NHD CPD eArticle 8.12 Ketogenic diet: let them eat fat! by NH Publishing Ltd

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Volume 8.12 - 19th July 2018

KETOGENIC DIET THERAPY: LET THEM EAT FAT! Susan Wood Specialist Dietitian; Ketogenic Therapies, Matthew’s Friends Clinics & Charity 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.

This article gives an insight into three very different adult cases; two with epilepsy, one with a brain tumour, and how ketogenic diet therapy has influenced the quality of their lives. A ketogenic diet (KD) is low in carbohydrate, high in fat and adequate in protein. It triggers a shift in metabolism that mimics the fasted state; leading to increased fat oxidation and ketogenesis. Ketogenic diet therapy (KDT) is widely implemented for children with drugresistant epilepsy and metabolic conditions such as Glut 1 deficiency disorders.1,2 Despite published evidence indicating feasibility, tolerability, and efficacy of KDT in adults similar to that in children, few epilepsy centres worldwide offer these therapies to adults.3 This also means that families

with children requiring KDT around the teenage to adult service transition stage, or those requiring continuation of their existing KDT beyond 18 years, have immense problems accessing services.4,5 The publication of randomised controlled trial evidence, equivalent to that endorsing KDT use in children, would make all the difference to adult service provision, but no such trial is on the horizon at present. In the meantime, around 30% of adults continue to live with drug-resistant epilepsy, enduring poor seizure control and an impaired quality of life.6

What is epilepsy?7 Epilepsy is simply a tendency to have seizures. A seizure happens when there is a sudden burst of intense electrical activity in the brain. This causes a temporary disruption to the way the brain normally works: an epileptic seizure. There are many different types of seizure with the effect dependent on where in the brain the seizure starts, the level of awareness during the seizure and whether the seizure involves movement or not. • A tonic clonic seizure can start in both sides of the brain, or one side of the brain and then spread to affect both sides. During the tonic phase, the person will lose consciousness, their muscles go stiff and, if standing, they will fall to the floor. They may make a sound as air is expelled from the chest, past the vocal chords and may bite down on their tongue, or the inside of their mouth. During the clonic phase, their limbs jerk quickly and rhythmically and they may lose control of their bladder and/or bowels. Breathing may also be affected, causing a blue tinge around their mouth. ®

