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MRI spectrum of cortical malformations in tuberous sclerosis complex
Brain & Development 22 (2000) 487±493
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Original article
MRI spectrum of cortical malformations in tuberous sclerosis complex Catherine Christophe a,*, Tayeb SeÂkhara b, FrancËoise Rypens c, France Ziereisen a, Florence Christiaens b, Bernard Dan b a
Department of Imaging, HoÃpital Universitaire des Enfants Reine Fabiola, 15 av. J.J.Crocq, B-1020 Brussels, Belgium b Department of Neurology, HoÃpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium c Department of Imaging, HoÃpital Erasme, Brussels, Belgium Received 18 July 2000; received in revised form 19 September 2000; accepted 18 October 2000
Abstract The diagnostic and prognostic value of magnetic resonance imaging in the tuberous sclerosis complex has increasingly been recognized. In this paper, we review the presumed pathogenesis of the cerebral dysgenesis seen in this condition in the light of magnetic resonance imaging features of selected patients. In addition to typical ®ndings related to tubers, we show and discuss varied cortical malformations (from simple localized cortical dysplasia to transmantle dysplasia and schizencephaly) similar to those seen in sporadic cerebral dysgenesis. These cases support the hypothesis that the tuberous sclerosis complex focally affects the radial glial-neuronal complex as a basic unit for brain development. Abnormal stem cells would create dysplastic glia and neurons that fail to differentiate, proliferate, migrate and form a normally organized cortex. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Neuronal migration; Tuberous sclerosis; Magnetic resonance imaging; Cortical dysgenesis
1. Introduction The tuberous sclerosis complex (TSC) is a dominantly inherited disorder with variable expression and a high incidence of new mutations. This condition is characterized by multifocal dysplasia, which may occur in numerous organ systems. Neurological manifestations are often prominent, as more than 75% of TSC patients have seizures and nearly half the patients have learning dif®culties. Four major cerebral ®ndings can be seen in TSC, namely cortical tubers, white matter abnormalities, subependymal nodules and subependymal giant cell astrocytoma. Two responsible genes, TSC1 and TSC2, have been identi®ed, respectively on chromosome 9q34 and 16p13. They code for proteins, hamartin and tuberin respectively, which are tumour suppressors and are thought to be involved in the regulation of cellular growth and differentiation [1±3]. The prevalence of TSC is approximately one in 6000± 10 000 births [1,2], but it may be underestimated because of paucisymptomatic forms. The latter render diagnosis, and therefore genetic counselling hazardous if solely based on clinical ®ndings. Therefore, radiological brain manifestations of TSC have * Corresponding author. Tel.: 132-2-4773220; fax: 132-2-4785439. E-mail address: [email protected] (C. Christophe).
a considerable importance, which is emphasized in the revised diagnostic criteria [4]. In particular, magnetic resonance imaging (MRI) has proved to allow identi®cation of typical ®ndings [6±17]. As a result, MRI is considered as the most sensitive imaging technique to make a presumptive diagnosis of TSC. The prognostic value of MRI in TSC [8,9] is still controversial [10,11]. However the causal role of cortical tubers in seizures has been demonstrated by topographic correlation between areas of abnormal cortical and subcortical MRI ®ndings and focal electroencephalographic discharges [8]. In addition to its diagnostic value, MRI may permit to approach processes underlying cerebral abnormalities associated with TSC. In the present paper, we aimed to review the presumed pathogenesis of the brain dysgenesis seen in TSC in the light of MRI obtained in selected illustrative cases. 2. Patients and methods The features of four patients with de®nite TSC [4] were reviewed with a special emphasis on cerebral abnormalities. These patients were selected because they illustrate the spectrum of brain lesions associated with TSC. MRI examinations were performed at 0.5 Tesla. The basic examination protocol included T1-weighted spin echo (SE) sequence in the sagittal and axial planes (TR 500 ms, TE 35 ms),
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(00)00186-8
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C. Christophe et al. / Brain & Development 22 (2000) 487±493
A 3-week-old boy presented with supraventricular extrasystoles. Family history, pregnancy and full-term delivery were unremarkable. Echocardiography revealed two tumours in the left ventricle, four in the right ventricle and one in the right atrium, suggestive of rhabdomyomas. Neurological, ophtalmological, dermatological (including Wood's lamp) examination and renal ultrasound were normal. MRI of the brain showed subependymal nodules hyperintense on T1-weighted (Fig. 1a) and proton-density (Fig. 1b) SE sequences and hypointense on T2-weighted SE sequence (Fig. 1c), consistent with subependymal hamartomas (Q). T1 and proton-density sequences also demonstrated multiple hyperintense islets ( ! ) and radial linear hyperintense bands ( b ) in the white matter. These were suggestive of heterotopic clusters of abnormal cells along the same direction as the radial glial ®bres along which neurons normally migrate from the germinal matrix to the cortex (Fig. 1a,b).
presented at 2 months of age with right-sided complex partial seizures. On admission, interaction was poor, axial and limb hypotonia was noted, and right side asymmetric tonic neck re¯ex was prominent. Wood's lamp examination revealed numerous hypopigmented macules on the trunk and limbs. Fundoscopy and echocardiography were normal. Electroencephalograms showed discharges in the left fronto-temporal region. Computed tomography showed a calci®ed lesion in the left mesial frontal lobe. Seizure control was dif®cult despite combinations of phenobarbital, phenytoin, sodium valproate, benzodiazepines, carbamazepine and steroids. MRI performed at 17 years of age showed calci®ed subependymal nodules ( ! ) and numerous cortical tubers (w). Moreover it showed an infolded cortical dysplasia in the left frontal lobe ( b ) (Fig. 3a). This appeared as a distortion of the macroscopic deep cortical architecture with loss of the normal grey/white matter junction. Diffuse hypointensity on T1- and hyperintensity on T2weighted sequences in the subcortical white matter possibly re¯ected tubers, gliosis or cystic degeneration. Parts of the affected cortex were mildly hyperintense on T1 and markedly hypointense on T2, corresponding to dystrophic calci®cations (®lled in, solid ) ) (Fig. 3b). After 20 years of follow-up, this young man still has severe mental retardation, an autistic syndrome with marked aggressiveness, epilepsy, and motor impairment making unsupported ambulation dif®cult.
