Issue 124 adult ketogenic diet therapy what we know thus far

CONDITIONS & DISORDERS

ADULT KETOGENIC DIET THERAPY: WHAT WE KNOW THUS FAR Kit Kaalund Hansen Senior Specialist Adult Ketogenic Diet Therapy Dietitian, University College London Hospitals NHS Foundation Trust Kit works in the National Hospital for Neurology and Neurosurgery in Queen Square, where she set up and leads the first UK based NHS funded Adult Ketogenic Diet Therapy Dietetic Service for individuals with epilepsy.

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‘Epilepsy is a brain disorder characterised by a persistent predisposition for the occurrence of epileptic seizures.’ ‘Seizures are transient occurrences of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.’1 The onset of epilepsy can occur at any age and the most common non-genetic causes of epilepsy are central nervous system infection, vascular disease, head trauma, congenital disorder, neoplasm, anoxia and drug and alcohol abuse.2 Approximately 50 million people are diagnosed with epilepsy worldwide, making it the fourth most common neurological disease globally.3 Around 70% of individuals respond and benefit from AEDs, leaving 30% with options of various drug combinations with either surgery, vagus nerve stimulation and/or homeopathic methods in the attempt to manage their epilepsy.3 Pharmacoresistant epilepsy in adults significantly impacts on quality of life as often the prospects for education, employment and independence are compromised. In view of this, adults can become socially isolated and dependent.4 It is, therefore, of increasing importance for adults to have the opportunity to access noninvasive treatment, such as ketogenic diet therapy (KDT), after two AEDs have failed, should they wish to, as per paediatric NICE guidelines.5 BACKGROUND TO KDT

Before anti-epileptic drugs, fasting was the first successful proposed therapy for managing epilepsy: “If there is no food to digest, more energy could be applied to recovering health.” (Bernarr Macfadden, 1899). In 1911, fasting as a treatment for epilepsy, resulted in seizure freedom in 90% of children and 50% of adults. However, once refeeding

commenced, seizures returned and the need for a sustainable treatment was realised.6 In 1921, with fasting as a precursor and ketones in mind, the ketogenic diet (KD) was developed in the hope that it would mimic starvation.7 In 1928, literature on the efficacy of KDT in teenagers and adults was published;28 56% of the individuals improved, 12% were seizure-free, while 32% showed no significant change.8 Based on these results and with the emergence of AEDs in 1938, it was concluded that the KD was not a significantly effective treatment for adults. It was rarely studied or advised again until the 1990s, when Charlie Abrahams caught the attention of the media and his dedicated parents founded the Charlie Foundation,27 which in turn funded several studies that led to the re-introduction of KDT.9 Several modifications of KDT have since been developed to aid palatability, sustainability and compliance and to meet the individual’s needs: classical, modified, low glycaemic index and medium chain triglyceride.9 The modified ketogenic diet (or Modified Atkins Diet) is based on ‘targets’ for carbohydrate and fat with the inclusion of moderate protein, but it does not require the restriction of fluids.10 Studies show that the overall adherence to KDT is 45%. 38% adherence to the classical and 56% to the modified diet. In addition, drop out levels are higher on the classical diet (10-88%) compared to that of the modified (063%).11,12 Ultimately, the modified, low www.NHDmag.com May 2017 - Issue 124

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Despite the fact that the reduction of overall seizure frequency and seizure freedom is marginally higher in children, KDT can significantly improve quality of life in adults . . .

GI and MCT diets are easier to adhere to than the classical, mainly because they allow more carbohydrate and protein.12 Based on this, these are more widely used in adult KDT and therapists are advised to initiate modified KDT for adults.

RESEARCH AND EVIDENCE

The evidence for the use of various KDTs in children with epilepsy is well established by many studies since its reintroduction in the 1990s.13-18 Research in adults is limited; however, it is not nonexistent and should be brought to the attention of those managing pharmacoresistant epilepsy.

