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Volume 9.09 11th Jul 2019

KETOGENIC DIETS FOR EPILEPSY: PAST, PRESENT AND FUTURE This article provides us with a timeline of the ketogenic diet, how it originated and how it has developed over the years, highlighting a 2017 survey that assessed the impact of NICE guidance. A STEP BACK IN TIME

Reports of starvation associated with a reduction or cessation of seizures in people with epilepsy, date as far back as the Hippocrates era. Centuries later, in the Gospels, Mark (9.29, King James Version) described a boy with seizures, which only ‘prayer and fasting’ could cure. In the early 1920s, Dr Wilder, from the Mayo Clinic, proposed to mimic the state of starvation and produce ketosis with a high-fat, low-carbohydrate diet.1 This led to the introduction of the socalled ‘classical ketogenic diet (KD)’, typically with a 4:1 ratio of grams of fat to grams of protein and carbohydrate, as a treatment for people with epilepsy. The initial enthusiasm for the KD was ousted by the discovery of diphenylhydantoin in 1938 and the advent of new easy-to-administer antiepileptic drugs (AEDs). Although widely used, concerns were quickly raised regarding adverse side effects of these drugs. In the 1970s, in an attempt to make dietary treatment more palatable, Huttenlocher introduced the Medium-

Chain Triglyceride (MCT) KD.2 Based on the premise that MCTs are more ketogenic per calorie, the MCT KD, which originally derived 60% of its calories from MCT oil, allowed a greater bulk of protein and carbohydrate compared with the predominantly long-chain classical KD. A modified MCT KD was later developed, designed to minimise gastrointestinal side effects, which derived 30% of its calories from MCT oil and 41% from long-chain fats.3 KDs experienced a new lease of life in 1994 following NBC-TV’s Dateline report on Charlie Abrahams, who became seizure-free with KD treatment started at Johns Hopkins Hospital, Baltimore. The Charlie Foundation was then formed by Charlie’s father, the film director Jim Abrahams, helping to further publicise dietary treatment in the public and academic domains with the film First Do No Harm in 1997, and supporting the first multicentre prospective study of the classical KD.4 To this day, the foundation continues to provide information for professionals and families regarding KDs.

Dr Natasha Schoeler, UCL Great Ormond Street Institute of Child Health

Kirsty Martin-McGill, University of Liverpool and University of Chester

Victoria Whiteley, Royal Manchester Children’s Hospital

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THE NOUGHTIES

In the early 2000s, Dr Eric Kossoff from Johns Hopkins Hospital, published on the use of the Atkin’s diet as a treatment for epilepsy5 and, later, on the development of the KD variant, the Modified Atkin’s Diet (MAD).6 The MAD was intended as a more liberal alternative to the classical KD, with fats ‘encouraged’ rather than specifically measured and protein ‘unlimited’. In 2005, colleagues from Massachusetts General Hospital published on a further ‘liberalised’ dietary regimen, the Low Glycaemic Index Treatment (LGIT), which aimed to minimise the increase of blood glucose following food consumption rather than producing ketones per se.7 The LGIT allowed a greater intake of carbohydrate (around 60% of total energy) compared with other KD types, with only lowglycaemic index foods allowed. In 2008, the first randomised controlled trial (RCT) of classical and MCT KDs to treat drugresistant epilepsy, was undertaken at Great Ormond Street Hospital for Children, London. 38% of children aged two to 16 achieved ≥50% seizure reduction after three months of dietary treatment, compared with 6% controls.8 No difference in effectiveness was found between the classical and MCT KDs.9 This study changed the perceptions of dietary treatment for epilepsy and KDs became more widely available in clinical practice. In 2000, there were 22 centres and 101 patients following KDs in the UK,10 increasing to 28 centres and 152 patients in 2010.11 74% of patients followed the classical KD in 2010 and the remainder followed the MCT KD, despite the aforementioned trend in modified versions of the KD from the USA. PRESENT DAY: THE UK PICTURE AND BEYOND

