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Starving Away Stubborn Seizures:
Food for Thought on the Ketogenic Diet for Refractory
Epilepsy in Children
Bernadette Espiritu, Pharm.D.
PGY1 Pharmacy Resident
Children’s Hospital of San Antonio
The University of Texas Health Science Center at San Antonio
The University of Texas at Austin College of Pharmacy
April 17, 2015
Learning Objectives
1.
2.
3.
4.
Discuss the background, dietary composition, adverse effects, and challenges of the ketogenic diet
Describe the pharmacist’s role in the management of the ketogenic diet patient
Evaluate the literature regarding use of the ketogenic diet in pediatric refractory epilepsy
Formulate an evidence-based strategy deciding the role of the ketogenic diet in the management of
pediatric refractory epilepsy compared to alternative pharmacotherapy
PEDIATRIC EPILEPSY
I.
Definitions
A. Seizure1-3
i. Clinical manifestation of excessive, synchronous abnormal electrical activity of
neurons in the cerebral cortex
ii. Interferes with normal functioning
iii. Due to shift in normal balance of excitation and inhibition in the central nervous
system
a. Glutamate is the major excitatory neurotransmitter
b. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter
Figure 1. International League Against Epilepsy (ILAE) Classification of Seizures6
B. Epilepsy2,3
i. > 2 unprovoked afebrile seizures > 24 hours apart
ii. Diagnosis of an epilepsy syndrome
iii. Recurrent seizures due to chronic, underlying process
C. Refractory epilepsy4,5
i. Inadequate seizure control despite appropriate therapy with > 2 antiepileptic drugs
(AEDs) at maximally tolerated doses for 18 months to 2 years
ii. Adequate seizure control with unacceptable drug-related adverse effects
II. Epidemiology
A. Seizures affect 4-10% of children at some point in their lifetime7
i. Approximately 150,000 children experience new-onset seizure annually
ii. Only 30,000 children with new-onset seizure will develop epilepsy
B. Currently 326,000 children with a diagnosis of epilepsy in the United States4,7,8
i. 60-70% of children become seizure free with moderate doses of one or two AEDs8
ii. Estimated 10-40% will continue to have seizures despite optimal management with
AEDs4
iii. Approximately one-third of epilepsy will be refractory4
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III. Prognosis and comorbidities2,5
A. Cognitive deficits and abnormalities
B. Psychiatric comorbidities
C. Non-fatal injuries
D. Risk of death is 2-3 times greater in patients with epilepsy
i. Underlying etiologies of seizure
ii. Accidents
iii. Status epilepticus
iv. Sudden unexpected death in epileptic patients (SUDEP)
IV. Treatment
A. Goal of therapy is improved quality of life3,8
i. Elimination or reduction in seizures
ii. Minimize adverse effects from therapy
iii. Manage comorbid conditions
a. Address underlying conditions contributing to epilepsy
b. Depression, anxiety, pain, sleep disorders
B. Approach to refractory epilepsy3-5
i. Non-pharmacologic
a. Avoid triggers
b. Surgical intervention
c. Vagal nerve stimulation
d. Dietary therapy
ii. Pharmacologic
THE KETOGENIC DIET (KD)
I.