Sirven et al19 found that at eight months of following ketogenic diet therapy, 3/11 patients achieved 90%, 3/11 noted 50-89% and 1/11 showed <50% reduction in seizures. The rest discontinued the diet. Mosek et al20 carried out a study on nine adults where two patients remained on a diet at 12 weeks as they achieved a seizure reduction of >50%. The remainder discontinued diet due to lack of efficacy. Klein et al21 showed that 50% of patients achieved >50% seizure reduction, and 33% had >85% reduction. Lambrechts et al22 assessed the efficacy of classical and modified KD in adults. 26.6% of the patients achieved >50% seizure reduction in the first month of KDT. Interestingly, when looking at the efficacy between the classical and modified versions of KDT, Klein et al11 found no significant difference.

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More specifically, 32% from the classical group and 29% from the modified group, achieved >50% seizure reduction, while 9% and 5% respectively achieved >90% reduction. Kverneland et al23 examined the efficacy and tolerability of KDT as an adjuvant therapy to antiepileptic drugs for adult patients with pharmacoresistant generalised epilepsy; 13 patients were treated with a modified Atkins diet for 12 weeks. Six participants completed the 12-week trial and four had >50% seizure reduction with reduced seizure severity and improved quality of life. At present, all epilepsy types are trialled on KDT as it is not known what seizure types might respond best to therapy. Interestingly, all responders from the Kverneland study were diagnosed with juvenile myoclonic epilepsy.

IMPROVED QUALITY OF LIFE

Despite the fact that the reduction of overall seizure frequency and seizure freedom is marginally higher in children, KDT can significantly improve quality of life in adults, which is often related to the fact that KDT helps to create a routine that focuses the mind, e.g. concentration and alertness, energy levels, relationships with family and friends, future outlook on life, hope and independence.22 Some might dismiss the efficacy of KDT in adults and focus on the adverse effects of KDT. However, it is important to emphasise that with regular monitoring and appropriate interventions, these side effects can be minimised and well managed.24,25 Yet, the rate of discontinuation remains approximately 50%. The challenge of changing an individualâ&#x20AC;&#x2122;s lifestyle cannot be underestimated, e.g. specific and rigid regimen, exclusion of some food preferences, economic cost, as well as the social cost, e.g. social eating, advance meal preparation etc, and lack of motivation, might account for poor compliance.

CONDITIONS & DISORDERS PREGNANCY

In addition to the above, and perhaps on a side note, therapists are facing further challenges in adulthood such as pregnancy. At present, it is not advised to fall pregnant whilst following KDT based on ketoacidosis evidence in diabetics.

However, van der Louw et al26 reported on two case studies of pregnant women who were treated with: a) a classical KD with 47g-75g CHO restriction, supplemented with MCT with ketones of 0.4-1.2mmol/L and b) a modified KD with a 20g-30g CHO restriction in adjunction with Lamotrigine, with unspecified ‘low urine ketones’.

Fetal and neonatal growth was normal for case study a), as was growth and development at 12 months. For case study b), the child was born with bilateral ear deformities of unknown significance, but the child’s neurodevelopment was reported to be normal at eight months.

Safety still needs to be established for nonpharmacological treatments in pregnancy; however, concerns are many and studies are ethically difficult to carry out.

CONCLUSION

The lack of ample evidence on the efficacy of KDT on adult patients with refractory epilepsy and the importance of such treatment, makes it crucial to investigate further. In order to justify treatment to GPs, NICE guidelines are in desperate need, as adult dietitians are faced with GPs refusing to fund KDT often due to lack of knowledge on the matter. However, without guidelines, GPs are perfectly in their right to decline involvement in KDT. Adult and paediatric centres in the UK gathered in April for the first ketogenic research meeting to discuss future prospects, in the hope that KDT will eventually be readily available and recognised as a second line treatment for adult with drug-resistant epilepsy.

References 1 Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P and Engel J Jr (2005). Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia, 46, 470-2 2 Lindsay K, Bone I (1997). Neurology and Neurosurgery Illustrated. 3rd Ed. UK: Churchill Livingstone 3 World Health Organisation (WHO) (2016). Epilepsy [online] available at: www.who.int/mediacentre/factsheets/fs999/en/. [accessed 5 May 2016] 4 UCB Pharma (2008). Epilepsy and quality of life: fact sheet. available at: www.ucb.com/_up/ucb_com_news/documents/epilepsy_and_quality_of_life.pdf [accessed 17 May 2016] 5 National Institute for Health and Care Excellence (NICE) (2012). Epilepsies: diagnosis and management.

