Steve Plogsted, PharmD, BCNSP, CNSC Nationwide Children s Hospital Columbus, OH Objectives Review the history of the Ketogenic Diet Provide an overview of the intricacies and utilization of the ketogenic diet Discuss alternative diets for seizure control 1
History Ancient Greece and India In the Hippocratic Corpus On the Sacred Disease described how diet alterations played a role in epilepsy This author also described in Epidemics from that collection how a man was cured of epilepsy when completely abstaining from consuming food or drink 1911 first scientific study in France using fasting as a cure for epilepsy 20 epilepsy patients follow low cal veggie diet combined with fasting 2 found significant improvement but the others couldn t follow the diet Improvement in seizures and mental alertness Bernarr Macfadden (early 20 th century) Proposed seizures were caused by toxins secreted in intestine Suggested fasting for 18 25 days would cause toxins to dissapate Subjects were put on water diet reporting a 90% cure in children and 50% in adults A combined total of 20% became totally seizure free and 50% demonstrated improvement History (cont) 1921 endocrinologist Rollin Woodyatt noted that three water soluble compounds, acetone, βhydroxybutyrate and acetoacetate (together called ketone bodies) were produced by the liver as a result of starvation or if they followed a diet rich in fat and low in carbohydrates 1921 Russel Wilder from the Mayo Clinic called this the ketogenic diet and used it as a treatment for epilepsy 2
History (cont) 1960 further research showed that more ketones are produced by medium chain triglycerides (MCTs) per unit of energy because they are transported quickly to the liver via the hepatic portal vein, as opposed to the lymphatic system 1971 Peter Huttenlocher devised a ketogenic diet where 60% of the calories came from MCT oil, which allowed more protein and carbohydrates to be included compared with the original ketogenic diet, meaning parents could prepare more enjoyable meals for their children with epilepsy Epileptic Seizures and the KD Most individuals who develop epilepsy will respond to pharmacologic treatment, however, approximately 20% 30% will develop medically refractory epilepsy For this population, alternative or nonpharmacologic treatments such as dietary therapy can be highly efficacious and should be seriously considered Traditionally, the KD has been reserved as a last treatment option after establishment of medical intractability, typically defined as the failure of three or more anticonvulsant medications 3
How the Diet Works The KD leads to changes in plasma levels of ketones, insulin, glucose, glucagon, and free fatty acids Formation of ketone bodies in the liver from long and medium chain fatty acids have a direct anticonvulsant effect when crossing the blood brain barrier How the Diet Works (cont) Increased mitochondrial biogenesis, oxidative phosphorylation, enhanced GABA levels, reduced neuronal excitability and firing, and stabilized synaptic function have been shown to occur in patients on the KD 4
How the Diet Works (cont) Additionally, the roles of carbohydrate reduction, activation of adenosine triphosphate sensitive potassium channels by mitochondrial metabolism, inhibition of the mtor pathway, and inhibition of glutamatergic excitatory synaptic transmission have been described Main Metabolic Pathway Politi et al, 2011. The Ketogenic Diet 2011: How It Works 5
Mechanism of Action Glucose is the primary cellular energy source in the body; however, patients on the ketogenic diet will use fatty acids as the obligatory source of energy production because they receive minimal amounts of carbohydrates About 80% to 90% of the total calories consumed on the ketogenic diet are because of the presence of fatty acids. The fatty acids undergo beta oxidation in the mitochondria to supply energy to extrahepatic sites Mechanism of Action (cont) When rates of fatty acid oxidation are increased there is a decreased efficiency of the Krebs cycle, resulting in excess acetyl CoA Excess acetyl CoA is hepatically converted to 3 ketone bodies (acetone, acetoacetate, and b hydroxybutyrate [BHB]) These ketone bodies spill into the general circulation where they cross the blood brain barrier as an energy source 6