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• An absence seizure results in the person being unconscious for a few seconds. They will suddenly stop doing whatever they are doing but will not fall. They may appear to be daydreaming or ‘switching off’, so sometimes these can be harder to notice. Their eyelids might flutter and there may be some slight jerking movements of their body or limbs. In longer absences, there might be some brief, repeated actions. They are unaware of their surroundings and cannot be brought out of it. Some people have hundreds of absences a day. They often have them in clusters of several, one after another, and they are often worse when they are waking up or drifting off to sleep. Typical absence seizures usually start in childhood or early adulthood. • Myoclonic seizures are sudden, short-lasting jerks that can affect some or all of the body. The jerking can be very mild, like a twitch, or it can be very forceful and may cause the person to throw something they are holding, or make them fall over. The following two cases illustrate the effect that KDT has had on the lives of very different adults with drug resistant epilepsy. MATTHEW Matthew is 22 years old. He lives with his parents who provide all his day-to-day care. Diagnosis: He has a complex syndrome with microcephaly, severe learning disability, drug resistant epilepsy, dysphagia (a gastrostomy was placed at one year of age), visual difficulties and intolerance to many additives. Epilepsy history: Matthew started having seizures at the age of seven. In 2016, prior to referral for KDT, he was having frequent absence seizures every few days and up to five times a day. He was also having clusters of tonic clonic seizures regularly every three to four weeks. For many days during the build up to these, he would become extremely irritable and hyperactive (shuffling around on his bottom), shouting, crying, hitting out and self-harming by biting, poking or punching himself. He would not sleep for days and, in desperation, to help other family members to sleep, his mum would drive him round in the night, so his continual noise would not disturb the others. He also had migraine activity in association with his seizures, would stop eating orally and would only manage relatively small volumes of his enteral feed before experiencing reflux. Despite having tried numerous anticonvulsive drugs with limited impact throughout his 14 years of living with epilepsy, and being unsuitable for epilepsy surgery, he was not referred for exploration of KDT until 21 years of age. Medications: Lacosamide, Gabapentin and regular use of Midazolam as rescue medication during seizure cycles. Over seven different anticonvulsant medications had been tried off and on over the years with inadequate control of seizures and associated symptoms. “We asked about ketogenic therapy when Matthew was a young teenager, but the neurologist at the time was dismissive and suggested that there were a couple of new drugs coming onto the market that they might try. Still, nothing worked and by 2016 Matthew’s quality of life was zero. The local neurology team were unable to give us any assistance to manage his seizures, pain and distressed behaviour and the whole family was at breaking point, even considering taking him to Switzerland to end his immense suffering. In desperation I called an Epilepsy Charity helpline and they suggested we ask for a referral to a specialist epilepsy centre for assessment. Eventually, after much chasing and waiting, we got there and the alteration of his medications led to a slight improvement in his distressing seizure, symptom cycle. We also got a chance to ask about ketogenic therapy again and a referral to a specialist ketogenic team was finally agreed. After many months delay, awaiting CCG funding, we started KDT. ” Matthew’s parents Pre KDT intake: • Enteral: Neocate Advance (now Neocate Junior - Nutricia), Prosource TF (Nutrinovo), LoSalt plus olive oil. Approx 118g carbohydrate, 34g protein, 43g fat and 1000kcal. • Oral: Stage 1 baby foods; fruit and fruit porridge variants, mashed banana, pureed prunes, soya yoghurt. • Total energy intake, very variable but likely around 1200-1400kcal. • Weight 34kg. Height estimated to be 1.2m. Continued overleaf Copyright © 2018 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.

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MATTHEW (continued)

KDT started March 2017. Current KDT intake: Matthew is on a Classical ketogenic diet; ratio 1.7 (i.e. 1.7g fat to every 1g (protein + carbohydrate combined)). • Enteral: Ketocal 4:1 powder (Nutricia), Prosource TF (Nutrinovo), Maxijul (Nutricia) and LoSalt (providing 9g carbohydrate, 37g protein, 74g fat and 850kcal). • Oral: Two portions daily of Coyo (coconut) yoghurt plus stewed fruit (providing 24gCHO, 10g protein and 82g fat and 875kcal). • Total energy intake estimated around 1700kcal. • Weight 40kg. • Blood glucose 3.2-4.9mmol/l, blood ketones 1.0-3.9mmol/l. Outcome Matthew responded extremely rapidly to his ketogenic feed and food change and his cycle of seizures and associated behaviours was halted immediately. It turns out that Matthew’s seizures are very responsive to KDT and he is now seizure free; a result we see in around 10% of cases of drug resistant epilepsy. “The epilepsy took Matthew’s quality of life away. As a result of the ketogenic diet, we’ve got Matthew back - he’s no longer hyperactive, now laid back about everything. He now sleeps much better at night’; he no longer needs to wear a bib all the time (he soaked over 20 thick towelling bibs per day due to dribbling) and the circulation in his hands and feet has improved immensely; they are not cold and white anymore. He is the heaviest he has ever been, seems stronger and no longer catches every bug that is going. His medications are being gradually tapered to see how much, if any needs to remain.” Matthew’s parents ELAINE Elaine is 51 years old and lives with her husband and their two children. Diagnosis: Elaine has a generalised epilepsy syndrome with tonic clonic seizures, absences and myoclonic jerks and a history of cervical dystonia, requiring regular botulinum injections across face, neck and shoulders. She also experiences generalised motor dysfunction and extreme muscle stiffness. Epilepsy history: Elaine developed absence seizures before school age, with tonic clonic and other seizure types emerging during her school years and continuing into adult hood. Seizure control worsened over the last 10-15 years, with daily life disrupted by 20-30 absence seizures per day with the peaks occurring first thing in the morning and then again in the afternoon. She slept very poorly at night. By 2016, the escalation in symptoms resulted in four hospital admissions in three months and she was unable to function normally.