2.2. Case 2
2.4. Case 4
A boy presented at 6 months of age with partial complex seizures. His paternal aunt died of a brain tumour and two of her daughters have epilepsy. The patient had numerous hypomelanotic macules and a forehead ®brous plaque. No other clinical abnormalities were found. The seizures were rapidly controlled with vigabatrin, which was discontinued at the age of 11 months. He has remained seizure-free and his neurological development has been normal (4 years follow-up). Initial electroencephalograms showed sharp and slow components predominating over the left posterior temporal region. Further electroencephalograms were normal. No abnormalities were found on fundoscopy, echocardiography and renal ultrasonography. MRI obtained at 4 years (Fig. 2) showed subependymal nodules which were isointense with respect to the white matter on T1-weighted sequence. MRI also revealed enlargement of numerous gyri in all the supratentorial brain, associated with a subcortical increased signal intensity on FLAIR sequence ( b ). These are consistent with cortical tubers surrounded by dysplastic cortex. T2-weighted sequences also showed hyperintense radially oriented white matter bands (Q) extending from the periventricular region to the cortical tubers and probably corresponding to so-called migration lines.
A 5-month-old girl presented with epileptic spasms. She had no family history of epilepsy or TSC. Except for mild axial hypotonia and left hemiparesis, general and neurological examinations were normal. In particular, there was no cutaneous abnormality, including on Wood's lamp examination. Fundoscopy revealed retinal changes suggestive of hamartomas. Electroencephalograms showed multifocal discharges predominating over the right hemisphere. Echocardiography and renal ultrasonography were normal. Initially, the spasms responded well to vigabatrin. However, after six weeks of treatment, the spasms recurred and complex partial seizures appeared. Thereafter, the epilepsy has remained poorly controlled under several antiepileptic drug combinations including vigabatrin, steroids, sodium valproate, benzodiazepines, lamotrigine and carbamazepine. At 4 years, she has moderate mental retardation and mild left hemiparesis. MRI showed three subependymal nodules as well as an area of grey matter intensity in the right frontal lobe, extending from the wall of the lateral ventricle to the cortex (®lled in, solid ) ). This area was considered as an infolded cortical dysplasia consistent with closed lip schizencephaly (Fig. 4).
2.3. Case 3
3. Discussion
followed by a combined proton-density/T2-weighted turbo SE sequence (TR 3700 ms, TE 35/150 ms) in the axial plane. A T2-weighted ¯uid-attenuated inversion recovery sequence (FLAIR) (TR 6000 ms, T1 2000 ms, TE 150 ms) in the coronal plane was also performed for children older than 2 years of age. 2.1. Case 1
A boy with no particular personal or family history,
TSC is characterized by multifocal lesions embedded in
C. Christophe et al. / Brain & Development 22 (2000) 487±493
otherwise normal tissue [18]. According to the `second hit' hypothesis, each of these lesions is thought to arise from a single cell carrying a TSC1 or TSC2 mutation [2,3]. Although TSC is dominantly inherited, it has been hypothesized that it is recessive at the cellular level, which would
489
account for the marked variability of the clinical condition. In individuals with TSC, one copy of the responsible genes has a germline mutation of TSC1 or TSC2. Lesions would arise from a single cell, only if a further event (or `second hit') causes a somatic mutation rendering both copies of the
Fig. 1. Case 1, aged 3 weeks. (a) Sagittal SE T1-weighted (TR 420, TE 15); (b) axial SE proton density (TR 2050, TE 30) sequences show subependymal tubers as bright nodules (Q), intraparenchymal tubers as hyperintense spots ( ! ) and abnormal white matter radial migration lines as hyperintense radial bands spanning through the white matter from the lateral ventricle to the cortex ( b ); (c) axial SE T2-weighted (TR 2050, TE 100) sequence shows subependymal tubers as hypointense nodules (Q).
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Fig. 2. Case 2, aged 4 years. Coronal T2-weighted FLAIR sequence (TR 6000, TE 150, TI 2000) shows cortical tubers surrounded by dysplastic cortex as smooth enlarged gyri with subcortical increased signal intensity ( b ) and migration tracts underlined by hyperintense radially-oriented white matter bands from a cortical tuber to the periventricular region (Q).
