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1/19/2006
Joint Annual Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society
Reformulating the ketogenic diet:eight decades overdue
Hot Topics SymposiumElizabeth A. Thiele, MD PhD
Massachusetts General HospitalHarvard Medical School
3
• Classic Ketogenic Diet– History and formulation– MCT Diet
• Ketogenic diet 2005
• Variations on a theme:– Modified Atkins Diet– Low Glycemic Index Treatment
• Where do we go from here?
Dietary treatments for Intractable Epilepsy
Reformulating the ketogenic diet:eight decades overdue
4The Ketogenic Diet: History
• Fasting as a treatment for epilepsy was described in the Bibleand in texts from the Middle Ages– Hippocrates, “Sacred Disease”, wrote that modification of diet required
to treat epilepsy– Erasistratus 3rd century BC “one inclining to epilepsy should be made
to fast without mercy and be put on short rations”– Galen, 2nd century AD recommended dietary restrictions in treatment of
epilepsy
• In 1911, first modern use of diet in medical literature by Frenchphysicians Guelpa and Marie.
The Ketogenic Diet: History
5
• In 1921, Dr. Rawle Geyelin reported to the AMA the successfultreatment of epilepsy by fasting, by osteopath Dr. HughConklin.
• Conklin believed epilepsy was caused by intoxication from thePeyer’s patches of the intestine, so he developed program to“put intestines at rest”.
• He would fast patients, with water only, for as long astolerated, up to 25 days
The Ketogenic Diet: History
The Ketogenic Diet: History
6
• 1924: The “Ketogenic Diet” was designed to mimic starvation.– First described at the Mayo Clinic, with 1 g of protein per kilogram of
body weight in children, 1015 g of carbohydrate per day, and theremainder of calories as fat. Subsequent reports from Harvard, Univ. ofRochester.
• 1927: Talbot at MGH, Harvard described the protocol still usedfor calculating and initiating diet:– 3648 hours of fasting to hasten production of ketosis– gradually increasing amounts of dietary fats introduced over several
days during hospitalization– Maintenance on diet:
• Specific meal plans requiring weighing of all foods• Caloric restriction to 75%• Fluid restriction to 80%
The Ketogenic Diet: History
The Ketogenic Diet: History
7
• Because bromides and phenobarbital were the onlymedications available at the time, there was a flurry of clinicaland research activities on the Ketogenic Diet.
• The diet was widely used during the 1930’s, but it fell out ofvogue when diphenylhydantoin was introduced in 1938.Compared with DPH treatment, the diet was viewed as difficult,rigid, and expensive.
The Ketogenic Diet: History
The Ketogenic Diet: History
8
• In 1971, Huttenlocher et al. described the Medium ChainTriglyceride (MCT) diet an attempt to make the classicketogenic diet more palatable.
• MCT oil is more ketogenic per calorie compared with otherfats, and therefore permits a greater bulk of other foods.
• However, the MCT diet is associated with nausea, diarrhea,and bloating.
The Ketogenic Diet: History
The Ketogenic Diet: History
9The Ketogenic Diet:
Resurgence of popularity
• Ketogenic diet in popular culture– 1993: First do no harm (Charlie Foundation)
• Ketogenic diet in medical literature:Medline citations (ketogenic diet and epilepsy):– 19651995 56 in 31 years– 19962005 243 in 9 years
• Ketogenic diet in the kitchen: The Atkins diet?
The Ketogenic Diet:Resurgence of popularity
10Ketogenic Diet vs American Diet
Ketogenic Diet vs American Diet
American Diet
CarbsFats
Protein
Ketogenic Diet
Fats
ProteinCarbs
American DietKetogenic Diet
ProteinCarbs
11Ketogenic Diet: Formulation
• Calories based on age, ideal body weight, and current intake.• Protein RDA or above.• Vitamins and minerals –RDI
• Ratio is limited by protein requirement
Ketogenic ratioRatio (by grams) Fat : (Protein + Carbohydrate)
i.e. 4:1 ratio implies 4 grams of fat to1 gram combined of protein and carbohydrate.
