Starving Away Stubborn Seizures: Food for Thought on the Ketogenic Diet for Refractory Epilepsy in Children

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1 Starving Away Stubborn Seizures: Food for Thought on the Ketogenic Diet for Refractory Epilepsy in Children Learning Objectives Bernadette Espiritu, Pharm.D. PGY1 Pharmacy Resident Children s Hospital of San Antonio The University of Texas Health Science Center at San Antonio The University of Texas at Austin College of Pharmacy April 17, Discuss the background, dietary composition, adverse effects, and challenges of the ketogenic diet 2. Describe the pharmacist s role in the management of the ketogenic diet patient 3. Evaluate the literature regarding use of the ketogenic diet in pediatric refractory epilepsy 4. Formulate an evidence-based strategy deciding the role of the ketogenic diet in the management of pediatric refractory epilepsy compared to alternative pharmacotherapy

2 PEDIATRIC EPILEPSY I. Definitions A. Seizure 1-3 i. Clinical manifestation of excessive, synchronous abnormal electrical activity of neurons in the cerebral cortex ii. Interferes with normal functioning iii. Due to shift in normal balance of excitation and inhibition in the central nervous system a. Glutamate is the major excitatory neurotransmitter b. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter Figure 1. International League Against Epilepsy (ILAE) Classification of Seizures 6 B. Epilepsy 2,3 i. > 2 unprovoked afebrile seizures > 24 hours apart ii. Diagnosis of an epilepsy syndrome iii. Recurrent seizures due to chronic, underlying process C. Refractory epilepsy 4,5 i. Inadequate seizure control despite appropriate therapy with > 2 antiepileptic drugs (AEDs) at maximally tolerated doses for 18 months to 2 years ii. Adequate seizure control with unacceptable drug-related adverse effects II. Epidemiology A. Seizures affect 4-10% of children at some point in their lifetime 7 i. Approximately 150,000 children experience new-onset seizure annually ii. Only 30,000 children with new-onset seizure will develop epilepsy B. Currently 326,000 children with a diagnosis of epilepsy in the United States 4,7,8 i % of children become seizure free with moderate doses of one or two AEDs 8 ii. Estimated 10-40% will continue to have seizures despite optimal management with AEDs 4 iii. Approximately one-third of epilepsy will be refractory 4 Espiritu 1

3 III. Prognosis and comorbidities 2,5 A. Cognitive deficits and abnormalities B. Psychiatric comorbidities C. Non-fatal injuries D. Risk of death is 2-3 times greater in patients with epilepsy i. Underlying etiologies of seizure ii. Accidents iii. Status epilepticus iv. Sudden unexpected death in epileptic patients (SUDEP) IV. Treatment A. Goal of therapy is improved quality of life 3,8 i. Elimination or reduction in seizures ii. Minimize adverse effects from therapy iii. Manage comorbid conditions a. Address underlying conditions contributing to epilepsy b. Depression, anxiety, pain, sleep disorders B. Approach to refractory epilepsy 3-5 i. Non-pharmacologic a. Avoid triggers b. Surgical intervention c. Vagal nerve stimulation d. Dietary therapy ii. Pharmacologic THE KETOGENIC DIET (KD) I. Background 9-11 A. Mimics the biochemical changes that occur during the starvation state leading to ketosis B. Majority of calories from fat, with moderate protein and very low carbohydrate i. Calories initially limited to 80-90% of daily recommended needs ii. Adjusted to accommodate ideal growth and patient safety iii. Historically included fluid restriction, though no longer done in practice Epilepsy Weight loss Autism Brain tumors Depression Narcolepsy Alzheimer s disease II. History in epilepsy A. Early history of KD Table 1. Potential uses of KD 11,12 Traumatic brain injury Parkinson s syndrome Amyotrophic lateral sclerosis Migraines Sleep disorders Schizophrenia Post-anoxic brain disorders i. Fasting for epilepsy recorded by Hippocrates in 5 th century BC ii. Gospel of Matthew describes Jesus curing epileptic boy with fasting and prayer Espiritu 2

4 B. Modern history of KD 9,14-16 i. 1911: French physicians, Guelpa and Marie, author first scientific report of fasting for epilepsy ii. 1921: Dr. R.M. Wilder at the Mayo Clinic proposes diet to mimic fasting state iii. 1938: Phenytoin discovered; decline in use of KD iv. 1971: Medium-chain triglyceride diet introduced v. 1994: Resurgence of KD due to success in Charlie Abrahams 15 a. Charlie was 2-year old son of a Hollywood producer who experienced intractable myoclonic, generalized tonic, and tonic-clonic seizures b. Gained national attention for successful use of KD to control his seizures c. The Charlie Foundation created for KD and epilepsy d. Made-for-television movie based on Charlie s experience with KD vi. 2008: First randomized, controlled trial of KD 17 III. Starvation state 18,19 A. Body forced to metabolize fatty acids B. Brain dependent on formation of ketone bodies in the liver, transported over blood-brain barrier i. β-hydroxybutyrate (BHOB) ii. Acetoacetate (ACAC) Figure 2. Production of ketones by the liver and utilization by the brain 20 IV. Mechanism of action 9,18 A. Despite decades of use, mechanism of action remains elusive B. Many postulated mechanisms, though likely a combination of simultaneous mechanisms C. Hypothesized mechanisms 9,11,18,21 i. Ketone bodies/ketosis a. ACAC and acetone have anticonvulsant properties 1. Demonstrated in animal models 2. Acetone levels elevated in brains of patients treated with KD b. BHOB structurally similar to GABA c. Consumption of oxaloacetate in ketotic state shunts glutamate to GABA synthesis Espiritu 3