gene non-functional in that cell and its progeny [2,3]. The de®nite link between abnormal function of hamartin and tuberin and the genesis of speci®c lesions has yet to be established. However the result of this dysfunction seems to be a change in the cell genetic programme affecting differentiation and/or proliferation. Therefore, most TSC lesions could be described as hamartias, hamartomas or hamartoblastomas according to the state of maturation of the precursor cell at the time of the `second hit'. This hypothesis is also consistent with the pathological similarities in the four major brain manifestations in TSC (cortical tuber, white matter abnormalities, subependymal nodule and subependymal giant cell astrocytoma). The common histological characteristics of these lesions can be found anywhere from the subependymal region to the cortex. They consist of highly cellular dysplastic masses, composed of abnormal giant (or balloon) cells. Some of these abnormal cells show characteristics of astrocytes while others exhibit neuronal differentiation or a form intermediate between the two with abnormal neuroglial interaction [18]. These hamartomas, or tubers, may undergo cellular degeneration which may result in iron and calcium deposits, small cysts [19,20], bands of myelination defect, ®brillary gliosis or tumoral transformation into subependymal giant cell astrocytoma. The major cerebral lesions of TSC are re¯ected on MRI, whose appearance varies with age. From the prenatal period to early infancy, most lesions are best seen on T1- and
proton density- weighted images as bright spots (Fig. 1a,b). These sharply limited lesions likely correspond to tubers in the subependymal region, cortex and white matter. They commonly follow the pathway of migrating neurons along the radial glial- neuronal unit [23]. The relative short T1 relaxation time of the tubers is probably due to the high water content of the infant's premyelinated brain [13,17,24]. In older children and adults, subependymal tubers have usually calci®ed. They are then best visualised on T1weighted images [11] as nodules of intermediate signal intensity. In contrast, cortical tubers and white matter lesions are best seen on T2-weighted images [12] and especially on FLAIR sequence [10] as hyperintense areas (Fig. 2). The prolonged T2 of cortical tubers is more notable in the subjacent subcortical white matter [8,12]. It is presumably related to the higher content of unbound water in this region [7,12]. Cortical tubers are of various size and cause distortion of the normal cortical architecture with gyral deformation [7,12,15]. In addition to detecting the four classical cerebral lesions as tubers and related lesions [6±17], MRI also shows varied cortical malformations as focal cortical dysplasia [21], hemimegalencephaly, focal megalencephaly [22] and schizencephaly (as in our case 4) similar to those of `sporadic' cerebral dysgenesis. Cortical tubers are very common in TSC. They are detected by MRI as often as in 88±95% of the patients [13,12,15]. Tubers in TSC may be unique in about 3±5% [21] of TSC and may therefore be confused with other cortical dysplasia such as `sporadic' focal cortical dysplasia. Severe transmantle anomalies compatible with transmantle dysplasia are less prevalent. They were present in two of the seven patients reported by Baron and Barkovich [17]. Hemimegalencephaly has been described in some neurocutaneous syndromes such as hypomelanosis of Ito, sebaceous naevus syndrome, neuro®bromatosis type 1 and Proteus syndrome. But, to our knowledge, only one case of hemimegalencephaly and one case of focal megalencephaly have been described in TSC [22]. MRI ®ndings in the present cases are of special interest in the light of the presumed pathogenesis of TSC. They support the hypothesis of a dysplastic mechanism speci®cally affecting the radial glial-neuronal unit [15]. The formation and maturation of the cerebral neocortex involve complex but orderly processes [23,25]. Giant pluripotential cells generated in the germinal matrix (in the subependymal and periventricular regions of the developing brain) eventually differentiate into glial and neuronal precursors. Whereas a proportion of these precursors undergo programmed cell death, most of the neurons that will form the cerebral cortex migrate to their destination along radial glial ®bers. The latter originate from glial cell precursors. They have speci®c chemotactic properties and serve as guides for neuron migration from the subependymal region to the cortical surface. Radial migration is most active during the third to ®fth month of gestation but it
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Fig. 3. Case 3, aged 17 years. (a) Sagittal SE T1-weighted (TR 550, TE 10); (b) axial SE T2-weighted (TR 3400, TE 120) sequences show numerous cortical tubers (w), infolded cortical dysplasia (as deep distortion of the normal cortical architecture) ( b ), dystrophic calci®cation as signal void on T2 (Q) and calci®ed subependymal nodules (®lled in, solid ) ).
continues until approximately 5 months after term age. Neurons destined for layer I, which is eventually the more super®cial layer of the cortex, are the ®rst to migrate. The other pools of neurons subsequently migrate inside-out, successively forming layers VI to II. After their coming to their predetermined place in the cortex, neurons establish synaptic contacts to complete cortical organization. Abnormalities in these processes result in malformations. A classi®cation scheme for cortical malformations is dif®cult to establish as a particular anomaly during corticogenesis may result in several morphological subcategories of brain malformations. Barkovitch proposes a classi®cation scheme based upon the ®rst identi®ed abnormal step [26]. Malformations of cortical development are classi®ed into four groups: (1) malformations due to abnormal neuronal and glial proliferation in the germinal matrix; (2) malformations due to abnormal neuronal migration; (3) malformations due to abnormal cortical organization and; (4) malformations not otherwise classi®ed. The ®rst abnormal step in TSC is illustrated by all our selected cases. It is likely due to abnormal neuronal and glial differentiation and proliferation [26]. Two populations of primitive pluripotential giant cells would be generated in the germinal matrix [15]. The ®rst one consists of normal primitive cells that become normal astroglia and neurons
forming the normal cerebral cortex. The second one consists of abnormal primitive cells which fail to clearly differentiate into neurons and glial cells [15]. An alternative, and possibly additional, mechanism could be disordered programmed cellular death in the germinal matrix. The second step determining abnormal cortical development in TSC is also illustrated by all our selected cases. It represents abnormal migration. Some of the abnormal giant primitive cells remain in the germinal matrix where they constitute subependymal tubers (all cases) and incidentally giant cell astrocytoma. Other abnormal giant cells may undergo incomplete migration, forming heterotopic clusters (case 1) and bands (case 2) of abnormal cells in the white matter extending from the subependymal zones to the subcortical white matter. Other dedifferentiated giant balloon cells may reach the cortex forming cortical tubers (cases 2 and 3). Finally abnormal cortical organization may account for some focal cortical dysplasia illustrated by cases 2±4. Barkovich et al. have classi®ed both TSC and focal cortical dysplasia with balloon cells as cortical malformations due to neuronal and glial proliferation [26]. Isolated focal cortical dysplasia may mimic the microscopic and MRI appearance of cortical tubers in TSC [21,27,28]. In this context, some authors have proposed that focal cortical
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Fig. 4. Case 4, aged 18 months. (a) Axial SE T2-weighted (TR 6300, TE 120); (b) axial 3D FFE T1-weighted (TR 32, TE 13, ¯ip angle 308) sequences showing transmantle cortical dysplasia consistent with closed lip schizencephaly or infolded cortical dysplasia. Signal intensity in the infolded cortex is similar as normal cortex (®lled in, solid ) ).
