Esclerosis tuberosa o Epiloia. Aspectos de su presentación clínica, y de su repercusión en cerebro, riñón y pulmón.

1. Emerging Treatment Strategies for Tuberous Sclerosis Complex David Neal Franz, MD Director, Tuberous Sclerosis Clinic Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

4. Clinical Diagnostic Criteria Roach ES, Sparagana SP. J Child Neurol. 2004;19:643-649. Major Features Minor Features Cortical tubers Multiple, randomly distributed pits in dental enamel Subependymal nodules Hamartomatous rectal polyps Subependymal giant cell astrocytoma Bone cysts Hypomelanotic macules (3 or more) Cerebral white matter radial migration lines Shagreen patch (connective tissue nevus) Gingival fibromas Facial angiofibromas or forehead plaque Nonrenal hamartoma Multiple retinal nodular hamartomas Retinal achromic patch Nontraumatic ungual or periungual fibromas “ Confetti” skin lesions Cardiac rhabdomyoma, single or multiple Multiple renal cysts Pulmonary lymphangioleiomyomatosis and/or renal angiomyolipomas

5. TSC: Onset of Symptoms

6. Hypopigmented Macule and Shagreen Patch

7. Facial Angiofibroma

8. Periungual Fibroma

9. Dental Pits and Gingival Fibromas

10. Retinal Hamartomas and Achromic Patches

11. Cardiac Rhabdomyoma

12. Lymphangioleiomyomatosis (LAM)

13. Renal Angiomyolipoma and Renal Cysts

14. Angiomyolipoma

15. Cerebral Manifestations of TSC

16. Cortical Tuber

17. Subependymal Nodules

24. Subependymal Giant Cell Astrocytoma (SEGA)

25. Acute Hydrocephalus With SEGA

26. Serial Monitoring for SEGA

27. Traditional Surgical Resection of SEGA

28. Stereotactic Angioplasty Balloon Technique Levine NB, et al. Minim Invasive Neurosurg. 2006;49:317-320.

29. Genetics of TSC 9 16 Autosomal dominant Near 100% penetrance Variable expression No Mutation Identified (10%-15%) TSC1 (15%-20%) TSC2 (60%-70%) PKD1

30. TSC1/TSC2 and mTORC1

31. Rapamycin and Everolimus (RAD001) Rapamycin (sirolimus) RAD001 (everolimus) O O O H O O O N O O O O O H O H O O O O H O O O N O O O O O O H O O H

32. Everolimus and Sirolimus Comparison of Properties a RAD001 Investigators Brochure (6 th ed). b Buech G, et al. J Ocul Pharmacol Ther . 2007;23:292. c Formica RN, et al. Transplant Proc . 2004;36(Suppl 25S):495S-499S. d Brattstrom C, et al. Ther Drug Monit . 2000;22:537-544.5. e Kahan BD, et al. Transplantation . 1991;52:185-191. f Serkova N, et al. Br J Pharmacol . 2001;133:875-885 . *Varies with formulation, dose, and co-medications. Everolimus has greater bioavailability than sirolimus. **Ratio of drug in blood (ng/mL) and brain (ng/g) following 6 days oral dosing at 3 mg/kg in rats. f Characteristic Everolimus Sirolimus Molecular weight (Kd) 958 a 914 b Solubility in water ( μ g/mL) 8-fold higher b 2.6 b Hydrophobicity Less c Extreme b Bioavailability (%) ≥ 11 a* 1.6 e* Blood:plasma (%) 26% free a Brain accumulation** 3.1:1 f 5.7:1 f Tmax (hrs) 1-2 0.8 d T1/2 (hrs) 30 a 86 d Vss (L/kg) 44 -52 a 23 d Clearance (mL/hr•kg) 1200 a (rat) 256 d (man)

33. Rapamycin for Treatment of Angiomyolipoma A B Bissler JJ, et al. N Engl J Med. 2008;358:140-151.

34. Rapamycin Effect on LAM Bissler JJ, McCormack FX, Young LR, et al. N Engl J Med. 2008;358:140-151.

35. Rapamycin for the Treatment of SEGA Franz DN, et al. Ann Neurol. 2006;59:490-498.

36. Everolimus Effect on SEGA in TSC Baseline 6 months RAD001

37. Cerebellar Tuber Growth

38. Cerebellar Tuber Before and After Treatment With Rapamycin

39. RAD001 Effect on SEGA Volume

40. Before Treatment Everolimus x 3 months Angiomyolipoma Before and After Treatment

41. Chylothorax in LAM

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