Abstract
Structural abnormalities of the brain are increasingly recognized in patients with neurodevelopmental delay and intractable focal epilepsies. The access to clinically well-characterized neurosurgical material has provided a unique opportunity to better define the neuropathological, neurochemical, and molecular features of epilepsy-associated focal developmental lesions. These studies help to further understand the epileptogenic mechanisms of these lesions. Neuropathological evaluation of surgical specimens from patients with epilepsy-associated developmental lesions reveals two major pathologies: focal cortical dysplasia and low-grade developmental tumors (glioneuronal tumors). In the last few years there have been major advances in the recognition of a wide spectrum of developmental lesions associated with a intractable epilepsy, including cortical tubers in patients with tuberous sclerosis complex and hemimegalencephaly. As an increasing number of entities are identified, the development of a unified and comprehensive classification represents a great challenge and requires continuous updates. The present article reviews current knowledge of molecular pathogenesis and the pathophysiological mechanisms of epileptogenesis in this group of developmental disorders. Both emerging neuropathological and basic science evidence will be analyzed, highlighting the involvement of different, but often converging, pathogenetic and epileptogenic mechanisms, which may create the basis for new therapeutic strategies in these disorders.
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References
Blumcke I, Vinters HV, Armstrong D, Aronica E, Thom M, Spreafico R. Malformations of cortical development and epilepsies: neuropathological findings with emphasis on focal cortical dysplasia. Epileptic Disord 2009;11:181-193.
Sisodiya SM, Fauser S, Cross JH, Thom M. Focal cortical dysplasia type II: biological features and clinical perspectives. Lancet Neurol 2009;8:830-843.
Aronica E, Becker AJ, Spreafico R. Malformations of cortical development. Brain Pathol 2012;22:380-401.
Thom M, Blumcke I, Aronica E. Long-term epilepsy-associated tumors. Brain Pathol 2012;22:350-379.
Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012. Brain 2012;135:1348-1369.
Blumcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158-174.
Luyken C, Blumcke I, Fimmers R, et al. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 2003;44:822-830.
Louis DN, Ohgaki H, Wiestler OD, Cavanee WK. WHO classification of tumours of the central nervous system, Lyon, IARC, 2007.
Aronica E, Leenstra S, van Veelen CW, et al. Glioneuronal tumors and medically intractable epilepsy: a clinical study with long-term follow-up of seizure outcome after surgery. Epilepsy Res 2001;43:179-191.
Yang I, Chang EF, Han SJ, et al. Early surgical intervention in adult patients with ganglioglioma is associated with improved clinical seizure outcomes. J Clin Neurosci 2011;18:29-33.
Englot DJ, Berger MS, Barbaro NM, Chang EF. Factors associated with seizure freedom in the surgical resection of glioneuronal tumors. Epilepsia 2012;53:51-57.
Giulioni M, Gardella E, Rubboli G, et al. Lesionectomy in epileptogenic gangliogliomas: seizure outcome and surgical results. J Clin Neurosci 2006;13:529-535.
Im SH, Chung CK, Cho BK, et al. Intracranial ganglioglioma: preoperative characteristics and oncologic outcome after surgery. J Neurooncol 2002;59:173-183.
Thom M, Toma A, An S, et al. One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol 2011;70:859-878.
Chang EF, Christie C, Sullivan JE, et al. Seizure control outcomes after resection of dysembryoplastic neuroepithelial tumor in 50 patients. J Neurosurg Pediatr 2010;5:123-130.
de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 2011;378:1388-1395.
Nolan MA, Sakuta R, Chuang N, et al. Dysembryoplastic neuroepithelial tumors in childhood: long-term outcome and prognostic features. Neurology 2004;62:2270-2276.
Takahashi A, Hong SC, Seo DW, Hong SB, Lee M, Suh YL. Frequent association of cortical dysplasia in dysembryoplastic neuroepithelial tumor treated by epilepsy surgery. Surg Neurol 2005;64:419-427.
Lee J, Lee BL, Joo EY, et al. Dysembryoplastic neuroepithelial tumors in pediatric patients. Brain Dev 2009;31:671-681.
Sakuta R, Otsubo H, Nolan MA, et al. Recurrent intractable seizures in children with cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumor. J Child Neurol 2005;20:377-384.
Hoischen A, Ehrler M, Fassunke J, et al. Comprehensive characterization of genomic aberrations in gangliogliomas by CGH, array-based CGH and interphase FISH. Brain Pathol 2008;18:326-337.
Prabowo AS, van Thuijl HF, Scheinin I, et al. Landscape of chromosomal copy number aberrations (CNAs) in glioneuronal tumors (GNTs): relatively frequent gain of chromosome 5 and/or 7; chromothripsis in small subset of cases. In: Society for Neuro-Oncology (SNO) Scientific Meeting, San Francisco, CA, USA, 2013.
Stephens PJ, Greenman CD, Fu B, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011;144:27-40.
Blumcke I, Wiestler OD. Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. J Neuropathol Exp Neurol 2002;61:575-584.
Fauser S, Becker A, Schulze-Bonhage A, et al. CD34-immunoreactive balloon cells in cortical malformations. Acta Neuropathol 2004;108:272-278.
