Issue 129 ketogenic diet therapy by NH Publishing Ltd

COVER STORY

KETOGENIC DIET THERAPY: WHAT’S ALL THE FUSS ABOUT? Susan Wood Specialist Dietitian; Ketogenic Therapies, Matthew's Friends Clinics and Charity

The referral of a young adult for ketogenic dietary therapy (KDT) certainly sent shivers of uncertainty down my spine in 2008 and nine years on, I still get a sense that many dietetic colleagues, particularly those in adult practice, are ill at ease when ketogenic diets (KD) are mentioned. However, the basic biochemical premise of a KD is simple . . .

Susan works full time for Matthew's Friends Clinics and Charity as a specialist Ketogenic Dietitian, treating children and adults with drug resistant epilepsy and adults with brain tumours.

When the body goes from the fed to the fasted state, the liver switches from an organ of carbohydrate utilisation and fatty acid synthesis to one of fatty acid oxidation and ketone body production.1 Ketones are circulated as an alternative energy source to glucose, ensuring uninterrupted fuelling of essential tissues with high energy demand (e.g. brain and heart muscle). A low carbohydrate KD mimics this fasting state and shifts us into fat burning mode, using fats consumed in the diet, supplemented with fats taken from body stores if the dietary fat intake is insufficient. It results in a sustained presence of ketones and a flattening of post-meal glucose and insulin peaks, with levels tending toward the mid to lower end of the normal ranges. The benign ketosis associated with a low carbohydrate KD must not be confused with ketoacidosis (Table 1).2 Beyond the changes in circulating ketones, glucose and insulin, a myriad of biochemical pathways and the gut

microbiota are altered, leading to many possible mechanisms of action by which the KD exerts a range of therapeutic effects. Almost a century on from its creation as a treatment for epilepsy, scientists still struggle to pin down ‘the ketogenic effect’. Nevertheless, its utility continues to deliver profound changes in around half the children and adults undergoing supervised KDT for drug resistant epilepsy and it remains the only treatment for Glucose transporter type-1 deficiency and Pyruvate Dehydrogenase Deficiency (PDHD). The potential for KD metabolism to influence the aberrant cellular function underpinning a broad range of medical conditions is creating significant research interest too, meaning that KDT is not going away anytime soon (Table 2 overleaf).3-6 KETOGENIC DIET BASICS

The most powerful, over simplified and misguided nutrition message to reach the UK population over the last few decades has been that; ‘fat is

Table 1: Ketosis is NOT Ketoacidosis The difference between the two conditions is a matter of volume and flow rate: Ketosis: benign nutritional ketosis is a controlled, insulin regulated process that results in a mild release of fatty acids and ketone body production in response to either a fast from food, or a reduction in carbohydrate intake. Ketoacidosis is driven by a lack of insulin in the body. Without insulin, blood glucose rises to high levels and stored fat streams from fat cells. This excess amount of fat metabolism results in the production of abnormal quantities of ketones. The combination of high blood glucose and high ketone levels can upset the normal acid/base balance in the blood and become dangerous. In order to reach a state of ketoacidosis, insulin levels must be so low that the regulation of blood sugar and fatty acid flow is impaired.