dysplasia may be a forme fruste of TSC, without associated ®ndings [27]. Cortical dysplasia may have variable pattern. The cortex can be ¯at or extends centripetally. When infolding of the cortex extends to the ventricle, it constitutes a focal transmantle dysplasia. It has been suggested that schizencephaly is an extreme variant of cortical dysplasia with the same pathogenetic process [29]. Therefore, although to our knowledge schizencephaly has not been described in TSC previously, its occurrence in case 4 appears to place this form of dysplasia at the far end of the TSC spectrum. As regards the pathophysiology of schizencephaly as we understand it in the broad context of TSC, it must be noted that although classically regarded as a disorder of cortical organization [26], it may alternatively result from abnormal neuronal and glial proliferation [25]. If genetic causes have been reported for focal cortical dysplasia and schizencephaly, inherited disorders seem less frequent in these focal malformations as a whole than in diffuse cortical malformations [30,31]. A genetic origin has been reported for example in the bilateral perisylvian pachygyria-like syndrome, schizencephaly and focal abnormalities of gyration. Some familial cases of schizencephaly may be associated with mutations of the EMX2 homeobox gene. This gene is expressed in the germinal matrix of the developing brain. Muntaner et al. [30] reported
different focal cortical malformations in the same family (focal cortical dysplasia, focal cortical infolding, schizencephaly, nodules of heterotopic grey matter) and postulated that a common genetic origin may underline, in some instances, what is basically the same type of lesion. As in other conditions, it is likely that cortical dysgenesis in TSC is the result of complex interaction between genetic susceptibility, environmental insults and the stage of the fetal brain maturation [31]. Genetic testing for TSC is not yet routinely available and it could be unreliable in some situations, such as germline mosaicism [5]. Currently, the relationship between paucisymptomatic forms of TSC and focal cortical dysplasia therefore remains problematic. 4. Conclusion The presented cases support the hypothesis that MRI brain lesions in TSC, though varied, form a spectrum of focal cerebral dysgenesis that spans along the extent and the presumed timing of the abnormal process at the cellular level. Speci®cally, they include schizencephaly, at the far end of this spectrum, which adds to previous experience of cortical dysplastic lesions in TSC. The different cortical malformations, the components of the tubers and their localization along the usual migrating pathway of neurons
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suggest that the brain manifestations of TSC result from focal abnormal cell differentiation, proliferation, migration and organization. TSC therefore appears to provide a framework in which MRI can increase the understanding of basic mechanisms of cortical dysgenesis. References [1] Crino PB, Henske EP. New developments in the neurobiology of the tuberous sclerosis complex. Neurology 1999;53:1384±1390. [2] Franz DN. Diagnosis and management of tuberous sclerosis complex. Semin Pediatr Neurol 1998;5:253±268. [3] Gutmann DH. Parallels between tuberous sclerosis complex and neuro®bromatosis 1: common threads in the same tapestry. Semin Pediatr Neurol 1998;5:276±286. [4] Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13:624±628. [5] Roach ES, DiMario FJ, Kandt RS, Northrup H. Tuberous sclerosis consensus conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. J Child Neurol 1999;14:401±407. [6] Martin N, de Broucker T, Cambier J, Marsault C, Nahum H. MRI evaluation of tuberous sclerosis. Neuroradiology 1987;29:437±443. [7] Nixon JR, Miller GM, Okazaki H, Gomez MR. Cerebral tuberous sclerosis: postmortem magnetic resonance imaging and pathologic anatomy. Mayo Clin Proc 1989;64:305±311. [8] Shepherd CW, Houser OW, Gomez MR. MR ®ndings in tuberous sclerosis complex and correlation with seizure development and mental impairment. Am J Neuroradiol 1995;16:149±155. [9] Inoue Y, Nakajima S, Fukuda T, Nemoto Y, Shakudo M, Murata R, et al. Magnetic resonance images of tuberous sclerosis. Further observations and clinical correlations. Neuroradiology 1988;30:379±384. [10] Takanashi J, Sugita K, Fujii K, Niimi H. MR evaluation of tuberous sclerosis: increased sensitivity with ¯uid-attenuated inversion recovery and relation to severity of seizures and mental retardation. Am J Neuroradiol 1995;16:1923±1928. [11] Menor F, Marti-Bonmati L, Mulas F, Poyatos C, Cortina H. Neuroimaging in tuberous sclerosis: a clinicoradiological evaluation in pediatric patients. Pediatr Radiol 1992;22:485±489. [12] Nixon JR, Houser OW, Gomez MR, Okazaki H. Cerebral tuberous sclerosis: MR imaging. Radiology 1989;170:869±873. [13] Altman NR, Purser RK, Post MJ. Tuberous sclerosis: characteristics at CT and MR imaging. Radiology 1988;167:527±532.
