mTOR dysregulation and tuberous sclerosis-related epilepsy

References

• Sabers CJ, Martin MM, Brunn GJ, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995;270:815–822.
   PubMed Web of Science ®Google Scholar
• Crino PB. Rapamycin and tuberous sclerosis complex: from Easter Island to epilepsy. Ann Neurol. 2008;63:415–417.
   PubMed Web of Science ®Google Scholar
• Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–293.
   PubMed Web of Science ®Google Scholar
• Switon K, Kotulska K, Janusz-Kaminska A, et al. Molecular neurobiology of mTOR. Neuroscience. 2017;341:112–153.
   PubMed Web of Science ®Google Scholar
• Graber TE, McCamphill PK, Sossin WS. A recollection of mTOR signaling in learning and memory. Learn Mem. 2013;20:518–530.
   PubMed Web of Science ®Google Scholar
• Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 2010;33:67–75.
   PubMed Web of Science ®Google Scholar
• Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci. 2014;7:28.
   PubMed Web of Science ®Google Scholar
• Bockaert J, Marin P. mTOR in brain physiology and pathologies. Physiol Rev. 2015;95:1157–1187.
   PubMed Web of Science ®Google Scholar
• Osborne LR. Caveat mTOR: aberrant signaling disrupts corticogenesis. J Clin Invest. 2010;120:1392–1395.
   PubMed Web of Science ®Google Scholar
• Crino PB. mTOR: a pathogenic signaling pathway in developmental brain malformations. Trends Mol Med. 2011;17:734–742.
   PubMed Web of Science ®Google Scholar
• Garza-Lombo C, Gonsebatt ME. Mammalian target of rapamycin: its role in early neural development and in adult and aged brain function. Front Cell Neurosci. 2016;10:157.
   PubMed Web of Science ®Google Scholar
• Lee DY. Roles of mTOR signaling in brain development. Exp Neurobiol. 2015;24:177–185.
   PubMed Web of Science ®Google Scholar
• Wood TL, Bercury KK, Cifelli SE, et al. mTOR: a link from the extracellular milieu to transcriptional regulation of oligodendrocyte development. ASN Neuro. 2013;5:e00108.
   PubMed Web of Science ®Google Scholar
• Bercury KK, Dai J, Sachs HH, et al. Conditional ablation of raptor or rictor has differential impact on oligodendrocyte differentiation and CNS myelination. J Neurosci. 2014;34:4466–4480.
   PubMed Web of Science ®Google Scholar
• Lebrun-Julien F, Bachmann L, Norrmen C, et al. Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination. J Neurosci. 2014;34:8432–8448.
   PubMed Web of Science ®Google Scholar
• Carson RP, Kelm ND, West KL, et al. Hypomyelination following deletion of Tsc2 in oligodendrocyte precursors. Ann Clin Transl Neurol. 2015;2:1041–1054.
   PubMed Web of Science ®Google Scholar
• Ercan E, Han JM, Di Nardo A, et al. Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex. J Exp Med. 2017;214:681–697.
   PubMed Web of Science ®Google Scholar
• Wong M. A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev Neurother. 2013;13:657–669.
   PubMed Web of Science ®Google Scholar
• Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014;84:275–291.
   PubMed Web of Science ®Google Scholar
• Crino PB. mTOR signaling in epilepsy: insights from malformations of cortical development. Cold Spring Harb Perspect Med. 2015;5. https://www.ncbi.nlm.nih.gov/pubmed/25833943.
   PubMed Web of Science ®Google Scholar
• Crino PB. The mTOR signalling cascade: paving new roads to cure neurological disease. Nat Rev Neurol. 2016;12:379–392.
   PubMed Web of Science ®Google Scholar
• Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–976.
   PubMed Web of Science ®Google Scholar
• Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia. 2012;53:1119–1130.
   PubMed Web of Science ®Google Scholar
• Liu J, Reeves C, Michalak Z, et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun. 2014;2:71.
   PubMed Web of Science ®Google Scholar
• Drion CM, Borm LE, Kooijman L, et al. Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats. Epilepsia. 2016;57:688–697.
   PubMed Web of Science ®Google Scholar
• Van Vliet EA, Otte WM, Wadman WJ, et al. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: magnetic resonance imaging. Epilepsia. 2016;57:59–69.
   PubMed Web of Science ®Google Scholar
• Curatolo P, Verdecchia M, Bombardieri R. Tuberous sclerosis complex: a review of neurological aspects. Eur J Paediatr Neurol. 2002;6:15–23.
   PubMedGoogle Scholar
• Bolton PF. Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis. Ment Retard Dev Disabil Res Rev. 2004;10:126–131.
   PubMedGoogle Scholar
• Connolly MB, Hendson G, Steinbok P. Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects. Childs Nerv Syst. 2006;22:896–908.
   PubMed Web of Science ®Google Scholar
• Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol. 2015;52:281–289.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Van Slegtenhorst M, Verhoef S, Tempelaars A, et al. Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. J Med Genet. 1999;36:285–289.
   PubMed Web of Science ®Google Scholar
• Au KS, Williams AT, Gambello MJ, et al. Molecular genetic basis of tuberous sclerosis complex: from bench to bedside. J Child Neurol. 2004;19:699–709.
   PubMed Web of Science ®Google Scholar
• Nellist M, Brouwer RW, Kockx CEM, et al. Targeted next generation sequencing reveals previously unidentified TSC1 and TSC2 mutations. BMC Med Genet. 2015. DOI:10.1186/s12881-015-0155-4.