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KETOGENIC DIET THERAPY Table 2: Ketogenic therapy; emerging clinical applications and future potential • Brain tumours • Cancer (various sites other than brain) • Alzheimer’s disease • Parkinson’s disease • Amyotrophic Lateral Sclerosis (ALS) • Multiple sclerosis • Mitochondrial disorders • Traumatic brain injury • Post stroke care • Autism • Migraine and cluster headaches • Depression • Aging • Cardiovascular health, obesity, Type 2 diabetes and metabolic syndrome Table 3: KD Protocols used in the clinical management of epilepsy Classical KD All foods are measured and combinations are selected to maintain a similar ratio of carbohydrate, protein and fats at meals and snacks. This is referred to as the ketogenic ratio (e.g. 2:1, 3:1, 4:1) and is calculated by dividing the total grams of fat by the total grams of carbohydrate and protein combined. While the higher classical ketogenic ratios (if required) may be easily achieved in the diets of younger children, ketogenic ratios beyond 3:1 are not so feasible for adults and older teenagers due to their higher daily protein requirement. Medium chain triglyceride (MCT) KD All foods are measured and combined to deliver a steady percentage of energy from carbohydrate, protein, long chain triglycerides (LCT fat from foods) and medium chain triglycerides (MCT from prescribed oil/emulsions, etc) in all meals and snacks. The MCTs provide 30-60% of total energy and are more ketogenic than LCTs; enabling a lower total fat intake and a slightly more liberal intake of carbohydrate and protein. Note: MCT oil or emulsion may be used as a fine-tuning option alongside any form of ketogenic therapy if enhanced ketone production is desired. Modified Atkins Diet (MAD) USA Protocol Only carbohydrate is carefully controlled (10-20g per day depending on age) and always combined with a generous source of fats. Protein foods are eaten liberally alongside, to appetite. In the UK, many centres use a slightly more controlled version of the MAD; providing some portion guidance to ensure an adequate fat intake and counselling towards a moderate intake of protein foods, to aid ketosis. We refer to this as a Modified KD (MKD). Low Glycaemic Index Treatment This is similar to a MAD, the essential difference being that the carbohydrate allowance is approximately 10% of energy requirement (25g CHO per 1,000kcals), but restricted to sources of carbohydrate with a Glycaemic Index of 50 or below. This approach may be an option for seizure management as its goal is glucose control rather than ketosis. However, this approach would not be favoured as adjuvant therapy in brain tumour management, or for conditions where ketone levels are perceived to play a more directly relevant role.

bad and carbohydrate is good’. KDT turns this perceived macronutrient hierarchy on its head and, therefore, requires a considerable mindshift for most. Understandably, concerns about the effect of a KD on blood lipids and weight feature highly. Both are monitored throughout as standard practice, with adjustments made to the KD prescription as required. Published data indicates that although total cholesterol levels may rise significantly in the first three months or so, they readily normalise by 12 months and it is 12

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possible that changes in circulating lipids have some part to play in the therapeutic outcome.7,8 Typically, we find that HDL levels increase and triglyceride levels remain normal, but responses are individual, hence the recommendation to monitor from baseline and throughout KDT, appraising this alongside the many variables contributing to the clinical condition and overall wellbeing of each individual. There are four basic approaches used in clinical KDT; however, the crossover between

them is significant (see Table 3). They all share the following: • A very low carbohydrate intake. • An increased fat intake to provide adequate calories, replacing those lost through carbohydrate restriction. • An adequate protein intake. • Overall energy control to match individual requirements, delivering growth, weight loss or weight stability as required. • Vitamin, mineral and trace element supplementation as required. • Medical assessment and biochemical screening pre-therapy with reviews throughout treatment at three, six and 12 monthly intervals depending on the age/wellbeing of the patient and stage of therapy.9 • Ongoing home-monitoring of symptoms, weight, growth, blood or urine checks. Regular discussions with the managing dietitian (by telephone, email or face to face) to review this data and agree on ‘finetuning’ of the diet prescription to optimise symptom management.9

FOOD, FEED OR BOTH?

A KD can be administered as a regular oral diet, a bottle feed, an enteral feed, or in a feed/food combination to match the individual requirements. KD meals can be created to suit any age and textural feeding requirement. Oral meals and snacks are generally based on regular fresh food ingredients; meat, fish, eggs, nuts, seeds, cheese, butter, cream, vegetable oils, vegetables and fruits. Food allergies and food preferences can generally be accommodated too. Specially formulated prescribed food products may be essential, optional, or not required, depending on the clinical and social presentation of the individual requiring KDT (Table 4 overleaf). ENTERAL OR BOTTLE FED KD

For infants and those requiring enteral feeding at any age, the KD can be provided entirely or partly in a liquid form. Ketocal (Nutricia) is currently the only ketogenic feed range available in the UK and based on the ratio system used in the classical ketogenic diet (e.g. 4:1 or 3:1 ratio). Although designed for children up to 10 years,

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MATTHEW’S FRIENDS WILL BE HOSTING THEIR ANNUAL KETOCOLLEGE PROGRAMME 19TH – 21ST JUNE 2018 - CROWNE PLAZA FELBRIDGE HOTEL, EAST GRINSTEAD, WEST SUSSEX, UK For further details please visit www.mfclinics.com or to register your interest please email: ketocollege@mfclinics.com

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KETOGENIC DIET THERAPY Table 4: Prescription products available to support ketogenic therapy

