Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial

Siobhan Titre-Johnson, Natasha Schoeler, Christin Eltze, Ruth Williams, Katharina Vezyroglou, Helen McCullagh, Nick Freemantle, Simon Heales, Rachel Kneen, Louise Marston, Tim Martland, Irwin Nazareth, Elizabeth Neal, Andrew Lux, Alasdair Parker, Shakti Agrawal, Penny Fallon, J Helen Cross, Siobhan Titre-Johnson, Natasha Schoeler, Christin Eltze, Ruth Williams, Katharina Vezyroglou, Helen McCullagh, Nick Freemantle, Simon Heales, Rachel Kneen, Louise Marston, Tim Martland, Irwin Nazareth, Elizabeth Neal, Andrew Lux, Alasdair Parker, Shakti Agrawal, Penny Fallon, J Helen Cross

Abstract

Background: The incidence of epilepsy is greatest in the first 2 years of life, an age group where there is generally a poor prognosis for both seizure control and neurodevelopmental outcome. Early control of seizures can be associated with better developmental outcome but many of the epilepsies presenting in infancy are poorly responsive to antiepileptic medication. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet designed to mimic the effects of starvation on the body. Dietary fat is converted into ketones in the body and used as an energy source by the brain. The KD has been shown to be successful in controlling seizures in many observational studies, and in two randomised controlled trials (RCTs) in older children. However, little evidence is available in the very young.

Methods/design: An open-label RCT where eligible children (age 3 months to 2 years with epilepsy who have failed two antiepileptic drugs (AEDs)) undergo baseline assessment, including medical and seizure history. Participants then start an observation period (7 or 14 days) with documentation of seizure frequency. Randomisation will occur on day 8 or day 15 to receive the KD or a further AED; the allocated treatment will commence on day 15, with instruction and training. A second assessment (4 weeks after start of treatment) will include a clinical review and tolerability questionnaire (modified Hague Scale of Side Effects - for those allocated to the KD group). Assessments will be repeated at 8 weeks after the start of treatment including biochemical investigations, after which, according to patient response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group who have failed to achieve seizure control at the 8-week assessment will then be offered KD outside the context of the trial. Those in the KD arm who fail to achieve seizure control will be changed to standard clinical management. All patients will be followed up for 12 months from randomisation for retention, seizure outcome, quality of life and neurodevelopmental status.

Discussion: The slow rate of recruitment is an ongoing practical issue. There is a limitation to the number of eligible patients compared to what was predicted, mainly due to the nature of this patient group. After a substantial amendment to widen inclusion criteria and reduce the baseline period to 7 days for patients with a high seizure burden, the rate of recruitment steadily increased. A number of operational concerns regarding dietetic time were also highlighted impacting on the recruitment rate. However, the combination of a low dropout rate and the opening of further centres, the trial should successfully meet the final recruitment target. All nine centres are now recruiting and we hope to open further centres within the UK.

Trial registration: ClinicalTrials.gov, identifier: NCT02205931 . Registered on 16 December 2013.

Keywords: Epilepsy; Infants; Ketogenic diet; Randomised controlled trial.

Figures

Fig. 1
Fig. 1
Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) figure; schedule of enrollment, interventions and assessments. *At baseline, all procedures should be done before randomisation. **Ketogenic diet group only. (X) – As indicated/appropriate. 1Complete physical includes weight, length, head circumference, general examination. 2Tests to be done: haematology – full blood count (FBC); biochemistry – liver function tests, renal function tests, calcium, urate, glucose, phosphate, vitamin D, selenium, zinc, cholesterol, carnitine profile and beta-hydroxybutyrate; urinalysis – organic acids, urine calcium and creatinine ratio. Results must be received prior to randomisation. 3Home monitoring urine dipstick and blood spot ketones done twice a day and recorded in Seizure Diary (only KD arm). 4Special assay or procedure – blood sample to be analysed by Simon Heales at ICH