   PubMed Web of Science ®Google Scholar
• Martin KR, Zhou W, Bowman MJ, et al. The genomic landscape of tuberous sclerosis complex. Nat Commun. 2017;8:15816.
   PubMed Web of Science ®Google Scholar
• Laplante M, Sabatini DM. mTOR signaling. Cold Spring Harb Perspect Biol. 2012 Feb 1;4(2), pii: a011593.
   PubMed Web of Science ®Google Scholar
• Tee AR, Sampson JR, Pal DK, et al. The role of mTOR signalling in neurogenesis, insights from tuberous sclerosis complex. Semin Cell Dev Biol. 2016;52:12–20.
   PubMed Web of Science ®Google Scholar
• Aronica E, Crino PB. Epilepsy related to developmental tumors and malformations of cortical development. Neurotherapeutics. 2014;11:251–268.
   PubMed Web of Science ®Google Scholar
• Aronica E, Mühlebner A. Neuropathology of epilepsy. In: Kovacs G, Alafuzoff I, editors. Handbook of clinical neurology. Amsterdam: Elsevier; 2017. 3rd Series
   Google Scholar
• Curatolo P, Moavero R, De Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14:733–745.
   PubMed Web of Science ®Google Scholar
• Mizuguchi M, Takashima S. Neuropathology of tuberous sclerosis. Brain Dev. 2001;23:508–515.
   PubMed Web of Science ®Google Scholar
• DiMario FJ Jr. Brain abnormalities in tuberous sclerosis complex. J Child Neurol. 2004;19:650–657.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Bollo RJ, Kalhorn SP, Carlson C, et al. Epilepsy surgery and tuberous sclerosis complex: special considerations. Neurosurg Focus. 2008;25:E13.
   PubMed Web of Science ®Google Scholar
• Wang Y, Greenwood JS, Calcagnotto ME, et al. Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Ann Neurol. 2007;61:139–152.
   PubMed Web of Science ®Google Scholar
• Madhavan D, Weiner HL, Carlson C, et al. Local epileptogenic networks in tuberous sclerosis complex: a case review. Epilepsy Behav. 2007;11:140–146.
   PubMed Web of Science ®Google Scholar
• Moshel YA, Elliott R, Teutonico F, et al. Do tubers contain function? Resection of epileptogenic foci in perirolandic cortex in children with tuberous sclerosis complex. Epilepsia. 2010;51:1242–1251.
   PubMed Web of Science ®Google Scholar
• Fallah A, Rodgers SD, Weil AG, et al. Resective epilepsy surgery for tuberous sclerosis in children: determining predictors of seizure outcomes in a multicenter retrospective cohort study. Neurosurgery. 2015;77: 517–524. discussion 24.
   PubMed Web of Science ®Google Scholar
• Fujiwara H, Leach JL, Greiner HM, et al. Resection of ictal high frequency oscillations is associated with favorable surgical outcome in pediatric drug resistant epilepsy secondary to tuberous sclerosis complex. Epilepsy Res. 2016;126:90–97.
   PubMed Web of Science ®Google Scholar
• Liang S, Zhang J, Yang Z, et al. Long-term outcomes of epilepsy surgery in tuberous sclerosis complex. J Neurol. 2017;264:1146–1154.
   PubMed Web of Science ®Google Scholar
• Kannan L, Vogrin S, Bailey C, et al. Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis. Brain. 2016;139:2653–2667.
   PubMed Web of Science ®Google Scholar
• Okanishi T, Akiyama T, Tanaka S, et al. Interictal high frequency oscillations correlating with seizure outcome in patients with widespread epileptic networks in tuberous sclerosis complex. Epilepsia. 2014;55:1602–1610.
   PubMed Web of Science ®Google Scholar
• Luat AF, Makki M, Chugani HT. Neuroimaging in tuberous sclerosis complex. Curr Opin Neurol. 2007;20:142–150.
   PubMed Web of Science ®Google Scholar
• Griffiths PD, Batty R, Warren D, et al. The use of MR imaging and spectroscopy of the brain in children investigated for developmental delay: what is the most appropriate imaging strategy? Eur Radiol. 2011;21:1820–30.
   PubMed Web of Science ®Google Scholar
• Marcotte L, Aronica E, Baybis M, et al. Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex. Acta Neuropathol. 2012;123:685–693.
   PubMed Web of Science ®Google Scholar
• Sosunov AA, McGovern RA, Mikell CB, et al. Epileptogenic but MRI-normal perituberal tissue in tuberous sclerosis complex contains tuber-specific abnormalities. Acta Neuropathol Commun. 2015;3:17.
   PubMed Web of Science ®Google Scholar
• Caban C, Khan N, Hasbani DM, et al. Genetics of tuberous sclerosis complex: implications for clinical practice. Appl Clin Genet. 2017;10:1–8.
   PubMedGoogle Scholar
• Bongaart A, Giannikou G, Reinten RJ, et al. Subependymal giant cell astrocytomas in tuberous sclerosis complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations. Oncotarget 2017 (in press).
   Google Scholar
• Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345–1356.
   PubMed Web of Science ®Google Scholar
• Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci. 2010;1184:87–105.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Grajkowska W, Kotulska K, Jurkiewicz E, et al. Brain lesions in tuberous sclerosis complex. Folia Neuropathol. 2010;48(3):139–149.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Aronica E, Becker AJ, Spreafico R. Malformations of cortical development. Brain Pathol. 2012;22:380–401.