Ketogenic Diet: Formulation
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Seizure ControlAuthor Year # Pts >90% 9050% <50%Peterman 1925 37 60% 35% 5%Helmholz 1927 91 31% 23% 46%Wilkins 1937 30 24% 21% 50%Livingston 1954 300 43% 34% 22%Huttenlocheret al. MCT
1971 12 50% 50%
Trauner MCT 1985 17 29% 29% 42%Sills et al. MCT 1986 50 24% 20% 56%Kinsman et al. 1992 58 29% 38% 33%Freeman et al. 1998 125 34% 26% 40%Katyal et al. 2000 42 38% 33% 29%
overall 762 37% 30% 33%
Ketogenic Diet:Efficacy in children with intractable epilepsy
Ketogenic Diet:Efficacy in children with intractable epilepsy
13Ketogenic Diet: Published data
• 22 retrospective and prospective studies publishedevaluating clinical efficacy in children with intractable epilepsyfrom 19252005 (13 over past 6 years)
• 2 retrospective studiesevaluating efficacy in treatment of infantile spasms
• 1 prospective studyevaluating efficacy in adults with refractory epilepsy
Ketogenic Diet: Published data
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The Ketogenic Diet in children:Outcome by Seizure Type
Seizure Type >90% Seizure ReductionMyoclonic 69%Atonicdrop 69%Absence 75%Atypical absence 75%Tonicclonic 48%Tonic 33%Complex partial 53%Simple partial 100%
from Swink et al. 1997
The Ketogenic Diet in children:Outcome by Seizure Type
15Ketogenic Diet 2005
• Classic diet: child fasts until in ketosis, hospitalization 57 days• Maybe not necessary:
– Wirrell et al JCN 200214 patients initiated on KGD without initial fast; 6 as outpatient
– Kim et al Pediatrics 200441 patients initiated without fast, with increasing calories over 3 days
– Bailey et al (in preparation)73 patients initiated without fast
• Charlie Foundation survey of ketogenic diet programs (2002present)– 27 programs responded:
• 16 programs initiate with a fast (most are overnight fast; max. 48h fast)• 9 programs initiate with no fast• 2 programs use both approaches
Is fasting necessary?
16Ketogenic Diet 2005
• Advantages of diet initiation without fast– Shortened hospitalization (2 vs. 7 days)
• But hospitalization still recommended for diet initiation– Less physiologically stressful
• Reduced acidosis• Reduced hypoglycemia
– Less psychologically stressful
Ketosis is readily achieved and efficacy appears similar
Is fasting necessary?
18Atkins for Seizures
Kossoff, et al Neurology 2003
• Case series of 6 patients (4 over age 18 yr); 2003• Prospective study of 20 patients, 16/20 completed 6 mo study;
in press65% with 50% reduction in seizure35% greater than 90% reduction in seizures
Atkins for Seizures
19Atkins for seizures, Kossoff et al
• Modified Atkins protocol:– Outpatient initiation– No initial fast– No caloric, fluid restriction– No weighing of foods; no specific meal plans– CHO limited to 10 gm/day for first month; subsequent liberalization to
1520 gm/day if too restrictive
Atkins for Seizures
21Glycemic Index (GI) defined
The two hour blood sugar response ofa highGI food versus a lowGI food
Reference food (Glucose, GI=100)
Bloo
d gl
ucos
e
Bloo
d gl
ucos
eTime Time
Test food with equal wt carbohydrateGI=40
Glycemic Index (GI)
22Glycemic Index (GI) examples
Examples of foods with various glycemic index:
Fruits Breads
HIGH Melons BagelsMODERATE Apple Whole Grain BreadLOW Grapefruit Whole Grain Bread 2.5 3 gms fiber
Glycemic Index (GI)
23Ketogenic Diet vs American Diet vs LGIT
American Diet
CarbsFats
Protein
Ketogenic Diet
Fats
ProteinCarbs
American DietKetogenic Diet
ProteinCarbs
Carbs 4%Protein 6%