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[14] McMurdo SK, Moore SG, Brant-Zawadzki M, Berg BO, Koch T, Newton TH, et al. MR imaging of intracranial tuberous sclerosis. Am J Roentgenol 1987;148:791±796. [15] Braffman Jr BH, Bilaniuk LT, Naidich TP, Altman NR, Post MJ, Quencer RM, et al. MR imaging of tuberous sclerosis: pathogenesis of this phakomatosis, use of gadopentetate dimeglumine, and literature review. Radiology 1992;183:227±238. [16] Pont MS, Elster AD. Lesions of skin and brain: modern imaging of the neurocutaneous syndromes. Am J Roentgenol 1992;158:1193±1203. [17] Baron Y, Barkovich AJ. MR imaging of tuberous sclerosis in neonates and young infants. Am J Neuroradiol 1999;20:907±916. [18] Trombley IK, Mirra SS. Ultrastructure of tuberous sclerosis: cortical tuber and subependymal tumor. Ann Neurol 1981;9:174±181. [19] Monaghan HP, Krafchik BR, MacGregor DL, Fitz CR. Tuberous sclerosis complex in children. Am J Dis Child 1981;135:912±917. [20] Van Tassel P, Cure JK, Holden KR. Cystlike white matter lesions in tuberous sclerosis. Am J Neuroradiol 1997;18:1367±1373. [21] Yagishita A, Arai N. Cortical tubers without other stigmata of tuberous sclerosis: imaging and pathological ®ndings. Neuroradiology 1999;41:428±432. [22] Grif®ths PD, Gardner SA, Smith M, Rittey C, Powell T. Hemimegalencephaly and focal megalencephaly in tuberous sclerosis complex. Am J Neuroradiol 1998;19:1935±1938. [23] Barkovich AJ, Gressens P, Evrard P. Formation, maturation, and disorders of brain neocortex. Am J Neuroradiol 1992;13:423±446. [24] Christophe C, Bartholome J, Blum D, Clerckx A, Desprechins B, De Wolf D, et al. Neonatal tuberous sclerosis US, CT, and MR diagnosis of brain and cardiac lesions. Pediatr Radiol 1989;19:446±448. [25] Barkovich AJ. In: Barkovich AJ, editor. Congential malformations of the brain and skull, Pediatric neuroimaging, 3rd ed. Philadelphia: Lippincott Williams and Wilkins, 2000. pp. 251±381. [26] Barkovich AJ, Kuzniecky RI, Dobyns WB, Jackson GD, Becker LE, Evrard P. A classi®cation scheme for malformations of cortical development. Neuropediatrics 1996;27:59±63. [27] Lee BC, Schmidt RE, Hat®eld GA, Bourgeois B, Park TS. MRI of focal cortical dysplasia. Neuroradiology 1998;40:675±683. [28] Jay V, Becker LE. Surgical pathology of epilepsy resections in childhood. Semin Pediatr Neurol 1995;2:227±236. [29] Barkovich AJ, Kjos BO. Schizencephaly: correlation of clinical ®ndings with MR characteristics. Am J Neuroradiol 1992;13:85±94. [30] Muntaner L, PeÂrez-Ferron JJ, Herrera M, Rosell J, Taboada D, Climent S. MRI of a family with focal abnormalities of gyration. Neuroradiology 1997;39:605±608. [31] Whiting S, Duchowny M. Clinical spectrum of cortical dysplasia in childhood: diagnosis and treatment issues. J Child Neurol 1999;14:759±771.
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Original article
MRI spectrum of cortical malformations in tuberous sclerosis complex Catherine Christophe a,*, Tayeb SeÂkhara b, FrancËoise Rypens c, France Ziereisen a, Florence Christiaens b, Bernard Dan b a
Department of Imaging, HoÃpital Universitaire des Enfants Reine Fabiola, 15 av. J.J.Crocq, B-1020 Brussels, Belgium b Department of Neurology, HoÃpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium c Department of Imaging, HoÃpital Erasme, Brussels, Belgium Received 18 July 2000; received in revised form 19 September 2000; accepted 18 October 2000
Abstract The diagnostic and prognostic value of magnetic resonance imaging in the tuberous sclerosis complex has increasingly been recognized. In this paper, we review the presumed pathogenesis of the cerebral dysgenesis seen in this condition in the light of magnetic resonance imaging features of selected patients. In addition to typical ®ndings related to tubers, we show and discuss varied cortical malformations (from simple localized cortical dysplasia to transmantle dysplasia and schizencephaly) similar to those seen in sporadic cerebral dysgenesis. These cases support the hypothesis that the tuberous sclerosis complex focally affects the radial glial-neuronal complex as a basic unit for brain development. Abnormal stem cells would create dysplastic glia and neurons that fail to differentiate, proliferate, migrate and form a normally organized cortex. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Neuronal migration; Tuberous sclerosis; Magnetic resonance imaging; Cortical dysgenesis
1. Introduction The tuberous sclerosis complex (TSC) is a dominantly inherited disorder with variable expression and a high incidence of new mutations. This condition is characterized by multifocal dysplasia, which may occur in numerous organ systems. Neurological manifestations are often prominent, as more than 75% of TSC patients have seizures and nearly half the patients have learning dif®culties. Four major cerebral ®ndings can be seen in TSC, namely cortical tubers, white matter abnormalities, subependymal nodules and subependymal giant cell astrocytoma. Two responsible genes, TSC1 and TSC2, have been identi®ed, respectively on chromosome 9q34 and 16p13. They code for proteins, hamartin and tuberin respectively, which are tumour suppressors and are thought to be involved in the regulation of cellular growth and differentiation [1±3]. The prevalence of TSC is approximately one in 6000± 10 000 births [1,2], but it may be underestimated because of paucisymptomatic forms. The latter render diagnosis, and therefore genetic counselling hazardous if solely based on clinical ®ndings. Therefore, radiological brain manifestations of TSC have * Corresponding author. Tel.: 132-2-4773220; fax: 132-2-4785439. E-mail address: [email protected] (C. Christophe).