Kam R, Chen J, Blumcke I, et al. The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation and expression analysis. Neuropathol Appl Neurobiol 2004; 30: 225-232.
Becker AJ, Blumcke I, Urbach H, Hans V, Majores M. Molecular neuropathology of epilepsy-associated glioneuronal malformations. J Neuropathol Exp Neurol 2006;65:99-108.
Boer K, Troost D, Timmerman W, Spliet WGM, van Rijen PC, Aronica E. Pi3K-mTOR signaling and AMOG expression in epilepsy-associated glioneuronal tumors. Brain Pathol 2010;20:234-244.
Samadani U, Judkins AR, Akpalu A, Aronica E, Crino PB. Differential cellular gene expression in ganglioglioma. Epilepsia 2007;48:646-653.
Crino PB. mTOR: A pathogenic signaling pathway in developmental brain malformations. Trends Mol Med 2011;17:734-742.
Prabowo AS, Iyer AM, Veersema TJ, et al. BRAF V600E mutation is associated with mTOR signalling activation in glioneuronal tumors. Brain Pathol 2014;24:52–66.
Parry L, Maynard JH, Patel A, et al. Molecular analysis of the TSC1 and TSC2 tumour suppressor genes in sporadic glial and glioneuronal tumours. Hum Genet 2000;107:350-356.
Becker AJ, Lobach M, Klein H, et al. Mutational analysis of TSC1 and TSC2 genes in gangliogliomas. Neuropathol Appl Neurobiol 2001;27:105-114.
Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. 2010;12:621-630.
Koelsche C, Wohrer A, Jeibmann A, et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol 2013;125:891–900.
Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397-405.
Dahiya S, Haydon DH, Alvarado D, Gurnett CA, Gutmann DH, Leonard JR. BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol 2013;125:901-910.
Koelsche C, Sahm F, Paulus W, et al. BRAF V600E expression and distribution in desmoplastic infantile astrocytoma/ganglioglioma. Neuropathol Appl Neurobiol 2013 Jul 4 [Epub ahead of print].
Chappe C, Padovani L, Scavarda D, et al. Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF mutation and expression. Brain Pathol 2013;23:574-583.
Eisenhardt AE, Olbrich H, Roring M, et al. Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J Cancer 2011;129:2297-2303.
Chen B, Tardell C, Higgins B, Packman K, Boylan JF, Niu H. BRAFV600E negatively regulates the AKT pathway in melanoma cell lines. PLoS One 2012,7:e42598.
Zheng B, Jeong JH, Asara JM, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 2009;33:237-247.
Esteve-Puig R, Canals F, Colome N, Merlino G, Recio JA. Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF. PLoS One 2009;4:e4771.
Faustino A, Couto JP, Populo H, et al. mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma. J Clin Endocrinol Metab 2012;97:E1139-E1149.
Resta N, Lauriola L, Puca A, et al. Ganglioglioma arising in a Peutz-Jeghers patient: a case report with molecular implications. Acta Neuropathol 2006;112:106-111.
De Tommasi A, Luzzi S, D'Urso PI, De Tommasi C, Resta N, Ciappetta P. Molecular genetic analysis in a case of ganglioglioma: identification of a new mutation. Neurosurgery 2008;63:976-980.
van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 2007;6:421-430.
Rajneesh KF, Binder DK. Tumor-associated epilepsy. Neurosurg Focus 2009;27:E4.
de Groot M, Reijneveld JC, Aronica E, Heimans JJ. Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment. Brain 2012;135:1002-1016.
Lee JW, Wen PY, Hurwitz S, et al. Morphological characteristics of brain tumors causing seizures. Arch Neurol 2010;67:336-342.
Barba C, Coras R, Giordano F, et al. Intrinsic epileptogenicity of gangliogliomas may be independent from co-occurring focal cortical dysplasia. Epilepsy Res 2011;97:208-213.
Chassoux F, Landre E, Mellerio C, Laschet J, Devaux B, Daumas-Duport C. Dysembryoplastic neuroepithelial tumors: epileptogenicity related to histologic subtypes. Clin Neurophysiol 2013;124:1068-1078.
Ferrier CH, Aronica E, Leijten FS, et al. Electrocorticographic discharge patterns in glioneuronal tumors and focal cortical dysplasia. Epilepsia 2006;47:1477-1486.
Wolf HK, Birkholz T, Wellmer J, Blumcke I, Pietsch T, Wiestler OD. Neurochemical profile of glioneuronal lesions from patients with pharmacoresistant focal epilepsies. J Neuropathol Exp Neurol 1995;54:689-697.
Wolf HK, Buslei R, Blumcke I, Wiestler OD, Pietsch T. Neural antigens in oligodendrogliomas and dysembryoplastic neuroepithelial tumors. Acta Neuropathol 1997;94:436-443.
Aronica E, Yankaya B, Jansen GH, et al. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumors from patients with intractable epilepsy. Neuropathol Appl Neurobiol 2001;27:1-16.
Aronica E, Boer K, Becker A, et al. Gene expression profile analysis of epilepsy-associated gangliogliomas. Neuroscience 2008;151:272-292.
