Ketogenic Diet Neurology & Beyond J Helen Cross UCL-Great Ormond Street Institute of Child Health, London & Young Epilepsy, Lingfield

Transcription

1 Ketogenic Diet Neurology & Beyond J Helen Cross UCL-Great Ormond Street Institute of Child Health, London & Young Epilepsy, Lingfield

2 The ketogenic diet What is it? A high fat diet, designed to mimic the metabolic effects of starvation, used in the treatment of epilepsy. Not a natural treatment

3 The ketogenic diet history 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

4 Normal UK diet, classical KD and MCT KD Normal Fat - 35% Protein - 15% Carbohydrate - 50% Classical Fat - 90% Protein - 6% Carbohydrate - 4% MCT Fat - 73% (30-60% MCT) Protein - 10% Carbohydrate - 17%

5 Data available Lefevre and Aronson 2000 Systematic review of 11 studies All 11 observational; only 2 prospective Uncontrolled studies 9/11 from single institution 300 Publications by year

6 Old treatment..new lease of life

7 The ketogenic diet Evidence base for efficacy in epilepsy Evidence base for alternative diets Evidence base for utilization Wider utilization

8 No Randomised controlled trials were found 4 Randomised Controlled Trials, 5 publications 7 Randomised Controlled Trials, 8 publications

9 Epilepsy: Evidence from RCTs? Martin et al: Cochrane Database Syst Rev 2016 Issue 2. Art. No.: CD RCT; 8 publications Kossoff 2007, Bergqvist 2005, Seo 2007, Neal 2008, Neal 2009, Raju 2011, Sharma 2013, El Rashidy 2013, Recruited total 427 children & adolescents, no adults No meta-analysis in view of heterogeneity of trials Seizure freedom reached as high as 55% in a 4 : 1 KD group seizure reduction as high as 85% after three months. MAD reported seizure freedom rates of up to 10% and seizure reduction rates of up to 60%. No studies evaluated effect on cognition or behaviour

10 Epilepsy: Evidence from RCTs? Martin et al: Cochrane Database Syst Rev 2016 Issue 2. Art. No.: CD RCT; 8 publications Kossoff 2007, Bergqvist 2005, Seo 2007, Neal 2008, Neal 2009, Raju 2011, Sharma 2013, El Rashidy 2013, Recruited total 427 children & adolescents, no adults No meta-analysis in view of heterogeneity of trials Seizure freedom reached as high as 55% in a 4 : 1 KD group seizure reduction as high as 85% after three months. MAD reported seizure freedom rates of up to 10% and seizure reduction rates of up to 60%. No studies evaluated effect on cognition or behaviour

11 Neal et al Epilepsia 2009:48:1-9 MCT vs classical diet 90 Responder rates MCT Classical Percentage of baseline seizures (mean and 95% CI) m 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

12 MCT vs classical diet 3 months 12 months Classical MCT Classical MCT N=47 N=42 N=20 N=23 Vomiting 28% 26% 45% 13% * Diarrhoea 15% 14% 10% 17% Abdominal pain 11% 19% 10% 17% Constipation 45% 33% 45% 39% Treatment 31% 26% 31% 26% Hunger 26% 33% 25% 17% Taste problems 21% 17% 15% 22% Lack of energy 36% 14% * 10% 13% Neal et al Epilepsia 2009;48:1-9

13 What about alternative diets?

14 Normal UK diet, classical KD, MCT KD & MKD 50% 35% Normal 15% % energy Fat Protein Carbohydrate 6% 4% 90% 10% 17% 73% (60%MCT) 30% 5% 65% Classical MCT MKD

15 Modified Ketogenic Therapy Sharma et al Epilepsia 2013;54: children, age 2-14 Daily seizures or 7/week > 3 AEDs Randomised to modified Atkins or control 3m primary outcome Constipation 23%

