1. What’s New in Epilepsy Research? What’s New in Epilepsy Research? Evan Fertig, MD Epileptologist Director of Research Northeast Regional Epilepsy Group Evan Fertig, MD Epileptologist Director of Research Northeast Regional Epilepsy Group

2. Outline Why is Epilepsy Research Important? Why is Epilepsy Research Important? What is a Clinical Trial? What is a Clinical Trial? Epilepsy Medications under Study at NEREG Epilepsy Medications under Study at NEREG New Surgical Approaches for Epilepsy New Surgical Approaches for Epilepsy

3. Case #1: Why Epilepsy Research is Important Todd age 15 Todd age 15 Grand mal seizures occur daily Grand mal seizures occur daily Last MD told mom nothing else to do Last MD told mom nothing else to do He is on 2 anti- seizure medications with bad side effects, doing poorly in school He is on 2 anti- seizure medications with bad side effects, doing poorly in school

4. More about Todd… One of his medication is carbamazepine which is a sodium channel blocker One of his medication is carbamazepine which is a sodium channel blocker Video-EEG: Seizures coming from multiple areas of his brain Video-EEG: Seizures coming from multiple areas of his brain MRI Brain: Normal MRI Brain: Normal

5. We learn that… Seizures began 6 months with fever Seizures began 6 months with fever Seizures occur more in the summer or with vigorous exercise (gym) Seizures occur more in the summer or with vigorous exercise (gym) New genetic blood test sent: sodium channel mutation! New genetic blood test sent: sodium channel mutation!

6. What’s Todd’s Diagnosis? Dravet Syndrome Dravet Syndrome Caused by a genetic problem with a brain protein (sodium channel). This was not understood before! Caused by a genetic problem with a brain protein (sodium channel). This was not understood before! Symptoms: Bad febrile seizures, then multiple sz types, worsens with sodium channel blockers Symptoms: Bad febrile seizures, then multiple sz types, worsens with sodium channel blockers

7. And so what happened? Carbamazepine is stopped (the sodium channel blocker), Atkins Diet (like the ketogenic diet) started. Carbamazepine is stopped (the sodium channel blocker), Atkins Diet (like the ketogenic diet) started. Seizure free for 2 years Seizure free for 2 years No side effects, doing very well in school No side effects, doing very well in school

8. Progress in Epilepsy Treatment Requires Teamwork between Patients and MDs Families agree to genetic testing (bloodwork) Dravet Mutation Found! Families with Dravet Mutation agree to participate in Diet Studies Benefit Seen! Todd’s Success with Diet treatment!

9. Key Points The better we understand the causes of epilepsy… The better we understand the causes of epilepsy… The better our treatments will be! The better our treatments will be! Clinical Research is the key but can’t happen without teamwork between patients, families, and MD’s Clinical Research is the key but can’t happen without teamwork between patients, families, and MD’s

10. What is Epilepsy? A disorder of spontaneously occurring unprovoked seizures (more than 2) A disorder of spontaneously occurring unprovoked seizures (more than 2) Seizures are electrical storms of brain cells that can cause many different symptoms Seizures are electrical storms of brain cells that can cause many different symptoms

11. How do Neurons (Brain Cells) work? Ion Channel Sodium Channel: Excites! Potassium, Choride Channel: Rests!

12. What causes Seizures? Ion Channel Problems Brain Tumors, Scar tissue, etc. Excessive firing SEIZURE

13. How Do Seizure Medication Work? Close Sodium Channels (CBZ) Open Chloride Channels (gabapentin) Block release Excessive firing SEIZURE

14. What are the Limits of Medical Therapy? Trial and Error Trial and Error Brain Side Effects Brain Side Effects Body Side Effects Body Side Effects

15. Seizure Control

16. How do We Move Forward? Basic Science Clinical Trials FDA Approval- Medication available for public

17. Clinical Trials What is a clinical trial? What is a clinical trial? Key terms (from Epilepsy Study Consortium) Key terms (from Epilepsy Study Consortium) Randomization and ControlRandomization and Control BlindingBlinding PlaceboPlacebo

18. What Should I Know? Previous safety record of study medication or device Chance of getting it vs. placebo? How long? What to expect at each visit? Access to study agent after the trial?

19. What Are Some Promising New Medical Treatments under study at NEREG? Everyday Treatment Everyday Treatment Lacosamide (Vimpat)Lacosamide (Vimpat) Ezogabine (Potiga)Ezogabine (Potiga) Pregabalin (Lyrica)Pregabalin (Lyrica) Diet TherapiesDiet Therapies Emergency Treatment Emergency Treatment Intranasal Midazolam Intrabuccal Diazepam IV Brivaracetam

20. Potiga Potassium Channel Opener Potassium Channel Opener Partial Seizures Partial Seizures Rare but serious side effects Rare but serious side effects Bottom Line Bottom Line

21. Potiga vs. Placebo in the Adjunctive Treatment of Subjects with Partial Onset Seizures (POS) How safe and effective is Potiga in adults with POS with poorly controlled seizures? Objective Age > 18, 1 AED (no VNS or KD), 3 or more sz per month Requirement Visits to Hackensack office over 31 weeks. All medication, visits, and travel are provided for free + stipend Study Procedure

22. Cognitive and Behavioral Effects of Lacosamide (Vimpat) for POS. PI- Marcelo Lancman, MD How does the new medicine Vimpat affect thinking (cognition) and mood (behavior)? Objective Age > 18, English, 2 or more sz per month Requirement Visits to Hackensack office over 36 weeks. All medications, visits, and neuropsychological testing are provided for free plus stipend Study Procedure