Fassunke J, Majores M, Tresch A, et al. Array analysis of epilepsy-associated gangliogliomas reveals expression patterns related to aberrant development of neuronal precursors. Brain 2008;131:3034-3050
Aronica E, Boer K, Redeker S, van Rijen PC, Troost D, Gorter JA. Differential expression patterns of Chloride transporters, NKCC1 and KCC2, in epilepsy-associated malformations of cortical development. Neuroscience 2007;145:185-196.
Yamada J, Okabe A, Toyoda H, Kilb W, Luhmann HJ, Fukuda A. Cl- uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1. J Physiol 2004;557:829-841.
de Groot J, Sontheimer H. Glutamate and the biology of gliomas. Glia 2011;59:1181-1189.
Seifert G, Carmignoto G, Steinhauser C. Astrocyte dysfunction in epilepsy. Brain Res Rev 2010;63:212-221.
Ye ZC, Rothstein JD, Sontheimer H. Compromised glutamate transport in human glioma cells: reduction- mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. J Neurosci 1999;19:10767-10777.
Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A. The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem Int 2000;37:163-170.
Aronica E, Gorter JA, Ijlst-Keizers H, et al. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 2003;17:2106-2118.
Ye ZC, Sontheimer H. Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 1999;59:4383-4391.
Buckingham SC, Campbell SL, Haas BR, et al. Glutamate release by primary brain tumors induces epileptic activity. Nat Med 2011;17:1269-1274.
Steinhauser C, Seifert G. Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. Eur J Pharmacol 2002;447:227-237.
Aronica E, Gorter JA, Jansen GH, Leenstra S, Yankaya B, Troost D. Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex. Acta Neuropathol 2001;101:449-459.
Zurolo E, de Groot M, Iyer A, et al. Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 beta. J Neuroinflammation 2012;9:280.
Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia 2011;52(Suppl. 3):26-32.
Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nature reviews. Neurology 2011;7:31-40.
Vezzani A, Auvin S, Ravizza T, Aronica E. Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators. In: Noebels, JL, Avoli, M, Rogawski, MA, Olsen, RW, Delgado-Escueta, AV (eds) Jasper's basic mechanisms of the epilepsies. Bethesda, MD, Oxford University Press, USA, 2012, pp. 618-629.
Aronica E, Ravizza T, Zurolo E, Vezzani A. Astrocyte immune responses in epilepsy. Glia 2012;60:1258-1268.
Aronica E, Gorter JA, Redeker S, et al. Distribution, characterization and clinical significance of microglia in glioneuronal tumours from patients with chronic intractable epilepsy. Neuropathol Appl Neurobiol 2005;31:280-291.
Prabowo AS, Iyer AM, Anink JJ, Spliet WG, van Rijen PC, Aronica E. Differential expression of major histocompatibility complex class I in developmental glioneuronal lesions. J Neuroinflammation 2013;10:12.
Ravizza T, Boer K, Redeker S, et al. The IL-1beta system in epilepsy-associated malformations of cortical development. Neurobiol Dis 2006;24:128-143.
Schmitz AK, Grote A, Raabe A, et al. Albumin storage in neoplastic astroglial elements of gangliogliomas. Seizure 2013;22:144-150.
Shamji MF, Fric-Shamji EC, Benoit BG. Brain tumors and epilepsy: pathophysiology of peritumoral changes. Neurosurg Rev 2009;32:275-284.
Schmitz F, Heit A, Dreher S, et al. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur J Immunol 2008;38:2981-2992.
Lim HK, Choi YA, Park W, et al. Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway. J Biol Chem 2003;278:45117-45127.
Weichhart T, Saemann MD. The multiple facets of mTOR in immunity. Trends Immunol 2009;30:218-226.
Dello Russo C, Lisi L, Tringali G, Navarra P. Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol 2009;78:1242-1251.
Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia 2012;53:1119-1130.
McDaniel SS, Wong M. Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis. Neurosci Lett 2011;497:231-239.
Vezzani A. Before epilepsy unfolds: finding the epileptogenesis switch. Nat Med 2012;18:1626-1627.
Wong M, Crino PB. mTOR and epileptogenesis in developmental brain malformations. In: Noebels, JL, Avoli, M, Rogawski, MA, Olsen, RW, Delgado-Escueta, AV (eds) Jasper's basic mechanisms of the epilepsies. Bethesda, MD: Oxford University Press, USA, 2012; pp. 835-842.
Aronica E, Yankaya B, Jansen GH, et al. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol 2001;27:223-237.
Aronica E, Redeker S, Boer K, et al. Inhibitory networks in epilepsy-associated gangliogliomas and in the perilesional epileptic cortex. Epilepsy Res 2007;74:33-44.
Conti L, Palma E, Roseti C, et al. Anomalous levels of Cl(-) transporters cause a decrease of GABAergic inhibition in human peritumoral epileptic cortex. Epilepsia 2011;52:1635-1644.
de Groot M, Iyer A, Zurolo E, et al. Overexpression of ADK in human astrocytic tumors and peritumoral tissue is related to tumor-associated epilepsy Epilepsia 2011;135:1002-1016.
Aronica E, Sandau US, Iyer A, Boison D. Glial adenosine kinase – A neuropathological marker of the epileptic brain. Neurochem Int 2013;63:688–695.
Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. A developmental and genetic classification for malformations of cortical development. Neurology 2005;65:1873-1887.
Spreafico R, Blumcke I. Focal cortical dysplasias: clinical implication of neuropathological classification systems. Acta Neuropathol 2010;120:359-367
Taylor DC, Falconer MA, Bruton CJ, Corsellis JA. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 1971;34:369-387.
Mischel PS, Nguyen LP, Vinters HV. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol 1995;54:137-153.
Tassi L, Colombo N, Garbelli R, et al. Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 2002;125:1719-1732.
Palmini A, Najm I, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2-S8.
Coras R, de Boer OJ, Armstrong D, et al. Good interobserver and intraobserver agreement in the evaluation of the new ILAE classification of focal cortical dysplasias. Epilepsia 2012;53:1341-1348.
Chamberlain WA, Cohen ML, Gyure KA, et al. Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development). Epilepsia 2009;50:2593-2598.
Krsek P, Pieper T, Karlmeier A, et al. Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II. Epilepsia 2009;50:125-137.
Tassi L, Garbelli R, Colombo N, et al. Type I focal cortical dysplasia: surgical outcome is related to histopathology. Epileptic Disord 2010;12:181-191.
Blumcke I, Pieper T, Pauli E, et al. A distinct variant of focal cortical dysplasia type I characterised by magnetic resonance imaging and neuropathological examination in children with severe epilepsies. Epileptic Disord 2010;12:172-180.
Rakic P, Lombroso PJ. Development of the cerebral cortex: I. Forming the cortical structure. J Am Acad Child Adolesc Psychiatry 1998;37:116-117.
Blumcke I, Muhlebner A. Neuropathological work-up of focal cortical dysplasias using the new ILAE consensus classification system – practical guideline article invited by the Euro-CNS Research Committee. Clin Neuropathol 2011;30:164-177.
Sisodiya S. Epilepsy: the new order-classifying focal cortical dysplasias. Nature Rev Neurol 2011;7:129-130.
Garbelli R, Meroni A, Magnaghi G, et al. Architectural (Type IA) focal cortical dysplasia and parvalbumin immunostaining in temporal lobe epilepsy. Epilepsia 2006;47:1074-1078.
Thom M, Eriksson S, Martinian L, et al. Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features. J Neuropathol Exp Neurol 2009;68:928-938.
Hadjivassiliou G, Martinian L, Squier W, et al. The application of cortical layer markers in the evaluation of cortical dysplasias in epilepsy. Acta Neuropathol 2010;120:517-528.
Shepherd C, Liu J, Goc J, et al. A quantitative study of white matter hypomyelination and oligodendroglial maturation in focal cortical dysplasia type II. Epilepsia 2013;54:898-908.
Muhlebner A, Coras R, Kobow K, et al. Neuropathologic measurements in focal cortical dysplasias: validation of the ILAE 2011 classification system and diagnostic implications for MRI. Acta Neuropathol 2012;123:259-272.
Fauser S, Essang C, Altenmuller DM, et al. Is there evidence for clinical differences related to the new classification of temporal lobe cortical dysplasia? Epilepsia 2013;54:909-917.
ECTS C. Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell 1993;75:1305-1315.
van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805-808.
Baybis M, Yu J, Lee A, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol 2004;56:478-487.
Miyata H, Chiang AC, Vinters HV. Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann Neurol 2004;56:510-519.
Orlova KA, Tsai V, Baybis M, et al. Early progenitor cell marker expression distinguishes type II from type I focal cortical dysplasias. J Neuropathol Exp Neurol 2010;69:850-863.
Lim KC, Crino PB. Focal malformations of cortical development: New vistas for molecular pathogenesis. Neuroscience 2013;252:262-276.
Schick V, Majores M, Koch A, et al. Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions. Epilepsia 2007;48(Suppl. 5):65-73.
Iyer A, Zurolo E, Spliet WG, et al. Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 2010;51:1763-1773.
Iyer A, Prabowo A, Anink J, Spliet WG, van Rijen PC, Aronica E. Cell injury and premature neurodegeneration in focal malformations of cortical development. Brain Pathol 2014;24:1–17.
Schick V, Majores M, Engels G, et al. Differential Pi3K-pathway activation in cortical tubers and focal cortical dysplasias with balloon cells. Brain Pathol 2007;17:165-173.
Han S, Santos TM, Puga A, et al. Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer Res 2004;64:812-816.
Trinh XB, Tjalma WA, Vermeulen PB, et al. The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer. Br J Cancer 2009;100:971-978.
Majores M, Blumcke I, Urbach H, et al. Distinct allelic variants of TSC1 and TSC2 in epilepsy-associated cortical malformations without balloon cells. J Neuropathol Exp Neurol 2005;64:629-637.
Lugnier C, Majores M, Fassunke J, et al. Hamartin variants that are frequent in focal dysplasias and cortical tubers have reduced tuberin binding and aberrant subcellular distribution in vitro. J Neuropathol Exp Neurol 2009;68:1136-1146.
Chen J, Tsai V, W.E. Parker, Aronica E, Baybis M, Crino PB. Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol 2012;72:881-892
Liu S, Lu L, Cheng X, Xu G, Yang H. Viral infection and focal cortical dysplasia. Ann Neurol 2013 Oct 4 [Epub ahead of print].
Spangle JM, Munger K. The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesis. J Virol 2010;84:9398-9407.
Ichimura Y, Komatsu M. Selective degradation of p62 by autophagy. Semin Immunopathol 2010;32:431-436.
Komatsu M, Kageyama S, Ichimura Y. p62/SQSTM1/A170: Physiology and pathology. Pharmacol Res 2012;66:457-462.
Yasin SA, Ali AM, Tata M, et al. mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis. Acta Neuropathol 2013;126:207-218.
Zhou X, Ikenoue T, Chen X, Li L, Inoki K, Guan KL. Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. Proc Natl Acad Sci U S A 2009;106:8923-8928.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274-293.
Boer K, Crino PB, Gorter JA, et al. Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors. Brain Pathol 2010;20:704-719.
Sisodiya SM, Thom M, Lin WR, Bajaj NP, Cross JH, Harding BN. Abnormal expression of cdk5 in focal cortical dysplasia in humans. Neurosci Lett 2002;328:217-220.
Boer K, Lucassen PJ, Spliet WG, et al. Doublecortin-like (DCL) expression in focal cortical dysplasia and cortical tubers. Epilepsia 2009;50:2629-2637.
Srikandarajah N, Martinian L, Sisodiya SM, et al. Doublecortin expression in focal cortical dysplasia in epilepsy. Epilepsia 2009;50:2619-2628.
Lamparello P, Baybis M, Pollard J, et al. Developmental lineage of cell types in cortical dysplasia with balloon cells. Brain 2007;130:2267-2276.
Palmini A, Gambardella A, Andermann F, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995;37:476-487.
Bast T, Ramantani G, Seitz A, Rating D. Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults. Acta Neurol Scand 2006;113:72-81.
Matsumoto R, Kinoshita M, Taki J, et al. In vivo epileptogenicity of focal cortical dysplasia: a direct cortical paired stimulation study. Epilepsia 2005;46:1744-1749.
Otsubo H, Iida K, Oishi M, et al. Neurophysiologic findings of neuronal migration disorders: intrinsic epileptogenicity of focal cortical dysplasia on electroencephalography, electrocorticography, and magnetoencephalography. J Child Neurol 2005;20:357-363.
Cepeda C, Andre VM, Flores-Hernandez J, et al. Pediatric cortical dysplasia: correlations between neuroimaging, electrophysiology and location of cytomegalic neurons and balloon cells and glutamate/GABA synaptic circuits. Dev Neurosci 2005;27:59-76.
Fauser S, Sisodiya SM, Martinian L, et al. Multi-focal occurrence of cortical dysplasia in epilepsy patients. Brain 2009;132:2079-2090.
Najm I, Ying Z, Babb T, et al. Mechanisms of epileptogenicity in cortical dysplasias. Neurology 2004;62:S9-S13.
Avoli M, Louvel J, Pumain R, Kohling R. Cellular and molecular mechanisms of epilepsy in the human brain. Prog Neurobiol 2005;77:166-200.
Cepeda C, Andre VM, Levine MS, et al. Epileptogenesis in pediatric cortical dysplasia: The dysmature cerebral developmental hypothesis. Epilepsy Behav 2006;9:219-235.
Ying Z, Babb TL, Mikuni N, Najm I, Drazba J, Bingaman W. Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex. Exp Neurol 1999;159:409-418.
Crino PB, Duhaime AC, Baltuch G, White R. Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology 2001;56:906-913.
Moddel G, Jacobson B, Ying Z, et al. The NMDA receptor NR2B subunit contributes to epileptogenesis in human cortical dysplasia. Brain Res 2005;1046:10-23.
Finardi A, Gardoni F, Bassanini S, et al. NMDA receptor composition differs among anatomically diverse malformations of cortical development. J Neuropathol Exp Neurol 2006;65:883-893.
Qu M, Aronica E, Boer K, et al. DLG3/SAP102 protein expression in malformations of cortical development: a study of human epileptic cortex by tissue microarray. Epilepsy Res 2009;84:33-41.
Finardi A, Colciaghi F, Castana L, et al. Long-duration epilepsy affects cell morphology and glutamatergic synapses in type IIB focal cortical dysplasia. Acta Neuropathol 2013;126:219-235.
Aronica E, Gorter JA, Jansen GH, et al. Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia. Epilepsia 2003;44:785-795.
Garbelli R, Munari C, De Biasi S, et al. Taylor's cortical dysplasia: a confocal and ultrastructural immunohistochemical study. Brain Pathol 1999;9:445-461.
Spreafico R, Battaglia G, Arcelli P, et al. Cortical dysplasia: an immunocytochemical study of three patients. Neurology 1998;50:27-36.