In 2017, the Ketogenic Dietitians Research Network (KDRN) undertook a survey in the UK and Ireland to assess the impact of the 2012 updated NICE guidance, recommending that children and young people with refractory

epilepsy should be referred for consideration of a KD.12 The results demonstrated a 77% increase in services compared with 2000, with patient numbers reaching 754 (KDRN, submitted for publication). Whilst NICE guidance only supports the use of KDs in children, there have also been developments in adult services, with the establishment of seven adult centres. Despite the rapid increase in services and increased availability of the diet, there is ongoing demand for patients to be considered for dietary treatment: 31 centres reported a waiting list (range 1-49 patients) with 267 patients in total waiting to start a KD. The main reasons stated for limited service capacity included inadequate funding for dietetic, nursing and medical time. This highlights the need for continued improvements in services nationally and an increasing number of KD dietitians supported by charity funding via The Daisy Garland and Matthew’s Friends. The 2017 survey showed that classical and MCT KDs are still in use, but use of the MCT KD has significantly declined and a new diet variant, termed ‘modified ketogenic diet’ (MKD) has been introduced.37 MKD in the UK and Ireland is a hybrid KD, adopting principles from other established KD protocols (predominantly high fat and low carbohydrate), but there is little research into its efficacy or cost-effectiveness. MAD is not in use in the UK and Ireland; LGIT was said to be used in 13 patients, predominantly adults. Additional MCT can be added to each of the dietary protocols as a fine-tuning tool to improve ketosis and seizure reduction. This is reflective of the overall trend in ketogenic practice of allowing more flexibility, but still achieving optimal clinical outcomes. There is now a growing body of evidence to support the use of KDs, particularly for children with refractory epilepsy,13 with a developing interest in the use of KDs for status epilepticus,14 although further research is required in this area. There is controlled evidence to show that the

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NHD CPD eArticle

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There is controlled evidence to show that KDs can positively impact cognition in people with epilepsy.

benefits of KDs expand beyond seizure control, with improvements in activity, productivity and anxiety in children.15 Our understanding of which epilepsy syndromes and metabolic conditions are likely to respond well to KDs is also improving. These include glucose transporter type 1 deficiency syndrome, pyruvate dehydrogenase deficiency, epilepsy with myoclonic-atonic seizures, infantile spasms, tuberous sclerosis complex and Dravet syndrome.16 The use of KDs in adults is growing in popularity following the publication of two recent trials,17,18 both of which illustrated a ‘moderate’ improvement in seizure control, although limited by small sample sizes. An adequately-powered RCT would be of benefit in this population to investigate both clinical and cost effectiveness. With the increase in use of KDs and the growing body of evidence supporting their efficacy in epilepsy, national and international guidelines have, and continue to be, produced. This includes an updated international consensus statement on use of KDs for children with epilepsy, with advice ranging from who is eligible for consideration of a KD, prevention and treatment of adverse effects and how to discontinue dietary treatment.16 Specific guidance has also been published on use of KDs in infants19 and work is underway on guidelines for the use of KDs in parenteral nutrition and within an intensive care setting for status epilepticus. As the indications for and number of patients on KD has increased, so has the number of prescribable products available to support patients, families and professionals. Products now include a specific formula for infants (Nutricia’s KetoCal 3:1) and for adults (Nutricia’s KetoCal 2.5:1 LQ), cereal bars and ready meals

(Ketoclassic range by Ketocare) and a chocolate pudding (Keyo by Vitaflo International Ltd). There has also been development of online support tools including EKM, MyKetogenicDiet (Vitaflo International Ltd) and Myketoplanner (Nutricia Metabolics), aiming to improve compliance and accessibility to KDs. FORWARD FACING

