Tuberous Sclerosis: New Treatment Strategies for an Old Disease

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1 Tuberous Sclerosis: New Treatment Strategies for an ld Disease bjectives History and Diagnostic Criteria for Tuberous Sclerosis Darcy A. Krueger, M.D., Ph.D. Tuberous Sclerosis Clinic and Research Center Cincinnati Children s Hospital Medical Center Cincinnati, hio, USA Current management of common disease manifestations New and emerging therapies "Sclérose tubéreuse des circonvolutions cérébrales". Vogt s Triad Epilepsy Idiocy Adenoma Sebaceum Désiré-Magloire Bourneville 1881 Tuberous Sclerosis Complex Clinical Manifestations of TSC Less than 1/3 have all three classic symptoms of Vogt s Triad 38% of patients with TSC have normal intelligence Incidence of TSC much higher than previously appreciated New Diagnostic Criteria for TSC Pan et al, Trends Cell Biol

2 Facial Angiofibroma Hypopigmental Macule and Shagreen Patch Periungual Fibroma Retinal Hamartoma Cardiac Rhabdomyoma Lymphangioleiomyomatosis (LAM) 2

3 Renal Angiomyolipoma (AML) Cortical Tuber Subependymal Nodules Subependymal Giant Cell Astrocytoma (SEGA) Acute Hydrocephalus with SEGA Dental Pits and Gingival Fibromas 3

4 Retinal Achromic Patch Connective Tissue Hamartoma Bone Cyst Liver Angiomyolipoma Uterine PEComa Clinical Diagnostic Criteria Definite Probable Possible MAJR MINR Roach and Sparagna, J. Child Neurol

5 Genetics of TSC Clinical Management of TSC Autosomal Dominant Near 100% Penetrance Variable Expression TSC2 (60-70%) PKD1 TSC1 (15-20%) 9 16 NMI (10-15%) Dermatological Management Dermatological Management Hypopigmented Macules, Shagreen Patches, and Facial plaques require no specific treatment Laser ablation of facial angiofibromas Differing techniques and laser types Cosmetic or symptomatic treatment Variable response Transient effect (6m-3 years) Ungal fibromas removed by surgical excision when symptomatic (bleeding, causing pain) Tend to recur over time May also be removed due to cosmetic concerns Bittencourt et al., J Am Acad Dermatol Michel et al., Med Laser Appl Cardiac Management Rhabdomyomas are benign growths Transthoracic ECH at birth or time of diagnosis Baseline ECG to evaluate for conduction defects F/U evaluations and interventions dependent on severity and course Most no hemodynamic interference and spontaneously resolve. Annual ECH until resolve, then only as needed. Repeat ECG only required if prior abnormal, clinical concern for arrhythmia, or treatment with medications associated with significant risk for such phthalmologic Management Baseline evaluation at birth or diagnosis Vision screening/slit lamp examination every 1-2 years through childhood 5

6 Dental Management No specific treatment good hygiene and preventative dentistry is general rule Dental pits generally not problematic and do not require specific treatment Gingival fibromas can be excised if causing bleeding, discomfort, or cosmetic concerns Infantile Spasms in TSC Infantile Spasms Neurological hallmark of TSC presenting sign of tuberous sclerosis in 10-15% affected individuals Start usually by 1 year of age in 75% of children (can be in 1 st month of life) Earlier onset = worse prognosis Developmental delay Intractable partial epilepsy Infantile Spasms in TSC Classic Hypsarrhythmia Infantile Spasms in TSC Hemi-Hypsarrhythmia Infantile Spasms (Saybril) is treatment of choice despite associated adverse effect on peripheral vision -- As high as 95% response rate Steroids are second line treatment (ACTH or oral prednisone) Valproate, Topamax, Clonazepam minimally effective as single agents but may have benefical adjunctive use Epilepsy in TSC 70-80% patients with TSC experience seizures Virtually all seizure types have been reported (simple partial, complex partial, generalized tonic-clonic, absence) Medically refractory epilepsy is common, despite even polytherapy with antiepileptic drugs Epileptic surgery can be very beneficial in TSC patients with medically-refractory epilepsy 6

7 Pharmacologic Management of Seizures in TSC Management of Autsim/Behavior in TSC 2/3 patients have Learning Difficulties and/or Mental Retardation 1/3 patients have Autism or Autistic Behaviors Significant Mood/Behavioral Difficulties and Sleep Problems Krueger and Franz, Pediatric Drugs 2008 Management of Neurobehavior in TSC Serial Monitoring for SEGA MRI + contrast at least every 1-2 years Krueger and Franz, Pediatric Drugs 2008 Traditional Surgical Resection of SEGA Stereotactic Angioplastic Balloon Technique 7

8 Diagnosis and Management of Renal AML Renal US or MRI Abdomen every 1-2 years Surgical Biopsy and excision is to be avoided if possible Vascular embolization or cryotherapy is treatment of choice Monitoring of renal function and management of comorbidities essential (Hypertension, Diabetes) Diagnosis and Management of LAM Baseline high-resolution chest CT in post-pubertal females Baseline pulmonary function tests High suspicion if pneumothorax, chylothorax, or persistent respiratory difficulties Avoid Estrogen therapies Novel Molecular-based TSC Therapy TSC1/TSC2 and mtrc1 Rapamycin and Everolimus (RAD001) Rapalog inhibition of mtrc1 H N H H H N H H Rapamycin (sirolimus) RAD001 (everolimus) 8

9 Rapamycin for the Treatment of SEGA Rapamycin for treatment of AML A B Tumor Volume (ml) Baseline Rapamycin 1L 1R Franz et al. Annals Neurol Bissler et al. New J. Engl. Med Rapamycin effect on LAM Everolimus Effect on SEGA in TSC Baseline 6 months RAD001 Bissler et al. New J. Engl. Med RAD001 effect on SEGA volume MR Spectroscopy of SEGA 0% SEGA Volume Change -10% -20% -30% -40% -50% mi Cho Cr NAA -60% Months on RAD001 NAA = N-Acetylaspartate Cr = Creatine Cho = Choline mi = myoinositol 9

10 MRS of SEGA at Baseline MRS of SEGA after RAD001 (3 months) MRS of SEGA after RAD001 (6 months) RAD001 effect on SEGA MR spectroscopy Patients with predicted change in MRS 100% 80% 60% 40% 20% 0% -20% -40% -60% 3m 6m 12m -80% -100% NAA Cho mi Summary Tuberous Sclerosis is multiorgan disorder with variable penetrance and severity 2 nd Annual TSC Summer Camp August 6-9, 2009 Molecular-based therapies for treatment of major clinical morbidities of TSC are in development 10

11 Acknowledgements Tuberous Sclerosis Clinic and Research Center Cincinnati Children s Hospital Medical Center Acknowledgements David N. Franz, MD Darcy Krueger, MD, PhD John J. Bissler, MD, PhD Francis Y. McCormack, MD Elizabeth Schorry, MD Cindy Tudor, CPNP Karen Agricola, CFNP Elizabeth Lynch, MS Prajakta Mangaeshkar, MS Jeannie Fiser, MSW Gail McMonigle, RN Katie Loew, RN Katie Wusik, MS Steve Fordyce, BS Melody Gulleman Kimberly Wilson Miok Kim, PhD Donald Gilbert, MD Margaret Care, MD Katherine Holland, MD, PhD Anna Byars, PhD Kimberly Cecil, PhD George Thomas, PhD Sara Kozma, PhD Anand Selveraj, PhD Acknowledgements Funding Support Doug Loftus Novartis Pharmaceuticals NIH TS Alliance AFRL CCHMC 11