23. Effect of Lyrica on Anxiety in POS How safe and effective is Lyrica for Anxiety in Patients with poorly controlled POS? Objective Age > 18, 1-2 AEDs, not presently treated for anxiety Requirement Visits to Hackensack office over 6 weeks. All medication, visits, travel free plus stipend Study Procedure

24. Emergency Treatment Rectal Diastat Rectal Diastat Clinically provenClinically proven Hard to giveHard to give Social StigmaSocial Stigma Can’t self administerCan’t self administer

25. Intranasal Midazolam Easy to give Easy to give Preferred route Preferred route Can be self- administered or given by caretaker Can be self- administered or given by caretaker Under study Under study

26. Intranasal Midazolam (IM) How safe and effective IM for Seizure Clusters? Objective Age 14-22, Seizure Clusters Requirement One visit to Hack ensa ck Hosp ital for test dose then follo w up visits. Trav el and med s are free Study Procedure

27. Intrabuccal Diazepam (Valium) How safe is Valium given in the mouth for seizure clusters? Objective Age > 2, epilepsy with a history of at least 1 grand mal seizure, to be admitted to EMU Requirement IV line is placed, med is given after a seizure, blood is taken off the IV line several times Study Procedure

28. What are the Limits of Surgical Therapy? What’s on the Horizon?

29. When Do We Consider Resective Epilepsy Surgery?  Partial Epilepsy  Treatment Resistant Epilepsy  Failure to become seizure free after > 2 adequate trials of 2 AEDs used appropriately  Intolerable adverse effects of AEDs?

30. Why? Rate of Seizure Freedom with continued trials of Sz med is low (5%) Rate of Seizure Freedom with continued trials of Sz med is low (5%) Potential for injury with uncontrolled epilepsy over a lifetime is high! Potential for injury with uncontrolled epilepsy over a lifetime is high! Rate of Seizure Control with Resective Epilepsy Surgery is in comparison is high (30-80%) with a low complication rate Rate of Seizure Control with Resective Epilepsy Surgery is in comparison is high (30-80%) with a low complication rate Reduction or Elimination of Sz med is frequently possible Reduction or Elimination of Sz med is frequently possible

31. How does Epilepsy surgery work? Brain Tumors, Scar tissue, etc. Excessive firing SEIZURE

32. Epilepsy Surgery http://www.rch.unimelb.edu.au/cep/Media/brain/mri6.jpg http://www.fleni.org.ar/files/servicio_193_8

33. Rates of Surgical Success* Temporal Lobectomy 70-80% Temporal Lobectomy 70-80% “Lesion” Resection 70-80% “Lesion” Resection 70-80% “Non-Lesional” Resection 30-50% “Non-Lesional” Resection 30-50% Medical Management 5% Medical Management 5% * Absence of Disabling Seizures

34. What are the Limits of Surgical Therapy? Small risk: bleeding and infection Small risk: bleeding and infection Not effective for all seizures types Not effective for all seizures types Not effective if seizures are come from more than one location Not effective if seizures are come from more than one location Not possible if seizures arise from critical brain tissue (hand area) Not possible if seizures arise from critical brain tissue (hand area)

35. Visualase Laser Treatment Evaluation is same as for epilepsy surgery No need for open brain operation

36. Visualase Implant Probe inserted in OR Transferred to MRI Treatment Laser Treatment MRI monitors safety of Laser Rx real-time Follow up Probe Removed Patient can leave same day

37. Neuromodulatory Treatments Device implanted to alter instead of destroy brain tissue Device implanted to alter instead of destroy brain tissue Range of treatment possible: Electrical, Cooling, local medications Range of treatment possible: Electrical, Cooling, local medications Limit body/brain side effectsLimit body/brain side effects Improve brain function? Improve brain function?

38. NeuroPace Implant Device under skull Leads to seizure focus Treatment Detects seizure Electrical treatment delivered Follow up MD reviews Fine tunes treatment

39. What will Epilepsy Care Look Like in Future? Personalized Medical Choices based on genetics Personalized Medical Choices based on genetics Truly Anti-epileptic therapy Truly Anti-epileptic therapy Treatment directed right at the seizure focus Treatment directed right at the seizure focus

40. Research at NEREG Jeff Politsky, MD MEG Tumor and Epilepsy Critical Care EEG Olga Laban- Grant, MD Women and Epilepsy IV Brivaracetam and Seizures Lorna Myers, PhD Non-Epileptic Seizures Spanish and Epilepsy Eric Segal, MD Diet Therapies for Epilepsy Sleep and Epilepsy Dravet Syndrome

41. Conclusion In most cases, seizures can be well controlled with medications with minimal side effects In most cases, seizures can be well controlled with medications with minimal side effects The correct diagnosis to guide treatment is essential The correct diagnosis to guide treatment is essential Epilepsy is more than just seizures, and the treatment may require a team approach Epilepsy is more than just seizures, and the treatment may require a team approach

42. Conclusion Some cases are more difficult to control, and treatment with diet therapy or surgery may be used, or clinical trials may be an option Some cases are more difficult to control, and treatment with diet therapy or surgery may be used, or clinical trials may be an option

43. Please Contact Us for More Information! Director of Research Evan Fertig, MD Director of Research Evan Fertig, MD Evan Fertig, MD Evan Fertig, MD Clinical Research Coordinator Munazza Malik, MD (201) 343-6676 munazza.malik@gmail.com Clinical Research Coordinator Munazza Malik, MD (201) 343-6676 munazza.malik@gmail.com Munazza Malik, MD munazza.malik@gmail.com Munazza Malik, MD munazza.malik@gmail.com Shweta Malhotra, TBA Shweta Malhotra, TBA