16 Low Glycaemic Index Therapy Glycaemic Index Calculated from incremental area under blood glc curve after feeding indexed to ingested glc Muzykewicz et al Epilepsia 2009;50: children; 50% >50% reduction at 3m, 49 discontinued after weeks Coppola et al Seizure 2011;20: patients years, Mean follow up 14.5+/- 6.5m 40% 75-90% seizure reduction, >50% in 2; 4 discontinued in first 5m No adverse events

17 Dietary therapy of epilepsy Ketosis KD 3:1 KD 4:1 MCT MAD LGIT Infant Pre-school School age Adolescent Adult

18 In whom should the diet be used? Syndrome specific efficacy?

19 Epilepsy Syndrome efficacy West syndrome/infantile spasms Newly diagnosed Kossoff et al Epilepsia 2008; Drug resistant Pires et al Epilepsy Res 2013;105: Dravet syndrome Compared to suboptimal treatment Caraballo et al Epilepsia 2005;46: Following optimal treatment Nabbout et al Epilepsia 2011;52:e54-7 Lennox Gastaut Syndrome 47% >50% reduction 3-36m Lemmon et al Dev Med Child Neurol 2012;54:464-8 Myoclonic astatic epilepsy Specific responsiveness Oguni et al 2002, Kirau & Bergqvist 2007 Early use associated with improved cognitive outcome, Stenger et al 2017?Underlying Glut 1 defect in proportion Mullen et al Arch Neurol 2011;68:

20 Epilepsy Syndrome efficacy West syndrome/infantile spasms Newly diagnosed Kossoff et al Epilepsia 2008; Drug resistant Pires et al Epilepsy Res 2013;105: Dravet syndrome Compared to suboptimal treatment Caraballo et al Epilepsia 2005;46: Following optimal treatment Nabbout et al Epilepsia 2011;52:e54-7 Lennox Gastaut Syndrome 47% >50% reduction 3-36m Lemmon et al Dev Med Child Neurol 2012;54:464-8 Myoclonic astatic epilepsy Specific responsiveness Oguni et al 2002, Kirau & Bergqvist 2007 Early use associated with improved cognitive outcome, Stenger et al 2017?Underlying Glut 1 defect in proportion Mullen et al Arch Neurol 2011;68:

21 1. Seizure types Co-morbidities Focal 2. Epilepsies classified by seizure type Generalized Generalized & Focal 3. Epilepsy Syndromes Unknown Genetic Structural Metabolic Immune Infectious Unknown 4. Epilepsy with Etiology

22 Glut 1 Deficiency Glut 1; 1 of 9 glucose transporters. Coded by SLC2A1 Wide range clinical presentation early onset absence epilepsy to later onset movement disorder Treatment with ketogenic diet 86% epilepsy respond to KD Less frequent for movement disorder Early diagnosis and initiation of KD may improve outcome Ramm-Pettersen et al Dev Med Child Neurol 2013;55:

23 A genetic basis to response? Candidate genes Only one new case of GLUT1 deficiency (SLC2A1), from 246 cases Responder (R) vs non-responder (NR) association analysis Responders = seizure-free at 3 month follow-up 8 R and 295 NR with KCNJ11 sequencing data 8 R and 238 NR with BAD sequencing data 14 previously-reported and 9 novel variants found from Sanger sequencing No variant significantly associated with KD response Dev Med Child Neurol 2015; 57: , Epilepsy Res 2015;118:22-8 GWAS Genetic outliers excluded, single-variant analysis 5 R and 177 NR, SNPs post quality-control filtering Cluster of top SNPs lowest p=3.32x10-6 minor alleles present in the ONLY two patients with 100% seizure-freedom maintained over 2 years, and one individual with 50% seizure reduction underpowered Exome sequencing 17 responders and 27 non-responders with whole exome-sequencing No differences validated so far, analysis ongoing In collaboration with Sanjay Sisodiya, UCL-Institute of Neurology