Background9-11
A. Mimics the biochemical changes that occur during the starvation state leading to ketosis
B. Majority of calories from fat, with moderate protein and very low carbohydrate
i. Calories initially limited to 80-90% of daily recommended needs
ii. Adjusted to accommodate ideal growth and patient safety
iii. Historically included fluid restriction, though no longer done in practice
Table 1. Potential uses of KD11,12
Epilepsy
Traumatic brain injury
Weight loss
Parkinson’s syndrome
Autism
Amyotrophic lateral sclerosis
Brain tumors
Migraines
Depression
Sleep disorders
Narcolepsy
Schizophrenia
Alzheimer’s disease
Post-anoxic brain disorders
II. History in epilepsy
A. Early history of KD13-15
i. Fasting for epilepsy recorded by Hippocrates in 5th century BC
ii. Gospel of Matthew describes Jesus curing epileptic boy with “fasting and prayer”
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B. Modern history of KD9,14-16
i. 1911: French physicians, Guelpa and Marie, author first scientific report of fasting
for epilepsy
ii. 1921: Dr. R.M. Wilder at the Mayo Clinic proposes diet to mimic fasting state
iii. 1938: Phenytoin discovered; decline in use of KD
iv. 1971: Medium-chain triglyceride diet introduced
v. 1994: Resurgence of KD due to success in Charlie Abrahams15
a. Charlie was 2-year old son of a Hollywood producer who experienced
intractable myoclonic, generalized tonic, and tonic-clonic seizures
b. Gained national attention for successful use of KD to control his seizures
c. The Charlie Foundation created for KD and epilepsy
d. Made-for-television movie based on Charlie’s experience with KD
vi. 2008: First randomized, controlled trial of KD17
III. Starvation state18,19
A. Body forced to metabolize fatty acids
B. Brain dependent on formation of ketone bodies in the liver, transported over blood-brain
barrier
i. β-hydroxybutyrate (BHOB)
ii. Acetoacetate (ACAC)
Figure 2. Production of ketones by the liver and utilization by the brain20
IV. Mechanism of action9,18
A. Despite decades of use, mechanism of action remains elusive
B. Many postulated mechanisms, though likely a combination of simultaneous mechanisms
C. Hypothesized mechanisms9,11,18,21
i. Ketone bodies/ketosis
a. ACAC and acetone have anticonvulsant properties
1. Demonstrated in animal models
2. Acetone levels elevated in brains of patients treated with KD
b. BHOB structurally similar to GABA
c. Consumption of oxaloacetate in ketotic state shunts glutamate to GABA
synthesis
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ii. Lack of glucose limits ability of brain to generate and promote seizure activity
iii. Direct anti-seizure activity of polyunsaturated fatty acids produced while on KD
iv. Opening of ATP-sensitive potassium (KATP) channels22
a. KATP channels normally inhibited by high intracellular ATP
b. Shift away from glycolytic ATP production allows KATP channels to open
c. Open KATP channels reduce neuronal excitability in the substantia nigra
Figure 3. Proposed mechanism of KD by opening of KATP channels23
V. Dietary composition9,11,24
A. Classic KD
i. Diet allotted in a 4:1 fat to carbohydrate/protein ratio per weight
ii. Lower ratios (3:1 or 2:1) may be used in younger children
iii. Oldest and most studied diet
B. Medium-chain triglycerides (MCT) diet
i. MCT more ketogenic than long-chain triglycerides (LCT)
ii. Greater allowance for protein and carbohydrates
iii. MCT sources include coconut oil, palm kernel oil, whole milk, butter
C. Modified Atkins diet
i. More tolerable than classic KD and MCT diet
