Diverse Ketogenic Therapies; Classic, Modified Atkins, and Low Glycemic Index Diet Treatment

Transcription

1 Diverse Ketogenic Therapies; Classic, Modified Atkins, and Low Glycemic Index Diet Treatment Kang, Hoon-Chul Pediatric Neurology, Severance Children s Hospital Pediatrics, Yonsei University College of Medicine Seoul, Korea, Republic of Pre-congress workshop 2 - Practical implementation of ketogenic therapy II

2 Ketogenic Diets Diets that bring on a metabolic condition comparable to fasting, a high-fat, low (moderate)-protein, low carbohydrate diet but usually without catabolism. "K / AK" = (0.9 F P) / (1.0 C F P) (K, Ketogenic; AK, antiketogenic; F, fat; P, protein; C, carbohydrate) Ketogenic Ratio = F / (C+P)

3 Ketone Bodies Acetyl CoA Nonenzymatic decarboxylation ß-hydroxybutyrate dehydroxygenase Acetoacetate C C Acetone ß-hydroxybutyrate

4 Diverse Ketogenic Therapies Ratio of Fat to Non-fat Types of Fat

5 Diverse Ketogenic Therapies Ratio of Fat to Non-fat Types of Fat

6 Modified Atkins Diet (% Cal) Fat Protein Carbohydrates Low Glycemic Index Diet (% Cal) Fat Protein Carbohydrates (Low GI) 17% 6% 77% 30% 10% 60% Classic Ketogenic Diet (% Cal) Fat Protein Carbohydrates 6% 4% Regular Diet (% Cal) Fat Protein Carbohydrates Calorie Restriction 90% 50% 30% 20% Fat Prot CHO

7 Modified Atkins Diet (% Cal) Fat Protein Carbohydrates Low Glycemic Index Diet (% Cal) Fat Protein Carbohydrates (Low GI) 17% 6% 77% 30% 10% 60% Classic Ketogenic Diet (% Cal) Fat Protein Carbohydrates 6% 4% Regular Diet (% Cal) Fat Protein Carbohydrates Calorie Restriction 90% 50% 30% 20% Fat Prot CHO

8 Classic Ketogenic Diet = F / (P+C) (% in gram scale) 80 / (15+5) = 4 : 1 (% in gram scale) 90 / 10 = 9 : 1 (% in Calorie scale) 1 gram of F = 9 Cal 1 gram of P or C = 4 Cal Diet Composition Fat (% in gram scale) Protein (% in gram scale) Carbohydrate (% in gram scale) Calories (% recommended daily allowance) Ketogenic Diet

9 Modified Atkins Diet (% Cal) Fat Protein Carbohydrates Low Glycemic Index Diet (% Cal) Fat Protein Carbohydrates (Low GI) 17% 6% 77% 30% 10% 60% Classic Ketogenic Diet (% Cal) Fat Protein Carbohydrates 6% 4% Regular Diet (% Cal) Fat Protein Carbohydrates Calorie Restriction 90% 50% 30% 20% Fat Prot CHO

10 Modified Atkins Diet (MAD) Akins diet, created by the late Dr. Robert C. Atkins for weight loss restricts CHO, but not restrict consumption of proteins or calories Modified Atkins diet, first reported by Johns Hopkins Hospital in 2003 stricter restriction of CHO intake Regular Diet (% Cal) Fat Protein Carbohydrates Modified Atkins Diet (% Cal) Fat Protein Carbohydrates Classic Ketogenic Diet (% Cal) Fat Protein Carbohydrates 50% 30% 17% 6% 6% 4% 20% 77% 90% Fat Prot CHO

11 Modified Atkins Diet Protocol in Current Use at Severance Hospital (Modifications to the JHH Protocol) Carbohydrates are restricted to 10 grams per day for the first month. Permit to increase by only 5 grams/day with an interval of at least one month up to grams/day as tolerated based on seizure control Calories are recommended to be restricted into 75% of recommended daily intake. L-carnitine, multivitamins, and calcium and vitamin D2 were given as supplements. All the patients had been advised to remain at the hospital for 3 or 4 days to ensure adequate diet adaptation to have their blood ketosis carefully monitored and for teaching of the caregivers on how to manage the diet at home. Seizure diary, blood or urine ketones semiweekly, and weight monthly, height every 6 months Medication changes to tablet or sprinkle (non liquid) preparations Low-carbohydrate, store-bought products (e.g., shakes, candy bars, baking mixes) discourage We recommend a trial of the diet for at least 2-3 months even in the face of unfavorable results. The other protocols including it for evaluating complications are accorded to the Severance Hospital s protocol for the conventional ketogenic diet. Kossof E, et al. Neurology 2003; Kang HC, et al. Epilepsia 2007