a considerable importance, which is emphasized in the revised diagnostic criteria [4]. In particular, magnetic resonance imaging (MRI) has proved to allow identi®cation of typical ®ndings [6±17]. As a result, MRI is considered as the most sensitive imaging technique to make a presumptive diagnosis of TSC. The prognostic value of MRI in TSC [8,9] is still controversial [10,11]. However the causal role of cortical tubers in seizures has been demonstrated by topographic correlation between areas of abnormal cortical and subcortical MRI ®ndings and focal electroencephalographic discharges [8]. In addition to its diagnostic value, MRI may permit to approach processes underlying cerebral abnormalities associated with TSC. In the present paper, we aimed to review the presumed pathogenesis of the brain dysgenesis seen in TSC in the light of MRI obtained in selected illustrative cases. 2. Patients and methods The features of four patients with de®nite TSC [4] were reviewed with a special emphasis on cerebral abnormalities. These patients were selected because they illustrate the spectrum of brain lesions associated with TSC. MRI examinations were performed at 0.5 Tesla. The basic examination protocol included T1-weighted spin echo (SE) sequence in the sagittal and axial planes (TR 500 ms, TE 35 ms),
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(00)00186-8
488
C. Christophe et al. / Brain & Development 22 (2000) 487±493
A 3-week-old boy presented with supraventricular extrasystoles. Family history, pregnancy and full-term delivery were unremarkable. Echocardiography revealed two tumours in the left ventricle, four in the right ventricle and one in the right atrium, suggestive of rhabdomyomas. Neurological, ophtalmological, dermatological (including Wood's lamp) examination and renal ultrasound were normal. MRI of the brain showed subependymal nodules hyperintense on T1-weighted (Fig. 1a) and proton-density (Fig. 1b) SE sequences and hypointense on T2-weighted SE sequence (Fig. 1c), consistent with subependymal hamartomas (Q). T1 and proton-density sequences also demonstrated multiple hyperintense islets ( ! ) and radial linear hyperintense bands ( b ) in the white matter. These were suggestive of heterotopic clusters of abnormal cells along the same direction as the radial glial ®bres along which neurons normally migrate from the germinal matrix to the cortex (Fig. 1a,b).
presented at 2 months of age with right-sided complex partial seizures. On admission, interaction was poor, axial and limb hypotonia was noted, and right side asymmetric tonic neck re¯ex was prominent. Wood's lamp examination revealed numerous hypopigmented macules on the trunk and limbs. Fundoscopy and echocardiography were normal. Electroencephalograms showed discharges in the left fronto-temporal region. Computed tomography showed a calci®ed lesion in the left mesial frontal lobe. Seizure control was dif®cult despite combinations of phenobarbital, phenytoin, sodium valproate, benzodiazepines, carbamazepine and steroids. MRI performed at 17 years of age showed calci®ed subependymal nodules ( ! ) and numerous cortical tubers (w). Moreover it showed an infolded cortical dysplasia in the left frontal lobe ( b ) (Fig. 3a). This appeared as a distortion of the macroscopic deep cortical architecture with loss of the normal grey/white matter junction. Diffuse hypointensity on T1- and hyperintensity on T2weighted sequences in the subcortical white matter possibly re¯ected tubers, gliosis or cystic degeneration. Parts of the affected cortex were mildly hyperintense on T1 and markedly hypointense on T2, corresponding to dystrophic calci®cations (®lled in, solid ) ) (Fig. 3b). After 20 years of follow-up, this young man still has severe mental retardation, an autistic syndrome with marked aggressiveness, epilepsy, and motor impairment making unsupported ambulation dif®cult.
2.2. Case 2
2.4. Case 4
A boy presented at 6 months of age with partial complex seizures. His paternal aunt died of a brain tumour and two of her daughters have epilepsy. The patient had numerous hypomelanotic macules and a forehead ®brous plaque. No other clinical abnormalities were found. The seizures were rapidly controlled with vigabatrin, which was discontinued at the age of 11 months. He has remained seizure-free and his neurological development has been normal (4 years follow-up). Initial electroencephalograms showed sharp and slow components predominating over the left posterior temporal region. Further electroencephalograms were normal. No abnormalities were found on fundoscopy, echocardiography and renal ultrasonography. MRI obtained at 4 years (Fig. 2) showed subependymal nodules which were isointense with respect to the white matter on T1-weighted sequence. MRI also revealed enlargement of numerous gyri in all the supratentorial brain, associated with a subcortical increased signal intensity on FLAIR sequence ( b ). These are consistent with cortical tubers surrounded by dysplastic cortex. T2-weighted sequences also showed hyperintense radially oriented white matter bands (Q) extending from the periventricular region to the cortical tubers and probably corresponding to so-called migration lines.
A 5-month-old girl presented with epileptic spasms. She had no family history of epilepsy or TSC. Except for mild axial hypotonia and left hemiparesis, general and neurological examinations were normal. In particular, there was no cutaneous abnormality, including on Wood's lamp examination. Fundoscopy revealed retinal changes suggestive of hamartomas. Electroencephalograms showed multifocal discharges predominating over the right hemisphere. Echocardiography and renal ultrasonography were normal. Initially, the spasms responded well to vigabatrin. However, after six weeks of treatment, the spasms recurred and complex partial seizures appeared. Thereafter, the epilepsy has remained poorly controlled under several antiepileptic drug combinations including vigabatrin, steroids, sodium valproate, benzodiazepines, lamotrigine and carbamazepine. At 4 years, she has moderate mental retardation and mild left hemiparesis. MRI showed three subependymal nodules as well as an area of grey matter intensity in the right frontal lobe, extending from the wall of the lateral ventricle to the cortex (®lled in, solid ) ). This area was considered as an infolded cortical dysplasia consistent with closed lip schizencephaly (Fig. 4).