Mechanism of Action (cont) The ketogenic diet is primarily used in children as it is thought that younger brains may have a greater capacity to transport ketone bodies across the blood brain barrier and to use them as a primary energy source Ketone bodies cross the blood brain barrier in proportion to the degree of ketosis The ketogenic diet may have antioxidant properties that may be beneficial in decreasing the oxidative stress leading to seizures Mechanism of Action (cont) Energy Metabolism: Fuel Sources Regular diet: CHO glucose Protein amino acids glucose Fat: Triglycerides fa y acids ketone 7
Gluconeogenesis From Protein Meat protein can be converted to glucose at about 50% efficiency, so approximately 100 g of protein can produce 50 g of glucose via gluconeogenesis Gluconeogenesis From Fat During prolonged fasting, glycerol released from lipolysis of triglycerides in adipose tissue may account for nearly 20% of gluconeogenesis As nearly 10% of triglyceride by weight is glycerol, and two molecules of glycerol combine to form one molecule of glucose, 80 g of triglycerides may be converted into 8 g of glucose (5% efficiency) 8
Use of the Ketogenic Diet Type II DM Cancer s (glioma, Pancreas, Prostate, Breast, Colon, Gastric, Lung) 9
Metabolic Conditions and the KD GLUT 1 deficiency defect of glucose transport into the brain resulting in hypoglycorrhachia causing epilepsy, developmental delay, and a complex motor disorder in early childhood Pyruvate dehydrogenase deficiency The glycolytic end product, pyruvate, is not optimally metabolized through the tricarboxylic acid cycle, leading to increased production of lactate and impaired production of adenosine triphosphatase (ATP) via the mitochondrial respiratory chain During carbohydrate deprivation, cellular energy is no longer derived from glycolysis but from degradation of fatty acids The ketone bodies (3 beta hydroxybutyrate, acetoacetate, and acetone) generated by fatty acid oxidation serve as an alternative energy substrate to glucose for the brain Classic Ketogenic Diet The classic diet is calculated using a ratio of the weight of fat to the sum of protein and carbohydrate In a 4:1 ratio, there are 4 g of fat for every 1 g of protein and carbohydrate combined Protein is provided to meet dietary reference intake, which is approximately 1 g per kilogram of body weight Carbohydrate completes the remaining allowance of the ratio 10
Classic Ketogenic Diet (cont) To achieve these ratios, foods rich in carbohydrate are eliminated from the diet, including sugar, pasta, bread, and grains low carbohydrate vegetables and fruit are allowed The main sources of fat are heavy cream, vegetable oils, and butter Typical 3 Meal Diet Breakfast: Scrambled egg and apple sauce meal 45 grams whole raw egg 13 grams olive oil 15 grams butter 10 grams butter 3 grams nuts 5 grams thickened Farmers Union 30 grams raw granny smith apple cream Lunch: Creamy Bacon Meal 20 grams raw green capsicum 64 grams 35% ideal dairy cream 20 grams raw celery 27 grams lean bacon 20 grams raw brown onion 22 grams Sundew margarine Dinner: Chicken and Vegetable Stir Fry 30 grams peeled raw carrot 5 grams commercial soy sauce 30 grams raw green capsicum 23 grams lean chicken breast 30 grams raw broccoli 42 grams olive oil 14 grams raw brown onion 11