   PubMed Web of Science ®Google Scholar
• Muhlebner A, Iyer AM, Van Scheppingen J, et al. Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis omplex (TSC): evidence from layer-specific marker expression. J Neurodev Disord. 2016;8:9.
   PubMed Web of Science ®Google Scholar
• Crino PB, Trojanowski JQ, Dichter MA, et al. Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc Natl Acad Sci U S A. 1996;93:14152–14157.
   PubMed Web of Science ®Google Scholar
• Lee A, Maldonado M, Baybis M, et al. Markers of cellular proliferation are expressed in cortical tubers. Annals Neurol. 2003;53:668–673.
   PubMed Web of Science ®Google Scholar
• Talos DM, Kwiatkowski DJ, Cordero K, et al. Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann Neurol. 2008;63:454–465.
   PubMed Web of Science ®Google Scholar
• Boer K, Lucassen PJ, Spliet WG, et al. Doublecortin-like (DCL) expression in focal cortical dysplasia and cortical tubers. Epilepsia. 2009;50:2629–2637.
   PubMedGoogle Scholar
• Muhlebner A, van Scheppingen J, Hulshof HM, et al. Novel histopathological patterns in cortical tubers of epilepsy surgery patients with tuberous sclerosis complex. PLoS One. 2016;11:e0157396.
   PubMed Web of Science ®Google Scholar
• Chu-Shore CJ, Major P, Montenegro M et al. Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex. Neurology. 2009;72:1165–1169.
   PubMed Web of Science ®Google Scholar
• Chu-Shore CJ, Frosch MP, Grant PE, et al. Progressive multifocal cystlike cortical tubers in tuberous sclerosis complex: clinical and neuropathologic findings. Epilepsia. 2009;50:2648–2651.
   PubMed Web of Science ®Google Scholar
• Sosunov AA, Wu X, Weiner HL, et al. Tuberous sclerosis: a primary pathology of astrocytes? Epilepsia. 2008;49(Suppl 2):53–62.
   PubMedGoogle Scholar
• Glenn OA, Barkovich AJ. Magnetic resonance imaging of the fetal brain and spine: an increasingly important tool in prenatal diagnosis, part 1. AJNR. Am J Neuroradiol. 2006;27:1604–1611.
   PubMed Web of Science ®Google Scholar
• Chen CP, Su YN, Hung CC, et al. Novel mutation in the TSC2 gene associated with prenatally diagnosed cardiac rhabdomyomas and cerebral tuberous sclerosis. J Formos Med Assoc. 2006;105:599–603.
   PubMed Web of Science ®Google Scholar
• Wortmann SB, Reimer A, Creemers JW et al. 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
   PubMed Web of Science ®Google Scholar
• Park SH, Pepkowitz SH, Kerfoot C, et al. Tuberous sclerosis in a 20-week gestation fetus: immunohistochemical study. Acta Neuropathol. 1997;94:180–186.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Tsai V, Parker WE, Orlova KA, et al. Fetal brain mTOR signaling activation in tuberous sclerosis complex. Cereb Cortex. 2014;24:315–327.
   PubMed Web of Science ®Google Scholar
• Scholl T, Muhlebner A, Ricken G, et al. Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex. Brain Pathol. 2016;27(6):770-780.
   Web of Science ®Google Scholar
• Wong M, Crino PB. mTOR and epileptogenesis in developmental brain malformations. In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper’s basic mechanisms of the epilepsies. Bethesda, MD: Oxford University Press. 2012.
   Google Scholar
• Barkovich AJ, Dobyns WB, Guerrini R. Malformations of cortical development and epilepsy. Cold Spring Harb Perspect Med. 2015;5:a022392.
   PubMed Web of Science ®Google Scholar
• Crome L. Infantile cerebral gliosis wtith giant nerve cells. J Neurol Neurosurg Psychiatry. 1957;20:117–124.
   PubMed Web of Science ®Google Scholar
• Taylor DC, Falconer MA, Bruton CJ, et al. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry. 1971;34(4):369–387.
   PubMed Web of Science ®Google Scholar
• Sims J. On hypertrophy and atrophy of the brain. Medico-Chirurgical Transactions. 1835;19:315–380.
   PubMedGoogle Scholar
• Flores-Sarnat L. Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol. 2002;17:373–384.
   PubMed Web of Science ®Google Scholar
• Flores-Sarnat L, Sarnat HB, Davila-Gutierrez G, et al. Hemimegalencephaly: part 2. Neuropathol Suggests Disorder Cell Lineage J Child Neurol. 2003;18:776–785.
   Google Scholar
• Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology. 2005;65:1873–1887.
   PubMed Web of Science ®Google Scholar
• Barkovich AJ, Guerrini R, Kuzniecky RI, et al. A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012;135:1348–1369.
   PubMed Web of Science ®Google Scholar
• Desikan RS, Barkovich AJ. Malformations of cortical development. Ann Neurol. 2016;80:797–810.
   PubMed Web of Science ®Google Scholar
• Crino PB. Focal brain malformations: a spectrum of disorders along the mTOR cascade. Novartis Found Symp. 2007;288: 260–272. discussion 72–81.