12 Classic vs Modified Atkins Chicken, 18.7 gram 재료 양 (g) 닭고기 18.7 깻잎 6.8 당근 5 오이 5 KD 닭살냉채 VS MAD 닭살냉채 재료 양 (g) 닭고기 67.7 깻잎 3.2 당근 3.8 오이 5 Chicken, 67.7 gram 땅콩 6.5 잣 3 마요네즈 7 마요네즈 20 올리브유 31.3 올리브유 16.7 Beef, 24.2 gram 재료 양 (g) 재료 Beef, 78 gram 양 (g) 소고기 24.2 소고기 78 파프리카 ( 빨강 ) 4 파프리카 ( 빨강 ) 5.3 파프리카 ( 노랑 ) 4 양송이버섯 11.8 VS 파프리카 ( 노랑 ) 5.2 양송이버섯 13 양파 11.3 양파 9 마카다미아 12.2 마카다미아 10 올리브유 16.8 올리브유 14.9 참기름 11 KD 찹스테이크 MAD 찹스테이크 참기름 3.3

13 MAD for Refractory Childhood Epilepsy: a Randomized Controlled Trial Among a total of 102 children, 50 were in the MAD group and 52 in the control group The mean seizure frequency at 3 months cf) a percentage of the baseline, p = in the MAD group: 59.0 ± 54 (95% CI ) in the control group: 95.5 ± 48 (95% CI ) The proportion of children with >90% seizure reduction at 3 months 30% (MAD) vs. 7.7% (control), p = The proportion of children with >50% seizure reduction at 3 months 52% (MAD) vs. 11.5% (control), p < Effective and well tolerated in children with drug-refractory epilepsy Sharma S, et al. Epilepsia 2013

14 Classic vs Modified Atkins In small pilot series, in reducing seizure frequency -> similar efficacy of the MAD with the classic KD (Kossoff EH, et al. Epilepsia 2006; Kang HC, et al. Epilepsia 2007; Weber S, et al. Seizure 2009; Miranda MJ, et al. Seizure 2011; Tonekaboni SH, et al. Arch Iran Med 2010) Higher incidence of responders (> 50% seizure reduction) in the classic KD group (Porta N, et al. Seizure 2009)

15 Comparison of MAD and the Classic KD : A Randomized Controlled Trial The open-label, randomized-controlled trial at Severance Children's Hospital in Korea Total In 3 months of DT Classic KD (n=51) MAD (n=53) P-value Seizure free 17 (33%) 90% seizure reduction % seizure reduction 19 (37%) 22 (43%) 13 (25%) 17 (32%) 22 (42%) The proportions of patients who showed seizure freedom, 90% seizure reduction and % seizure reduction were not significantly different between the two groups. Kim JA, et al. Epilepsia 2016

16 Comparison of MAD and the Classic KD : A Randomized Controlled Trial The open-label, randomized-controlled trial at Severance Children's Hospital in Korea Age, 1 to <2 years old In 3 months of DT Classic KD (n=17) MAD (n=20) P-value Seizure free 9 (53%) 90% seizure reduction % seizure reduction 9 (53%) 10 (59%) 4 (20%) 5 (25%) 8 (40%) The analysis revealed that for patients aged <2 years, the rate of seizure freedom was significantly higher in the patients who had the classic KD. Kim JA, et al. Epilepsia 2016

17 Comparison of MAD and the Classic KD : A Randomized Controlled Trial (about Complications and Tolerability) During the first 3 months, more patients in the classic KD group discontinued their dietary therapy due to too restrictive and medical side effects. In the MAD group, even in those patients who eventually dropped out, dietary therapy was maintained longer than it was by the dropouts from the classic KD group. Hypercalciuria occurred more frequently in the classic KD group during the early and late periods of diet therapy, so renal stones and osteopenia were frequent complications in the classic KD group later during the study period. However, the frequencies of dyslipidemia were similar in both groups and this result has occurred in other studies of long-term MADs. Kim JA, et al. Epilepsia 2016

18 Comparison of MAD and the Classic KD : A Randomized Controlled Trial (about Complications and Tolerability) During the first 3 months, more patients in the classic KD group discontinued their dietary therapy due to too restrictive and medical side effects. Modified Atkins Diet In the MAD group, even in those patients who eventually dropped out, dietary therapy had was less maintained frequent longer complications than it was by the dropouts from the classic KD group. and more comfortable. Hypercalciuria occurred more frequently in the classic KD group during the early and late periods of diet therapy, so renal stones and osteopenia were frequent complications in the classic KD group later during the study period. However, the frequencies of dyslipidemia were similar in both groups and this result has occurred in other studies of long-term MADs. Kim JA, et al. Epilepsia 2016