ii. Carbohydrate restricted, unlimited protein, fat, and fluids
a. Carbohydrate initially limited to 10 grams
b. Planned increase to 15-20 grams of carbohydrates/day in 1-3 months
c. Fats highly encouraged
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Figure 4. Comparison of the calorie composition of the typical American diet and dietary therapies for epilepsy11,19,24
VI. Tolerability (Appendix A)
A. Not a “natural” treatment for epilepsy13
i. Parents should not start the diet without medical guidance
ii. Should be initiated and monitored by a physician working with the health-care
team
B. Compliance11
i. Difficult to tolerate
a. 40-50% will discontinue diet within first 6 months9
b. Requires accurate measurement of all components of the diet
c. Hidden sources of carbohydrates in diet and other products
d. Strict compliance is necessary for benefits of the diet
1. Small lapses are enough to stop ketosis9
a. Not finishing a meal
b. Consuming too much carbohydrate or protein
2. Non-compliance may lead to seizures
ii. More palatable diets available11
a. Less restrictions and adverse effects
b. Modified Atkins diet
c. MCT diet
iii. All-liquid formulations of the diet are available for infants and enterally fed children
a. Easier to implement
b. More compliance and greater efficacy25
iv. When attempted, should be tried for at least 3 months
v. Patients who respond to and tolerate diet should continue for at least 2 years
VII. Safety
A. Adverse effects11,13,21,24
i. Initiation phase11,24
a. Dehydration
b. Hypoglycemia
c. Vomiting
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ii. Maintenance phase
a. Gastrointestinal11,21,24
1. Constipation
2. Exacerbation of gastroesophageal reflux disease (GERD)
b. Nephrolithiasis11,13,21,24
1. 3-10% experience nephrolithiasis
2. Prevent with adequate hydration and avoidance of medications
that may cause nephrolithiasis
3. Oral potassium citrate may decrease prevalence
c. Hypertriglyceridemia11,13,21,24
1. Particularly in first six months
2. Kwiterivoch et al. studied effect on lipid profile after six months of
diet26
a. Significant increase in total cholesterol, low-density
lipoprotein, very low-density lipoprotein, and triglycerides
b. Significant decrease in high-density lipoprotein
3. Used successfully in children with pre-existing hyperlipidemia
d. Growth/nutrition11,13,16,21
1. Significant reduction in height and weight after prolonged use
2. Catch-up growth observed after diet discontinuation27
3. Increased risk of bone fractures
4. All children on KD must receive supplements
a. Vitamins and minerals (including trace minerals)
b. Calcium and vitamin D
c. Oral citrates and carnitine optional
B. Contraindications11,24
i. Relative contraindications: patients who have more curative alternatives, difficulty
with compliance, or comorbidities that may be exacerbated by KD
ii. Absolute contraindications: inborn errors of metabolism where biochemical
changes due to KD are dangerous
•
•
•
•
•
Table 2. Relative and absolute contraindications of KD11,24
Relative
Absolute
Epilepsy surgery candidates
• Primary carnitine deficiency
Failure to thrive/poor nutritional status
• Carnitine palmitoyltransferase I or II deficiency
Special diet needs/preferences
• Carnitine translocase deficiency
Parent/caregiver noncompliance
• Fatty oxidation defects
Medical conditions aggravated by diet
• Porphyria
• Pyruvate carboxylase deficiency
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ROLE OF A PHARMACIST IN KD
I.