   PubMedGoogle Scholar
• Crino PB. Focal brain malformations: seizures, signaling, sequencing. Epilepsia. 2009;50(Suppl 9):3–8.
   PubMedGoogle Scholar
• Wong M. Animal models of focal cortical dysplasia and tuberous sclerosis complex: recent progress toward clinical applications. Epilepsia. 2009;50(Suppl 9):34–44.
   PubMedGoogle Scholar
• Crino PB. mTOR: A pathogenic signaling pathway in developmental brain malformations. Trends Mol Med. 2011;17:734–742.
   PubMed Web of Science ®Google Scholar
• Crino PB. The enlarging spectrum of focal cortical dysplasias. Brain. 2015;138:1446–1448.
   PubMed Web of Science ®Google Scholar
• Trounce JQ, Rutter N, Mellor DH. Hemimegalencephaly: diagnosis and treatment. Dev Med Child Neurol. 1991;33:261–266.
   PubMed Web of Science ®Google Scholar
• Janszky J, Ebner A, Kruse B, et al. Functional organization of the brain with malformations of cortical development. Ann Neurol. 2003;53:759–767.
   PubMed Web of Science ®Google Scholar
• Sanghvi JP, Rajadhyaksha SB, Ursekar M. Spectrum of congenital CNS malformations in pediatric epilepsy. Indian Pediatrics. 2004;41:831–838.
   PubMedGoogle Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Tinkle BT, Schorry EK, Franz DN, et al. Epidemiology of hemimegalencephaly: a case series and review. Am J Med Genet A. 2005;139:204–211.
   PubMedGoogle Scholar
• DeLone DR, Brown WD, Gentry LR. Proteus syndrome: craniofacial and cerebral MRI. Neuroradiology. 1999;41:840–843.
   PubMed Web of Science ®Google Scholar
• Cusmai R, Curatolo P, Mangano S, et al. Hemimegalencephaly and neurofibromatosis. Neuropediatrics. 1990;21:179–182.
   PubMed Web of Science ®Google Scholar
• Tagawa T, Futagi Y, Arai H, et al. Hypomelanosis of Ito associated with hemimegalencephaly: a clinicopathological study. Pediatr Neurol. 1997;17:180–184.
   PubMed Web of Science ®Google Scholar
• Torregrosa A, Marti-Bonmati L, Higueras V, et al. Klippel-Trenaunay syndrome: frequency of cerebral and cerebellar hemihypertrophy on MRI. Neuroradiology. 2000;42:420–423.
   PubMed Web of Science ®Google Scholar
• Cartwright MS, McCarthy SC, Roach ES. Hemimegalencephaly and tuberous sclerosis complex. Neurology. 2005;64:1634.
   PubMed Web of Science ®Google Scholar
• Solomon LM, Esterly NB. Epidermal and other congenital organoid nevi. Curr Probl Pediatr. 1975;6:1–56.
   PubMedGoogle Scholar
• Sakuta R, Aikawa H, Takashima S, et al. Epidermal nevus syndrome with hemimegalencephaly: neuropathological study. Brain Dev. 1991;13:260–265.
   PubMed Web of Science ®Google Scholar
• Manoranjan B, Provias JP. Hemimegalencephaly: a fetal case with neuropathological confirmation and review of the literature. Acta Neuropathol. 2010;120:117–130.
   PubMed Web of Science ®Google Scholar
• Jonas R, Nguyen S, Hu B, et al. Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology. 2004;62:1712–1721.
   PubMed Web of Science ®Google Scholar
• Bulteau C, Otsuki T, Delalande O. Epilepsy surgery for hemispheric syndromes in infants: hemimegalencepahly and hemispheric cortical dysplasia. Brain Dev. 2013;35:742–747.
   PubMed Web of Science ®Google Scholar
• Luders H, Schuele SU. Epilepsy surgery in patients with malformations of cortical development. Curr Opin Neurol. 2006;19:169–174.
   PubMed Web of Science ®Google Scholar
• Ramey WL, Martirosyan NL, Lieu CM, et al. Current management and surgical outcomes of medically intractable epilepsy. Clin Neurol Neurosurg. 2013;115:2411–2418.
   PubMed Web of Science ®Google Scholar
• Cuddapah VA, Thompson M, Blount J, et al. Hemispherectomy for hemimegalencephaly due to tuberous sclerosis and a review of the literature. Pediatr Neurol. 2015;53:452–455.
   PubMed Web of Science ®Google Scholar
• Adamsbaum C, Robain O, Cohen PA, et al. Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations. Pediatr Radiol. 1998;28:583–590.
   PubMed Web of Science ®Google Scholar
• Robain O, Floquet C, Heldt N, et al. Hemimegalencephaly: a clinicopathological study of four cases. Neuropathol Appl Neurobiol. 1988;14:125–135.
   PubMed Web of Science ®Google Scholar
• De Rosa MJ, Secor DL, Barsom M, et al. Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric, and ultrastructural study. Acta Neuropathol. 1992;84:250–260.
   PubMed Web of Science ®Google Scholar
• Yasha TC, Santosh V, Das S, et al. Hemimegalencephaly–morphological and immunocytochemical study. Clinical Neuropathology. 1997;16:17–22.
   PubMed Web of Science ®Google Scholar
• Antonelli A, Chiaretti A, Amendola T, et al. Nerve growth factor and brain-derived neurotrophic factor in human paediatric hemimegalencephaly. Neuropediatrics. 2004;35:39–44.