Medications: Lamotrigine. At least another 10 anticonvulsant medications had been tried over the years. “I was on a combination of three anticonvulsants and the side effects were atrocious. I had no support at all. It was my family who brought me through multiple hospital admissions through A & E. In May 2016, I was having one seizure after another. I was referred to neurology services twice as an emergency. No neurologists available. There was a massive emotional impact on my children and my husband and there were many tears as I was becoming more dysfunctional. I was having absences all the time; I was unable to follow a phone conversation; I would have to ask what an object was, in the same way that a two-year-old would ask. I walked like I’d had a few vodkas with breakfast. I could have fallen asleep while sitting on a pin. I could no longer feel life. “August 2016 was my pivotal moment. I was very unwell. My muscles were moving involuntarily. I had been awake constantly for days. I couldn’t close my eyes. Every drawer in my brain was open and I was being bombarded with images. And then, everything stopped working. I crumpled and couldn’t talk. An ambulance was called. I was locked into a body that wasn’t responding. I told myself to stay calm and breath. When I came out of hospital after a number of days I had two sticks and had to learn how to do things again. I felt locked into my body.” Elaine ®

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ELAINE (continued) Pre KDT intake: Elaine initiated a ketogenic diet in November 2016, after reading research papers and ketogenic diet books extensively. Weight 68kg approx. Height 1.65m. BMI 25 kg/m2. Supervised KDT started October 2017. Current KDT intake: • A modified ketogenic diet of 13-14g carbohydrate and 225g fat. • Protein intake not measured but moderate. Total energy intake estimated around 2360kcal. • Elaine chooses to keep her meals simple due to her history of intolerance to certain items. Meals are made from: coconut oil, olive oil, butter, double cream, meats cheese, eggs, nuts, nut flours and nut butters, berries, and vegetables. • Micronutrient supplementation; a one-a-day multivitamin and mineral, plus additional magnesium supplementation. • Weight stable at 56-56.5kg. A 12kg loss (desired) in one year on self-initiated KD. • Elaine feels her best symptomatic control is when blood glucose in the 3-4mmol/l range and blood ketones are 5-6mmol/l. Outcome “I withdrew all sugar. Easy? Definitely not. The healthy plate that had been the mainstay in our house had to be psychologically binned. That’s difficult. If I wanted ketones to keep my brain happy, then I had to fuel with intelligence and knowledge. I felt no changes for 14 days. And then (I just cannot explain what happened), my world changed. Two weeks that’s all it took. TWO WEEKS.” Elaine Elaine initiated a ketogenic diet in November 2016 after reading research papers and ketogenic diet books extensively and managed extremely well under the difficult circumstances. Our specialist role was to help her to fine tune the regime to stabilise her fuelling through her day to gain more consistent control over her symptoms. The absence seizures have all but disappeared, her sleeping has improved significantly and her muscle tone has relaxed. However, recent episodes of pneumonia and hospitalisation have challenged her metabolic control significantly. Elaine is a very unusual case, with seizures and motor dysfunction that may connected in some way. She has a family history of epilepsy and Friedreich’s Ataxia and is currently awaiting the results of genetic screening for Glucose Transporter 1 Deficiency.

WHY ARE SOME ADULTS WITH BRAIN TUMOURS CHOOSING TO PURSUE KDT?