5 ii. Lack of glucose limits ability of brain to generate and promote seizure activity iii. Direct anti-seizure activity of polyunsaturated fatty acids produced while on KD iv. Opening of ATP-sensitive potassium (K ATP ) channels 22 a. K ATP channels normally inhibited by high intracellular ATP b. Shift away from glycolytic ATP production allows K ATP channels to open c. Open K ATP channels reduce neuronal excitability in the substantia nigra Figure 3. Proposed mechanism of KD by opening of K ATP channels 23 V. Dietary composition 9,11,24 A. Classic KD i. Diet allotted in a 4:1 fat to carbohydrate/protein ratio per weight ii. Lower ratios (3:1 or 2:1) may be used in younger children iii. Oldest and most studied diet B. Medium-chain triglycerides (MCT) diet i. MCT more ketogenic than long-chain triglycerides (LCT) ii. Greater allowance for protein and carbohydrates iii. MCT sources include coconut oil, palm kernel oil, whole milk, butter C. Modified Atkins diet i. More tolerable than classic KD and MCT diet ii. Carbohydrate restricted, unlimited protein, fat, and fluids a. Carbohydrate initially limited to 10 grams b. Planned increase to grams of carbohydrates/day in 1-3 months c. Fats highly encouraged Espiritu 4

6 Figure 4. Comparison of the calorie composition of the typical American diet and dietary therapies for epilepsy 11,19,24 VI. Tolerability (Appendix A) A. Not a natural treatment for epilepsy 13 i. Parents should not start the diet without medical guidance ii. Should be initiated and monitored by a physician working with the health-care team B. Compliance 11 i. Difficult to tolerate a % will discontinue diet within first 6 months 9 b. Requires accurate measurement of all components of the diet c. Hidden sources of carbohydrates in diet and other products d. Strict compliance is necessary for benefits of the diet 1. Small lapses are enough to stop ketosis 9 a. Not finishing a meal b. Consuming too much carbohydrate or protein 2. Non-compliance may lead to seizures ii. More palatable diets available 11 a. Less restrictions and adverse effects b. Modified Atkins diet c. MCT diet iii. All-liquid formulations of the diet are available for infants and enterally fed children a. Easier to implement b. More compliance and greater efficacy 25 iv. When attempted, should be tried for at least 3 months v. Patients who respond to and tolerate diet should continue for at least 2 years VII. Safety A. Adverse effects 11,13,21,24 i. Initiation phase 11,24 a. Dehydration b. Hypoglycemia c. Vomiting Espiritu 5

7 ii. Maintenance phase a. Gastrointestinal 11,21,24 1. Constipation 2. Exacerbation of gastroesophageal reflux disease (GERD) b. Nephrolithiasis 11,13,21, % experience nephrolithiasis 2. Prevent with adequate hydration and avoidance of medications that may cause nephrolithiasis 3. Oral potassium citrate may decrease prevalence c. Hypertriglyceridemia 11,13,21,24 1. Particularly in first six months 2. Kwiterivoch et al. studied effect on lipid profile after six months of diet 26 a. Significant increase in total cholesterol, low-density lipoprotein, very low-density lipoprotein, and triglycerides b. Significant decrease in high-density lipoprotein 3. Used successfully in children with pre-existing hyperlipidemia d. Growth/nutrition 11,13,16,21 1. Significant reduction in height and weight after prolonged use 2. Catch-up growth observed after diet discontinuation Increased risk of bone fractures 4. All children on KD must receive supplements a. Vitamins and minerals (including trace minerals) b. Calcium and vitamin D c. Oral citrates and carnitine optional B. Contraindications 11,24 i. Relative contraindications: patients who have more curative alternatives, difficulty with compliance, or comorbidities that may be exacerbated by KD ii. Absolute contraindications: inborn errors of metabolism where biochemical changes due to KD are dangerous Table 2. Relative and absolute contraindications of KD 11,24 Relative Absolute Epilepsy surgery candidates Failure to thrive/poor nutritional status Special diet needs/preferences Parent/caregiver noncompliance Medical conditions aggravated by diet Primary carnitine deficiency Carnitine palmitoyltransferase I or II deficiency Carnitine translocase deficiency Fatty oxidation defects Porphyria Pyruvate carboxylase deficiency Espiritu 6

