1. Ketogenic diet Jason Doescher, MD Pediatric Neurology & Epilepsy Minnesota Epilepsy Group, PA Saint Paul, Minnesota 651.241.5290 Minnesota Epilepsy Group, P.A.

2. Ketogenic diet ADK (adenosine kinase stain) Li et al. J Clin Invest. 2008;118(2):571–582. Discussion goals: Why: ketogenic diet in epilepsy therapy What: ketogenic diet mechanism Who: syndrome & seizure types Where does it get you: results How: strategy for tolerance & goals

3. Understand pathology / understand diverse therapy Seizure: abnormal neuronal & inter- neuron connections leading to recurrent imbalance in excitation & inhibition altering normal function & signaling Molecular: Genes  proteins, neurotransmitters; toxins, electrolytes, energy/metabolism Cellular: Channels, receptors; neurons, astroglia Neuronal networks: Malformations of cortical development, inflammation, neoplasia, mesial temporal sclerosis/gliosis, trauma

4. Therapeutic strategy: think pathology & review results Minnesota Epilepsy Group, P.A.

5. Newly Diagnosed Epilepsy (n=470) Seizure-free 47% (n=221) Uncontrolled Seizures 53% (n=245) Seizure-free 13% (n=32) Uncontrolled Seizures 40% (n=100) Seizure-free 1% (n=1) Uncontrolled Seizures 39% (n=39) Seizure-free 3% (n=1) Uncontrolled Seizures 36% (n=14) Monotherapy 1st AED Monotherapy 2nd AED Monotherapy 3rd AED Adjunctive Therapy AED efficacy: 64% total seizure free (301/470) Ref: Brodie & Kwan, Neurology Vol 58, Number 8, April 23, 2002 Minnesota Epilepsy Group, P.A.

6. Ketogenic diet: place in therapy Anti-epileptic medications provide approximately 60-75% of patient’s with seizure control If patient fails 3 medication trials, only 1-15% will achieve seizure control with additional medication combinations Surgery: 50-90% of appropriate epileptogenic zone resection candidates attain seizure control, but only 5-15% total qualify Minnesota Epilepsy Group, P.A.

7. KETOGENIC DIET

8. Metabolism map

9. Metabolism review: Typical diet: glucose  pyruvate  acetyl CoA Ketogenic diet: fatty acid  acetyl CoA

10. Mitochondria uses ‘citric acid cycle’ to make ATP. Acetyl CoA is common substrate of both fatty acid & glucose metabolism. Minnesota Epilepsy Group, P.A.

11. Ketogenic diet ‘transition of energy production from carbohydrates to fats’ Effectiveness depends on the degree of carbohydrate restriction & maintenance of ketone level (BHB goal 3-4) Fat: carbohydrate + protein ratio of 3:1 - 4:1 3:1 diet has long-chain saturated fat (87% calories), carbohydrate (6%), protein (7%) Minnesota Epilepsy Group, P.A.

12. Ketogenic diet Mechanism of action: metabolism v anti- epileptic properties of ketones/fatty acid metabolites – Ex. Neurosteroids on GABA-a receptors Ref: Benaroch EE. Neurology 2007;68(8):612-614.

13. Ketogenic diet: therapy

14. Seizure & syndrome types: typically responsive to ketogenic diet Seizure types: Atypical absence (refractory) Atonic – myoclonic atonic * Tonic Myoclonic Syndromes: Myoclonic atonic epilepsy – Doose syndrome Lennox-Gastaut syndrome Glucose transporter deficiency syndrome Pyruvate dehydrogenase deficiency Metabolic/mitochondrial encephalopathies – Caution to exclude fatty oxidation disorder Intractable focal or generalized epilepsy Dravet syndrome Minnesota Epilepsy Group, P.A.

15. Ketogenic diet: results

16. In 1923, Conklin treated epilepsy by prescribing “rest of gastrointestinal system” for 25 days. He reported 90% ‘success’ rate in children and 50% in adults. In 1921, Wilder introduced the ketogenic diet. Later reported 95% of patients showing improvement through treatment. Minnesota Epilepsy Group, P.A.

17. Ketogenic diet: results Maydell (2001 USA): classic diet 4:1 ratio over 12 months, 143 patients – Seizure free: 16% – >90% seizure reduction: 27% – >50% seizure reduction: 38% Kang (2005 Korea): 199 patients – Seizure free: 25% – >50% seizure reduction: 41% Minnesota Epilepsy Group, P.A.

18. Ketogenic diet: results In children, composite of many studies… Seizure free at 6 months15% >90% seizure control: 37% 90-50% seizure control: 30% <50% seizure control: 33% Keene 2006 meta-analysis Minnesota Epilepsy Group, P.A.

19. EEG : before ketogenic diet

21. Normal EEG : after ketogenic diet

22. Keys to success: patience, consistency & teamwork Team Dietician Parent/Caregiver Patient – G-Tube possible Physician/Nurse Minnesota Epilepsy Group, P.A.

23. Ketogenic Diet: application Careful patient selection: exclude fatty acid oxidation disorder – Lab: Carnitine & acyl-carnitine profiles; urine organic acids Gradual introduction (5-7 days), no fasting, no fluid restriction Ensure energy & growth Follow acidosis, glucose, & electrolytes (Na) Supplements: vitamins (D, B) & minerals (Calcium, Selenium, Zinc) Caution: – Depakote (follow liver function & carnitine stores) – Acetazolamide, topiramate & zonisamide (acidosis & kidney stones) – “Syrups & Elixirs” – sugar/carbohydrates KNOW THE CARBOHYDRATE CONTENT!! ‘2 week honeymoon’ then advance ratio Minnesota Epilepsy Group, P.A.

24. Risks & complications Growth delay & reduction Hyperlipidemia Cardiac dysfunction Kidney stones Disordered bone metabolism Bone marrow dysfunction Liver dysfunction Minnesota Epilepsy Group, P.A.

25. Alternatives Modified atkins diet Low glycemic index diet Minnesota Epilepsy Group, P.A.

26. Ketogenic diet Why: role ketogenic diet in epilepsy therapy – Roughly 1 in 4 patients need new strategy beyond medications & surgery What: ketogenic diet mechanism – Shift in energy metabolism with direct or indirect anti-epileptogenic properties Who: syndrome & seizure types – Select patients & others who fail medication trials or who are not surgical candidates Where does it get you: results – 15% seizure freedom, 30% excellent results, 30% modest improvement How: strategy for tolerance & goals – Patience, consistency & teamwork Minnesota Epilepsy Group, P.A.

27. Thank You Jason Doescher, MD Pediatric Neurology & Epilepsy Minnesota Epilepsy Group, PA Saint Paul, Minnesota 651.241.5290 Minnesota Epilepsy Group