Flanagan N, O''Connor WJ, McCartan B, et al. Developmental enamel defects in tuberous sclerosis: a clinical genetic marker?. J Med Genet. 1997 Aug. 34(8):637-9. [Medline].
Goodman M, Lamm SH, Engel A, et al. Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol. 1997 Feb. 12(2):85-90. [Medline].
Everolimus Reduces Kidney Tumors in Tuberous Sclerosis Complex. Medscape Medical News. Jan 11, 2013. [Full Text].
Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013 Jan 10. [Medline].
French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, 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 Oct 29. 388 (10056):2153-2163. [Medline]. [Full Text].
Van Slegtenhorst M, Nellist M, Nagelkerken B. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet. 7(6):1053-7. [Medline].
Nobukini T, Thomas G. The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. Novartis Found Symp. 2004. 262:148-54; discussion 154-9, 265-8. [Medline].
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 Jan. 68(1):64-80. [Medline].
Gates J, Jordan JE. Tuberous sclerosis in old age. South Med J. 1978 Aug. 71(8):974-6. [Medline].
Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct. 49(4):243-54. [Medline]. [Full Text].
Sampson JR, Attwood D, al Mughery AS, Reid JS. Pitted enamel hypoplasia in tuberous sclerosis. Clin Genet. 1992 Jul. 42(1):50-2. [Medline].
Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med. 1996 Oct 24. 335(17):1275-80. [Medline].
Beltramello A, Puppini G, Bricolo A, et al. Does the tuberous sclerosis complex include intracranial aneurysms? A case report with a review of the literature. Pediatr Radiol. 1999 Mar. 29(3):206-11. [Medline].
Krueger DA and Northrup H on behalf of the InternationalTuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013. 49(4):255-265.
Takanashi J, Sugita K, Fujii K, Niimi H. MR evaluation of tuberous sclerosis: increased sensitivity with fluid- attenuated inversion recovery and relation to severity of seizures and mental retardation. AJNR Am J Neuroradiol. 1995 Oct. 16(9):1923-8. [Medline].
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10. 358(2):140-51. [Medline].
Dabora SL, Franz DN, Ashwal S, et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One. 2011. 6(9):e23379. [Medline].
Franz, DN, Leonard, J, Tudor, C. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Annals of Neurology. 2006 March. 59(3):490-498. [Medline].
Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010 Nov 4. 363(19):1801-11. [Medline].
Franz DN, Belousova E, Sparagana S et al. Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study. PLoS ONE. 2016. 11(6):e0158476:
DeKlotz CM, Ogram AE, Singh S, Dronavalli S, MacGregor JL. Dramatic improvement of facial angiofibromas in tuberous sclerosis with topical rapamycin: optimizing a treatment protocol. Arch Dermatol. 2011 Sep. 147(9):1116-7. [Medline].
Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol. 1999 Feb. 14(2):71-4. [Medline].
Camposano SE, Major P, Halpern E, Thiele EA. Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile. Epilepsia. 2008 Jul. 49(7):1186-91. [Medline].
Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain Dev. 2001 Nov. 23(7):649-53. [Medline].
Parisi P, Bombardieri R, Curatolo P. Current role of vigabatrin in infantile spasms. Eur J Paediatr Neurol. 2007 Nov. 11(6):331-6. [Medline].
Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD. Vigabatrin: 2008 update. Epilepsia. 2009 Feb. 50(2):163-73. [Medline].
Glauser TA. Topiramate. Epilepsia. 1999. 40 Suppl 5:S71-80. [Medline].
Franz DN, Tudor C, Leonard J, et al. Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia. 2001 Jul. 42(7):935-40. [Medline].
Avellino AM, Berger MS, Rostomily RC, et al. Surgical management and seizure outcome in patients with tuberous sclerosis. J Neurosurg. 1997 Sep. 87(3):391-6. [Medline].