   PubMed Web of Science ®Google Scholar
• Salamon N, Andres M, Chute DJ, et al. Contralateral hemimicrencephaly and clinical-pathological correlations in children with hemimegalencephaly. Brain. 2006;129:352–365.
   PubMed Web of Science ®Google Scholar
• Boer K, Troost D, Spliet WG, et al. A neuropathological study of two autopsy cases of syndromic hemimegalencephaly. Neuropathol Appl Neurobiol. 2007;33:455–470.
   PubMed Web of Science ®Google Scholar
• Barkovich AJ, Kuzniecky RI, Jackson GD, et al. A developmental and genetic classification for malformations of cortical development. Neurology. 2005;65:1873–1887.
   PubMed Web of Science ®Google Scholar
• Sarnat HB, Flores-Sarnat L, Crino P, et al. Hemimegalencephaly: foetal tauopathy with mTOR hyperactivation and neuronal lipidosis. Folia Neuropathol. 2012;50:330–345.
   PubMed Web of Science ®Google Scholar
• Lang SS, Goldberg E, Zarnow D, et al. Prenatal diagnosis of hemimegalencephaly. World Neurosurg. 2014;82, 241:e5–8.
   Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Poduri A, Evrony GD, Cai X, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012;74:41–48.
   PubMed Web of Science ®Google Scholar
• Riviere JB, Mirzaa GM, O’Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44:934–940.
   PubMed Web of Science ®Google Scholar
• Mirzaa GM, Poduri A. Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology. Am J Med Genet C Semin Med Genet. 2014;166C:156–172.
   PubMedGoogle Scholar
• D’Gama AM, Geng Y, Couto JA, et al. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol. 2015;77:720–725.
   PubMed Web of Science ®Google Scholar
• Jansen LA, Mirzaa GM, Ishak GE, et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain. 2015;138:1613–1628.
   PubMed Web of Science ®Google Scholar
• Mirzaa GM, Campbell CD, Solovieff N, et al. Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. 2016;73:836–845.
   PubMed Web of Science ®Google Scholar
• Roy A, Skibo J, Kalume F, et al. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. Elife. 2015 Dec 3;4. pii: e12703. https://www.ncbi.nlm.nih.gov/pubmed/?term=skibo+and+overgrowth+and+kalume.
   Web of Science ®Google Scholar
• Baek ST, Gibbs EM, Gleeson JG, et al. Hemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disorders. Curr Opin Neurol. 2013;26:122–127.
   PubMed Web of Science ®Google Scholar
• Sarnat HB, Flores-Sarnat L. Morphogenesis timing of genetically programmed brain malformations in relation to epilepsy. Prog Brain Res. 2014;213:181–198.
   PubMed Web of Science ®Google Scholar
• Sarnat HB, Philippart M, Flores-Sarnat L, et al. Timing in neural maturation: arrest, delay, precociousness, and temporal determination of malformations. Pediatr Neurol. 2015;52:473–486.
   PubMed Web of Science ®Google Scholar
• Parrini E, Conti V, Dobyns WB, et al. Genetic basis of brain malformations. Mol Syndromol. 2016;7:220–233.
   PubMed Web of Science ®Google Scholar
• Harvey AS, Cross JH, Shinnar S, et al. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia. 2008;49:146–155.
   PubMed Web of Science ®Google Scholar
• Blümcke I, Vinters HV, Armstrong D, et al. Malformations of cortical development and epilepsies: neuropathological findings with emphasis on focal cortical dysplasia. Epileptic Disord. 2009;11:181–193.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Barkovich AJ, Guerrini R, Kuzniecky RI, et al. A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012;135:1348–1369.
   PubMed Web of Science ®Google Scholar
• Palmini A, Najm I, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology. 2004;62:S2–S8.
   PubMed Web of Science ®Google Scholar
• Blumcke I, Spreafico R. An international consensus classification for focal cortical dysplasias. Lancet Neurol. 2011;10:26–27.
   PubMed Web of Science ®Google Scholar
• Schick V, Majores M, Engels G, et al. Activation of Akt independent of PTEN and CTMP tumor-suppressor gene mutations in epilepsy-associated Taylor-type focal cortical dysplasias. Acta Neuropathol. 2006;112:715–725.
   PubMed Web of Science ®Google Scholar
• Conti V, Pantaleo M, Barba C, et al. Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene. Clin Genet. 2014;88(3):241-247.
   PubMed Web of Science ®Google Scholar
• Baulac S, Ishida S, Marsan E, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol. 2015;77:675–683.
   PubMed Web of Science ®Google Scholar
• Sim JC, Scerri T, Fanjul-Fernandez M, et al. Familial cortical dysplasia caused by mutation in the mTOR regulator NPRL3. Ann Neurol. 2016 Jan;79(1):132–137.
   PubMed Web of Science ®Google Scholar
• Scerri T, Riseley JR, Gillies G, et al. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol. 2015;2:575–580.
   PubMed Web of Science ®Google Scholar
• Lim JS, Kim WI, Kang HC, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med. 2015;21:395–400.
   PubMed Web of Science ®Google Scholar
• Nakashima M, Saitsu H, Takei N, et al. Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann Neurol. 2015 Sep;78(3):375–386.
   PubMed Web of Science ®Google Scholar
• Samadani U, Judkins AR, Akpalu A, et al. Differential cellular gene expression in ganglioglioma. Epilepsia. 2007;48:646–653.
