1. Epilepsy in TSC Kevin C. Ess, MD, PhD Vanderbilt Children’s Hospital Vanderbilt Brain Institute Vanderbilt Center for Stem Cell Biology Vanderbilt University Medical Center Nashville TN USA

2. December 2014 survey: If you could choose one question for researchers to answer over the next five years, what would it be? 2

3. Historical Perspective 19 th Century, von Recklinghausen, Bourneville, Vogt’s – Seizures – Mental retardation – Facial adenoma sebaceum 20 th Century – Seizures – Intellectual disability – Facial angiofibromas forehead plaque facial angiofibroma (adenoma sebaceum) -K. Ess

4. Definitions Seizures Epilepsy

5. Seizure Types/Epilepsy Syndromes Focal/partial – Medical, diet therapies, surgically amenable Generalized – Medical, diet therapies, newer devices

6. Focal Seizures

7. L R L R Left Hemisphere Dysfunction

8. Normal baby EEG

9. Hypsarrhythmia -Mike Wong and Ed Trevathan

10. Infantile Spasms Onset-Birth to Two years Median 6 months Flexion, sometimes extension spasms Clusters, usually associated with waking Portends poor prognosis Treatment – vigabatrin (now FDA approved, $$$$) – ACTH ($$$$$$) – Ketogenic diet – topiramate – Benzodiazepines

11. Infantile Spasms Treatment

12. Lennox-Gastaut Syndrome Multiple Seizure types – Tonic seizures – Atypical absence – Atonic Intellectual Disability Pediatric Onset

13. Medical Treatments Everything………. Minimize side effects, polypharmacy

14. Dietary Treatments Ketogenic diet Modified Atkins diet Low glycemic index diet Mechanism of action? – mTOR inhibition? – Autophagy augmentation?

15. CBD Oil Source – Realm of Caring (Charlotte’s Web, Colorado) – GW Pharmaceuticals Legal/Political Issues Clinical Trials Hype/Hope

16. Right Frontal Tuber -K. Ess Surgical Treatment

17. Right Frontal Tuber Surgical Treatment Variety of approaches used: – “grids and strips”, chronic monitoring – EEG in OR only (ECoG) – “Lesionectomy” – Stereo EEG

18. Grid Implantation Pre-op: EEG and neuroimaging to determine site of likely seizure onset Then electrode grids to precisely determine onset Electrodes also used to define eloquent cortex –Motor control –Language

19. -K. Ess

20. Resection of Cortical Tubers Primary Motor Cortex -K. Ess

22. Resection of Cortical Tubers Primary Motor Cortex -K. Ess

23. New Therapies for TSC Treat the symptoms? Treat the underlying problem? Exploitable window of therapeutic opportunity in early life?

24. Rapalog therapy for epilepsy? Great for mice! Some anecdotal evidence in patients with TSC SEGA trial seizures as a secondary endpoint (EXIST-1)

26. Prenatal Diagnosis

27. Top 3 Priorities for Epilepsy in TSC 1)identify biomarkers that predict an individual’s risk of developing epilepsy 2)determine means to predict which medical or surgical approach will best treat, or ideally, prevent an individual’s epilepsy and improve outcomes 3)explore the mTOR and non-mTOR pathways contributing to epilepsy and epileptogenesis

28. Questions?