Fat 90%
Carbs 5060%Protein 1020%
Fat 3040%
24Ketogenic Diet vs American Diet vs LGIT
American Diet
CarbsFats
Protein
Ketogenic Diet
Fats
ProteinCarbs
American DietKetogenic Diet
ProteinCarbs
Protein
Fat
Low GI Carbs
LGITLGI Carbs 10%Protein 2030%
Fat 6070 %
Carbs 4%Protein 6%
Fat 90%
Carbs 5060%Protein 1020%
Fat 3040%
25Pfeifer and Thiele, Neurology, in press
20 patients initiated on LGIT: 9 after a trial of the classic KGD 11 prior to initiation of the classic KGD
§ Ages: 5 34 years§ 7 boys, 13 girls§ average # of previous AED’s = 7§ Seizure frequency: 100/day one/6wks§ Length of treatment: average 20 weeks
(range 2.5 124 weeks)
MGH LGIT Program
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MGH –LGIT Protocol compared to KGD
40 gm/dayGI < 50
10 gm/dayCarbohydrate
Daily Multivitamin and Calcium supplement
General guidelinesRough portion control
Precise menu planPrecise weighing
Management
Roughly limited by CHOlimitation
Strictly calculatedTotal calories
LGITKGD
Pfeifer and Thiele, Neurology, in press
27
§ Seizure type:§ Generalized: 10§ Partial onset: 8§ Lennox Gastaut: 2
§ Various seizure etiologies:§ Aicardi syndrome§ NF1§ complex 1 mitochondrial disease§ frontal encephalocele§ meconium aspiration§ cerebral hemorrhage§ unknown
MGH LGIT Cases:Seizure characterization
Pfeifer and Thiele, Neurology, in press
28
0
1
2
3
4
5
6
7
8
No Change <50% 5090% >90%
Percent Seizure Reduction
# of
Pat
ient
s
GeneralizedPartial OnsetLennoxGastaut
50%
25%15%
MGH LGIT Cases:Efficacy by Seizure type
Pfeifer and Thiele, Neurology, in press
29The low glycemic index treatment in pediatric epilepsy
MGH LGIT program: an update
– 36 patients now started on LGIT with no prior dietary therapy:• 25 F, 11 M• Average age: 10.4 (319 years)• 69% with numerous daily seizures• 2.5 ACDs at initiation (17); 3 prior ACDs (09)
30The low glycemic index treatment in pediatric epilepsy
MGH LGIT program: an update
– 36 patients now started on LGIT with no prior dietary therapy:• 25 F, 11 M• Average age: 10.4 (319 years)• 69% with numerous daily seizures• 2.5 ACDs at initiation (17); 3 prior ACDs (09)
0
2
4
6
8
10
12
14
No Change <50% 5090% >90%
Percent Seizure Reduction
# of
Pat
ient
s 25%31%
25%19%
31KGD, modified Atkins and LGIT
how do they compare?
Calculated diet compositions for:• 8 year old child, 50% weight and height• Calculations with Nutritionist Pro and Keto Calculator• KGD Modified Atkins LGIT
KGD, modified Atkins and LGITHow do they compare?
32KGD, modified Atkins and LGIT
how do they compare?
Calculated diet compositions for:• 8 year old child, 50% weight and height• Calculations with Nutritionist Pro and Keto Calculator
KGD, modified Atkins and LGITHow do they compare?
0.7 : 14 : 1Diet ratio182018201820Total calories
61%12390%182Fat28%1276%31Protein11%502.3%104%14.5Carbohydrate
%kcalgm%kcalgm%kcalgm
Low glycemicindex (LGIT)
Modified Atkinsdiet
Ketogenic diet(4:1)
33Dietary therapy in epilepsy:where do we go from here?
• Classic KGD– ? Most effective treatment available for intractable epilepsy– However, implementation and restrictions difficult for child and family– Would initiation without fast, and liberalization of fluids make more
“doable”?• Current alternativesmodified Atkins and LGIT
– Both very promising initial observationsneed broader experience.– Multicenter trials comparing efficiacy and tolerability
• But why do these diets work?
Dietary therapy in epilepsy:where do we go from here?
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