2.3. Case 3
3. Discussion
followed by a combined proton-density/T2-weighted turbo SE sequence (TR 3700 ms, TE 35/150 ms) in the axial plane. A T2-weighted ¯uid-attenuated inversion recovery sequence (FLAIR) (TR 6000 ms, T1 2000 ms, TE 150 ms) in the coronal plane was also performed for children older than 2 years of age. 2.1. Case 1
A boy with no particular personal or family history,
TSC is characterized by multifocal lesions embedded in
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otherwise normal tissue [18]. According to the `second hit' hypothesis, each of these lesions is thought to arise from a single cell carrying a TSC1 or TSC2 mutation [2,3]. Although TSC is dominantly inherited, it has been hypothesized that it is recessive at the cellular level, which would
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account for the marked variability of the clinical condition. In individuals with TSC, one copy of the responsible genes has a germline mutation of TSC1 or TSC2. Lesions would arise from a single cell, only if a further event (or `second hit') causes a somatic mutation rendering both copies of the
Fig. 1. Case 1, aged 3 weeks. (a) Sagittal SE T1-weighted (TR 420, TE 15); (b) axial SE proton density (TR 2050, TE 30) sequences show subependymal tubers as bright nodules (Q), intraparenchymal tubers as hyperintense spots ( ! ) and abnormal white matter radial migration lines as hyperintense radial bands spanning through the white matter from the lateral ventricle to the cortex ( b ); (c) axial SE T2-weighted (TR 2050, TE 100) sequence shows subependymal tubers as hypointense nodules (Q).
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Fig. 2. Case 2, aged 4 years. Coronal T2-weighted FLAIR sequence (TR 6000, TE 150, TI 2000) shows cortical tubers surrounded by dysplastic cortex as smooth enlarged gyri with subcortical increased signal intensity ( b ) and migration tracts underlined by hyperintense radially-oriented white matter bands from a cortical tuber to the periventricular region (Q).
gene non-functional in that cell and its progeny [2,3]. The de®nite link between abnormal function of hamartin and tuberin and the genesis of speci®c lesions has yet to be established. However the result of this dysfunction seems to be a change in the cell genetic programme affecting differentiation and/or proliferation. Therefore, most TSC lesions could be described as hamartias, hamartomas or hamartoblastomas according to the state of maturation of the precursor cell at the time of the `second hit'. This hypothesis is also consistent with the pathological similarities in the four major brain manifestations in TSC (cortical tuber, white matter abnormalities, subependymal nodule and subependymal giant cell astrocytoma). The common histological characteristics of these lesions can be found anywhere from the subependymal region to the cortex. They consist of highly cellular dysplastic masses, composed of abnormal giant (or balloon) cells. Some of these abnormal cells show characteristics of astrocytes while others exhibit neuronal differentiation or a form intermediate between the two with abnormal neuroglial interaction [18]. These hamartomas, or tubers, may undergo cellular degeneration which may result in iron and calcium deposits, small cysts [19,20], bands of myelination defect, ®brillary gliosis or tumoral transformation into subependymal giant cell astrocytoma. The major cerebral lesions of TSC are re¯ected on MRI, whose appearance varies with age. From the prenatal period to early infancy, most lesions are best seen on T1- and
proton density- weighted images as bright spots (Fig. 1a,b). These sharply limited lesions likely correspond to tubers in the subependymal region, cortex and white matter. They commonly follow the pathway of migrating neurons along the radial glial- neuronal unit [23]. The relative short T1 relaxation time of the tubers is probably due to the high water content of the infant's premyelinated brain [13,17,24]. In older children and adults, subependymal tubers have usually calci®ed. They are then best visualised on T1weighted images [11] as nodules of intermediate signal intensity. In contrast, cortical tubers and white matter lesions are best seen on T2-weighted images [12] and especially on FLAIR sequence [10] as hyperintense areas (Fig. 2). The prolonged T2 of cortical tubers is more notable in the subjacent subcortical white matter [8,12]. It is presumably related to the higher content of unbound water in this region [7,12]. Cortical tubers are of various size and cause distortion of the normal cortical architecture with gyral deformation [7,12,15]. In addition to detecting the four classical cerebral lesions as tubers and related lesions [6±17], MRI also shows varied cortical malformations as focal cortical dysplasia [21], hemimegalencephaly, focal megalencephaly [22] and schizencephaly (as in our case 4) similar to those of `sporadic' cerebral dysgenesis. Cortical tubers are very common in TSC. They are detected by MRI as often as in 88±95% of the patients [13,12,15]. Tubers in TSC may be unique in about 3±5% [21] of TSC and may therefore be confused with other cortical dysplasia such as `sporadic' focal cortical dysplasia. Severe transmantle anomalies compatible with transmantle dysplasia are less prevalent. They were present in two of the seven patients reported by Baron and Barkovich [17]. Hemimegalencephaly has been described in some neurocutaneous syndromes such as hypomelanosis of Ito, sebaceous naevus syndrome, neuro®bromatosis type 1 and Proteus syndrome. But, to our knowledge, only one case of hemimegalencephaly and one case of focal megalencephaly have been described in TSC [22]. MRI ®ndings in the present cases are of special interest in the light of the presumed pathogenesis of TSC. They support the hypothesis of a dysplastic mechanism speci®cally affecting the radial glial-neuronal unit [15]. The formation and maturation of the cerebral neocortex involve complex but orderly processes [23,25]. Giant pluripotential cells generated in the germinal matrix (in the subependymal and periventricular regions of the developing brain) eventually differentiate into glial and neuronal precursors. Whereas a proportion of these precursors undergo programmed cell death, most of the neurons that will form the cerebral cortex migrate to their destination along radial glial ®bers. The latter originate from glial cell precursors. They have speci®c chemotactic properties and serve as guides for neuron migration from the subependymal region to the cortical surface. Radial migration is most active during the third to ®fth month of gestation but it
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Fig. 3. Case 3, aged 17 years. (a) Sagittal SE T1-weighted (TR 550, TE 10); (b) axial SE T2-weighted (TR 3400, TE 120) sequences show numerous cortical tubers (w), infolded cortical dysplasia (as deep distortion of the normal cortical architecture) ( b ), dystrophic calci®cation as signal void on T2 (Q) and calci®ed subependymal nodules (®lled in, solid ) ).