Contrary to improvements in the quality of life and survival for many cancers, the outcome for those with malignant brain tumours has not improved in decades. Research conducted by Otto Warburg in the 1920s onwards, led to his proposal that tumour cells typically display a shift in metabolism characterised by an increased reliance on glycolysis even in the presence of oxygen; a fundamental difference from the metabolic characteristics of healthy cells of the same origin. While knowledge of oncogenetics and the development of targeted therapies has expanded and progressed significantly, exploitation of the basic metabolic variance between healthy cells and cancer cells has been slow to progress. Preclinical studies in mouse models of high grade brain tumours and metastatic cancer suggest that a KD alters the regulation of multiple pathways associated with tumour growth and progression; reducing blood glucose and insulin levels, modulating

oxidative stress, down regulating inflammatory pathways, upregulating the host immune response and modifying tumour gene expression.8 Therefore, it is no surprise that those facing a brain tumour diagnosis may consider their options and decide to try a KD alongside their standard care (surgery, chemotherapy and radiotherapy) and ask for professional clinical help with this. With KDT services not even readily accessible to adults with epilepsy, it is no surprise that support for adults with brain tumours is practically non-existent. It is for this reason that we provide charitable dietetic support to adult brain tumour cases who approach us for help; enabling them to explore KDT appropriate to their needs as a means of, a) improving their quality of life (particularly in relation to fatigue and seizure management) and b) achieving nutritional ketosis. It will be some time before mechanisms and any certainty about the impact of KDT on brain tumours emerge. In the meantime, those who want further information can read the existing evidence and make their own decisions.

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NHD CPD eArticle

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What is a brain tumour?9 The commonest type of primary brain tumours are the gliomas. They develop from the glial cells that support the nerve cells of the brain. Grade 1 tumours are benign, whereas Grade 2-4 gliomas are malignant. Symptoms, treatment and prognosis can vary widely, even for patients with the same histological subtype of tumour, being also dependent on molecular profile and tumour location within the central nervous system. The median survival for Grade 2 gliomas is seven to 10 years while Grade 4 gliomas have a median survival of 12-15 months. Brain tumours are the leading cause of cancer-related death in patients under the age of 40. HEATHER Heather is 46 years old and lives with her husband and their two children. Diagnosis: Heather had a glioblastoma multiforme (a Grade 4 glioma) diagnosed in July 2017. Treatment: She had surgery to remove the tumour followed by six weeks of radiotherapy and chemotherapy. Heather is currently undergoing monthly cycles of high dose temozolomide chemotherapy. “I had a Grade 4 Glioblastoma removed in July 2017 following a collapse or fit-type of episode. My surgeon mentioned looking into a low carb diet. The neurosurgical nurse told me to make it my business to research the diet, but no one gave us further information. I then met with my neurologist who is also a friend and she asked me if I knew about the ketogenic diet and to look into it. Stefan my husband looked at the research with mice and if there were any negatives about the diet and we decided it was a very important thing to do. I was recovering from brain surgery and started eating low carb within a couple of weeks of coming out of hospital albeit a bit of guessing! I recovered from surgery very quickly and after a couple of weeks of feeling tired and dizzy (may have been the diet, but mixed with recovery), I felt as though I had a lot more energy and didn’t feel as tired as normal and was able to get out for long dog walks very quickly. I have continued to feel very well. I have to admit that I found the process of changing diet quite difficult to begin with. I was very anxious and threw myself into it without knowing what I was doing. I had very little appetite due to anxiety at the time. I craved carbohydrate a lot! Especially cereal which I had been snacking on pretty much all day most days on top of my meals I had been what I considered to be very healthy with a very healthy diet. I ate a lot of carbohydrate and exercised until I was exhausted a lot of the time. I could not relax unless I had trained so that I could eat. Mentally, it was quite a lot to try to ‘retrain’ my brain into thinking that fat is not bad and that I actually don’t need to eat my own weight in fruit and veg to be healthy. This has become a lot easier seeing the results and feeling so much better. Not only have the changes been maintained, but my whole family has changed how they eat and feel better for it. We are getting used to building meals from scratch and working out the content of meals.” Heather Initial KDT intake: • Dietary intake at the early stages of adopting her ketogenic diet was approximately: 12g carbohydrate, 70g protein, 130g fat and 1400kcal. • Weight 51kg, Height 1.65m, BMI 18.7kg/m2. Current KDT intake: A Modified ketogenic diet providing: 18-20g carbohydrate and around 160g added fats perday. Protein is not measured but around 70g per day. • Energy intake around 2000kcal. • Weight 47kg, BMI 17kg/m2. • Blood ketones generally 1.5-2mmol/l currently. Heather uses our Colour & Shine adult recipe booklet as a basis for some of her meals and has adapted and added to these to suit her tastes and requirements. “A typical breakfast would be a breakfast pancake (I add a little Stevia to the mix and I have a bit more cream on the pancake). I might make a porridge from milled flaxseed with double cream and a bit of MCT oil added to the mix and serve with more cream and berries. I also use the nut granola and make a batch to draw on as it’s quick. Lunch and dinner vary from a made recipe to more frequently a piece of fish/chicken with either salad or cooked veg and a coconut roll with butter. I add more fat by either cooking the vegetables in coconut oil or adding olive oil / MCT oil to salad. I have found that a lot of my meals can look traditionally healthy with salads and fish. That surprised me when I had visions of having to eat butter out of the packet. My taste buds have changed a huge amount. I can taste things so much better and really enjoy all the food I eat.” Heather Copyright © 2018 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.

