Alternative Treatments for Epilepsy: Maximizing Seizure Control and Quality of Life

1. Epilepsy: Alternative Treatments Juliann M Paolicchi, MA, MD Clinical Professor, Pediatrics Rutgers University Pediatric Epilepsy, Co-Director, Pediatric Clinical Research Northeastern Regional Epilepsy Group

2. Choices in the Treatment of Epilepsy: Alternatives to Medications Epilepsy, especially when not responsive to medication, affects the patient’s and familes’ social life, peer interactions, educational and career decisions, driving ability, and reproductive life.Communication on treatment options based on discussion of patient’s treatment goalsThe challenge: Minimizing seizures and maximizing QOL

3. Choices in the Treatment of Epilepsy: What, When, and Who? Epilepsy, especially when not responsive to medication, affects the patient’s and familes’ social life, peer interactions, educational and career decisions, driving ability, and reproductive life.Communication on treatment options based on discussion of patient’s treatment goalsThe challenge: Minimizing seizures and maximizing QOL What: are my options? When: should I consider these options? Who are the best candidates for these options?

4. Treatment Goals for Epilepsy Newly Diagnosed Refractory Epilepsy Surgical Evaluation AED Trial 1 Monotherapy VNS Therapy AEDs (Polytherapy) Ketogenic Diet Epilepsy Surgery AED Trial 2 Monotherapyor Polytherapy • Treatment Goal • Maximize quality of life • Optimize Long-term seizure control • Minimize AED side effects • Maximize adherence • Treatment Goal • Seizure freedom

5. Refractory Population 50% Mohanraj R and Brodie MJ. Eur J Neurol. 2006;13:277-282

6. Treatment Goals for Epilepsy Newly Diagnosed Refractory Epilepsy Surgical Evaluation AED Trial 1 Monotherapy NeurostimulationAEDs (Polytherapy) Dietary Therapy Cannibidoils Epilepsy Surgery AED Trial 2 Monotherapyor Polytherapy • Treatment Goal • Maximize quality of life • Optimize Long-term seizure control • Minimize AED side effects • Maximize adherence • Treatment Goal • Seizure freedom

7. Treatment Goals for Epilepsy Newly Diagnosed Refractory Epilepsy Surgical Evaluation AED Trial 1 Monotherapy NeurostimulationAEDs (Polytherapy) Dietary Therapy Cannibidoils Epilepsy Surgery AED Trial 2 Monotherapyor Polytherapy • Treatment Goal • Maximize quality of life • Optimize Long-term seizure control • Minimize AED side effects • Maximize adherence • Treatment Goal • Seizure freedom

8. Treatments for MRE Dietary Treatments

9. Ketogenic Diet: The “Cadillac”of the Dietary treatments • The typical dietary intake is “inverted” from predominantly carbohydrates in the typical diet, to predominantly fat and protein • 75% of cals from fat, with 1g/kg protein, and 5-10g carbohydrate/day • The ratio of fat: protein-carb ranges from 2:1 -4:1, with higher ratios seen as more restrictive, and typically more effective • ABSOLUTELY requires the supervision of a trained nutritionist/dietician, trained in familiarity with the diet.

10. KetogenicDiet • Meals include typical protein/fat sources: • Bacon, eggs, tuna, shrimp, mayonnaise, heavy cream, sausage, beef jerky • Fat is dietary, but supplemented by dairy ( cream), nut (sesame/peanut), vegetable ( coconut) or MCT ( medium chain triglyceride) oil which has made the diet better tolerated, palpated, less side effects • Available for multi-cultures, customable to the patient • Can continue infants on breastfeeding • Easiest for patients who are bottle or GT fed • Variety of formulas available for use on the diet

11. Ketogenic Diet • Best Indications? • Studied most extensively in children, but NOT restricted to use in this population. • Certain Epilepsy conditions: • 1. Epileptic spasms: • Abdelmoity ( 2014) prospective: >50% achieved in 70% of pts in 3mos, majority after 1mos of the diet ( 60%). Less EEG improvement (60%) • Kosoff, et al ( 2002): New onset, >50% in 70% in 3 mos, > in mos, 38% > 90% improved, Less EEG improvement ( 50%); 56% remained on diet for 12 mos, all were > 50% improved • Developmental improvements noted in both studies tied to seizure control

12. Ketogenic Diet • 2. Dravet Syndrome ( SCN1a mutation) • Multiple, small, adjunctive treatment trials of MRE pts demonstrate benefit of KD in this group of patients [Caraballo, et al, 2011 : >75% reduction in 10/13 children] • Prospective trial of 14 pts ( Nabbout et al, 2011): 75% improvement in 10/15 pts ( 67%), 40% continued to respond at 9 mos. Behavioral improvement ( hyperactivity/inattention) 56% • 3.Lennox-Gastaut Syndrome • Frequently used for this syndrome • JHU trial of 41 pts after 6 mos on diet:(Lemmon et al, 2012):51% > 50% improvement, 23%>90%, 1% SF (41 pts) • 4.Tuberous Sclerosis Complex: multiple, small studies indicating longterm safety, and indication that children with TSC more likely to have ruecurrence after weaning KD (Nangia, et al, 2012) • 5. NCL ( neuronal CeroidLipofusinosis) • 6. FIRES ( Febrile infection-related epilepsy syndome