Spreafico R, Tassi L, Colombo N, et al. Inhibitory circuits in human dysplastic tissue. Epilepsia 2000;41:S168-S173.
Zamecnik J, Krsek P, Druga R, et al. Densities of parvalbumin-immunoreactive neurons in non-malformed hippocampal sclerosis-temporal neocortex and in cortical dysplasias. Brain Res Bull 2006;68:474-481.
D'Antuono M, Louvel J, Kohling R, et al. GABAA receptor-dependent synchronization leads to ictogenesis in the human dysplastic cortex. Brain 2004;127:1626-1640.
Aronica E, Boer K, Redeker S, et al. Differential expression patterns of chloride transporters, Na + -K + -2Cl–cotransporter and K + -Cl–cotransporter, in epilepsy-associated malformations of cortical development. Neuroscience 2007;145:185-196.
Talos DM, Sun H, Kosaras B, et al. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann Neurol 2012;71:539-551.
Aronica E, Boer K, Doorn KJ, et al. Expression and localization of voltage dependent potassium channel Kv4.2 in epilepsy associated focal lesions. Neurobiol Dis 2009;36:81-95.
Binder DK, Steinhauser C. Functional changes in astroglial cells in epilepsy. Glia 2006;54:358-368.
Wong M. Mechanisms of epileptogenesis in tuberous sclerosis complex and related malformations of cortical development with abnormal glioneuronal proliferation. Epilepsia 2008;49:8-21.
Seifert G, Steinhauser C. Neuron-astrocyte signaling and epilepsy. Exp Neurol 2011;244:4-10.
Garbelli R, Frassoni C, Condorelli DF, et al. Expression of connexin 43 in the human epileptic and drug-resistant cerebral cortex. Neurology 2011;76:895-902.
Ulu MO, Tanriverdi T, Oz B, et al. The expression of astroglial glutamate transporters in patients with focal cortical dysplasia: an immunohistochemical study. Acta Neurochir 2010;152:845-853.
Medici V, Frassoni C, Tassi L, Spreafico R, Garbelli R. Aquaporin 4 expression in control and epileptic human cerebral cortex. Brain Res 2011;1367:330-339.
Konopka A, Grajkowska W, Ziemianska K, et al. Matrix metalloproteinase-9 (MMP-9) in human intractable epilepsy caused by focal cortical dysplasia. Epilepsy Res 2013;104:45-58.
Zamecnik J, Homola A, Cicanic M, et al. The extracellular matrix and diffusion barriers in focal cortical dysplasias. Eur J Neurosci 2012;36:2017-2024.
Boer K, Spliet WG, van Rijen PC, Redeker S, Troost D, Aronica E. Evidence of activated microglia in focal cortical dysplasia. J Neuroimmunol 2006;173:188-195.
Choi J, Nordli DR, Jr., Alden TD, et al. Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflammation 2009;6:38.
Iyer AM, Zurolo E, Boer K, et al. Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies. Neuroscience 2010;19:929-945.
Heinemann U, Kaufer D, Friedman A. Blood-brain barrier dysfunction, TGFbeta signaling, and astrocyte dysfunction in epilepsy. Glia 2012;60:1251-1257.
Zurolo E, Iyer A, Maroso M, et al. Activation of Toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development. Brain 2011;134:1015-1032.
Balosso S, Maroso M, Sanchez-Alavez M, et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain 2008;131:3256-3265.
Maroso M, Balosso S, Ravizza T, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 2010;16:413-419 .
Iori V, Maroso M, Rizzi M, et al. Receptor for advanced glycation endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures. Neurobiol Dis 2013;58C:102-114.
Curatolo P, Verdecchia M, Bombardieri R. Tuberous sclerosis complex: a review of neurological aspects. Eur J Paed Neurol 2002;6:15-23.
Bolton PF. Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis. Ment Retard Dev Disabil Res Rev 2004;10:126-131.
Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68:64-80.
Nellist M, Sancak O, Goedbloed MA, et al. Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur J Hum Genet 2005;13:59-68.
Au KS, Williams AT, Roach ES, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med 2007;9:88-100.
Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol 2013;125:317-332.
Mizuguchi M, Takashima S. Neuropathology of tuberous sclerosis. Brain Dev 2001;23:508-515.
DiMario FJ, Jr. Brain abnormalities in tuberous sclerosis complex. J Child Neurol 2004;19:650-657.
Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345-1356.
Boer K, Troost D, Jansen F, et al. Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex. Neuropathology 2008;28:577-590.
Grajkowska W, Kotulska K, Jurkiewicz E, Matyja E. Brain lesions in tuberous sclerosis complex. Review. Folia Neuropathol 2010;48:139-149.
Crino PB, Trojanowski JQ, Dichter MA, Eberwine J. Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc Natl Acad Sci U S A 1996;93:14152-14157.
Lee A, Maldonado M, Baybis M, et al. Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol 2003;53:668-673.
Talos DM, Kwiatkowski DJ, Cordero K, Black PM, Jensen FE. Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann Neurol 2008;63:454-465.
Chen CP, Su YN, Hung CC, Shih JC, Wang W. Novel mutation in the TSC2 gene associated with prenatally diagnosed cardiac rhabdomyomas and cerebral tuberous sclerosis. J Formos Med Assoc 2006;105:599-603.