Typical 4 Meal Diet Meal 1: Meal 3: Cream, 56 g Cream, 46 g Canola oil, 6 Canola oil, 4 g Fresh egg, 16 g Butter, 6 g Crisp bacon, 5 g Spaghetti squash, 20 g Strawberries, 14 g Cheddar cheese, 15 g Meal 2: Meal 4: Cream, 45 g Sugar free mayo, 32 g Canola oil, 4 g Shredded chicken breast, 16 g Ranch dressing, 20 g Dill pickles, 11 g Iceberg lettuce, 16 g Red grapes, 11 g Fresh spinach, 16 g Grilled chicken breast, 9 g 120 g total fat 30 g protein + carbs Tube Feeding Options Ketocal Nutritionally complete powdered product 4:1 Ratio Convenient one step preparation with a non modular approach Nutrient dense for children with low energy requirements RCF + Microlipid + Polycose Powder Ketocal + Polycose Powder (Modified Adkins) Designer formulas 12
Other Diets 3:1 ratio Generally used for older children who have greater body mass and therefore higher protein needs 2.5:1 ratio Used when weaning from diet, occasionally in older adolescents and when adverse effects seen with other diet Modified Adkins Diet Low Glycemic Index Diet (LGIT) Medium Chain Triglyceride Diet (MCT) Modified Atkins Diet Limits carbohydrate and provides 65% of calories from fat Result in an approximate ratio of 1:1 (fat to nonfat) No fasting or hospital admission required No weighing of foods Can be used long term 13
Low Glycemic Index Diet Glycemic Index = measure of the tendency of a food to elevate blood glucose Foods that have an individual glycemic index of 50 or greater are eliminated 60% of calories are provided from fat, and protein is provided at approximately 1 g/kg of body weight Allows for some typical no foods rye bread, some cereals Medium Chain Triglyceride Diet (MCT) Introduced in the 1970 s by Haltenlocher et al Replace LCT with MCT oil at 60% of the calories MCT oil is AKA fractionated coconut oil Rapid conversion of Ketone bodies in the liver Problems not as palatable as originally thought, abdominal cramps, diarrhea, N/V More recent use is 30% MCT oil, 40 50% of other fat sources to total 75 85% fat 14
Comparison of four major KDs. Pie charts depict relative proportion of calories provided by fat, protein, and carbohydrates for the classic KD (4:1 ratio by weight of fats to carbohydrate plus protein), the MCT diet, the MAD, and the LGIT 15
Barriers to the Diets Child won t like the food and won t eat it Child eats and drinks poorly Adolescent won t comply with the diet Adverse Effects of the Diet Constipation (most common SE) Acidosis Hyperlipidemias Hypoglycemia Nephrolithaisis Lethargy Decreased bone density Growth retardation Diet intolerability Vitamin and nutrient deficiencies Steatorrhea (less common) 16
Food Drug Interactions Phenobarbital levels may increase significantly in patients receiving the diet and may cause profound sedation This is related to the acidotic state induced by the ketogenic diet and the low pka of phenobarbital, resulting in phenobarbital accumulation in the CNS Valproate can interfere with ketone production, causing carnitine deficiency and a Reye s like Syndrome Results in lethargy, nausea, vomiting, hepatic failure, and encephalopathy Carnitine Carnitine is responsible for transporting long chain fats from outside to inside the mitochondria Prolonged KD produces chronic ketosis with increased formation of acetylcarnitine eventually leading to decrease in serum carnitine May need to supplement with exogenous carnitine at ~50 mg/kg/day 17
Medications Affecting the Diet High CHO containing Syrups, tablets and capsules Intravenous dextrose solutions Topiramax, zonisamide and acetazolaminde Used as antiepileptic meds Carbonic anhydrase inhibitors naturally removes carbon dioxide from the body resulting in acidosis Fluids Traditionally, fluids have been restricted to 80 90% of daily requirements Early studies from the 1920s and 1930s suggested that tissue hydration was one of the mechanisms by which the KD worked, and created a perception that overhydration reduces efficacy The KD may predispose to nephrolithiasis because of hypercalciuria, acid urine, low urinary citrate, and low fluid intake Approximately 2 4% of patients treated with a traditional KD develop stones; those with hypercalciuria tend to be a higher risk 18