24 Structural epilepsies Long term outcome of the ketogenic diet for intractable childhood epilepsy with focal malformation of cortical development Jung et al Paediatrics 2008;122:e children; focal malformation cortical development 3m 21 (44.7%) SF 24m 16 (34%) SF f/up 9 (19.1%) SF Kobow and Blümcke, 2011, 2012, 2013 epileptogenesis cell death pharmacoresistance cognitive defects 75 PILO PILO+KD seizures/week Role in HIE? Thammongkol et al Epilepsia 2012;53:e55-9 Villaluz et al Dev Med Child Neurol in press week

25 Pathways involved in ketogenic diet treatment Kim & Rho, Curr Opin Clin Nutr Metab Care, 2008

26 Medium Chain Fatty Acids Chang et al Neuropharmacology 2013; 69: Chang et al Brain 2016; 139: Hughes et al Neurochem (3): Acetyl carnitine at baseline significantly higher in responders (p<0.007); no association at 3m Schoeler et al Epilepsia 2017

27 Is there evidence in all age groups?

28 Ketogenic diet in adults Restrictive Very low carbohydrate, unpalatable, hunger Mosek et al Seizure 2009;18: patients; classical diet, yrs, x2 focal seizures/month only 2 completed 12 weeks, both >50% reduction seizures discontinuation from lack of efficacy, hunger

29 Data in adults The ketogenic and related diets in adolescents and adults Payne et al Epilepsia 2011;52: adults/82 adolescents open label on KD 56 adults/10 adolescents MAD Sides effects similar to children, main reason for discontinuation lack of efficacy Efficacy & compliance; a meta-analysis Ye et al J Clin Neurology 2015;11: studies, 270 patients Efficacy All diets 42% CKD 52% MAD 34% Compliance All diets 45% CKD 38% MAD 56%

30 Wider applications?

31 Status epilepticus Anecdotal case reports of success Eg Nam et al Epilepsia 2011;52:e181-4 Refractory status epilepticus Four children & one adult refractory to standard therapy Seizure frequency decreased to <50% baseline median 8 days At one month 2 SF, 1>90% reductionand 2>75% High rate side effects Open label suggestion of benefit in FIRES? Nabbout et al Epilepsia 2010;51:

32 Cervenka et al Neurology 2017;88: Prospective feasibility study super refractory status years 5 centres 15/24; classic KD through gastrostomy 14 completed; SRSE resolved in 11 Side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss. Five patients (33%) ultimately died

33 Role in brain tumours? Retrospective and animal data suggest low glc in treatment for GBM improves outcome Data suggest normalised glc with KD as adjuvant to standard therapy;?improved outcome Champ et al J Neuro-onc 2014;117: ERGO: feasibility KD in recurrent GBM in 20 patients, feasible & safe, no clinical activity Reiger et al Int J Onc 2014;44: KEATING: prospective, non randomised blinded study 12 patients, outcome 12 wks & 12m

34 Dietary therapies Have we moved forward? KD established therapy in childhood epilepsy Increasing evidence for use in adults Syndrome and aetiology specific use Enhancing understanding & management of the epilepsies Global acceptance enhanced choice, although resistance to resource remains Insight into underlying mechanisms of action, leading toward translation of new therapy to clinical practice Wider applications

35 Elizabeth Neal Hannah Chaffe Nicole Edwards Sanjay Sisodiya Matthew Walker Robin Williams Simon Heales Christiana Papamichael Liverpool University Natasha Schoeler Rumana Jalil Michael Orford Simon Hughes Katia Kobow Ingmar Blumcke Manchester, Liverpool, Bristol, Birmingham, GOSH, Evelina/Kings Johns Hopkins Edinburgh, Rome, Florence, Vogthereuth, Bonn, Bielefeld Strasbourg, Lyon Prague Vienna Geneva Christin Eltze Katharina Vezyroglou Georgiana Fitzsimmons Niamh Landy Baheerathi Van de Bor Marion Sewell Zoe Simpson Ruth Williams Mary-Anne Leung Siobhan Titre Johnson PRMENT CTU Manchester Liverpool St Georges Leeds Cambridge Bristol Sheffield Birmingham Newcastle