Use, and the potential uses of KDs is expanding, both for epilepsy and beyond. Following a plethora of case series over the past few decades, a nationwide RCT is currently underway to determine the efficacy of the classical KD in infants.20 Evidence, although preliminary, is also mounting for use of KDs in cancer,21,22 neurodegenerative diseases,23 Alzheimer’s 24 disease, autism spectrum disorder25 and migraines,26,27 to name but a few. There is continued interest in the potential mechanisms of action of KDs, with the ultimate aim of making dietary treatment easier and more accessible. There is particular focus on medium chain fatty acids,28 including decanoic acid29,30 and triheptanoin,31 and the role of the gut microbiota32 at present. In addition, enhancing understanding of predictors of response to KDs continues to be at the forefront of research interests, with particular regard to genetics,33 epilepsy syndromes and seizures types34,35 and biochemical parameters.36 The UK and Ireland’s contribution to KD research is ever-mounting with the creation of national groups, such as KDRN, promoting communication, idea and resource-sharing and supporting dietitian-led research and international collaborations.

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NHD CPD eArticle CONCLUSION

KDs are more accessible than ever. However, in this rapidly developing field of dietetics, further research is required. Networks, such

Volume 9.09 - 11th July 2019

as KDRN, are essential in fostering research collaborations, clinical support systems and promoting the excellent work of ketogenic dietitians.