References

    1. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365:919–926. doi: 10.1056/NEJMra1004418.
    1. Cardinali S, Canafoglia L, Bertoli S, Franceschetti S, Lanzi G, Tagliabue A, Veggiotti P. A pilot study of a ketogenic diet in patients with Lafora body disease. Epilepsy Res. 2006;69:129–134. doi: 10.1016/j.eplepsyres.2006.01.007.
    1. Eltze CM, Chong WK, Cox T, Whitney A, Cortina-Borja M, Chin RF, Scott RC, Cross JH. A population-based study of newly diagnosed epilepsy in infants. Epilepsia. 2013;54:437–445. doi: 10.1111/epi.12046.
    1. Freitag H, Tuxhorn I. Cognitive function in preschool children after epilepsy surgery: rationale for early intervention. Epilepsia. 2005;46:561–567. doi: 10.1111/j.0013-9580.2005.03504.x.
    1. Chevrie JJ, Aicardi J. Convulsive disorders in the first year of life: neurological and mental outcome and mortality. Epilepsia. 1978;19:67–74. doi: 10.1111/j.1528-1157.1978.tb05013.x.
    1. Deonna TaR-P, E. Cognitive and behavioural disorders of epileptic origin in children. Mac Keith Press; 2005.
    1. Altunbasak S, Incecik F, Herguner O, Refik Burgut H. Prognosis of patients with seizures occurring in the first 2 years. J Child Neurol. 2007;22:307–313. doi: 10.1177/0883073807300540.
    1. Groesbeck DK, Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol. 2006;48:978–981. doi: 10.1017/S0012162206002143.
    1. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, O’Callaghan FJ, Verity CM, Osborne JP. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. 2004;364:1773–1778. doi: 10.1016/S0140-6736(04)17400-X.
    1. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, O’Callaghan FJ, Verity CM, Osborne JP, United Kingdom Infantile Spasms Study. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial. Lancet Neurol. 2005;4:712–7.
    1. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B, Ebrahimi N. Two-year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia. 2001;42:1553–1562. doi: 10.1046/j.1528-1157.2001.21101.x.
    1. Kossoff EH, Pyzik PL, McGrogan JR, Vining EP, Freeman JM. Efficacy of the ketogenic diet for infantile spasms. Pediatrics. 2002;109:780–783. doi: 10.1542/peds.109.5.780.
    1. Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial. Epilepsia. 2013;54:481–486. doi: 10.1111/epi.12069.
    1. Keene DL. A systematic review of the use of the ketogenic diet in childhood epilepsy. Pediatr Neurol. 2006;35:1–5. doi: 10.1016/j.pediatrneurol.2006.01.005.
    1. Henderson CB, Filloux FM, Alder SC, Lyon JL, Caplin DA. Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol. 2006;21:193–198.
    1. Levy RG CP, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2012;2:CD001903.
    1. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008;7:500–506. doi: 10.1016/S1474-4422(08)70092-9.
    1. Nordli DR, Jr, Kuroda MM, Carroll J, Koenigsberger DY, Hirsch LJ, Bruner HJ, Seidel WT, De Vivo DC. Experience with the ketogenic diet in infants. Pediatrics. 2001;108:129–133. doi: 10.1542/peds.108.1.129.
    1. Dressler A, Stocklin B, Reithofer E, Benninger F, Freilinger M, Hauser E, Reiter-fink E, Seidl R, Trimmel-Schwahofer P, Feucht M. Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy—The Austrian experience. Seizure. 2010;19:404–408. doi: 10.1016/j.seizure.2010.06.006.
    1. Kayyali HR, Gustafson M, Myers T, Thompson L, Williams M, Abdelmoity A. Ketogenic diet efficacy in the treatment of intractable epileptic spasms. Pediatr Neurol. 2014;50:224–227. doi: 10.1016/j.pediatrneurol.2013.11.021.
    1. Pires ME, Ilea A, Bourel E, Bellavoine V, Merdariu D, Berquin P, Auvin S. Ketogenic diet for infantile spasms refractory to first-line treatments: an open prospective study. Epilepsy Res. 2013.