8 ROLE OF A PHARMACIST IN KD I. Combined with AEDs A. Evidence supporting pharmacodynamics interactions between KD and AEDs is weak 24 B. Valproic acid 24,28 i. Valproic acid is a short-chain fatty acid ii. Enhanced fatty acid oxidation with KD may enhance valproic acid-related hepatotoxicity iii. Carnitine deficiency 24 a. Both valproic acid and KD alone cause carnitine deficiency b. May be worsened in combination C. Carbonic anhydrase inhibition i. Metabolic acidosis 24 a. Carbonic anhydrase inhibitors (CAIs), topiramate and zonisamide, may worsen transient metabolic acidosis associated with KD b. Serum bicarbonate 1. Monitor when initiating KD with topiramate and/or zonisamide 2. Supplement with bicarbonate in clinically symptomatic patients ii. Nephrolithiasis 21 a. CAIs increase risk of nephrolithiasis b. Monitor patients carefully when initiating KD c. Consider empiric oral citrates D. Phenobarbital 28 i. Elimination slower in acidotic state, resulting in higher levels ii. Patients on phenobarbital may not respond as well to KD II. Medications containing carbohydrates (Appendix B) 28,29 A. Formulations of AEDs and other medications may contain carbohydrates or sugar additives i. Sugar-free products may still contain other carbohydrate fillers ii. IV fluids, TPNs, diluents B. Strategies for reducing carbohydrate content of medications 29,30 i. Liquids > chewable/disintegrating tablets > tablets/capsules in carbohydrate content a. Crush tablets or open capsules of products able to be crushed or opened b. Generics may contain more carbohydrate fillers than brand name products c. IV formulations may be given orally ii. Avoid dextrose containing diluents, if alternatives compatible III. Pharmacologic management and prevention of adverse effects 10 A. Proton-pump inhibitors for GERD B. Potassium citrate to prevent nephrolithiasis C. Vitamin and mineral supplementation D. Constipation management IV. Alternative to AEDs A. Good responders to KD may discontinue AEDs 31 i. Possible seizure exacerbations when AEDs are weaned ii. During withdrawal while on KD, phenobarbital and benzodiazepines are most associated with breakthrough seizures B. Must weigh benefits of starting KD versus trying another AED Espiritu 7

9 CLINICAL QUESTION I. When should KD be considered over alternative AEDs in pediatric patients with refractory epilepsy? II. International Ketogenic Diet Study Group 24 A. Neurologists and dieticians commissioned by The Charlie Foundation B. Recommend strong consideration of KD after 2-3 failed AEDs III. Approach to pharmacotherapy in refractory epilepsy Figure 4. Mechanisms of action of AEDs 32 A. Address causes for treatment failure 5,8 i. Inappropriate choice of first-line AED ii. Poor compliance iii. Lifestyle factors iv. Intolerable adverse effects B. Considerations in AED selection 5,8,33 i. Seizure/epilepsy type (Appendix C) ii. Adverse effects (Appendix D) iii. Drug interactions iv. Cost v. Pharmacokinetics & drug monitoring Espiritu 8

10 IV. Efficacy in epilepsy trials A. Efficacy measures 8,34 i. Mean percentage (%) of baseline a. Compares baseline seizure control against seizure control after intervention b. Often involves total number of seizures before and after intervention ii. 50% responder rate 8 a. Proportion of patients with more than 50% reduction in seizures b. Common efficacy measure reported in literature and randomized, controlled trials c. Patients will be considered responders or non-responders based on 50% responder rate iii. 90% responder rate a. Proportion of patients with more than 90% reduction in seizures b. Corresponds to very good responders iv. Seizure freedom a. Patients experiencing freedom from seizures b. Corresponds to total or complete response to therapy B. Efficacy of pharmacotherapy in refractory epilepsy 5,35 i % of patients may achieve > 6 months of seizure remission with additional drug trials ii % of refractory patients will receive > 50% reduction in seizure frequency with adjunctive polytherapy iii. Average drop-out rates in most AED trials for refractory epilepsy range from 5-10% Table 3. Efficacy of AEDs in adjunctive treatment of refractory epilepsy AED 50% Responder Rate AED 50 % Responder Rate Clobazam 43-65% Pregabalin 14-51% Felbamate 33-56% Rufinamide % Gabapentin 34.4% Tiagabine 25% 33-45% 20-88% Lacosamide 38-41% Valproic Acid 50-60% Levetiracitam 27-52% Vigabatrin 28-80% 41% Zonisamide 26-67% Espiritu 9

11 LITERATURE REVIEW Neal EG et al. The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial. Lancet Neuro. 2008;7: Overview To investigate whether there are clear benefits in terms of seizure control in children with epilepsy Objective who were treated with the classic KD for 3 months compared with a control group of children whose treatment did not change Trial Design Open-label, parallel-group, randomized-controlled trial in the United Kingdom (UK) Inclusion Criteria Exclusion Criteria Age between 2-16 years History of: Patients Daily seizures or > 7 seizures per week o Hyperlipidemia Non-responder to > 2 AEDs o Nephrolithiasis Not previously treated with KD o Organic-acid-deficiency syndromes Primary Secondary % change in baseline seizures Tolerability of diet Outcomes Proportion of children with: o Adverse effects o >90% reduction in seizures o Compliance o >50% reduction in seizures o Growth Children randomly assigned to start diet immediately after 4-week baseline (diet group) or delayed by 3 months after 4-week baseline (control group) Control group remained on regular diet with no changes in AEDs Diet group given an individual KD based on child s food preferences with no changes in AEDs Interventions KD started at home, non-fasting o 2:1 ratio to begin, with initiation to 3:1 or 4:1 over 1-2 weeks as tolerated o Diets supplemented with vitamins and minerals Patients reviewed outpatient at 6 weeks and 3 months with telephone calls between visits Seizures frequency assessed and recorded by parents daily during baseline and study period Sample size of 47 patients per group needed to detect a 25% difference in mean percentage of baseline seizures significant at 5% with 90% power Mean % of baseline seizures compared with unpaired t-test; verified with Mann-Whitey U test Multiple linear regression to assess association between diet and % baseline seizures taking Statistical into account baseline characteristics of age group and gender Analysis Fisher s exact test for calculating difference in diet and control groups for responder rates of 50% or 90% seizure reduction Unpaired t-test comparing mean % of baseline seizures between diet and control group for generalized and focal seizures Results Provided table of baseline characteristics for gender and age but no clear analysis o Most children in diet group in 2-6 year age group (N=37), followed by 7-11 year age group (N=27) and the year age group (N=9) Baseline characteristics 6 children on no epilepsy medications at entry, 20 children on one medication, 53 children on 2 medications, and 54 children on 3 medications o No mention of how many failed AED treatments prior to enrollment Epilepsy types and syndromes similar in control and diet groups Mean of 13.3 seizures/day in KD group and 10.1 seizures/day in control group Espiritu 10

12 Primary outcomes Secondary outcomes Author s conclusions Critique Take-home points 16 patients (8 from each group) dropped out before study period began 26 patients (11 from KD group and 15 from control group) not included in final analysis due to drop-outs or inadequate data after study period began Table 4. Comparison of seizures as percentage of baseline after 3 months Outcome Diet group (N=54) Control group (N=49) p-value Mean % of baseline seizures (95% CI) 62.0 (50-74%) 136.9% ( %) < Median % of baseline seizures (SD, IQR) 47.7% (43, 0-200%) 106.3% (111, %) Difference in mean % of baseline seizures remained significant after accounting for outliers o Linear regression model: difference between mean % baseline seizures increased to 76.6% (95% CI ; p<0.0001) o Removal of extreme outliers in control group: difference between mean % baseline seizures reduced to 50.9% (95% CI %; p<0.0001) No significant differences found when comparing mean % of baseline seizures for generalized or focal seizures in either the control or diet group Table 5. Responder rate in diet group vs control group Outcome Diet group (N=73) Control group (N=72) p-value >90% reduction in seizures 5 (7%) 0 (0%) >50% reduction in seizures 28 (38%) 4 (6%) < <50% reduction in seizures 45 (62%) 68 (94%) < Adverse effects in the diet group included constipation (33%), constipation requiring medication (24%), lack of energy (24%), vomiting (25%), hunger (22%), diarrhea (13%), and abdominal pain (9%) 10 patients withdrew from dietary treatment o 3 due to parental unhappiness with restrictions, 2 due to behavioral food refusal, 1 due to increased seizures and 4 due to adverse effects (extreme drowsiness, vomiting, diarrhea, and constipation) One patient, who remained on the diet, had evidence of nephrolithiasis treated with potassium citrate Conclusions The diet has efficacy and should be included in management of children with drug-resistant epilepsy. Side effects should be considered alongside with the risk/benefit of other treatments. Strengths Limitations Randomized, controlled Non-blinded Enrollment achieved power Compared with placebo Responder rates reported as Subjective recording of seizures and adverse effects intention-to-treat No details on failed AEDs Results robust after accounting Per-protocol with high drop-out rate for outliers Cultural diet differences Lacked clear analysis of baseline characteristics First randomized, controlled trial of KD High number of drop-outs and non-starters Effective in reducing seizures but not without adverse effects/intolerability No data on number of failed AEDs Cultural diet differences Espiritu 11

13 Sharma S et al. Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial. Epilepsia. 2013;54(3): Overview To evaluate the efficacy of the modified Atkins diet in a randomized controlled trial in children with Objective refractory epilepsy Trial Design Open-label, parallel-group, randomized-controlled trial in India Inclusion Criteria Exclusion Criteria Age between 2-14 years Known/suspected inborn errors of metabolism Patients Daily seizures or > 7 seizures per week Systemic illness Failure of > 3 AEDs Motivational issues with family Primary Secondary % change in seizure frequency compared Tolerability of diet to baseline Adverse effects Outcomes Proportion of children with: o Seizure freedom o >90% reduction in seizures o >50% reduction in seizures Assigned to modified Atkins diet group or control group (no diet changes) 4-week baseline observation period followed by study period o Recorded daily seizure log by parents (seizure type, duration, and frequency) Both groups remained on same AEDs during 3 month trial period and throughout the study, unless medically indicated Intervention arm began modified Atkins diet as outpatients at end of baseline period o Carbohydrate intake of 10 grams/day o Intake of fats encouraged Interventions o Calories and protein intake not restricted o Received sugar-free, fat-soluble vitamin supplement and calcium supplement o Recipes provided, based on patient s dietary habits (e.g. vegetarian) o Urine ketones checked by parents daily during the first week and twice weekly thereafter Reviewed as outpatients at 1, 2, and 3 months Three-day dietary intake chart reviewed at each visit in diet group to calculate carbohydrate and calorie intake, and to reinforce compliance Tolerability and adverse effects evaluated by parental interview Calculated sample size of 48 in each group to detect 25% difference in primary outcome at 5% with 90% power All analysis intention-to-treat Statistical Drop outs were treated as worst case scenario in the treatment group (0% seizure control) and Analysis as best case scenario in the control group (100% seizure control) Mean % of seizures compared with unpaired t-test/mann-whitney U test Responder rates (seizure freedom, >50% and >90% seizure reduction) compared using Fisher s exact test Results 102 children enrolled (diet group=50, control group=52) No significant differences in baseline characteristics between groups Baseline Average age of 4.7 years in diet group and 5.2 years in control group characteristics Median of 5 (range 3-9) AEDs tried in diet group; median of 4 (range 3-9) tried in control group) Median of 3 ongoing AEDs (range 2-4) in both groups during study period Espiritu 12

14 Primary outcomes Secondary outcomes Author s conclusions Critique Take-home points No significant differences in response between epilepsy syndromes Table 6. Seizure outcome at 3 months Diet group (N=50) Control group (N=52) p-value Mean % of seizures compared to baseline 59 ± (95% CI ) (95% CI, ) Median % of seizures as compared to baseline (IQR) >90 % responder rate 30% 7.7% >50% responder rate 52% 11.5% Proportion of children seizure free 10% 5.8% (drop-outs) Adverse effects in the diet group included constipation (46%), anorexia (18%), vomiting (10%), lethargy (6%), lower respiratory tract infections (4%), hyperammonemic encephalopathy (2%) 4 patients discontinued the diet o 3 due to adverse effects (2 with frequent chest infections, 1 for hyperammonemic encephalopathy 1 week after starting the diet) o 1 child discontinued because family found diet too restrictive Older children complained that diet was too restrictive and difficult Diet more difficult to tolerate in patients with dietary restrictions (vegetarians) Conclusions The modified Atkins diet was found to be effective and well tolerated in children with refractory epilepsy. However, the diet does have adverse effects, and careful medical supervision is warranted. Strengths Limitations Randomized, controlled Non-blinded Enrollment achieved power Compared with placebo Intention-to-treat analysis Excluded families with motivational issues Cultural diet differences Subjective recording of seizures and adverse effects Diet effective in reducing seizures, though not without adverse effects 50% responder rate = 52% Average of 4-5 failed AEDs before starting treatment Difficult to tolerate in older children and patients with diet restrictions Cultural dietary differences Espiritu 13

15 Kossoff EH et al. A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins diet. Epilepsy Behav. 2007;10(3): Overview To identify the ideal starting limit of carbohydrates on the modified Atkins diet to maximize efficacy, Objective ketosis, and tolerability Trial Design Prospective, randomized, crossover study in the United States (US) Inclusion Criteria Exclusion Criteria Age between 3-18 years Use of Atkins diet < 7 days previously Failure of > 2 AEDs Known hypercholesterolemia, kidney dysfunction, Patients At least daily, countable seizures or heart disease Recent (<1 year)/current use of KD BMI <3% for age Primary Secondary Proportion of children with: Ketosis Outcomes o Seizure freedom Tolerability of diet o >90% reduction in seizures Adverse effects o >50% reduction in seizures Patients randomized to begin diet with 10 grams or 20 grams per day o Baseline blood counts, fasting lipid profile, comprehensive metabolic profile, urine calcium and creatinine levels obtained o 3-day pre-diet food record analyzed o Diet explained to families in hour long visit o Monthly calendar to record seizures daily, ketones semi-weekly, and weight weekly o Frequent contact with physician and dietitians via phone and o Each patient received multivitamin and calcium supplement Interventions o At 3 months, patients were crossed over to opposite amount (i.e. 10 gram 20 gram, 20 gram 10 gram) Children evaluated at baseline, 3 months and 6 months o Urine ketones checked semi-weekly and urine/laboratory tests repeated at 3 months and 6 months o Medication changes allowed after 2 weeks if requested by families o Families given the option to continue diet with carbohydrate limit of their choice, or discontinue diet after 6 months Calculated total number of 20 patients needed to show difference of 20% between group assuming a 40% dropout rate Statistical Categorical data analyzed with Fisher s exact test Analysis Medians compared using Wilcoxon two-sample test; means with paired two-sample t test Significance level set at P=0.05 Intention-to-treat analysis Results N=20 (10 patients in each carbohydrate group) No differences in baseline characteristics between groups Average age of 7.5 years in 10 gram group and 9.8 years in 20 gram group Baseline Average number of 6 AEDs previously tried in each group characteristics Average of 2 concurrent AEDs in each group 4 patients previously attempted on KD with no reported improvement (randomized 2 patients to each group) Espiritu 14

16 Primary outcomes Secondary outcomes Author s conclusions Critique Take-home points Table 7. Seizure outcomes at 1, 3, and 6 months 10 gram group (N=10) 20 gram group (N=10) p-value 1 month >50% seizure reduction 6 (60%) 4 (40%) 0.33 >90% seizure reduction 0 (0%) 1 (10%) months >50% seizure reduction 6 (60%) 1 (10%) 0.03 >90% seizure reduction 3 (30%) 0 (0%) months >50% seizure reduction 5 (50%) 5 (50%) 0.67 >90% seizure reduction 3 (30%) 4 (40%) 0.50 Table 8. Tolerability outcomes in diet group 10 gram group (N=10) 20 gram group (N=10) p-value Diet duration (in months) 9.0 (3-22) 4.5 (0-19) 0.12 Number completing 6-month study 7 (70%) 5 (50%) 0.33 Of the 12 patients who completed the study, 9 decided to continue on modified Atkins diet after 6 months 4 patients reported significant constipation while on diet Conclusions A starting carbohydrate limit of 10 grams/day for children starting the modified Atkins diet may be ideal, with a planned increase to 20 grams/day after 3 months. The study adds further prospective evidence for the efficacy and safety of the modified Atkins diet for refractory pediatric seizures. Strengths Limitations Randomized Non-blinded, not controlled Enrollment achieved Subjective recording of seizures Intention-to-treat analysis Small sample Conducted in the US High drop-out rate Data on number of failed AEDs Diet effective in reducing seizures (50% responder rate of 10-60%) High drop-out rates suggest poor tolerability Average of 6 failed AEDs before starting diet Conducted in the United States SUMMARY I. Summary of literature A. Responder rate (>50% reduction in seizures) i. Range from 10-60% in prospective, randomized trials ii % in prospective, randomized, controlled trials B. Average of 4-6 AEDs tried prior to trying KD C. Tolerability i. Most common side effects are gastrointestinal, particularly constipation ii. High drop-out rates, particularly in the UK and US iii. More difficult to tolerate in older patients and those with diet restrictions D. Lack of head-to-head trials comparing alternative AED and KD in refractory epilepsy, or starting KD earlier in management II. KD treatment A. Effective treatment for pediatric refractory epilepsy B. Requires strict compliance to achieve benefits C. Pharmacists can play a role in the management of a child on KD Espiritu 15

17 RECOMMENDATIONS I. Recommendations A. Due to availability and efficacy of alternative AEDs, KD should not be considered in most children until failure of at least 4 AEDs i. Difficulties with tolerability and compliance limit use of KD ii. High drop-out rates in studies iii. Alternative AEDs or polytherapy should be considered first in refractory epilepsy B. Considerations of starting KD vs. AED i. Type of seizure/epilepsy syndrome ii. Patient age iii. Diet preferences and cultural considerations iv. Family compliance and motivation v. Cost vi. Enteral feeding vii. Adverse effects of KD and AEDs viii. Concurrent medications ix. Available alternative treatment(s) II. Future directions A. Discovering mechanism of KD may provide targets for future AEDs B. Head-to-head trials of KD vs. starting another AED C. Trials of KD earlier in treatment Espiritu 16