19 Modified Atkins Diet (% Cal) Fat Protein Carbohydrates Low Glycemic Index Diet (% Cal) Fat Protein Carbohydrates (Low GI) 17% 6% 77% 30% 10% 60% Classic Ketogenic Diet (% Cal) Fat Protein Carbohydrates 6% 4% Regular Diet (% Cal) Fat Protein Carbohydrates Calorie Restriction 90% 50% 30% 20% Fat Prot CHO

20 Rationale for Low Glycemic Index Diet Treatment Stabilization of blood glucose levels and lower ketone bodies by LGID would prevent seizures and cognitive dysfunction. mg/dl standard (glucose or white bread) test food Glycemic Index (GI) = AUC of test food/ AUC of standard food hour cf) AUC area under the two hour blood glucose response curve

21 Low-glycemic Index Diet Therapy (LGID) LGID for epilepsy, first reported by Massachusetts General Hospital in 2005 The LGID limits the percentage of CHO to g/d (20-30 g/d for MAD), while protein contributes 20 30% and fat contributes 60% of daily calorie. All CHO foods glycemic index are lower than 50. The balance of low glycemic CHO in combination with fat results in steady glucose levels. Low Glycemic Index Diet (% Cal) Fat Protein Carbohydrates (Low GI) Modified Atkins Diet (% Cal) Fat Protein Carbohydrates 10% 17% 6% 30% 60% 77% Fat Prot CHO

22 Glycemic Index of Foods Classificat ion GI range Examples Low GI 55 or less most fruits and vegetables (except potatoes and watermelon), grainy breads[ 거친빵 ], pasta, legumes[ 콩류 ]/pulses[ 두류 ], milk, yoghurt, products extremely low in carbohydrates (some cheeses, nuts[ 견과 ]), fructose Medium GI whole wheat products, basmati rice, sweet potato, table sugar High GI 70 and above corn flakes[ 콘플레이크 ], rice krispies, baked potatoes, watermelon, croissants[ 크루아상 ], white bread, extruded breakfast cereals, most white rices (e.g. jasmine), straight glucose (100) cf) Low glycemic index Particle size (large) Type of starch (straight chains of amylose compared to amylopectin) Presence of fat (buttered bread has lower GI than bread alone) Acidity (the higher acidity of a food) The fiber content (more) -> Fermented fiber is converted into beta-hydroxybutyrate. -> The presence of fiber can also prolong the absorption rate.

23 Low Glyemic Index Diet Vegetables 1~2 sorts/one meal Fats 5~10g/one meal Fish or Meat 2-3 sorts/one meal Grains ¼~⅓ bowl/one meal cf) staple food for Asians Fruits GI <50 Milk or Dairy Products 1~2 cups/day +

24 Efficacy of Low-glycemic Index Diet Treatment Copploa G, et al. Seizure 2011 (Italian Experience) Of 15 patients, after a mean follow-up period of months, 8 patients (53.3%), >50% reduction in seizure frequency, Karimazdeh P, et al. Seizure 2014 (Middle East Report) Of 42 patients, at the end of the second month, 33 patients (77.8%), >50% reduction in seizure frequency Kim SH, et al. Brain & Dev 2017 (Severance Hospital in Korea) Of 36 patients, after 3 months of therapy, 20 patients (56%), >50 reduction in seizure frequency including 2 (6%) patients, became seizure-free after 3 months of LGIT

25 Efficacy of Low-glycemic Index Diet Treatment Muzykewics DA, et al. Epilepsia 2009 cf) A greater than 50% reduction from baseline seizure frequency was observed in 42%, 50%, 54%, 64%, and 66% of the population with follow-up available at 1, 3, 6, 9, and 12 months, respectively. cf) Intention to Treat (N=76) At 12 months, 12/76 patients (16%), >50% reduction in seizure frequency

26 Indications for Lower Fat Diet Therapy (MAD & LGID) Lower fat diet therapy can be first applied for patients if they (1) have too restrictive or some serious unwanted events of classic KD even though it was effective to control seizures (2) require a long-term trial of diet therapy for over several years or throughout, (glucose transporter type I deficiency, pyruvate dehydrogenase deficiency ) Safer and more comfortable diet therapy

