The ketogenic diet; clinical update J Helen Cross UCL-Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, & NCYPE, Lingfield, UK
The ketogenic diet what is it? A high fat diet, designed to mimic the metabolic effects of starvation 1910 Conklin patient deprived of food up to 25 days Cure rate for epilepsy 50-90% 1921 Wilder..benefits of fasting could be obtained if ketonemia was produced by other means 1924 Peterman Calculation and effectiveness of the proposed ketogenic diet 17 patients, 10 seizure free, 4 marked improvement 1971 Huttenlocher Medium chain triglyceride oil more ketogenic per calorie, permitted greater bulk of other foods, MCT diet
Does it work? Author Year No >90% >50% <50% Wilkins 1937 30 24% 21% 50% Livingston 1954 300 43% 34% 22% Kinsman et al Huttenlocher et al 1992 58 29% 38% 33% 1971 12-50% 50% Sills et al 1986 50 24% 20% 56%
Types of Ketogenic Diet Classical diet MCT diet Modified MCT diet 4:1/3:1 fat to CHO Use of MCT oil Low CHO
Indications Metabolic defects where unable to effectively metabolise glucose GLUT 1 deficiency Drug resistant epilepsy if not a candidate for epilepsy surgery? Poor tolerance to AEDs Not a natural diet
Evidence base for efficacy? Lefevre and Aronson 2000 Systematic review of studies Uncontrolled studies 9/11 from single institution Freeman et al 1998 N=150 LCT (27<2yrs) Consecutive children, follow up > 12m 3m (N=125) 31%>90%reduction 12m (N=83) 20%>90%reduction Kang et al 2005 N=199 LCT (49<2yrs) Retrospective study, 12m review 3m (N=175) 35% seizure free (62%>50% reduction) 12m (N=91) 25% seizure free (41%>50% reduction)
Evidence base for efficacy? Henderson et al J Child Neurol 2006;21:193-198 A meta-analysis 392 abstracts 1970-2003; 19 met inclusion criteria Collective population 1084, mean age 5.78 +/-3.43 Pooled odds ratio using random effect model of treatment success amongst patients staying on diet relative to discontinuation 2.25 (1.69-2.98) Future study requires definition of seizure types, long term review patient drop out analysis
Evidence base for efficacy? D Keene Ped Neurol 2006;35:1-5 A systematic review 26 studies;14 met criteria for inclusion Outcome measures degree of seizure control, duration patient remained on diet, occurrence of adverse events Total collective population N=972 At 6m 15.6% (CI 10.4-20.8) seizure free 33.0% (CI 24-41.8) >50% reduction
Evidence base for drug use Class 1 Randomised controlled trial a: Meta-analysis b: Single study Class II At least one controlled study without randomisation or at least one other quasi experimental study Class III Non experimental descriptive study Class IV Case reports
Randomised Controlled Trials Randomisation limits the potential for selection bias Blinding minimises information and investigator bias Precision determined by sufficient sample size, accurate assessment of outcome endpoints
SMEI Neonatal Absence UCL - Institute of Child Health RCTs in childhood epilepsy 16 14 12 10 8 6 4 2 0 No of RCTs Partial epilepsy GTC LGS Infantile spasms JME
The ketogenic diet Why should we require a different standard of a further antiepileptic treatment?
A randomised controlled trial of the efficacy and tolerability of two ketogenic diets EG Neal, HM Chaffe, R Schwartz, M Lawson, N Edwards, G Fitzsimmons, A Whitney, JH Cross Inclusion criteria Age 2-16 years Minimum 7 seizures/week > 2 AEDs previously Exclusion criteria Family history of hyperlipidaemia Organic aciduria Previous trial of ketogenic diet
Randomised controlled trial Randomise MCT Subject entry Classical Screening visit Diet 12m 4 weeks Controls 12 weeks Neal et al 2007
Demographics Diet group Control group Boys Girls Allocated to study group (n=73) 38 (52.1%) 35 (47.9%) Included in final analysis (n=54) 30 (55.6%) 24 (44.4%) Allocated to study group (n=72) 38 (52.8%) 34 (47.2%) Included in final analysis (n=49) 25 (51.0%) 24 (49.0%) Aged 2-6 yrs Aged 7-11 yrs Aged 12-16 yrs 37 (50.7%) 27 (37.0%) 9 (12.3%) 28 (51.9%) 20 (37.0%) 6 (11.1%) 29 (40.3%) 32 (44.4%) 11 (15.3%) 20 (40.8%) 20 (40.8%) 9 (18.4%) Focal epilepsy 27 24 30 22 Generalised epilepsy 39 27 39 19 Mean daily seizures 13.3 10.1 At recruitment : no medication 6, one medication 20, two medications 53, three medications 54, four medications 11, five medications one
Randomised (n=145) Allocated to a ketogenic diet 73 Received dietary treatment 64 Did not receive treatment 9: changed mind 5 seizures improved 2 diagnosis changed 2 Allocation Allocated to control period before diet start 72 Received control period intervention 64 Did not receive intervention, 8 changed mind, 5 died 1 seizures improved, 1 diagnosis changed 1 Lost to follow-up 0 Discontinued intervention 9 Follow-Up Lost to follow-up 0 Discontinued intervention 0 Analyzed 54 Excluded from analysis as inadequate data 1 Analysis Analyzed 49 Excluded from analysis as inadequate data 15