    1. Rubenstein JE, Kossoff EH, Pyzik PL, Vining EP, McGrogan JR, Freeman JM. Experience in the use of the ketogenic diet as early therapy. J Child Neurol. 2005;20:31–34. doi: 10.1177/08830738050200010501.
    1. Eun S, Kang H, Kim D. Ketogenic diet for treatment of infantile spasms. Brain Dev. 2006;28:566–571. doi: 10.1016/j.braindev.2006.03.011.
    1. Hong A, Turner Z, Hamdy R. Infantile spasms treated with the ketogenic diet: prospective single-center experience in 104 consecutive infants. Epilepsia. 2010;51:1403–1407. doi: 10.1111/j.1528-1167.2010.02586.x.
    1. Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia. 2004;45:1116–1123. doi: 10.1111/j.0013-9580.2004.10004.x.
    1. Dressler A, Trimmel-Schwahofer P, Reithofer E, Groppel G, Muhlebner A, Samueli S, Grabner V, Abraham K, Benninger F, Feucht M. The ketogenic diet in infants—Advantages of early use. Epilepsy Res. 2015;116:53–58. doi: 10.1016/j.eplepsyres.2015.06.015.
    1. Kossoff EH, Hedderick EF, Turner Z, Freeman JM. A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms. Epilepsia. 2008;49:1504–1509. doi: 10.1111/j.1528-1167.2008.01606.x.
    1. Hughes SD, Kanabus M, Anderson G, Hargreaves IP, Rutherford T, O’Donnell M, Cross JH, Rahman S, Eaton S, Heales SJ. The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells. J Neurochem. 2014;129:426–433. doi: 10.1111/jnc.12646.
    1. Chang P, Terbach N, Plant N, Chen PE, Walker MC, Williams RS. Seizure control by ketogenic diet-associated medium chain fatty acids. Neuropharmacology. 2013;69:105–114. doi: 10.1016/j.neuropharm.2012.11.004.
    1. Chang P, Augustin K, Boddum K, Williams S, Sun M, Terschak JA, Hardege JD, Chen PE, Walker MC, Williams RS. Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain. 2016;139:431–443. doi: 10.1093/brain/awv325.
    1. Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, Shaw R, Smith Y, Geiger JD, Dingledine RJ. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol. 2006;60:223–235. doi: 10.1002/ana.20899.
    1. Wojtczak L, Schonfeld P. Effect of fatty acids on energy coupling processes in mitochondria. Biochim Biophys Acta. 1993;1183:41–57. doi: 10.1016/0005-2728(93)90004-Y.
    1. Landgraf J, Abetz L. The Infant/Toddler Child Health Questionnaire: conceptual framework, logic content, and preliminary psychometric results. Final report to Schering—Plough Laboratories and Health Technology Associates. New England Medical Centre; 1994.
    1. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales. Circle Pines: American Guidance Service; 1984.
    1. Neal E. Dietary treatment of epilepsy and other neurological disorders: a practical guide. Wiley Blackwell; 2012.
    1. Department of Health. Infant feeding recommendation. 2003.
    1. Hartzel J, Agresti A. TUTORIAL IN BIOSTATISTICS: strategies for comparing treatments on a binary response with multi-centre data. Wiley; 2004.
    1. Pina-Garza JE, Espinoza R, Nordli D, Bennett DA, Spirito S, Stites TE, Tang D, Sturm Y. Oxcarbazepine adjunctive therapy in infants and young children with partial seizures. Neurology. 2005;65:1370–1375. doi: 10.1212/01.wnl.0000186800.18456.72.
    1. Pina-Garza JE, Levisohn P, Gucuyener K, Mikati MA, Warnock CR, Conklin HS, Messenheimer J. Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months. Neurol. 2008;70:2099–2108. doi: 10.1212/01.wnl.0000285493.08622.35.
    1. Pina-Garza JE, Nordli DR, Jr, Rating D, Yang H, Schiemann-Delgado J, Duncan B, Levetiracetam NSG. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia. 2009;50:1141–1149. doi: 10.1111/j.1528-1167.2008.01981.x.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere