Impact of Ketogenic Diet on Lipoproteins in Refractory Epilepsy (Ketonutri)

Classic Ketogenic Diet and Modified: Evaluation of the Therapeutic Potential and Impact on the Oxidative Profile, Lipidomic, Inflammatory and Size of Lipoproteins in Children and Adolescents With Refractory Epilepsy

The ketogenic diet is a non-pharmacological treatment prescribed especially for children and indicated in most specialized centers for patients with refractory epilepsy. The composition of the ketogenic diet is based on high-fat, low-carbohydrate, moderate protein content, and the production of ketone bodies is the probable mechanism involved in the control of seizures. The relationship between the treatment of the ketogenic diet and changes in oxidative characteristics, physical and lipid are not well established. Some studies show a significant increase in total cholesterol and triglycerides in children being treated with ketogenic diet, but other studies have shown that changes in lipid profile in the long term do not appear to be significant, beyond the influence of these changes on coronary heart disease are unknown. The studies performed in the last two decades have shown that besides the changes in the lipid profile, oxidative modification of lipoproteins are essential for the initiation and progression of atherosclerosis and physical properties of lipoproteins also appear to be involved in this process, suggesting that the particle size of lipoproteins, through the analysis of subfractions can provide more details of the cardiovascular risk. Thus, this projetct aims to compare the effects of the classical ketogenic diet with the ketogenic diet modified with lower content of saturated fatty acids and a higher content of monounsaturated and polyunsaturated, the oxidative changes of LDL, lipidomic profile, the concentration of antioxidants in production inflammatory cytokines and the subfractions of LDL and HDL in children and adolescents with refractory epilepsy, the clinical effect on controlling epilepsy.

Study Overview

• Status: Unknown
• Conditions: Epilepsy; Quality of Life; Cardiovascular Disease; Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Dietary supplement: ketogenic diet

Detailed Description

Controlled clinical trial composed of children of adolescents aged 1 to 19 years with refractory epilepsy drug polytherapy (antiepileptic drugs). Children of both sexes are being included. The control group receive the diet classical ketogenic while the case group receive the ketogenic diet modified reduction of at least 20% of the supply of saturated fat and increase> 50% of the acid supply monounsaturated fatty, increase> 50% of acid content polyunsaturated fatty and a lower ratio w6 / w3 at least 50% compared to classical diet used by the control group. Patients are followed in 3 times: baseline, 3 months and 6 months after the intervention.

Exclusion criteria: Children and adolescents who use any type of hormone replacement; Children and adolescents who present diagnosis of diabetes mellitus and hypothyroidism or hyperthyroidism; Children and adolescents with acute illnesses such as heart disease and kidney disease that prevent indication of the DC evaluated by medical history and complete physical examination by the neurologist doctor in charge of the clinic.

Outcome Measures:

a. Characterize the sample as the demographics (gender, age), scioeconomic, quality of life and clinical; B. To assess dietary intake through food records; c. Evaluate the anthropometric profile and classify the nutritional status (Z score of body mass index for age [ZBMI / I]); d. Assess body composition (percentage of fat, lean mass, total body water and phase angle); e. Determine the concentration of cholesterol and triglycerides, lipoproteins (TC, TG, LDL and HDL); f. Determine the concentration of apolipoproteins: APOA-1 and APO-B; g. Detect the concentration of ketone bodies in the plasma (β-hydroxybutyrate); H. Detecting LDL (-) and oxidized LDL in plasma; i. To detect anti-LDL autoantibodies (-) and anti-oxLDL autoantibodies in plasma; j. Determine subfractions HDL, LDL and high LDL particle size; k. To evaluate the concentration of non-esterified fatty acids (NEFAs); l. Assess the concentration of fatty acids in plasma; m. To assess the concentration of substances reactive to thiobarbituric acid (TBARS) in plasma.

n. Determine the concentration of antioxidants in plasma: α-tocopherol, beta-carotene and retinol.

O. Determining the lipidomic plasma profile gathering lipid species in more classes associated with the risk of cardiovascular disease; P. Detecting inflammatory markers: Tumor necrosis factor (TNF-α), interleukin (IL-6) in plasma.

Q. Determine the concentration of hepatic enzymes R. Determine the leptin, adiponectin, ghrelin and resistin S. To evaluate the liver ultrasound and carotid ultrasound

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nagila Raquel Teixeira Damasceno, Ph D; Phone Number: +55(11) 3061-7865; Email: nagila@usp.br
• Study Contact Backup: Name: Patricia Azevedo, Ph D Student; Phone Number: 1130617865; Email: patricia.azlima@yahoo.com.br

Study Locations

• Brazil
  • SP
    • Sao Paulo, SP, Brazil, 01246-904
      • Recruiting
      • Nagila Raquel Teixeira Damasceno
      • Contact: Patricia Azevedo, PhD Student; Phone Number: 1130617865; Email: patricia.azlima@yahoo.com.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: Participate in the study children and adolescents of both sexes with age 1-19 years diagnosed with refractory epilepsy drug polytherapy ( antiepileptic drugs ) and indication of treatment with KD .

-

Exclusion Criteria: Children and adolescents who use any type of hormonal replacement ;

• Children and adolescents who submit diagnosis of diabetes mellitus and hypothyroidism or hyperthyroidism ;
• Children and adolescents showing acute disorders as heart disease and kidney diseases .

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group control; classical ketogenic diet	Dietary supplement: ketogenic diet; Ketogenic diet with high fat (90%)
Active Comparator: Group case; Group case: modified ketogenic diet to reduce at least 20% saturated fat, up> 50% of the acid supply monounsaturated, increasing> 50% polyunsaturated fatty acid content and a lower ratio w6 / w3 at least 50% compared to classic diet used by the control group	Dietary supplement: ketogenic diet; Ketogenic diet with high fat (90%)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Socioeconomic and clinical profile	age, income, disease, parent´s education, use of drugs and supplements, type of seizures, questions about quality of life	average of 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Mass Index	BMI according growth charts	average of 3 months
Fat mass	Fat mass by impedance bioeletrical	average of 3 months
Fat free mass	fat free mass by impedance bioeletrical	average of 3 months
Phase angle	phase angle mass by impedance bioeletrical	average of 3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessement of food intake	Food record applied during 3 days to each time	average of 3 months
Ketone bodies	Concentration of B-hydroxybutirate in plasma. Determination with kit Ranbut (Randox Laboratories Limited, Reino Unido).	average of 3 months
Lipid profile	Total cholesterol, LDL, HDL, TG	average of 3 months
NEFAS	Concentration in plasma. Determination with kit NEFAS(Randox Laboratories Limited, Reino Unido)	average of 3 months
LDL oxidized	Determination in plasma	average of 3 months
Antioxidant	Determination of antioxidant concentration in plasma by HPLC	average of 3 months
Metabolomic (lipidomic)	Determination in plasma by mass spectrometry	average of 3 months
Subfractions of Lipoproteins	Determination in plasma by Lipoprint	average of 3 months
Liver enzymes	Concentration of AST, ALT, GGT	average of 3 months
Hepatic function	Ultrasound liver	average of 3 months
Leptin	Determination in plasma	average of 3 months
Resistin	Determination in plasma	average of 3 months

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Investigators: Study Chair: Mariana Baldini Prudencio, Master, Universidade of Sao Paulo

Publications and helpful links

General Publications

• Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. doi: 10.1111/epi.12550. Epub 2014 Apr 14.
• Avogaro P, Bon GB, Cazzolato G. Presence of a modified low density lipoprotein in humans. Arteriosclerosis. 1988 Jan-Feb;8(1):79-87. Erratum In: Arteriosclerosis 1988 Nov-Dec;8(6):857.
• Avogaro P, Cazzolato G, Bittolo-Bon G. Some questions concerning a small, more electronegative LDL circulating in human plasma. Atherosclerosis. 1991 Nov;91(1-2):163-71. doi: 10.1016/0021-9150(91)90198-c.
• Faulin Tdo E, de Sena-Evangelista KC, Pacheco DB, Augusto EM, Abdalla DS. Development of immunoassays for anti-electronegative LDL autoantibodies and immune complexes. Clin Chim Acta. 2012 Jan 18;413(1-2):291-7. doi: 10.1016/j.cca.2011.10.004. Epub 2011 Oct 18.
• Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005 Apr;46(4):470-2. doi: 10.1111/j.0013-9580.2005.66104.x.
• Freeman JM, Kossoff EH, Hartman AL. The ketogenic diet: one decade later. Pediatrics. 2007 Mar;119(3):535-43. doi: 10.1542/peds.2006-2447.
• Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Helen Cross J, Dahlin MG, Donner EJ, Klepper J, Jehle RS, Kim HD, Christiana Liu YM, Nation J, Nordli DR Jr, Pfeifer HH, Rho JM, Stafstrom CE, Thiele EA, Turner Z, Wirrell EC, Wheless JW, Veggiotti P, Vining EP; Charlie Foundation, Practice Committee of the Child Neurology Society; Practice Committee of the Child Neurology Society; International Ketogenic Diet Study Group. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 2009 Feb;50(2):304-17. doi: 10.1111/j.1528-1167.2008.01765.x. Epub 2008 Sep 23.
• Kwiterovich PO Jr, Vining EP, Pyzik P, Skolasky R Jr, Freeman JM. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA. 2003 Aug 20;290(7):912-20. doi: 10.1001/jama.290.7.912.
• Lee PR, Kossoff EH. Dietary treatments for epilepsy: management guidelines for the general practitioner. Epilepsy Behav. 2011 Jun;21(2):115-21. doi: 10.1016/j.yebeh.2011.03.008. Epub 2011 Apr 21.
• Libby P, Ridker PM, Hansson GK; Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009 Dec 1;54(23):2129-38. doi: 10.1016/j.jacc.2009.09.009.
• Liu YM, Williams S, Basualdo-Hammond C, Stephens D, Curtis R. A prospective study: growth and nutritional status of children treated with the ketogenic diet. J Am Diet Assoc. 2003 Jun;103(6):707-12. doi: 10.1053/jada.2003.50136.
• WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl. 2006 Apr;450:76-85. doi: 10.1111/j.1651-2227.2006.tb02378.x.
• de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007 Sep;85(9):660-7. doi: 10.2471/blt.07.043497.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): July 1, 2020

Study Registration Dates

• First Submitted: October 13, 2015
• First Submitted That Met QC Criteria: December 28, 2015
• First Posted (Estimate): December 31, 2015

Study Record Updates

• Last Update Posted (Estimate): December 31, 2015
• Last Update Submitted That Met QC Criteria: December 28, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Epilepsy; Cardiovascular Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Drug Resistant Epilepsy
• Other Study ID Numbers: Faculdade de Saúde Pública USP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No