continues until approximately 5 months after term age. Neurons destined for layer I, which is eventually the more super®cial layer of the cortex, are the ®rst to migrate. The other pools of neurons subsequently migrate inside-out, successively forming layers VI to II. After their coming to their predetermined place in the cortex, neurons establish synaptic contacts to complete cortical organization. Abnormalities in these processes result in malformations. A classi®cation scheme for cortical malformations is dif®cult to establish as a particular anomaly during corticogenesis may result in several morphological subcategories of brain malformations. Barkovitch proposes a classi®cation scheme based upon the ®rst identi®ed abnormal step [26]. Malformations of cortical development are classi®ed into four groups: (1) malformations due to abnormal neuronal and glial proliferation in the germinal matrix; (2) malformations due to abnormal neuronal migration; (3) malformations due to abnormal cortical organization and; (4) malformations not otherwise classi®ed. The ®rst abnormal step in TSC is illustrated by all our selected cases. It is likely due to abnormal neuronal and glial differentiation and proliferation [26]. Two populations of primitive pluripotential giant cells would be generated in the germinal matrix [15]. The ®rst one consists of normal primitive cells that become normal astroglia and neurons
forming the normal cerebral cortex. The second one consists of abnormal primitive cells which fail to clearly differentiate into neurons and glial cells [15]. An alternative, and possibly additional, mechanism could be disordered programmed cellular death in the germinal matrix. The second step determining abnormal cortical development in TSC is also illustrated by all our selected cases. It represents abnormal migration. Some of the abnormal giant primitive cells remain in the germinal matrix where they constitute subependymal tubers (all cases) and incidentally giant cell astrocytoma. Other abnormal giant cells may undergo incomplete migration, forming heterotopic clusters (case 1) and bands (case 2) of abnormal cells in the white matter extending from the subependymal zones to the subcortical white matter. Other dedifferentiated giant balloon cells may reach the cortex forming cortical tubers (cases 2 and 3). Finally abnormal cortical organization may account for some focal cortical dysplasia illustrated by cases 2±4. Barkovich et al. have classi®ed both TSC and focal cortical dysplasia with balloon cells as cortical malformations due to neuronal and glial proliferation [26]. Isolated focal cortical dysplasia may mimic the microscopic and MRI appearance of cortical tubers in TSC [21,27,28]. In this context, some authors have proposed that focal cortical
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Fig. 4. Case 4, aged 18 months. (a) Axial SE T2-weighted (TR 6300, TE 120); (b) axial 3D FFE T1-weighted (TR 32, TE 13, ¯ip angle 308) sequences showing transmantle cortical dysplasia consistent with closed lip schizencephaly or infolded cortical dysplasia. Signal intensity in the infolded cortex is similar as normal cortex (®lled in, solid ) ).
dysplasia may be a forme fruste of TSC, without associated ®ndings [27]. Cortical dysplasia may have variable pattern. The cortex can be ¯at or extends centripetally. When infolding of the cortex extends to the ventricle, it constitutes a focal transmantle dysplasia. It has been suggested that schizencephaly is an extreme variant of cortical dysplasia with the same pathogenetic process [29]. Therefore, although to our knowledge schizencephaly has not been described in TSC previously, its occurrence in case 4 appears to place this form of dysplasia at the far end of the TSC spectrum. As regards the pathophysiology of schizencephaly as we understand it in the broad context of TSC, it must be noted that although classically regarded as a disorder of cortical organization [26], it may alternatively result from abnormal neuronal and glial proliferation [25]. If genetic causes have been reported for focal cortical dysplasia and schizencephaly, inherited disorders seem less frequent in these focal malformations as a whole than in diffuse cortical malformations [30,31]. A genetic origin has been reported for example in the bilateral perisylvian pachygyria-like syndrome, schizencephaly and focal abnormalities of gyration. Some familial cases of schizencephaly may be associated with mutations of the EMX2 homeobox gene. This gene is expressed in the germinal matrix of the developing brain. Muntaner et al. [30] reported
different focal cortical malformations in the same family (focal cortical dysplasia, focal cortical infolding, schizencephaly, nodules of heterotopic grey matter) and postulated that a common genetic origin may underline, in some instances, what is basically the same type of lesion. As in other conditions, it is likely that cortical dysgenesis in TSC is the result of complex interaction between genetic susceptibility, environmental insults and the stage of the fetal brain maturation [31]. Genetic testing for TSC is not yet routinely available and it could be unreliable in some situations, such as germline mosaicism [5]. Currently, the relationship between paucisymptomatic forms of TSC and focal cortical dysplasia therefore remains problematic. 4. Conclusion The presented cases support the hypothesis that MRI brain lesions in TSC, though varied, form a spectrum of focal cerebral dysgenesis that spans along the extent and the presumed timing of the abnormal process at the cellular level. Speci®cally, they include schizencephaly, at the far end of this spectrum, which adds to previous experience of cortical dysplastic lesions in TSC. The different cortical malformations, the components of the tubers and their localization along the usual migrating pathway of neurons
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