Fluids (cont) While concerns have been raised that concurrent use of carbonic anhydrase inhibitors, such as topiramate, zonisamide, or acetazolamide, may exacerbate stone formation in children on the diet, a 2007 study refuted this theory There is no scientific evidence to suggest that fluid restriction is needed or beneficial Because of concerns of possible nephrolithiasis, most centers no longer restrict fluids Management or Prevention of Adverse Effects Change the diet s carbohydrate ratio 3:1 or 2.5:1 MAD Citrate alkalization Vitamin and mineral supplementation Product meq per tsp mg per tsp Table Salt 102 sodium 2360 sodium Morton Lite Salt 50 sodium 35 potassium 1160 sodium 1400 potassium Morton s Salt Sub 62.5 potassium 2440 potassium 19
Reasons for Discontinuation or Failure of the Diet Due to side effects Due to lack of efficacy Due to side effects and lack of efficacy For other reasons (parent discontinued diet for unknown reasons, stealing food, bowel perforation unrelated to diet) Consuming hidden CHO 20
Carbs to Be Aware Of Sugars Starches Polyols Polyols are: Sugar free, low digestible carbohydrate sweeteners Referred to as sugar alcohols in Nutrition Facts Panel but are neither sugar, nor alcohols Others such as found in dried fruits Polyols Used in the U.S. Erythritol HSH (polyglucitol) Isomalt Lactitol Maltitol Mannitol Sorbitol Xylitol 21
How Do Their Calories Compare? Polyol Caloric Density (kcal/g) Erythritol 0.2 Mannitol 1.6 Isomalt 2.0 Lactitol 2.0 Maltitol 2.1 Xylitol 2.4 Sorbitol 2.6 HSH (polyglucitol) 3.0 Note: Sugar provides approximately 4.0 calories per gram Advantages of Polyols Polyols taste like sugar, yet provide fewer calories than sugar Polyols do not cause sudden increases in blood glucose levels, and are generally very low in blood glucose effect They are only partially absorbed by the body Absorbed portions are either metabolized (generally by insulin independent mechanisms) or excreted via the urinary tract Unabsorbed polyols are partially fermented in the colon and excreted 22
Effectiveness of the KD 1/3 will discontinue the KD due to ineffectiveness or difficulty with adherence or tolerability 1/3 will have a 50 90% reduction in seizures 1/3 will have >90% seizure reduction Half of those individuals will become seizure free (15 17%) Highest success rate in children <5 yrs Case 5 yo female, 22 kg Dx: NAT, SDH, diffuse bilateral HIE and super refractory status epilepticus Current meds: Tegretol susp 100 mg BID Valproic acid syrup 250 mg QID Keppra Solution 500 mg BID Zantac liq 75 mg BID 23
Case Estimated nutritional needs: 1400 kcal, 28 g protein Ketogenic Diet 4:1 4 parts fat to 1 part CHO+Prot 140 g fat, 28 g prot + 7 g CHO Can eat some but cannot swallow pills/capsules What food cannot be eaten is given via G tube Carbohydrate Content of Meds Tegretol susp 100 mg/5 ml = 3350 mg CHO/5 ml Daily CHO = 6.7 g Valp acid syrup 250 mg/5 ml = 4320 mg CHO/5 ml Daily CHO = 8.64 g Keppra solution 500 mg/5 ml = 1000 mg CHO/5 ml Daily CHO = 2 g Zantac syrup 150 mg/15 ml = 1500 mg CHO/15mL Daily CHO = 1.5 g Grand Total = 18.84 g 24
Issue With Case Patient s Meds Total CHO intake is limited to 7 g per day Meds would provide ~19 g/day Suggested Meds Tegretol 200 mg tab ½ tab BID 100 mg chew tab = 275.7 mg CHO 200 mg tab = 51.4 mg CHO Depakote 250 mg 1 tab BID 250 mg tab = 50 mg CHO Keppra 500 mg tab 1 tab BID 500 mg tab = Zero CHO Zantac 75 mg tab 1 tab BID Zantac 75 mg = Zero CHO Grand Total= 0.154 g 25
Conclusion The use of the ketogenic diet has been shown to be a non pharmacologic option for seizure control The diet is not without its own list of potential adverse effects and should be managed by qualified healthcare professionals Proper selection of medications can have a significant impact on the outcome of the diet 26