Combined with AEDs
A. Evidence supporting pharmacodynamics interactions between KD and AEDs is weak24
B. Valproic acid24,28
i. Valproic acid is a short-chain fatty acid
ii. Enhanced fatty acid oxidation with KD may enhance valproic acid-related
hepatotoxicity
iii. Carnitine deficiency24
a. Both valproic acid and KD alone cause carnitine deficiency
b. May be worsened in combination
C. Carbonic anhydrase inhibition
i. Metabolic acidosis24
a. Carbonic anhydrase inhibitors (CAIs), topiramate and zonisamide, may
worsen transient metabolic acidosis associated with KD
b. Serum bicarbonate
1. Monitor when initiating KD with topiramate and/or zonisamide
2. Supplement with bicarbonate in clinically symptomatic patients
ii. Nephrolithiasis21
a. CAIs increase risk of nephrolithiasis
b. Monitor patients carefully when initiating KD
c. Consider empiric oral citrates
D. Phenobarbital28
i. Elimination slower in acidotic state, resulting in higher levels
ii. Patients on phenobarbital may not respond as well to KD
II. Medications containing carbohydrates (Appendix B)28,29
A. Formulations of AEDs and other medications may contain carbohydrates or sugar
additives28-30
i. “Sugar-free” products may still contain other carbohydrate fillers
ii. IV fluids, TPNs, diluents
B. Strategies for reducing carbohydrate content of medications29,30
i. Liquids > chewable/disintegrating tablets > tablets/capsules in carbohydrate
content
a. Crush tablets or open capsules of products able to be crushed or opened
b. Generics may contain more carbohydrate fillers than brand name products
c. IV formulations may be given orally
ii. Avoid dextrose containing diluents, if alternatives compatible
III. Pharmacologic management and prevention of adverse effects10
A. Proton-pump inhibitors for GERD
B. Potassium citrate to prevent nephrolithiasis
C. Vitamin and mineral supplementation
D. Constipation management
IV. Alternative to AEDs
A. Good responders to KD may discontinue AEDs31
i. Possible seizure exacerbations when AEDs are weaned
ii. During withdrawal while on KD, phenobarbital and benzodiazepines are most
associated with breakthrough seizures
B. Must weigh benefits of starting KD versus trying another AED
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CLINICAL QUESTION
I. When should KD be considered over alternative AEDs in pediatric patients with refractory epilepsy?
II. International Ketogenic Diet Study Group24
A. Neurologists and dieticians commissioned by The Charlie Foundation
B. Recommend strong consideration of KD after 2-3 failed AEDs
III. Approach to pharmacotherapy in refractory epilepsy
Figure 4. Mechanisms of action of AEDs32
A. Address causes for treatment failure5,8
i. Inappropriate choice of first-line AED
ii. Poor compliance
iii. Lifestyle factors
iv. Intolerable adverse effects
B. Considerations in AED selection5,8,33
i. Seizure/epilepsy type (Appendix C)
ii. Adverse effects (Appendix D)
iii. Drug interactions
iv. Cost
v. Pharmacokinetics & drug monitoring
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IV. Efficacy in epilepsy trials
A. Efficacy measures8,34
i. Mean percentage (%) of baseline
a. Compares baseline seizure control against seizure control after
intervention
b. Often involves total number of seizures before and after intervention
ii. 50% responder rate8
a. Proportion of patients with more than 50% reduction in seizures
b. Common efficacy measure reported in literature and randomized,
controlled trials
c. Patients will be considered “responders” or “non-responders” based on
50% responder rate
iii. 90% responder rate
a. Proportion of patients with more than 90% reduction in seizures
b. Corresponds to “very good” responders
iv. Seizure freedom
a. Patients experiencing freedom from seizures
b. Corresponds to total or complete response to therapy
B. Efficacy of pharmacotherapy in refractory epilepsy5,35
i. 15-20% of patients may achieve > 6 months of seizure remission with additional
drug trials
ii. 30-40% of refractory patients will receive > 50% reduction in seizure frequency with
adjunctive polytherapy
iii. Average drop-out rates in most AED trials for refractory epilepsy range from 5-10%
Table 3. Efficacy of AEDs in adjunctive treatment of refractory epilepsy35-42
AED
50% Responder Rate
AED
50 % Responder Rate
Clobazam
43-65%
Pregabalin
14-51%
Felbamate
33-56%
Rufinamide
28.2-46.7%
Gabapentin
34.4%
Tiagabine
25%
Lamotrigine
33-45%
Topiramate
20-88%
Lacosamide
38-41%
Valproic Acid
50-60%
Levetiracitam
27-52%
Vigabatrin
28-80%
Oxcarbazepine
41%
Zonisamide
26-67%
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LITERATURE REVIEW
Neal EG et al. The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial. Lancet
Neuro. 2008;7:500-06.17
Overview
To investigate whether there are clear benefits in terms of seizure control in children with epilepsy
Objective