Enteral feeding products

• Ketocal (Nutricia) • Ketocal 4:1 LQ. Ready to feed in 200ml carton • Ketocal 4:1 powder. Suitable as a sole source of nutrition from 1-10 years or as a supplementary feed beyond 10 years • Ketocal 3:1 powder. Suitable as a sole source of nutrition from birth to 6 years of age or as a supplementary feed beyond 6 years All variants available in unflavoured or vanilla flavour

Oral feeding

• Ketocal (Nutricia) Range as for enteral feeding (above) • Keyo (Vitaflo) Ready to eat semi-solid 3:1 ratio food. Chocolate flavour. Suitable from 3 years of age onwards. Suitable as a sole source of nutrition up to 10 years of age

Supplementary fats

• Long chain triglycerides (LCT) fats: Calogen (Nutricia), Carbzero (Vitaflo) • Medium chain triglycerides (MCT) fats: MCT oil (Nutricia), Liquigen (Nutricia), Betaquik (Vitaflo), MCT Procal (Vitaflo) • LCT and MCT combined: Fresubin 5 kcal shot (Fresenius Kabi)

Supplementary proteins

• ProSource TF (Nutrinovo), Protifar (Nutricia)

Special foods

• New range from Ketocare • Ketoclassic savoury 3:1(bread roll) • Ketoclassic bar 3:1 (snack bar) • Ketoclassic chicken meal 3:1 (ready-meal in a pouch)

Vitamins and minerals (complete)

• Phlexy-Vits (Nutricia). Tablets or powder sachets. Suitable from 11 years to adult. • FruitiVits (Vitaflo). Powder sachets. Suitable from 3-10 years

Therapy monitoring equipment

• Blood ketone monitoring strips (measure β-hydroxybutyrate only) and blood glucose monitoring strips to match available metre, e.g. - Freestyle Optium Neo - GlucoRX HCT - GlucoMen LX 2 • Urine ketone monitoring strips (measure Acetoacetate only): - Ketostix (Bayer) and others

Ketocal formulations can easily be adjusted to match the KD prescription requirements of the majority of older children and adults by adding protein, carbohydrate and fat modules as required. New enteral feeds aimed at meeting the KD prescription needs of older children and adults are currently in development and eagerly awaited by the clinical ketogenic world. For those with milk protein allergy, it is also possible to devise ketogenic enteral feeds using individual protein, fat and carbohydrate sources, with the addition of appropriate electrolyte, vitamin mineral and trace elements. Transition from a normal enteral feed to a ketogenic feeding regime is generally achieved using a step-wise approach over a few days as tolerated. This can be implemented by either introducing the ketogenic feed as a percentage 14

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of the existing enteral feed, or introducing full ketogenic feeds at a reduced ketogenic ratio. THINKING ABOUT KETOGENIC MEALS

As already mentioned, the shift from prioritising carbohydrate to prioritising fats, takes quite a bit of getting used to, for most. To ease patients and families into this, it is helpful to consider some initial first-steps during the four to six weeks running up to KD initiation. In this way, they have a chance to try out new ideas and become familiar with the types of food to focus on. This can make the ketogenic changeover much easier to cope with. First steps • Swapping high sugar snacks such as cakes, biscuits, sweets and chocolates for alternatives such as cubes of cheese, slices of

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ham, chunks of chicken, berries with cream, vegetable sticks with full fat dips, etc. Swapping full sugar drinks for sugar-free versions. Introducing lower carbohydrate vegetables such as broccoli, cauliflower, celeriac, celery, courgette, kale, mushrooms, salad leaves and spinach; adding butter, oils or creamy sauces to them. Experimenting with different breakfast choices such as egg-based cooked breakfasts or exploring adapted recipes for KD porridge, KD muffins or perhaps KD pancakes. Experimenting with KD bread and cracker recipes and shop bought lower carbohydrate alternatives. Trying out alternatives to milk (e.g. unsweetened almond or soya milks) and any prescribed products, such as the Ketocal range, Carbzero, Calogen, Betaquik, or Liquigen, if any are to be incorporated into the diet plan.