   PubMed Web of Science ®Google Scholar
• Boer K, Troost D, Timmerman W, et al. Pi3K-mTOR signaling and AMOG expression in epilepsy-associated glioneuronal tumors. Brain Pathol. 2010;20:234–244.
   PubMed Web of Science ®Google Scholar
• Prabowo AS, Iyer AM, Veersema TJ, et al. BRAF V600E mutation is associated with mTOR signalling activation in glioneuronal tumors. Brain Pathol. 2014 Jan;24(1):52–66.
   PubMed Web of Science ®Google Scholar
• Blumcke I, Aronica E, Becker A, et al. Low-grade epilepsy-associated neuroepithelial tumours - the 2016 WHO classification. Nat Rev Neurol. 2016;12:732–740.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Becker AJ, Lobach M, Klein H, et al. Mutational analysis of TSC1 and TSC2 genes in gangliogliomas. Neuropathol Appl Neurobiol. 2001;27:105–114.
   PubMed Web of Science ®Google Scholar
• Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. 2010 Jul;12(7):621–630.
   PubMed Web of Science ®Google Scholar
• Koelsche C, Wohrer A, Jeibmann A, et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol. 2013.
   Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Dahiya S, Haydon DH, Alvarado D, et al. BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma. Acta Neuropathol. 2013;125:901–910.
   PubMed Web of Science ®Google Scholar
• Chappe C, Padovani L, Scavarda D, et al. Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF mutation and expression. Brain Pathol. 2013 Sep;23(5):574–583.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Esteve-Puig R, Canals F, Colome N, et al. Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF. PloS One. 2009;4:e4771.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Orlova KA, Parker WE, Heuer GG, et al. STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice. J Clin Invest. 2010;120:1591–1602.
   PubMed Web of Science ®Google Scholar
• Puffenberger EG, Strauss KA, Ramsey KE, et al. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain. 2007;130:1929–1941.
   PubMed Web of Science ®Google Scholar
• Bi W, Glass IA, Muzny DM, et al. Whole exome sequencing identifies the first STRADA point mutation in a patient with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE). Am J Med Genet A. 2016;170:2181–2185.
   PubMed Web of Science ®Google Scholar
• Evers C, Staufner C, Granzow M, et al. Impact of clinical exomes in neurodevelopmental and neurometabolic disorders. Mol Genet Metab. 2017;121:297–307.
   PubMed Web of Science ®Google Scholar
• Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med. 2013;5:182ra53.
   PubMed Web of Science ®Google Scholar
• Pitkanen A. Therapeutic approaches to epileptogenesis–hope on the horizon. Epilepsia. 2010;51(Suppl 3):2–17.
   PubMed Web of Science ®Google Scholar
• Pitkanen A, Engel J Jr. Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics. 2014;11:231–241.
   PubMed Web of Science ®Google Scholar
• Pitkanen A, Lukasiuk K, Dudek FE, et al. Epileptogenesis. Cold Spring Harb Perspect Med. 2015 Sep 18;5(10).
   PubMed Web of Science ®Google Scholar
• White HS. Animal models of epileptogenesis. Neurology. 2002;59:S7–S14.
   PubMed Web of Science ®Google Scholar
• Sloviter RS. Epileptogenesis meets Occam’s Razor. Curr Opin Pharmacol. 2017;35:105-110.
   PubMed Web of Science ®Google Scholar
• Franco V, French JA, Perucca E. Challenges in the clinical development of new antiepileptic drugs. Pharmacol Res. 2016;103:95–104.
   PubMed Web of Science ®Google Scholar
• Pitkanen A, Lukasiuk K. Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behav. 2009;14(Suppl 1):16–25.
   PubMedGoogle Scholar
• Pitkanen A, Lukasiuk K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol. 2011;10:173–186.
   PubMed Web of Science ®Google Scholar
• Szilagyi T, Szava I, Metz EJ, et al. Untangling the pathomechanisms of temporal lobe epilepsy–the promise of epileptic biomarkers and novel therapeutic approaches. Brain Res Bull. 2014;109:1–12.
   PubMed Web of Science ®Google Scholar
• Mazarati A, Sankar R. Common mechanisms underlying epileptogenesis and the comorbidities of epilepsy. Cold Spring Harb Perspect Med. 2016;6. https://www.ncbi.nlm.nih.gov/pubmed/27371669.
   PubMed Web of Science ®Google Scholar
• Aronica E, Bauer S, Bozzi Y, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia. 2017;58(Suppl 3):27–38.
   PubMedGoogle Scholar
• Korotkov A, Mills JD, Gorter JA, et al. Systematic review and meta-analysis of differentially expressed miRNAs in experimental and human temporal lobe epilepsy. Sci Rep. 2017;7:11592.
   PubMed Web of Science ®Google Scholar
• Abs E, Goorden SM, Schreiber J, et al. TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice. Ann Neurol. 2013;74:569–579.
   PubMed Web of Science ®Google Scholar
• Abdijadid S, Mathern GW, Levine MS, et al. Basic mechanisms of epileptogenesis in pediatric cortical dysplasia. CNS Neurosci Ther. 2015;21:92–103.
   PubMed Web of Science ®Google Scholar
• Kubova H, Lukasiuk K, Pitkanen A. New insight on the mechanisms of epileptogenesis in the developing brain. Adv Tech Stand Neurosurg. 2012;39:3–44.