Does it work? 160 % baseline seizures 140 120 100 80 60 40 20 Controls Ketogenic diet ** 50% reduction in seizures 28/73 (38%) diet vs 4/72 (6%) controls (p<0.001) >90% reduction in seizures 5/72 (7%) diet vs no controls (p<0.03) 0 **Diet vs control p<0.001 Neal et al 2008
Comparative randomised controlled trials with newer AEDs in refractory epilepsy % >50% reduction in seizures 70% 60% 50% 40% 30% 20% 10% 0% Agent Topiramate Lamotrigine Ketogenic diet Control/placebo Biton et al 1999, Motte et al 1997, Neal et al 2008
Ketogenic diet Efficacy according to syndrome 100 90 Mean % baseline seizures 80 70 60 50 40 30 20 10 0 Symptomatic Generalised (N=44) Symptomatic Focal (N=41) Lennox Gastaut (N=11) Infantile Spasms (N=6) Myoclonic Astatic Epilepsy (N=4) SMEI (N=5) Neal et al 2008
Tolerability Reported at 3m (N=55) Withdrawals (N=10) Vomiting 13(23.6%) 1 Diarrhoea 7 (12.7%) 1 Abdominal pain 5 (9.1%) Constipation 18 (32.7%) 1 Medication 13 (23.6%) Lack of energy 13 (23.6%) Hunger 12 (21.8%) Increased seizures 1 Parental unhappiness 3 Behavioural food refusal 2 Extreme drowsiness 1
Randomised (n=145) Allocated to a classical diet 73 Received dietary treatment 61 Allocation Allocated to MCT diet 72 Received MCT intervention 64 Lost to follow-up 0 Discontinued intervention 10 Follow-Up Lost to follow-up 0 Discontinued intervention 15 Analysis 3m 45 Analysis 6m 30 Analysis 12m 22 Analysis Analysis 3m 49 Analysis 6m 34 Analysis 12m 25
Should a specific diet be used? 90 Responder rates MCT Classical Percentage of baseline seizures (mean and 95% CI) 80 70 60 50 40 30 20 3m N=72 N=73 >50% reduction 21 (29.2%) 18 (24.7%) >90% reduction 2(2.7%) 5(6.8%) 6m >50% reduction 14 (19.4%) 18(23.7%) >90% reduction 4(5.6%) 6(8.2%) 12m >50% reduction 16(22.2%) 13(17.8%) Classical diet Diet group MCT diet >90% reduction 7(9.7%) 7(9.6%) P>0.1 Neal et al 2008
Tolerability at 3 months Classical MCT p N=47 N=42 Vomiting 28% 26% >0.05 Diarrhoea 15% 14% >0.05 Abdominal pain 11% 19% >0.05 Constipation Treatment 45% 31% 33% 26% >0.05 >0.05 Hunger 26% 33% >0.05 Taste problems 21% 17% >0.05 Lack of energy 17/47 (36%) 6/42 (14%) <0.05 Neal et al 2008
Tolerability at 12 months Classical N=20 MCT N=23 p Vomiting 45% 13% <0.05 * Diarrhoea 10% 17% >0.05 Abdominal pain 10% 17% >0.05 Constipation Treatment 45% 31% 39% 26% >0.05 >0.05 Hunger 25% 17% >0.05 Taste problems 15% 22% >0.05 Lack of energy 10% 13% >0.05 Neal et al 2008
Additional benefits at 3 months Classical MCT Increased alertness Increased awareness Increased responsiveness 83% 76% 83% 71% 83% 74%
Withdrawals before 3 months Classical (10/61) MCT (15/64) Increased seizures 4 1 Parental unhappiness 2 4 Diarrhoea 0 3 Constipation 1 0 Extreme drowsiness 0 1 0 1 Textural food problems Behavioural food refusal 3 4 Vomiting 0 1 Lamotrigine 4% Topiramate 10% Neal et al 2008
Growth Classical diet MCT diet Mean paired difference P value Mean paired difference P value Weight Height Baseline 3mo Baseline 6 mo Baseline 12 mo Baseline 3mo Baseline 6 mo -0.121 (n=37) -0.131 (n=29) -0.341 (n=19) 0.013 (n=31) -0.184 (n=20) 0.146 0.332 0.041 0.884 0.029-0.188 (n=38) -0.291 (n=30) -0.303 (n=21) -0.007 (n=29-0.189 (n=22) 0.014 0.014 0.014 0.911 0.003 Baseline 12 mo -0.495 (n=18) 0.000-0.520 (n=15) 0.000 Neal et al 2008
Growth - trends over 12 months Slopes of the best-fit regression lines of serial weight and height Z-score measures were used as values to represent growth trend during the year in 40 children who completed 12 months of treatment. There were no significant differences in mean slope between the classical (n=19) and MCT (n=21) diet groups for either weight (p=0.611) or height (p=0.912). Neal et al 2008
Growth mean energy and protein intakes over 12 months Diet Mean intake over 12 months Energy (kcal/kg) Protein (g/kg) MCT (n=21) Classical (n=19) 63.2 61.1 1.67 1.13 P value 0.651 0.000 Neal et al 2008
Conclusions Ketogenic diet is effective in the treatment of drug resistant epilepsy & is well tolerated Results of RCT (Class I evidence) suggest efficacy comparable to any new AED No evidence of benefit one diet over another No evidence of efficacy in one syndrome over another Children should be monitored throughout
Acknowledgements Hospital Services Association Charitable Trust Milk Development Council THE HENRY SMITH CHARITY All the patients & parents who participated in the trial as well as paediatricians who referred them