13. Ketogenic Diet • Direct Indications • 1 Doose Syndrome/Epilepsy with Myoclonic-Atonic Seizures: • Multiple, small clinical trials have demonstrated significant benefit on seizures, AND EEG • ieCaraballo et al ( 2006): after 18 mos on KD, 66%> 50% improved, 44% > 75% improved, 22% SF • 2. GLUT1 deficiency ( glucose transporter 1 deficiency • 3. PDH: pyruvatedehydrogenase deficiency

14. Ketogenic diet and other dietary treatments for epilepsyRobert G Levy1,*, et alEditorial Group: Cochrane Epilepsy Group Published Online: 14 MAR 2012Assessed as up-to-date: 28 JAN 2012DOI: 10.1002/14651858.CD001903.pub2The Cochrane Library Review of Results: - Kossoff 2007: less seizures in 10g Carb KD vs 20g MA - Neal 2008: KD seizure improvement > control, p>.0001 -Seo 2007: KD 4:1 less seizures than 3:1, p<0.05 Side effects: -GI: 30%; Long term potential: Cardiovascular -Discontinuation primarily due to lack of effectiveness or restrictive nature: -only 10% on diet at 3-6 yrs.

15. Epilepsy Behav. 2013 Dec;29(3):437-42. A decade of the modified Atkins diet (2003–2013): Results, insights, and future directions. Kossoff EH, Cervenka MC, Henry BJ, Haney CA, Turner Z. Abstract -The modified Atkins diet has been used since 2003 for the treatment of children and adults with MRE -10 years of continued use, approximately 400 patients have been reported in over 30 studies of the modified Atkins diet as treatment for intractable seizures -Results demonstrating similar efficacy to the ketogenic diet and improved tolerability. -The modified Atkins diet is being increasingly used in the adult population.

16. LGI: Low-glycemic index diet • Less available research for epilepsy, but extensive use in metabolic syndrome ( pre-diabetes) • Easily accessible for most families, and more straightforward as an add-on adjunctive treatment • Does not require the complete “buy-in” and weighing of all foods as the keto diet

17. Low Glycemic Index Diet Essential basis is to limit the TYPE of carbohydrates, as opposed to the the proportion: -Low glycemic index carbohydrates: --Whole grain rice --Whole grain bread --Whole grain pasta --Eliminate fruit juices, starches, dried fruits --NO PROCESSED SUGARS; sugar substitutes accessible

18. New/Emerging Therapies • New(er) AEDs: Novel Mechanisms • Ezogabine: partial seizures (Volt gated K channels) • Vigabatrin: ES and refractory partial seizures ( irreversible inhibition of GABA transaminase) • Perampanel: partial seizures ( antagonist of AMPA receptors - glutamate) • Eslicarbazepineacetate: Oxcarbmaxepine analog/daily dosing schedule • Specific AEDs: • Stiripentol ( alcohol compound than increases opening of GABA channels) • More specific efficacy for Dravet’s/ SMEI • Anecdotal reports in ESES • Herbal/Organic: Cannabidiol • Epidiolex : Class I in many states, IND in US, RCT trial for Dravet, LGS • Medical Marijuana: State-wide registration laws vary • “Self Trials” common

19. Initial Focus on a Particularly Difficult to Treat Genetic Epileptic Syndrome: Dravet’s Syndrome

20. Preclinical Models of Efficacy: • Mg-free Hippocampal Slices • 4-AP Hippocampal Slices • PTZ- induced seizures in rats • Electro-shock seizures in mice • Audiogenic seizures in mice • Pilocarpine-induced seizures in rats

22. Epilepsia. 2014 Jun;55(6):787-90. doi: 10.1111/epi.12635. Epub 2014 May 22.The case for assessing cannabidiol in epilepsy.Cilio MR1, Thiele EA, Devinsky O. • Current studies: • Open label IND-directed trials • Multiple symptoms • FDA approved Randomized, double-blind , placebo-controlled trials for: Dravet’s syndrome and LGS

23. Current need and initiation of double-blind randomized control trials

24. Current need and initiation of double-blind randomized control trials -8 pts had EEGs before and after treatment, and showed no effect -Response of pts who had MOVED to CO, 2x that of pts who resided in state

25. Current Cannibidoil Trials • 1. ‘Availability” or IND trial: 137 pts treated, mean reduction in seizure number, 54% • 2. Effect of Cannibidoil on Neuropsychological profile for patients with refractory Epilepsy- • 3. Randomized, placebo-controlled, clinical trial in pts with Dravet syndrome • 4. Randomized, placebo-controlled, clinical trial in pts with Lennox-Gastaut syndrome • 5. Smaller trials in specific patient populations

28. Choices in the Treatment of Epilepsy: What, When, and Who? What: are my options? When: should I consider these options? Who are the best candidates for these options? Timely referral can alter the progressive disability of medically intractable epilepsy Timely referral can potentially Improve the developmental outcome of patients with chronic Epilepsy Timely referral can potentially reduce the need for more extensive resections/therapies

29. Treatment of Epilepsy : If medically- resistant, the treatment goal switches to QOL: • Maximizing QOL, minimizing seizures and sedation • Goals are determined by the team of the patient, caregivers, and medical staff as to realistic and individual attainable goals • The family and patient are key members of that determination • Frequently asses the goals of the patients and caregivers as to the success of the goals, not just seizure count • Questions? • JM Paolicchi, MA, MD, FANA • NEREG • Manhattan, NY • Hackensack, NJ • White Plains, NY • Middleton, NY • @JMPaolicchiMD