   PubMedGoogle Scholar
• Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5:380–391.
   PubMed Web of Science ®Google Scholar
• Ruffolo G, Iyer A, Cifelli P, et al. Functional aspects of early brain development are preserved in tuberous sclerosis complex (TSC) epileptogenic lesions. Neurobiol Dis. 2016;95:93–101.
   PubMed Web of Science ®Google Scholar
• Curatolo P, Aronica E, Jansen A, et al. Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC. Eur J Paediatr Neurol. 2016;20:203–211.
   PubMed Web of Science ®Google Scholar
• Holmes GL, Stafstrom CE. Tuberous sclerosis study G. Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia. 2007;48:617–630.
   PubMed Web of Science ®Google Scholar
• Wong M. Mechanisms of epileptogenesis in tuberous sclerosis complex and related malformations of cortical development with abnormal glioneuronal proliferation. Epilepsia. 2008;49:8–21.
   PubMed Web of Science ®Google Scholar
• Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol. 2013;125:317–332.
   PubMed Web of Science ®Google Scholar
• Tavazoie SF, Alvarez VA, Ridenour DA, et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci. 2005;8:1727–1734.
   PubMed Web of Science ®Google Scholar
• Bateup HS, Johnson CA, Denefrio CL, et al. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron. 2013;78:510–522.
   PubMed Web of Science ®Google Scholar
• Lozovaya N, Gataullina S, Tsintsadze T, et al. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat Commun. 2014;5:4563.
   PubMed Web of Science ®Google Scholar
• White R, Hua Y, Scheithauer B, et al. 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.
   PubMed Web of Science ®Google Scholar
• Wang Y, Greenwood JS, Calcagnotto ME, et al. Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Ann Neurol. 2007;61:139–152.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Zeng LH, Bero AW, Zhang B, et al. Modulation of astrocyte glutamate transporters decreases seizures in a mouse model of Tuberous Sclerosis Complex. Neurobiol Dis. 2010;37:764–771.
   PubMed Web of Science ®Google Scholar
• Cepeda C, Andre VM, Levine MS, et al. Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral developmental hypothesis. Epilepsy Behav. 2006;9:219–235.
   PubMed Web of Science ®Google Scholar
• Talos DM, Kwiatkowski DJ, Cordero K, et al. Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann Neurol. 2008;63(Issue):454–465.
   PubMedGoogle Scholar
• Bateup HS, Takasaki KT, Saulnier JL, et al. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J Neurosci. 2011;31:8862–8869.
   PubMed Web of Science ®Google Scholar
• Talos DM, Sun H, Kosaras B, et al. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann Neurol. 2012;71:539–551.
   PubMed Web of Science ®Google Scholar
• Cepeda C, Andre VM, Hauptman JS, et al. Enhanced GABAergic network and receptor function in pediatric cortical dysplasia Type IIB compared with Tuberous Sclerosis Complex. Neurobiol Dis. 2012;45:310–321.
   PubMed Web of Science ®Google Scholar
• Coulter DA, Steinhauser C. Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med. 2015;5:a022434.
   PubMed Web of Science ®Google Scholar
• Steinhauser C, Grunnet M, Carmignoto G. Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience. 2016;323:157–169.
   PubMed Web of Science ®Google Scholar
• Wong M, Crino PB. Tuberous sclerosis and epilepsy: role of astrocytes. Glia. 2012;60:1244–1250.
   PubMed Web of Science ®Google Scholar
• Boison D, Aronica E. Comorbidities in neurology: is adenosine the common link? Neuropharmacology. 2015;97:18–34.
   PubMed Web of Science ®Google Scholar
• Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia. 2011;52(Suppl 3):26–32.
   PubMed Web of Science ®Google Scholar
• Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7:31–40.
   PubMed Web of Science ®Google Scholar
• Vezzani A, Auvin S, Ravizza T. Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators. In: Noebels JL, Avoli M, Rogawski MA, et al. editors. Jasper’s basic mechanisms of the epilepsies. Bethesda, MD: Oxford University Press. 2012.
   Google Scholar
• Aronica E, Ravizza T, Zurolo E, et al. Astrocyte immune responses in epilepsy. Glia. 2012;60:1258–1268.
   PubMed Web of Science ®Google Scholar
• Van Vliet EA, Aronica E, Vezzani A, et al. Recent insights into neuroinflammatory pathways in epilepsy. Neuropathol Appl Neurobiol. 2017 in press.
   PubMedGoogle Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Fuso A, Iyer AM, Van Scheppingen J, et al. Promoter-specific hypomethylation correlates with IL-1 beta overexpression in Tuberous Sclerosis Complex (TSC). J Mol Neurosci. 2016;59:464–470.
   PubMed Web of Science ®Google Scholar
• Mills JD, Iyer AM, Van Scheppingen J, et al. Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment. Sci Rep. 2017;7:8089.
   PubMed Web of Science ®Google Scholar
• Prabowo AS, Anink JJ, Lammens M, et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol. 2012;23(1):45-59.
   PubMed Web of Science ®Google Scholar
• Zhang B, Zou J, Rensing NR, et al. Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol Dis. 2015;80:70–79.
   PubMed Web of Science ®Google Scholar
• Broekaart DWM, Van Scheppingen J, Geijtenbeek KW, et al. Increased expression of (immuno) proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway. Epilepsia. 2017;58:1462–1472.