Levine NB, Collins J, Franz DN, Crone KR. Gradual formation of an operative corridor by balloon dilation for resection of subependymal giant cell astrocytomas in children with tuberous sclerosis: specialized minimal access technique of balloon dilation. Minim Invasive Neurosurg. 2006 Oct. 49(5):317-20. [Medline].
Coppola G, Klepper J, Ammendola E et al. The effects of the ketogenic diet in refractory partial seizures with reference to tuberous sclerosis. Eur J Paediatr Neur. 2006 May. 10(3):148-51.
Kossoff EH, Thiele EA, Pfeifer HH et al. Tuberous sclerosis complex and the ketogenic diet. Epilepsia. 2005 Oct. 46(10):1684-6.
Larson AM; Pfeifer HH; Thiele EA. Low glycemic index treatment for epilepsy in tuberous sclerosis complex. Epilepsy Research. 2012 Mar. 99(1-2):180-2.
Asano E, Chugani DC, Muzik O, et al. Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology. 2001 Oct 9. 57(7):1269-77. [Medline].
Asano E, Chugani DC, Muzik O, et al. Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology. 2000 May 23. 54(10):1976-84. [Medline].
Bolton PF, Griffiths PD. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet. 1997 Feb 8. 349(9049):392-5. [Medline].
Bowen J, Beasley SW. Rare pulmonary manifestations of tuberous sclerosis in children. Pediatr Pulmonol. 1997 Feb. 23(2):114-6. [Medline].
Bruni O, Cortesi F, Giannotti F, Curatolo P. Sleep disorders in tuberous sclerosis: a polysomnographic study. Brain Dev. 1995 Jan-Feb. 17(1):52-6. [Medline].
Christophe C, Sekhara T, Rypens F, et al. MRI spectrum of cortical malformations in tuberous sclerosis complex. Brain Dev. 2000 Dec. 22(8):487-93. [Medline].
Chugani DC, Chugani HT, Muzik O, et al. Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann Neurol. 1998 Dec. 44(6):858-66. [Medline].
Crino, PB, Nathanson, KL, Henske, EP. The tuberous sclerosis complex. New England Journal of Medicine. 2006 Sep 28. 355(13):1345-56. [Medline].
El-Hashemite N, Zhang H, Walker V, et al. Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment. Cancer Res. 2004 May 15. 64(10):3436-43. [Medline].
Enbergs A, Borggrefe M, Kurlemann G, et al. Ventricular tachycardia caused by cardiac rhabdomyoma in a young adult with tuberous sclerosis. Am Heart J. 1996 Dec. 132(6):1263-5. [Medline].
Franz DN. Diagnosis and management of tuberous sclerosis complex. Semin Pediatr Neurol. 1998 Dec. 5(4):253-68. [Medline].
Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med. 2001 Aug 15. 164(4):661-8. [Medline].
Harding B, Copp AJ. Malformations: tuberous sclerosis. In: Greenfield's Neuropathology. 6th ed. Arnold Edward. 1997:497-502.
Harrison JE, Bolton PF. Annotation: tuberous sclerosis. J Child Psychol Psychiatry. 1997 Sep. 38(6):603-14. [Medline].
Henske EP, Wessner LL, Golden J, et al. Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol. 1997 Dec. 151(6):1639-47. [Medline].
Holley DG, Martin GR, Brenner JI, et al. Diagnosis and management of fetal cardiac tumors: a multicenter experience and review of published reports. J Am Coll Cardiol. 1995 Aug. 26(2):516-20. [Medline].
Hyman MH, Whittemore VH. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000 May. 57(5):662-5. [Medline].
Inoki K, Ouyang H, Li Y, Guan KL. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev. 2005 Mar. 69(1):79-100. [Medline].
Jost CJ, Gloviczki P, Edwards WD, et al. Aortic aneurysms in children and young adults with tuberous sclerosis: report of two cases and review of the literature. J Vasc Surg. 2001 Mar. 33(3):639-42. [Medline].
Jozwiak S, Pedich M, Rajszys P, Michalowicz R. Incidence of hepatic hamartomas in tuberous sclerosis. Arch Dis Child. 1992 Nov. 67(11):1363-5. [Medline].