18 REFERENCES 1. Welty TE, Faught E. Chapter 30. Epilepsy. In: Chisholm-Burns MA, Kolesar JM, Malone PM, ed. Pharmacotherapy Principles and Practice. 2nd ed. New York, NY: McGraw-Hill; 2010: Lowenstein DH. Chapter 369. Epilepsy. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J, ed. Harrison's Principles Of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; Available at: Accessed March 6, Rogers SJ, Cavazos JE. Chapter 40. Epilepsy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, ed. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; Available at: ultclick=2. Accessed March 3, Go C, Snead OC. Pharmacologically intractable epilepsy in children: diagnosis and preoperative evaluation. Neurosurg Focus. 2008;25(3):E2. 5. Schuele SU, Lüders HO. Intractable epilepsy: management and therapeutic alternatives. Lancet Neurol. 2008;7(6): Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, Epilepsia. 2010;51(4): Agarwal M, Fox SM. Pediatric seizures. Emerg Med Clin North Am. 2013;31(3): Raspall-Chaure M, Neville BG, Scott RC. The medical management of the epilepsies in children: conceptual and practical considerations. Lancet Neurol. 2008;7(1): Greener M. Food for thought: the ketogenic diet for epilepsy. Prog Neuro Psychiatry May/June. 18(3): Kossoff EH, Zupec-Kania BA, Rho JM. Ketogenic diets: an update for child neurologists. J Child Neurol. 2009;24(8): Sharma S, Jain P. The ketogenic diet and other dietary treatments for refractory epilepsy in children. Ann Indian Acad Neurol. 2014;17(3): Barañano KW, Hartman AL. The ketogenic diet: uses in epilepsy and other neurologic illnesses. Curr Treat Options Neurol. 2008;10(6): Sinha SR, Kossoff EH. The ketogenic diet. Neurologist. 2005;11(3): Wheless JW. Chapter 2. History and Origin of the Ketogenic Diet. In: Stafstrom C, Rho J, ed. Epilepsy and the Ketogenic Diet. 1st ed. Totowa, NJ: Humana Press, Inc.; 2004: Wheless JW. History of the ketogenic diet. Epilepsia. 2008;49 Suppl 8: Papandreou D, Pavlou E, Kalimeri E, Mavromichalis I. The ketogenic diet in children with epilepsy. Br J Nutr. 2006;95(1): Neal EG, Chaffe H, Schwartz RH, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008;7(6): Kim DY, Rho JM. The ketogenic diet and epilepsy. Curr Opin Clin Nutr Metab Care. 2008;11(2): Nordli DR, De Vivo DC. Chapter 14. Effects of the Ketogenic Diet on Cerebral Energy Metabolism. In: Stafstrom C, Rho J, ed. Epilepsy and the Ketogenic Diet. 1st ed. Totowa, NJ: Humana Press, Inc.; 2004: Melø TM, Nehlig A, Sonnewald U. Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem Int. 2006;48(6-7): Huffman J, Kossoff EH. State of the ketogenic diet(s) in epilepsy. Curr Neurol Neurosci Rep. 2006;6(4): Hartman AL, Gasior M, Vining EP, Rogawski MA. The neuropharmacology of the ketogenic diet. Pediatr Neurol. 2007;36(5): Yellen G. Neuronal Metabolism and Excitability. Gary Yellen's Lab at Harvard Medical School Neurobiology Available at: Accessed March 14, Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 2009;50(2): Kossoff EH, Mcgrogan JR, Freeman JM. Benefits of an all-liquid ketogenic diet. Epilepsia. 2004;45(9): Kwiterovich PO, Vining EP, Pyzik P, et al. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA. 2003;290(7): Espiritu 17

19 27. Kim JT, Kang HC, Song JE, et al. Catch-up growth after long-term implementation and weaning from ketogenic diet in pediatric epileptic patients. Clin Nutr. 2013;32(1): Lebel D, Morin C, Laberge M, Achim N, et al. The carbohydrate and caloric content of concomitant medications for children with epilepsy on the ketogenic diet. Can J Neurol Sci. 2001;28(4): Misiewicz Runyon A, So TY. The use of ketogenic diet in pediatric patients with epilepsy. ISRN Pediatr. 2012;2012: Feldstein TJ. Carbohydrate and alcohol content of 200 oral liquid medications for use in patients receiving ketogenic diets. Pediatrics. 1996;97(4): Kossoff EH, Pyzik PL, Mcgrogan JR, Rubenstein JE. The impact of early versus late anticonvulsant reduction after ketogenic diet initiation. Epilepsy Behav. 2004;5(4): Löscher W, Schmidt D. Epilepsy: perampanel-new promise for refractory epilepsy? Nat Rev Neurol. 2012;8(12): Sullivan JE, Dlugos DJ. Antiepileptic drug monotherapy: pediatric concerns. Semin Pediatr Neurol. 2005;12(2): Ben-Menachem E, Sander JW, Privitera M, Gilliam F. Measuring outcomes of treatment with antiepileptic drugs in clinical trials. Epilepsy Behav. 2010;18(1-2): French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2004;45(5): Barnes SE, Bower BD. Sodium valproate in the treatment of intractable childhood epilepsy. Dev Med Child Neurol. 1975;17(2): Chu-Shore CJ, Thiele EA. New drugs for pediatric epilepsy. Semin Pediatr Neurol. 2010;17(4): Hwang H, Kim KJ. New antiepileptic drugs in pediatric epilepsy. Brain Dev. 2008;30(9): Jarrar RG, Buchhalter JR. Therapeutics in pediatric epilepsy, Part 1: The new antiepileptic drugs and the ketogenic diet. Mayo Clin Proc. 2003;78(3): Keene DL, Metrakos K, Watters GV, Sherwin A. Sodium valproate in the treatment of the intractable childhood epileptic. Can J Neurol Sci. 1982;9(3): Khurana DS, Riviello J, Helmers S, et al. Efficacy of gabapentin therapy in children with refractory partial seizures. J Pediatr. 1996;128(6): Verrotti A, Loiacono G, Coppola G, et al. Pharmacotherapy for children and adolescents with epilepsy. Expert Opin Pharmacother. 2011;12(2): Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial. Epilepsia. 2013;54(3): Kossoff EH, Turner Z, Bluml RM, et al. A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins diet. Epilepsy Behav. 2007;10(3): Kalra V, Seth R, Mishra D, Saha NC. Clobazam in refractory childhood epilepsy. Indian J Pediatr. 2010;77(3): g ketogenic pudding 44 g cream cheese 13 g eggs 29 g heavy cream APPENDICES Appendix A. Example of Typical 4:1 KD Meal using 1100 kcal/day 10 Breakfast Lunch Dinner Snack 40 g 36% heavy cream 35 g 36% heavy cream 8 g MCT oil Ground beef and cheese Dark meat chicken salad 11 g ground beef 20 g dark meat chicken 10 g cheese 8 g mayonnaise 8 g butter 20 g avocado 26 g cooked broccoli 11 g butter Ketogenic chocolate 3 g cocoa 6 g butter 6 g coconut oil Espiritu 18