Meals generally need to be made from fresh, basic ingredients, so a willingness to plan a menu and prepare meals from first principles is essential. Lots of practical help with identification of macronutrient sources, lower carbohydrate replacements and meal planning is required in the early days (Table 5). However, in time, most families and adults can be supported to become knowledgeable and confident in this respect. Lots of practise and a bit of positive encouragement certainly does make ketogenic meal creation easier. The increased popularity

of low carbohydrate diets in the public domain has led to some very inspirational websites and books with recipes ideas that can readily be tweaked to match individual meal prescriptions. TRANSLATING PRESCRIPTION NUMBERS INTO MEALS

This is the aspect of KDT that seems to create the most anxiety in new starters and it is the responsibility of the managing team to ensure that patients and families are provided with appropriate tools and are enabled to learn the basics, so that they can build on this knowledge and gain confidence over time. There are two main counting methods: Food choice lists (e.g. 1g CHO choices, 10g fat choices, 6g protein choices) and meal planning sheets are the simplest way to start out. By focusing on building meals around the three essential macronutrients, a portion of protein (measured or portion guided), a source of carbohydrate (always measured) and a generous supply of fats (measured or portion guided), families quickly get an eye for their frequently used food sources and soon learn to spot when the balance of foods in the meal doesn’t look quite right. It’s a good idea to encourage starting out with a few simple meals and lots of repeats of the favourites in the first few months. It’s the effect of the macronutrient shift on symptoms that is under scrutiny, rather than the fanciness of the recipes. As a boost to ease menu planning for adults and older children starting out on MKDs, we have produced a guide and recipe booklet www.NHDmag.com November 2017 - Issue 129

KETOGENIC DIET THERAPY Table 5: Useful foods for ketogenic diets Ketogenic diet alternatives to high carbohydrate staples

Bread

• KD recipes based on ingredients such as nuts, seeds and their flours, eggs, cream cheese, baking powder (low carbohydrate versions), psyllium husk and xanthan gum • Commercial low carbohydrate breads: Livlife bread loaf, Atkins (bread mix), Sukrin (bread mix), Jo-Lo (bread mix) • PRESCRIPTION ONLY: 3:1 Ketoclassic Savoury (Ketocare Foods); similar to a bread roll

Pizza bases

• KD recipes based on cauliflower, or ketogenic bread ideas as above • Commercial pizza base options, e.g. Lo-dough flatbread/pizza base

Crackers and crispbread

• KD recipes based on nuts, seeds and their flours • Commercial alternatives such as Atkins Fibre Crackers

Pasta

• KD pasta recipes using eggs, psyllium husk, cream cheese, etc • Spiralised vegetables; courgette, butternut squash, etc, can be used in place of spaghetti • Cabbage leaves and lettuce leaves can be used in place of lasagne sheets • Egg omelette can be cut into narrow strips and used in place of spaghetti • Commercial pasta alternatives; Shirataki noodles based on Konjac root; e.g. Miracle Noodle, Zero Noodles, Slim Pasta, Bare Naked Noodles

Potato

• Celeriac can be used to make crisps, chips, wedges and mash • Cauliflower can be roasted or mashed • Swede can be roasted, mashed or made into chips

Rice

• Cauliflower can be grated and stir fried • Commercial rice alternatives: Konjac root ‘pasta’ in a rice grain shape

Flour

• Nuts and seeds (ground or as ‘flours’) such as almond, coconut, flax and sesame can be used in KD recipes for pastry, muffins, cakes and biscuits • Psyllium Husk, xanthan gum, flour-free baking powders and eggs are readily used in low carbohydrate baking to help with the structure of baked goods • PRESCRIPTION ONLY: Ketocal 4:1 and 3:1 powder (Nutricia) and MCT Procal (Vitaflo) as high fat low carbohydrate ‘powders’ may be used in meal recipes See www.matthewsfriends.org/keto-kitchen/keto-recipes/cooking-with-prescription-products/ Other ketogenic essentials and helpful additions

A mix of versatile and palatable fat sources

• Double cream, crème fraiche, butter, cream cheese, lard, vegetable oils; eg olive oil, coconut oil, other vegetable oils, mayonnaise, hollandaise sauce, avocados, etc • New high fat, low carb products such as Coyo coconut yoghurt

Low carbohydrate milk substitutes for general use

• Unsweetened almond and soya milks provide a fraction of the carbohydrate found in cows’ or goat milk

Sweeteners

• Some choose to avoid artificial sweeteners and any products containing them. Others use products such as sugar-free drinks, sugar-free jellies and Da Vinci flavoured syrups (contain sucralose) finding these useful. For baking, we may recommend carbohydrate and calorie free options such as Hermesetas liquid (liquid saccharin), or Stevia powder products without maltodextrin. Low carb products with sugar alcohols (e.g. sorbitol, xylitol, erythritol) are best avoided in the early months of ketogenic therapy, but may be incorporated once a more stable ketogenic state has been reached and tolerance can be observed