Kandt RS, Haines JL, Smith M, et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet. 1992 Sep. 2(1):37-41. [Medline].
Kenerson H, Dundon TA, Yeung RS. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res. 2005 Jan. 57(1):67-75. [Medline].
Koprowski C, Rorke LB. Spinal cord lesions in tuberous sclerosis. Pediatr Pathol. 1983 Oct-Dec. 1(4):474-80. [Medline].
Langkau N, Martin N, Brandt R. TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios. Eur J Pediatr. 2002 Jul. 161(7):393-402. [Medline].
Louis DN, Scheithauer BW, Budka H. Meningiomas. In: Pathology and Genetics of Tumours of the Nervous System. London: Oxford University Press. 2000:176-84.
Maeda M, Tartaro A, Matsuda T, Ishii Y. Cortical and subcortical tubers in tuberous sclerosis and FLAIR sequence. J Comput Assist Tomogr. 1995 Jul-Aug. 19(4):660-1. [Medline].
Mak BC, Yeung RS. The tuberous sclerosis complex genes in tumor development. Cancer Invest. 2004. 22(4):588-603. [Medline].
Miller SP, Tasch T, Sylvain M, et al. Tuberous sclerosis complex and neonatal seizures. J Child Neurol. 1998 Dec. 13(12):619-23. [Medline].
Pui MH, Kong HL, Choo HF. Bone changes in tuberous sclerosis mimicking metastases. Australas Radiol. 1996 Feb. 40(1):77-9. [Medline].
Roach ES, DiMario FJ, Kandt RS, Northrup H. Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. J Child Neurol. 1999 Jun. 14(6):401-7. [Medline].
Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998 Dec. 13(12):624-8. [Medline].
Sener N. Tuberous sclerosis: diffusion MRI findings in the brain. Eur Radiol. 2002 Jan. 12(1):138-43. [Medline].
Seri S, Cerquiglini A, Pisani F, et al. Frontal lobe epilepsy associated with tuberous sclerosis: electroencephalographic-magnetic resonance image fusioning. J Child Neurol. 1998 Jan. 13(1):33-8. [Medline].
Shepherd CW, Houser OW, Gomez MR. MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. AJNR Am J Neuroradiol. 1995 Jan. 16(1):149-55. [Medline].
Webb DW, Fryer AE, Osborne JP. Morbidity associated with tuberous sclerosis: a population study. Dev Med Child Neurol. 1996 Feb. 38(2):146-55. [Medline].
Webb DW, Thomas RD, Osborne JP. Cardiac rhabdomyomas and their association with tuberous sclerosis. Arch Dis Child. 1993 Mar. 68(3):367-70. [Medline].
Weber AM, Egelhoff JC, McKellop JM, Franz DN. Autism and the cerebellum: evidence from tuberous sclerosis. J Autism Dev Disord. 2000 Dec. 30(6):511-7. [Medline].
Thiele E, Bebin EM, Bhathal H, et al. Cannabidiol (CBD) treatment in patients with seizures associated with tuberous sclerosis complex: A randomized, double-blind, placebo-controlled phase 3 trial (GWPCARE6) (Abst 1.293). Presented at the American Epilepsy Society 73rd Annual Meeting. 2019 Dec 6-10. Baltimore, MD. [Full Text].

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Enhancing subependymal nodules, including a probable giant cell astrocytoma in the region of the foramen of Monro. Subependymal nodules may increase in size over time from one scan to the next, and then stabilize. This lesion had not changed with serial imaging over 2 years. The patient remains asymptomatic and is monitored closely for any deterioration.
Hydrocephalus from a subependymal giant cell astrocytoma in a patient with tuberous sclerosis. The patient presented with acute blindness and ataxia.
Facial angiofibromas in a young man with tuberous sclerosis complex.
Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.