6 Wheless JW (2004). History and origin of the ketogenic diet. Epilepsy and the ketogenic diet. Springer 7 Schwartz RH, Eaton J, Bower BD and Aynsley-Green A (1989). Ketogenic diets in the treatment of epilepsy: short-term clinical effects. Dev Med Child Neurol, 31, 145-51 8 Barborka CJ (1928). Ketogenic diet treatment of epilepsy in adults. Journal of the American Medical Association, 91, 73-78 9 Wheless JW (2008). History of the ketogenic diet. Epilepsia, 49 suppl 8, 3-5 10 Kossoff EH and Dorward JL (2008). The Modified Atkins Diet. Epilepsia, 49 suppl 8, 37-41 11 Klein P, Tyrlikova I and Mathews GC (2014). Dietary treatment in adults with refractory epilepsy: a review. Neurology, 83, 1978-85 12 Payne NE, Cross JH, Sander JW and Sisodiya SM (2011). The ketogenic and related diets in adolescents and adults - a review. Epilepsia, 52, 1941-8 13 Henderson CB, Filloux FM, Alder SC, Lyon JL and Caplin DA (2006). Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol, 21, 193-8 14 Keene DL (2006). A systematic review of the use of the ketogenic diet in childhood epilepsy. Pediatr Neurol, 35, 1-5 15 Lefevre F and Aronson N (2000). Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics, 105, e46 16 Pfeifer HH and Thiele EA (2005). Low-glycaemic-index treatment: a liberalised ketogenic diet for treatment of intractable epilepsy. Neurology, 65, 1810-2 17 Sharma S, Sankhyan N, Gulati S and Agarwala A (2013). Use of the Modified Atkins Diet for treatment of refractory childhood epilepsy: a randomised controlled trial.

Epilepsia, 54, 481-6 18 Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, Shinnar S, Shuman R, Trevathan E and Wheless JW (1998). A multicentre study of the efficacy of the ketogenic diet. Arch Neurol, 55, 1433-7 19 Sirven J, Whedon B, Caplan D, Liporace J, Glosser D, O'Dwyer J and Sperling MR (1999). The ketogenic diet for intractable epilepsy in adults: preliminary results.

Epilepsia, 40, 1721-6 20 Mosek A, Natour H, Neufeld MY, Shiff Y and Vaisman N (2009). Ketogenic diet treatment in adults with refractory epilepsy: a prospective pilot study. Seizure, 18, 30-3 21 Klein P, Janousek J, Barber A and Weissberger R (2010). Ketogenic diet treatment in adults with refractory epilepsy. Epilepsy Behav, 19, 575-9 22 Lambrechts DA, Wielders LH, Aldenkamp AP, Kessels FG, de Kinderen RJ and Majoie MJ (2012).The ketogenic diet as a treatment option in adults with chronic refractory epilepsy: efficacy and tolerability in clinical practice. Epilepsy Behav, 23, 310-4 23 Kverneland M, Selmer KK, Nakken Ko, Iversen PO, Tauboll E (2015). A prospective study of the Modified Atkins Diet for adults with idiopathic generalised epilepsy.

Epilepsy Behav. 53: 197-201 24 Winesett SP, Bessone SK and Kossoff EH (2015). The ketogenic diet in pharmacoresistant childhood epilepsy. Expert Rev Neurother, 15, 621-8 25 Schoeler NE and Cross JH (2016). Ketogenic dietary therapies in adults with epilepsy: a practical guide. Pract Neurol, 16, 208-14 26 van der Louw EJ, Williams TJ, Henry-Barron BJ, Olieman JF, Duvekot JJ, Vermeulen MJ, Bannink N, Williams M, Neuteboom RF, Kossoff EH, Catsman-Berrevoets CE, Cervenka MC (2017). Ketogenic diet therapy for epilepsy during pregnancy: a case series. Seizure, 45: 198-201 27 The Charlie Foundation (2014). Classic ketogenic and modified ketogenic. The Charlie Foundation for Ketogenic Therapies. available at: www.charliefoundation.org/ explore-ketogenic-diet/explore-2/classic-ketogenic [accessed 3 may 2016] 28 Helmholz HF (1927). The treatment of epilepsy in childhood: five years' experience with the ketogenic diet. Journal of the American Medical Association, 88, 2028-2032

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