27 Tips for Successful Usage of Lower Fat Diet Therapy (MAD & LGID) Ketosis can drifts easily downward with a loss of seizure control. -> encourage to keep more strictly the ratio of diet constituents Tips to regain ketosis -> fasting for one meal -> replacing one meal with a ketogenic milk (the ratio of fat to non-fat, 4:1 in gram scale) Kossoff EH & Dorward JL. Epilepsia 2008 KETONIA, 120 Kcal/100 ml

28 Diverse Ketogenic Therapies Ratio of Fat to Non-fat Types of Fat

29 Triglyceride or Triglycerol glycerol with three molecules of fatty acid hydroxyl (HO-) groups of glycerol + carboxyl group (COOH) of fatty acid

30 Fatty Acid cf) according to the number of carbons Short-chain fatty acid (SCFA), -5 carbons Medium-chain fatty acid (MCFA), 6-12 carbons Long-chain fatty acid (LCFA), carbons Very long-chain fatty acid (VLCFA), 22- carbons

31 Medium Chain Triglycerides (MCT) Medium chain triglycerides usually chemically derived from coconut oil, (8.3 Cal/1 gram MCT oil) contain trioctanoin (C8 FAs) and tridecanoin (C10 FAs) cf) tasteless, easily be added to regular meals (e.g. salad dressing) Medium chain fatty acids diffuse directly into blood and mitochondria of all tissues. cf) long chain fatty acids are first transported by the lymph and require transport proteins. MCT s antiseizure, antioxidant and neuroprotective profile, evidenced in animal models

32 Medium Chain Triglycerides Ketogenic Diet Composition of 3 major KDs Calculation based on MCT LCFA Protein CHO Classic (4:1) 75 % of RDI; 36 cals from fat to 4 cals from protein 1g protein/kg and carbohydrate bodyweight 90% 10% MCT RDI 60% 11% 10% 19% Modified MCT RDI 30% 41% 10% 19% MCT = medium-chain triglyceride; RDI = recommended daily intake LCFA = long-cahin fatty acid; CHO = carbohydrate Cf) more ketogenic than long-chain triglycerides Therefore, the MCT KD allows larger amounts of CHO and protein, which makes the diet more palatable

33 MCT Ketogenic Diet for Epilepsy Introduced by Huttenlocher in 1971 The efficacy of the MCT KD, similar to that achieved by the classic KD, which has been verified in several subsequent retrospective, prospective, and randomized studies. These studies have shown that more than 50% of the children had achieved >50% reduction in seizure control. Schwartz directly compared MCT KD with classic KD and found no difference in seizure control. Liu and Sell also indicated similar efficacy between MCT KD and classic KD. Neal s randomized trial comparing classic KD and MCT KD indicated there were no significant differences between these two diets. Schwartz RH, et al. Dev Med Child Neurol 1989; Liu YM. Epilepsia 2008; Neal EG, et al. Epilepsia 2009

34 Demerits and Overcoming Complications of MCT KD Demerits associated gastrointestinal side effects from the MCT KD, such as diarrhea, vomiting, bloating, and cramps reports of liver failure when MCT KD and valproate are combined Overcoming complications increasing the amount of MCT oil gradually to lower the risk of complications close monitoring by physician, trained dietitians and nurses Liu YC & Wang HS. Biomed J 2013 During the fine-tuning stage, the diet is initially calculated at 50% MCT, 21% LCT, 19% CHO, and 10% protein. During the diet initiation, if diarrhea or vomiting occurs, the MCT is lowered by 10% and LCT is increased by 10% for the next feed until the patient is able to tolerate the diet. If vomiting recurs within 6 h, oral fluids are discontinued and hydration proceeds with IV normal saline; feedings are continued at a 10% lower MCT dose. Medication with a dimenhydrinate suppository can be tried.

35 Fatty Acid cf) according to the number of double bonds 0, saturated fatty acid (SFA) 1, monounsaturated fatty acid (MUFA) 2 or more, polyunsaturated fatty acid (PUFA)

36 ω-3 PUFA During Ketogenic Diet Peroxisome proliferatoractivated receptors (PPARs ) is activated by the PUFA. -> PPARs expression is inversely correlated with IL-1β cytokine expression. -> diminished expression of ILβ cytokines directly by PUFAs or via activated PPARs could lead to improved seizure control. Bough KJ & Rho JM, Epilepsia 2007

37 ω-3 PUFA During Ketogenic Diet PUFAs would induce the expression of UCPs and coordinately up-regulate several dozen genes related to oxidative energy metabolism. -> limit ROS generation, neuronal dysfunction, and resultant neurodegeneration. -> stimulate mitochondrial biogenesis and enhance energy reserves, leading to stabilized synaptic function and improve seizure control. Bough KJ & Rho JM, Epilepsia 2007

