conclusion Hippocampal malformations appear to be frequent findings in idic(15), and this is supported by a recent pathologic study. The severity of the malformation does not appear to correlate with the epileptic phenotype, as malformations may be present in individuals without epilepsy or with refractory epilepsy. Hippocampal sclerosis may be more frequent in Dup15q than in other epilepsy-causing syndromes, and our results suggest that hippocampal malformations may not be present or may be less severe in interstitial dup(15) than in idic(15). More neuroimaging studies are needed to better characterize the relationship between epilepsy, hippocampal malformations, and Dup15q. Acknowledgments We would like to thank the Dup15q Alliance for their support of this study. We would also like to thank all of the families who have visited the Dup15q Center at the Massachusetts General Hospital.
Author Contributions SB designed the project, reviewed the charts, and did the gathering and analysis of the data and drafting of the manuscript. EAS and RLT contributed to the drafting of the paper and revised the manuscript. WM and PC revised the brain magnetic resonance images. PC contributed to the drafting, supervised the study and revised the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: SB is supported by a BAE (beca de ampliacio´n de estudios) grant from the Carlos III Institute, Spain.
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Journal of Child Neurology
Ethical Approval This study was approved by the Institutional Review Board of the Massachusetts General Hospital (IRB Approval No. 2012P001128).
11. 12.
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