Gingival fibromas (see arrows) in a patient with tuberous sclerosis. A stain outlines dental pits and craters. Gingival hyperplasia from other causes (eg, phenytoin use) is more diffuse and usually not nodular/focal in nature.
Typical ash leaf macules; the reddish, nodular area at the upper lumbar area is a shagreen patch.
Atrial rhabdomyoma as seen on cardiac CT scan in a patient with tuberous sclerosis.
Nonobstructive ventricular rhabdomyomas in a patient with tuberous sclerosis.
Ventricular rhabdomyomas may diffusely infiltrate the myocardium, as in this patient with tuberous sclerosis. The patient presented with cardiac failure and hydrops at birth. After a period of intensive supportive care and inotropic therapy, she now has essentially normal cardiac function and is on no medications.
Multifocal pulmonary cysts characteristic of lymphangiomyomatosis. As many as 40% of women with tuberous sclerosis have pulmonary cysts on chest CT scan.
Massive bilateral angiomyolipomas in a woman with tuberous sclerosis. She also has lymphangiomyomatosis.
Pre-embolization angiography of the patient with angiomyolipomas shown the previous image. Dysplastic arterial vessels are demonstrated.
Vessels to the angiomyolipoma shown in the previous image have been occluded with coils. This should produce regression of the lesion and prevention of hemorrhage. Functional intervening renal parenchyma is preserved.
Enamel pitting in tuberous sclerosis. Pinpoint size pitting (A) and crater size pitting (B) are visible. Red dye is used to enhance recognition.
Basilar artery aneurysm in a 2-year-old girl with tuberous sclerosis. The arrow shows the anterior aspect of the aneurysm where it abuts the clivus. The lesion was not present on MRI performed 11 months earlier.
This presumed tuber was first noted in the left frontal region. It expanded in size, affecting adjacent structures across the midline and resulting in calcifications still evident in the right frontal region. The tuber then spontaneously involuted. About 20% of tubers may show changes in imaging characteristics over time, requiring close imaging follow-up. This patient remained asymptomatic from the mass effect, and his seizures resolved as the lesion involuted.
This father and all 3 children have tuberous sclerosis complex. The children are now grown up and of normal intelligence, including the young lady at left who is cushingoid from therapy with adrenocorticotropic hormone for infantile spasms.
The child whose CT scan is shown presented with medically intractable epilepsy thought to be due to partial hemimegalencephaly. She became seizure free after partial hemispherectomy. Pathology was consistent with a cortical tuber. She was subsequently found to have multiple ash leaf macules and diagnosed with tuberous sclerosis.
Multiple tubers in a child with tuberous sclerosis, normal intelligence, and well-controlled seizures. High tuber count does not invariably mean poor neurological outcome.
All tubers are not equal. This child has a smaller number of tubers than the patient shown in the previous image, but the tubers are larger in size. She too has normal intelligence and is seizure free on medication.
Mammalian target of rapamycin (mTOR) activates the protein S6 kinase, which enhances cell growth and protein synthesis. It, in turn, is regulated by multiple factors, including insulin, amino acids, the drugs rapamycin and its congeners (eg, RAD001), and the TSC gene products via the GTPase-activating protein Rheb.
Subependymal giant cell astrocytoma prior to stereotactic insertion of balloon catheter as seen on T2-weighted MRI.
Modified angioplasty catheter used in creation of surgical tract for astrocytoma resection.
Catheter placed in proximity to lesion, balloon inflated.
Postoperative T2-weighted MRI in a patient with subependymal giant cell astrocytoma showing gross total resection of giant cell astrocytoma with minimal disruption of overlying cortex.
Mean reduction in simple and complex partial seizures in patients with tuberous sclerosis complex (TSC) who were treated with vagus nerve stimulator at the author's institution at 6 and 12 months. Overall reduction in secondarily generalized seizures was 22% at 12 months (N = 17; 10 boys, 7 girls, aged 3-12 y).
Regression of a giant cell astrocytoma after approximately 15 months oral rapamycin therapy in a 4-year-old patient with tuberous sclerosis.

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