38 Recommended Ratio for PUFAs omega-6 : omega-3 = 4:1 ~ 1:1 -> ratio of omega 6 to omega 3 (especially the ratio of LA to ALA) fatty acid, important to maintain cardiovascular health -> the conversion of ALA to DHA can be optimized when omega-6, LA was coadministered with omega-3, ALA at a 4:1 ratio in rat brain (Yehuda S, et al. Int J Neurosci 1996) The ratios of omega-6 to omega-3 fatty acids in vegetable oils -> canola oil, ~2:1 cf) corn oil 46:1, soybean oil 7:1, grapeseed oil (almost no omega 3), sunflower oil (no omega 3), peanut oil (no omega 3)

39 Oils Safer and More Comfortable KD More Favorable Response and Prognosis by KD Olive oil Canola oil Sesame oil Corn oil Soybean oil Grapeseed oil Sunflower oil Peanut oil

40 Modified Atkins Diet of 1,200 Calorie for one day fishes, nut olive oil SFA MUFA PUFA 17.9 gram 61.7 gram 17.6 gram 18.4% 63.5% 18.1% ω 6 : ω 3 = 18.6:1 canola oil SFA MUFA PUFA 14.4 gram 54.7 gram 30.5 gram 14.5% 54.9% 30.6% ω 6 : ω 3 = 2.8:1

41 Triheptanoin O C7 C7 Uneven medium chain triglyceride, namely of the C7 heptanoate Derived from castor beans (minute amounts), commercially produced through chemical breakdown of long-chain triglycerides O O O O O C7 Triheptanoin cf) Anaplerosis, Anaplerotic (replenishing) reaction for efficient production of energy, the TCA cycle is dependent on intermediates containing four or five carbons (via anaplerosis), e.g. pyruvate (C4), propionyl-coa (C5) McDonald T, et al. Frontiers in Cellular Neuroscience 2018

42 Triheptanoin Triheptanoin Heptanoate Heptanoate C7 Fatty acid Acetyl-CoA + Pentoyl-CoA Beta-Ketopentoyl-CoA (BKP-CoA) Acetyl-CoA and Propionyl-CoA 5 Carbon Ketone Body formation and export BHP + BKP BLOODSTRERAM BHP + BKP Acetyl-CoA + Propionyl-CoA Krebs cycle ATP Succinyl-CoA beta-hydroxypentanoate (BHP) beta-ketopentanoate (BKP) Three seven-carbon fatty acids -> 5 C ketone bodies (easily penetrate into BBB) Triheptanoin for the treatment of various metabolic disorders including pyruvate carboxylase deficiency, long-chain fat oxidation disorders

43 European J of Pediatric Neurology (In press) cf) Of 8 children, who finished the trial and tolerated between 30 and 100 ml of triheptanoin per day for >12 weeks (23-36% caloric intake). Five children (62.5%), showed sustained >50% reductions in seizure frequency, including one patient who became seizure free for 30 weeks. The most common adverse effects were diarrhea and other gastrointestinal effects in seven kids.

44 Discussion & Summary

45 Management of Intractable Childhood Epilepsy Surgical Newly Develped Anti-epileptic Drugs Steroid Diet Therapy (DT)

46 Considerations for an Additional Treatment with Anti-epileptic Drugs Different action mechanism or synergic effect Considerations about complications of polytherapy Starting the drug at a lower dose and gradually increasing the dose Sometimes, a low or maintenance dose can control seizures and improve EEG findings. On contrary, high dose medications are often used as first-line agents for specific epilepsy syndromes, e.g. West syndrome.

47 Considerations for an Additional Treatment with Ketogenic Diet Therapies Different action mechanism or synergic effect Consider complications and too restrictive of diet therapy Starting the diet therapy at a lower ratio of fat to non-fat and gradually increasing the ratio more fat and fewer seizures but sometimes or often, a lower ratio fat diet can control seizures and improve EEG findings too. On contrary, classic ketogenic diet are often required for early onset epilepsy syndromes, e.g. West syndrome. (even as the firstline therapy) Various sources of fat constituents including medium chain triglycerides, polyunsaturated fatty acids and even triheptanoin (analerosis) can be considered.

48 Diverse Options of Menu & Cooking Class Dietician s Role to make more tolerable KD, to develop diverse options of menu & educate the recipe of them to parents Socialization Tool

49 Fine Tuning (Individual Approach) The ratio of this diet and types of fat can be adjusted to affect better seizure control and can also be liberalized for better tolerability.

50 Thank You for Your Attention!