Other flavour enhancing ingredients

• Dried herbs and spices; checking labels of ‘mixes’ for added sugars or flour. Commercial stocks; looking for lowest carbohydrate versions. Savoury spreads and flavours; Bovril, Marmite, Worcestershire sauce, mustard, vinegar, a dash of soya sauce • Essences, e.g. vanilla essence may be used in drinks and for cooking

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entitled Colour & Shine. (Ketogenic meals should always be shiny and ideally colourful too!) Each breakfast, lunch and dinner recipe provides approximately 5g carbohydrate, 40g fat, 18g protein and 450kcal. Each snack recipe provides approximately 1g-2g carbohydrate, 15g fat, 2-4g protein and 150kcal. For those requiring more than 5g carbohydrate or 40g fat as their guideline meal prescription, additional 1g carbohydrate and 10g fat choices can simply be added from the lists provided. It can really help new starters in the early days when they are learning about making KD meals and exploring the impact of the KDT therapy on symptoms too. Computer based ketogenic meal planners can be used from the outset by computer/app confident families or introduced part way through the ketogenic treatment when they are becoming more confident and wish to expand their meal horizons. Programs such as the Electronic Ketogenic Manager (EKM) are an invaluable help for more complex multi-ingredient recipes, particularly for Classical and MCT KDs where protein carbohydrate and fat are all measured.

Note: prescription adjustment may be required when moving from a slightly looser choice lists generated menu to a tighter electronic program generated menu. KDT remains under-utilised within the world of complex epilepsy, and is only just being explored as a potential therapy or supplementary therapy for other conditions for which modern medicine has no cure.10 With its potential to alter cellular fuelling, downregulate inflammatory pathways, control glucose levels and deliver effective weight control, it is a wonder that broader exploration of its potential is taking so long. Could the ‘fat is bad and carbohydrate is good’ message be clouding our willingness to explore KDT and lower carbohydrate diets, to evaluate the metabolic potential beyond? As interest in low carbohydrate/ketogenic nutrition is increasing outside clinical dietetics, I sense a readiness to dismiss this as a fad and passing phase from within. Eight years ago, I would have dismissed the apparent hype too, but now that I have seen the clinical impact that ‘more fat, less carbohydrate’ can deliver, I have been forced to re-examine and ‘shift’ my own long-held preKDT beliefs.

References 1 www.diapedia.org/metabolism-insulin-and-other-hormones/51040851169/ketone-body-metabolism. Accessed 28.9.17 2 www.ketogenic-diet-resource.com/ketoacidosis.html. Accessed 28.9.17 3 Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013; 67(8): 789-796 4 Paoli A, Bianco A, Damiani E, Bosco G. Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases. Biomed Res Int. 2014; 2014: 474296 5 Feinman RD, Pogozelski WK, Astrup A, Bernstein RK et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015; 31(1): 1-13 6 Klement R. Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation. Med Oncol. 2017; 34:132 7 Liu YM, Lowe H, Zak MM, Kobayashi J et al. Can children with hyperlipidaemia receive ketogenic diet for medication-resistant epilepsy? J Child Neurol. 2013 Apr; 28(4): 479-83 8 Cervenka MC, Patton K, Eloyan A, Henry B et al. The impact of the modified Atkins diet on lipid profiles in adults with epilepsy. Nutr Neurosci. 2016; 19(3): 131-7 9 Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR et al. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. Epilepsia Volume 50, Issue 2 2009, p 304-317 10 Masino SA (Editor). Ketogenic Diet and Metabolic Therapies: Expanded roles in health and disease. Oxford University Press. 2017.

WHO ARE MATTHEW'S FRIENDS? Matthew’s Friends is a charity that specialises in medical ketogenic dietary therapies and has been working alongside NHS ketogenic therapy teams, offering information and support for those on a medically supervised therapy since 2004. In September 2011, we opened the first Matthew's Friends Clinic at Young Epilepsy as a means of providing a tertiary level clinical service to increase the availability of ketogenic dietary therapy to children and adults with drug resistant epilepsy in the UK where NO local provision is currently available. The small experienced team of ketogenic dietitians, ketogenic diet assistants and a neurologist is led by neurologist Professor J Helen Cross OBE. In 2016, we launched Matthew’s Friends KetoCollege, which is an annual training meeting for medical professionals wanting to work in the field of medical ketogenic dietary therapies.