References 1 Wilder RM. The Effect of Ketonemia on the Course of Epilepsy. Mayo Clinic Bull 1921(2):307 2 Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology. 1971;21(11):1097-103 3 Schwartz RM, Boyes S, Aynsley-Green A. Metabolic effects of three ketogenic diets in the treatment of severe epilepsy. Dev Med Child Neurol. 1989;31(2):152-60 4 Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, et al. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol. 1998;55(11):1433-7 5 Kossoff EH, Krauss GL, McGrogan JR, Freeman JM. Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology. 2003;61:1789-91 6 Kossoff EH, McGrogan JR, Bluml RM, Pillas DJ, Rubenstein JE, Vining EP. A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia. 2006;47(2):421-4 7 Pfeifer HH, Thiele EA. Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology. 2005;65(11):1810-2 8 Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet neurology. 2008;7:500-6 9 Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia. 2009;50:1109-17 10 Magrath G, MacDonald A, Whitehouse W. Dietary practices and use of the ketogenic diet in the UK. Seizure. 2000;9(2):128-30 11 Lord K, Magrath G. Use of the ketogenic diet and dietary practices in the UK. J Hum Nutr Diet. 2010;23(2):126-32 12 National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (update).2012 13 Martin-McGill KJ, Jackson CF, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev. 2018;11:CD001903. 14 Smith G, Press CA. Ketogenic Diet in Super-Refractory Status Epilepticus. Pediatr Neurol Briefs. 2017;31(3):8 15 IJff D, Postulart D, Lambrechts D, Majoie M, de Kinderen RJA, Hendriksen JGM, et al. Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: A randomized controlled trial. Epilepsy Behav. 2016;60:153-7 16 Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018;3(2):175-92 17 Zare M, Okhovat AA, Esmaillzadeh A, Mehvari J, Najafi MR, Saadatnia M. Modified Atkins diet in adult with refractory epilepsy: A controlled randomized clinical trial. Iran J Neurol. 2017;16(2):72-7 18 Kverneland M, Molteberg E, Iversen PO, Veierod MB, Tauboll E, Selmer KK, et al. Effect of modified Atkins diet in adults with drug-resistant focal epilepsy: A randomized clinical trial. Epilepsia. 2018;59(8):1567-76 19 van der Louw E, van den Hurk D, Neal E, Leiendecker B, Fitzsimmon G, Dority L, et al. Ketogenic diet guidelines for infants with refractory epilepsy. Eur J Paediatr Neurol. 2016;20(6):798-809 20 Titre-Johnson S, Schoeler N, Eltze C, Williams R, Vezyroglou K, McCullagh H, et al. Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial. Trials. 2017;18(1):195 21 Martin-McGill KJ, Srikandarajah N, Marson AG, Tudur Smith C, Jenkinson MD. The role of ketogenic diets in the therapeutic management of adult and paediatric gliomas: a systematic review. CNS Oncol. 2018;7(2):CNS17 22 Sremanakova J, Sowerbutts AM, Burden S. A systematic review of the use of ketogenic diets in adult patients with cancer. J Hum Nutr Diet. 2018;31(6):793-802. 23 Wlodarek D. Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease). Nutrients. 2019;11(1) 24 Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:28-36 25 Doenyas C. Dietary interventions for autism spectrum disorder: New perspectives from the gut-brain axis. Physiol Behav. 2018;194:577-82 26 Barbanti P, Fofi L, Aurilia C, Egeo G, Caprio M. Ketogenic diet in migraine: rationale, findings and perspectives. Neurol Sci. 2017;38(Suppl 1):111-5 27 Di Lorenzo C, Coppola G, Di Lenola D, Evangelista M, Sirianni G, Rossi P, et al. Efficacy of Modified Atkins Ketogenic Diet in Chronic Cluster Headache: An Open-Label, Single-Arm, Clinical Trial. Front Neurol. 2018;9:64 28 Augustin K, Khabbush A, Williams S, Eaton S, Orford M, Cross JH, et al. Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol. 2018;17(1):84-93 29 Khabbush A, Orford M, Tsai YC, Rutherford T, O’Donnell M, Eaton S, et al. Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium-chain triglyceride ketogenic diet. Epilepsia. 2017;58(8):1423-9 30 Augustin K, Williams S, Cunningham M, Devlin AM, Friedrich M, Jayasekera A, et al. Perampanel and decanoic acid show synergistic action against AMPA receptors and seizures. Epilepsia. 2018;59(11):e172-e8 31 Calvert S, Barwick K, Par M, Ni Tan K, Borges K. A pilot study of add-on oral triheptanoin treatment for children with medically refractory epilepsy. Eur J Paediatr Neurol. 2018;22(6):1074-80 32 Lindefeldt M, Eng A, Darban H, Bjerkner A, Zetterstrom CK, Allander T, et al. The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy. NPJ Biofilms Microbiomes. 2019;5:5 33 Schoeler NE, Leu C, Balestrini S, Mudge JM, Steward CA, Frankish A, et al. Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy. Epilepsia. 2018;59(8):1557-66 34 Ko A, Jung DE, Kim SH, Kang HC, Lee JS, Lee ST, et al. The Efficacy of Ketogenic Diet for Specific Genetic Mutation in Developmental and Epileptic Encephalopathy. Front Neurol. 2018;9:530 35 Falco-Walter JJ, Roehl K, Ouyang B, Balabanov A. Do certain subpopulations of adults with drug-resistant epilepsy respond better to modified ketogenic diet treatments? Evaluation based on prior resective surgery, type of epilepsy, imaging abnormalities, and vagal nerve stimulation. Epilepsy Behav. 2019 36 Schoeler NE, Bell G, Yuen A, Kapelner AD, Heales SJR, Cross JH, et al. An examination of biochemical parameters and their association with response to ketogenic dietary therapies. Epilepsia. 2017;58(5):893-900 Copyright © 2019 NH Publishing Ltd - All rights reserved. Available for printing and sharing for the use of CPD activities for personal use. Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.

NHD CPD eArticle Volume 9.09 - 11th July 2019

Questions relating to: Ketogenic diets for epilespy: past, present and future Type your answers below, download and save or print for your records, or print and complete by hand. Q.1

What were the principles behind the classical KD and why was it ousted?

Q.2

How does the MCT KD differ from the classical version of the diet?

Q.3

Explain how the 2017 KDRN survey supports the 2012 updated NICE guidance on KDs.

Q.4

Why is a flexible approach to ketogenic practice beneficial?

Q.5

What are the advantages of a KD for children with refractory epilepsy?

Q.6

Explain what the focus and research interested are on KDs for the future.

Please type additional notes here . . .

Copyright ÂŠ 2019 NH Publishing Ltd - All rights reserved. Available for printing and sharing for the use of CPD activities for personal use. Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.