Wortmann SB, Reimer A, Creemers JW, Mullaart RA. Prenatal diagnosis of cerebral lesions in Tuberous sclerosis complex (TSC). Case report and review of the literature. Eur J Paediatr Neurol 2008;12:123-126.
Glenn OA. MR imaging of the fetal brain. Pediatr Radiol 2010;40:68-81.
Park SH, Pepkowitz SH, Kerfoot C, et al. Tuberous sclerosis in a 20-week gestation fetus197immunohistochemical study. Acta Neuropathol 1997;94:180-186.
Prabowo AS, Anink JJ, Lammens M, et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 2013;23:45-59
Boer K, Jansen F, Nellist M, et al. Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res 2008;78:7-21.
Sosunov AA, Wu X, Weiner HL, et al. Tuberous sclerosis: a primary pathology of astrocytes? Epilepsia 2008;49(Suppl. 2):53-62.
Wong M, Crino PB. Tuberous sclerosis and epilepsy: role of astrocytes. Glia 2012;60:1244-1250.
Chu-Shore CJ, Major P, Montenegro M, Thiele E. Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex. Neurology 2009;72:1165-1169.
Chu-Shore CJ, Frosch MP, Grant PE, Thiele EA. Progressive multifocal cystlike cortical tubers in tuberous sclerosis complex: Clinical and neuropathologic findings. Epilepsia 2009;50:2648-2651.
207Gallagher A, Grant EP, Madan N, Jarrett DY, Lyczkowski DA, Thiele EA. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol 2010;257:1373-1381.
Parker WE, Orlova KA, Heuer GG, et al. Enhanced epidermal growth factor, hepatocyte growth factor, and vascular endothelial growth factor expression in tuberous sclerosis complex. Am J Pathol 2011;178:296-305.
Marcotte L, Aronica E, Baybis M, Crino PB. Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex. Acta Neuropathol 2012;123:685-693.
Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 2004;63:1236-1242.
Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008;412:179-190.
Tsai V, Parker WE, Orlova KA, et al. Fetal Brain mTOR signaling activation in tuberous sclerosis complex. Cereb Cortex 2012 Oct 18 [Epub ahead of print].
Al-Saleem T, Wessner LL, Scheithauer BW, et al. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 1998;83:2208-2216.
Green AJ, Smith M, Yates JR. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet 1994;6:193-196.
Jozwiak J, Jozwiak S. Giant cells: contradiction to two-hit model of tuber formation? Cell Mol Neurobiol 2005;25:795-805.
Crino PB, Aronica E, Baltuch G, Nathanson KL. Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 2010;74:1716-1723.
Qin W, Chan JA, Vinters HV, et al. Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events. Brain Pathol 2010;20:1096-1105.
Connolly MB, Hendson G, Steinbok P. Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects. Childs Nervous System 2006;22:896-908.
Weiner HL, Carlson C, Ridgway EB, et al. Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics 2006;117:1494-1502.
Bollo RJ, Kalhorn SP, Carlson C, Haegeli V, Devinsky O, Weiner HL. Epilepsy surgery and tuberous sclerosis complex: special considerations. Neurosurg Focus 2008;25:E13.
Major P, Rakowski S, Simon MV, et al. Are cortical tubers epileptogenic? Evidence from electrocorticography. Epilepsia 2009;50:147-154.
Ma TS, Elliott RE, Ruppe V, et al. Electrocorticographic evidence of perituberal cortex epileptogenicity in tuberous sclerosis complex. J Neurosurg Pediatr 2012;10:376-382.
Koh S, Jayakar P, Dunoyer C, et al. Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome. Epilepsia 2000;41:1206-1213.
Wang Y, Greenwood JS, Calcagnotto ME, Kirsch HE, Barbaro NM, Baraban SC. Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Ann Neurol 2007;61:139-152.
Holmes GL, Stafstrom CE, Tuberous Sclerosis Study G. Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia 2007;48:617-630
White R, Hua Y, Scheithauer B, Lynch DR, Henske EP, Crino PB. Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers. Ann Neurol 2001;49:67-78.
Boer K, Troost D, Timmermans W, et al. Cellular localization of metabotropic glutamate receptors in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Neuroscience 2008;156:203-215.
Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 2005;8:1727-1734.
Xu L, Zeng LH, Wong M. Impaired astrocytic gap junction coupling and potassium buffering in a mouse model of tuberous sclerosis complex. Neurobiol Dis 2009;34:291-299.
Trounce JQ, Rutter N, Mellor DH. Hemimegalencephaly: diagnosis and treatment. Dev Med Child Neurol 1991;33:261-266.
Janszky J, Ebner A, Kruse B, et al. Functional organization of the brain with malformations of cortical development. Ann Neurol 2003;53:759-767.
Sanghvi JP, Rajadhyaksha SB, Ursekar M. Spectrum of congenital CNS malformations in pediatric epilepsy. Indian Pediatr 2004;41:831-838.
Sasaki M, Hashimoto T, Furushima W, et al. Clinical aspects of hemimegalencephaly by means of a nationwide survey. J Child Neurol 2005;20:337-341.