   PubMed Web of Science ®Google Scholar
• Van Scheppingen J, Broekaart DW, Scholl T, et al. Dysregulation of the (immuno)proteasome pathway in malformations of cortical development. J Neuroinflammation. 2016;13:202.
   PubMed Web of Science ®Google Scholar
• Giorgi FS, Biagioni F, Lenzi P, et al. The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations. J Neural Transm (Vienna). 2015;122:849–862.
   PubMed Web of Science ®Google Scholar
• McMahon J, Huang X, Yang J, et al. Impaired autophagy in neurons after disinhibition of Mammalian target of rapamycin and its contribution to epileptogenesis. J Neurosci. 2012;32:15704–15714.
   PubMed Web of Science ®Google Scholar
• Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63:444–453.
   PubMed Web of Science ®Google Scholar
• Meikle L, Pollizzi K, Egnor A, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci. 2008;28:5422–5432.
   PubMed Web of Science ®Google Scholar
• Carson RP, Van Nielen DL, Winzenburger PA, et al. Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiol Dis. 2012;45:369–380.
   PubMed Web of Science ®Google Scholar
• Way SW, Rozas NS, Wu HC, et al. The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. Hum Mol Genet. 2012;21:3226–3236.
   PubMed Web of Science ®Google Scholar
• Chu-Shore CJ, Thiele EA. New drugs for pediatric epilepsy. Semin Pediatr Neurol. 2010;17:214–223.
   PubMed Web of Science ®Google Scholar
• Chiron C, Dumas C, Jambaque I, et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res. 1997;26:389–395.
   PubMed Web of Science ®Google Scholar
• Curatolo P, Jozwiak S, Nabbout R, et al. Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol. 2012;16:582–586.
   PubMed Web of Science ®Google Scholar
• Bombardieri R, Pinci M, Moavero R, et al. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol. 2010;14:146–149.
   PubMed Web of Science ®Google Scholar
• Cusmai R, Moavero R, Bombardieri R, et al. Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav. 2011;22:735–739.
   PubMed Web of Science ®Google Scholar
• Kossoff EH, Thiele EA, Pfeifer HH, et al. Tuberous sclerosis complex and the ketogenic diet. Epilepsia. 2005;46:1684–1686.
   PubMed Web of Science ®Google Scholar
• McDaniel SS, Rensing NR, Thio LL, et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia. 2011;52:e7–e11.
   PubMed Web of Science ®Google Scholar
• Zamponi N, Petrelli C, Passamonti C, et al. Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis. Pediatr Neurol. 2010;43:29–34.
   PubMed Web of Science ®Google Scholar
• Jeong A, Wong M. Tuberous sclerosis complex as a model disease for developing new therapeutics for epilepsy. Expert Rev Neurother. 2016;16:437–447.
   PubMed Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Levy RH et al. Progress report on new antiepileptic drugs: a summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII). Epilepsia 2017 58, 181–221
   Google Scholar
• Krueger DA, Wilfong AA, Holland-Bouley K et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74:679–687.
   PubMed Web of Science ®Google Scholar
• Krueger DA, Wilfong AA, Mays M, et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology. 2016;87:2408–2415.
   PubMed Web of Science ®Google Scholar
• Wiegand G, May TW, Ostertag P, et al. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol. 2013;17:631–638.
   PubMed Web of Science ®Google Scholar
• Cardamone M, Flanagan D, Mowat D, et al. Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr. 2014;164:1195–1200.
   PubMed Web of Science ®Google Scholar
• Samueli S, Abraham K, Dressler A, et al. Efficacy and safety of everolimus in children with TSC - associated epilepsy - pilot data from an open single-center prospective study. Orphanet J Rare Dis. 2016;11:145.
   PubMed Web of Science ®Google Scholar
• Overwater IE, Rietman AB, Bindels-de Heus K, et al. Sirolimus for epilepsy in children with tuberous sclerosis complex: a randomized controlled trial. Neurology. 2016;87:1011–1018.
   PubMedGoogle Scholar
• French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388:2153–2163.
   PubMed Web of Science ®Google Scholar
• Chung CWT, Lawson JA, Sarkozy V, et al. Early detection of tuberous sclerosis complex: an opportunity for improved neurodevelopmental outcome. Pediatr Neurol. 2017;76:20–26.
   PubMed Web of Science ®Google Scholar
• Mingarelli A, Vignoli A, La Briola F, et al. Dramatic relapse of seizures after everolimus withdrawal. Eur J Paediatr Neurol. 2017;22(1):203-206.
   PubMedGoogle Scholar
• Aronica E, Sisodiya SM, Gorter JA. Cerebral expression of drug transporters in epilepsy. Adv Drug Deliv Rev. 2012 Jul;64(10):919–929.
   PubMed Web of Science ®Google Scholar
• Zhang B, McDaniel SS, Rensing NR, et al. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLoS One. 2013;8:e57445. https://doi.org/10.1016/j.celrep.2017.11.106.
   PubMed Web of Science ®Google Scholar
• https://doi.org/10.1016/j.celrep.2017.11.106.
   Google Scholar
• Lim JS, Gopalappa R, Kim SH, et al. Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia. Am J Hum Genet. 2017 Mar 2;100(3):454–472.
   Google Scholar
• The binding of TBC1D7 to TSC1 is required to maintain the integrity of the TSC1–TSC2 complex. Hum Mutat. 2014;35:447–451.
   Google Scholar