20 Appendix B. Carbohydrate content of antibiotics, AEDs, and over-the-counter medications Medication (Brand Name) Dosage Unit Grams of carbohydrate per dosage unit Over-the-counter pain medications Acetaminophen liquid suspension (Tylenol ) 160 mg/5 ml 5 grams/5 ml Ibuprofen suspension (Motrin ) 100 mg/5 ml 0.63 grams/5 ml Antibiotics Amoxicillin oral suspension (Amoxil ) 400 mg/5 ml 1.88 grams/5 ml Azithromycin oral suspension (Zithromax ) 100 mg/5 ml 3.86 grams/5 ml Cephalexin oral suspension (Keflex ) 250 mg/5 ml 3.03 grams/5 ml AEDs Carbamazepine suspension (Tegretol ) 100 mg/5 ml 2.65 grams/5 ml Gabapentin tablets (Neurontin ) 100 mg 0.03 grams tablets (Lamictal) 25 mg 0.03 grams Levetiracetam oral solution (Keppra ) 100 mg/ml 0.3 grams/ml Phenobarbital elixir 20 mg/5 ml 3.4 grams/5 ml Phenytoin suspension (Dilantin ) 125 mg/5 ml 1.39 grams/5 ml tablets (Topamax ) 25 mg 0.04 grams Valproic acid syrup (Depakene ) 250 mg/5 ml 4.5 grams/5 ml Multivitamins Poly-vi-sol grams/5 ml Appendix C. Recommended AEDs according to epilepsy syndrome 8 Epilepsy Syndrome First-line AEDs Alternative AEDs Do not use (may worsen) Ethosuximide Levetiracetam Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with generalized tonic-clonic seizures Focal epilepsies: cryptogenic or symptomatic Carbamazepine Carbamazepine Levetiracitam Clobazam Clonazepam Levetiracitam Levetiracetam Clobazam Phenobarbital Phenytoin Primidone Clobazam Gabapentin Levetiracetam Phenytoin Tiagabine Clonazepam Phenobarbital Primidone Carbamezepine Phenytoin Tiagabine Vigabatrin Tiagabine Vigabatrin Espiritu 19

21 Infantile spasms Benign epilepsy with centrotemoral spikes or occipital paroxysms Dravet syndrome Appendix C (continued). Recommended AEDs according to epilepsy syndrome 8 Continuous spike wave of slow sleep Lennox-Gastaut syndrome Landau-Kleffner syndrome Myoclonic astatic epilepsy Vigabatrin Carbamazepine Clobazam Clonazepam Clobazam Clonazepam Ethosuximide Clobazam Clonazepam Clobazam Clonazepam Levetiracetam Levetiracetam Phenobarbital Levetiracetam Clobazam Clonazepam Ethosuximide Levetiracetam Felbamate Levetiracetam Levetiracetam Carbamezapine Carbamazpeine Vigabatrin Carbamazepine Vigabatrin Carbamazepine Carbamazepine Carbamazepine AED Clobazam Felbamate Gabapentin Lacosamide Levetiracitam Pregabalin Rufinamide Tiagabine Valproic Acid Vigabatrin Zonisamide Appendix D. Adverse reactions in AEDs for refractory epilepsy 38,40,42,45 Adverse Reactions Sedation, hyperactivity, behavioral problems, irritability, fatigue, salivation, weight gain, sleep disturbances Anorexia, weight loss, insomnia, gait disturbance, aplastic anemia, hepatotoxicity Emotional lability, aggression, hyperactivity, weight gain, somnolence, dizziness, dyspepsia, constipation, nausea, fatigue, ataxia Dizziness, sedation, headache, diplopia, ataxia, skin rash Dizziness, headache, nausea, diplopia Somnolence, asthenia, headache, anorexia, noninvasive infections, hostility, emotional lability, nervousness, depersonalization, psychotic behavior Dizziness, diplopia, nausea, ataxia, hyponatremia Dizziness, somnolence, ataxia, weight gain, euphoric effects Dizziness, fatigue, headache, somnolence, nausea Dizziness, asthenia, tremor, fatigue, nervousness Somnolence, fatigue, problems with concentration and word finding, difficulty with memory, decreased appetite and weight loss, nervousness, headache, asthenia Weight gain, vomiting, tremor, nausea, thrombocytopenia, impaired coagulation, drowsiness alopecia, encephalopathy, hyperammonemia Peripheral visual-field defect, hyperactivity, irritability, aggression, self-injurious behavior, selfdefiance, weight gain, facial edema, headache, drowsiness, insomnia, ataxia, somnolence, stupor Sleepiness, loss of appetite, weight loss, ataxia, oligohydrosis, hyperthermia Espiritu 20