Tinkle BT, Schorry EK, Franz DN, Crone KR, Saal HM. Epidemiology of hemimegalencephaly: a case series and review. Am J Med Genet A 2005;139:204-211.
Jonas R, Nguyen S, Hu B, et al. Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 2004;62:1712-1721.
Flores-Sarnat L. Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 2002;17:373-384.
Sarnat HB, Flores-Sarnat L. Integrative classification of morphology and molecular genetics in central nervous system malformations. Am J Med Genet A 2004;126:386-392.
Kwa VI, Smitt JH, Verbeeten BW, Barth PG. Epidermal nevus syndrome with isolated enlargement of one temporal lobe: a case report. Brain Dev 1995;17:122-125.
D'Agostino MD, Bastos A, Piras C, et al. Posterior quadrantic dysplasia or hemi-hemimegalencephaly: a characteristic brain malformation. Neurology 2004;62:2214-2220.
Nakahashi M, Sato N, Yagishita A, et al. Clinical and imaging characteristics of localized megalencephaly: a retrospective comparison of diffuse hemimegalencephaly and multilobar cortical dysplasia. Neuroradiology 2009;51:821-830.
Flores-Sarnat L, Sarnat HB, Davila-Gutierrez G, Alvarez A. Hemimegalencephaly: part 2. Neuropathology suggests a disorder of cellular lineage. J Child Neurol 2003;18:776-785.
Manoranjan B, Provias JP. Hemimegalencephaly: a fetal case with neuropathological confirmation and review of the literature. Acta Neuropathol 2010;120:117-130.
Robain O, Floquet C, Heldt N, Rozenberg F. Hemimegalencephaly: a clinicopathological study of four cases. Neuropathol Appl Neurobiol 1988;14:125-135.
De Rosa MJ, Secor DL, Barsom M, Fisher RS, Vinters HV. Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric, and ultrastructural study. Acta Neuropathol 1992;84:250-260
Yasha TC, Santosh V, Das S, Shankar SK. Hemimegalencephaly—morphological and immunocytochemical study. Clin Neuropathol 1997;16:17-22.
Antonelli A, Chiaretti A, Amendola T, Piastra M, Di Rocco C, Aloe L. Nerve growth factor and brain-derived neurotrophic factor in human paediatric hemimegalencephaly. Neuropediatrics 2004;35:39-44.
Salamon N, Andres M, Chute DJ, et al. Contralateral hemimicrencephaly and clinical-pathological correlations in children with hemimegalencephaly. Brain 2006;129:352-365.
Boer K, Troost D, Spliet WG, Redeker S, Crino PB, Aronica E. A neuropathological study of two autopsy cases of syndromic hemimegalencephaly. Neuropathol Appl Neurobiol 2007;33:455-470.
Sarnat HB, Flores-Sarnat L, Crino P, Hader W, Bello-Espinosa L. Hemimegalencephaly: foetal tauopathy with mTOR hyperactivation and neuronal lipidosis. Folia Neuropathol 2012;50:330-345.
Takashima S, Chan F, Becker LE, Kuruta H. Aberrant neuronal development in hemimegalencephaly: immunohistochemical and Golgi studies. Pediatr Neurol 1991;7:275-280.
Kato M, Mizuguchi M, Sakuta R, Takashima S. Hypertrophy of the cerebral white matter in hemimegalencephaly. Pediatr Neurol 1996;14:335-338.
Yu J, Baybis M, Lee A, et al. Targeted gene expression analysis in hemimegalencephaly: activation of beta-catenin signaling. Brain Pathol 2005;15:179-186.
Crino PB. Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly. J Child Neurol 2005;20:330-336.
Aronica E, Boer K, Baybis M, Yu J, Crino P. Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly. Acta Neuropathol 2007;114:287-293.
Crino PB. Focal brain malformations: seizures, signaling, sequencing. Epilepsia 2009;50(Suppl. 9):3-8.
Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia 2010;51:27-36.
Baybis M, Aronica E, Nathanson KL, Crino PB. Deletion of 15q11.2-15q13.1 in isolated human hemimegalencephaly. Acta Neuropathol 2009;118:821-823.
Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 2012;44:941-945.
Baybis M, Lynch D, Lee A, et al. Altered expression of neurotransmitter-receptor subunit and uptake site mRNAs in hemimegalencephaly. Epilepsia 2004;45:1517-1524.
Acknowledgments
EA is supported by the National Epilepsy Fund, “Power of the Small”; the Hersenstichting Nederland (NEF 012-12); and KIKA (Stichting Kinderen Kankervrij) and European Union Seventh Framework Programme FP7/2007-2013 under the project EPISTOP (grant agreement n°: 602391). PBC is supported by R01NS082343-01 and Citizens United for Research in Epilepsy.
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Aronica, E., Crino, P.B. Epilepsy Related to Developmental Tumors and Malformations of Cortical Development. Neurotherapeutics 11, 251–268 (2014). https://doi.org/10.1007/s13311-013-0251-0
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DOI: https://doi.org/10.1007/s13311-013-0251-0