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In this article, we have discussed three cases to tell you what ketogenic therapy has meant to each person. There are many more adults out there for whom KDT could make a difference. If you would like to learn more about KDT, do join us at our three-day course: KetoCollege 2018.10 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 since 2004, for those on a medically supervised therapy. 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. References 1 Neal EG, Chaffe HM, Schwartz RH, Lawson M, Edwards N et al. The ketogenic diet in the treatment of epilepsy in children: a randomised, controlled trial. Lancet Neurology 2008; 7:500-506 2 Kass HR, Winesett SP, Bessone SK, Turner Z, Kossoff EH. Use of dietary therapies amongst patients with GLUT1 deficiency syndrome. Seizure 2016; 35:83-7 3 Fang Y, Xiao-Jai L, Wan-Lin J, Hong-Bin S, Jie L. Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: A meta-analysis. J Clin Neurol 2015; 11(1): 26-31 4 Nabbout R, Camfield CS, Andrade DM, Arzimanoglou A, Chiron C et al. Treatment issues for children with epilepsy transitioning to adult care. Epilepsy Behav. 2017; 69:153-160 5 www.matthewsfriends.org/medical-section/keto-centres 6 www.epilepsy.org.uk/press/facts (accessed 23.3.18) 7 www.epilepsy.org.uk/info/seizures-explained (accessed 23.3.18) 8 Poff A, Koutnik AP, Egan KM, Sahebjam S, D’Agostino D, et al. Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma. Seminars in Cancer Biology 2018, https://doi.org/ 10.1016/j.semcancer.2017.12.011 9 www.braintumourresearch.org/info-support/what-is-a-brain-tumour (accessed 23.3.18) 10 www.mfclinics.com/keto-college/ (accessed 23.3.18)

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Questions relating to: Ketogenic diet therapy: let them eat fat! Type your answers below, download and save or print for your records, or print and complete by hand. Q.1 Explain why a ketogenic diet is widely used as a therapy for children with drug-resistant epilepsy and metabolic conditions.

Q.2

What is the difference between a tonic clonic seizure and an absence seizure?

Q.3

What is a myoclonic seizure?

Q.4

Describe the KDT regimen that helped Matthew and the resulting outcome.

Q.5

In case study 2, what was Elaine’s condition and medication pre-KDT?

Q.6

Explain how KDT helped control Elaine’s seizures.

Q.7

How do the commonest type of primary brain tumours develop?

Q.8

Can KDT help patients control symptoms of brain tumour?

Please type additional notes here . . .