who were treated with the classic KD for 3 months compared with a control group of children
whose treatment did not change
Trial Design
Open-label, parallel-group, randomized-controlled trial in the United Kingdom (UK)
Inclusion Criteria
Exclusion Criteria
 Age between 2-16 years
 History of:
o Hyperlipidemia
Patients
 Daily seizures or > 7 seizures per week
o Nephrolithiasis
 Non-responder to > 2 AEDs
o Organic-acid-deficiency syndromes
 Not previously treated with KD
Primary
Secondary
 % change in baseline seizures
 Tolerability of diet
Outcomes
o Adverse effects
 Proportion of children with:
o Compliance
o >90% reduction in seizures
o Growth
o >50% reduction in seizures
 Children randomly assigned to start diet immediately after 4-week baseline (diet group) or
delayed by 3 months after 4-week baseline (control group)
 Control group remained on regular diet with no changes in AEDs
 Diet group given an individual KD based on child’s food preferences with no changes in AEDs
Interventions
 KD started at home, non-fasting
o 2:1 ratio to begin, with initiation to 3:1 or 4:1 over 1-2 weeks as tolerated
o Diets supplemented with vitamins and minerals
 Patients reviewed outpatient at 6 weeks and 3 months with telephone calls between visits
 Seizures frequency assessed and recorded by parents daily during baseline and study period
 Sample size of 47 patients per group needed to detect a 25% difference in mean percentage of
baseline seizures significant at 5% with 90% power
 Mean % of baseline seizures compared with unpaired t-test; verified with Mann-Whitey U test
 Multiple linear regression to assess association between diet and % baseline seizures taking
Statistical
into account baseline characteristics of age group and gender
Analysis
 Fisher’s exact test for calculating difference in diet and control groups for responder rates of
50% or 90% seizure reduction
 Unpaired t-test comparing mean % of baseline seizures between diet and control group for
generalized and focal seizures
Results
 Provided table of baseline characteristics for gender and age but no clear analysis
o Most children in diet group in 2-6 year age group (N=37), followed by 7-11 year age group
(N=27) and the 12-16 year age group (N=9)
Baseline
 6 children on no epilepsy medications at entry, 20 children on one medication, 53 children on 2
characteristics
medications, and 54 children on 3 medications
o No mention of how many failed AED treatments prior to enrollment
 Epilepsy types and syndromes similar in control and diet groups
 Mean of 13.3 seizures/day in KD group and 10.1 seizures/day in control group
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

Primary
outcomes
16 patients (8 from each group) dropped out before study period began
26 patients (11 from KD group and 15 from control group) not included in final analysis due to
drop-outs or inadequate data after study period began
Table 4. Comparison of seizures as percentage of baseline after 3 months
Outcome
Diet group (N=54) Control group (N=49) p-value
Mean % of baseline seizures (95% CI)
62.0 (50-74%)
136.9% (105-169%) <0.0001
Median % of baseline seizures
47.7%
106.3%
----(SD, IQR)
(43, 0-200%)
(111, 28-575%)
 Difference in mean % of baseline seizures remained significant after accounting for outliers
o Linear regression model: difference between mean % baseline seizures increased to 76.6%
(95% CI 44.4-108.9; p<0.0001)
o Removal of extreme outliers in control group: difference between mean % baseline seizures
reduced to 50.9% (95% CI 30-7-71.2%; p<0.0001)
 No significant differences found when comparing mean % of baseline seizures for generalized
or focal seizures in either the control or diet group
Table 5. Responder rate in diet group vs control group
Outcome
Diet group (N=73) Control group (N=72) p-value
>90% reduction in seizures
5 (7%)
0 (0%)
0.0582
>50% reduction in seizures
28 (38%)
4 (6%)
<0.0001
<50% reduction in seizures
45 (62%)
68 (94%)
<0.0001

Secondary
outcomes
Author’s
conclusions
Critique
Take-home
points
Adverse effects in the diet group included constipation (33%), constipation requiring
medication (24%), lack of energy (24%), vomiting (25%), hunger (22%), diarrhea (13%), and
abdominal pain (9%)
 10 patients withdrew from dietary treatment
o 3 due to parental unhappiness with restrictions, 2 due to behavioral food refusal, 1 due to
increased seizures and 4 due to adverse effects (extreme drowsiness, vomiting, diarrhea,
and constipation)
 One patient, who remained on the diet, had evidence of nephrolithiasis treated with potassium
citrate
Conclusions
The diet has efficacy and should be included in management of children with drug-resistant
epilepsy. Side effects should be considered alongside with the risk/benefit of other treatments.
Strengths
Limitations
 Randomized, controlled
 Non-blinded
 Enrollment achieved power
 Compared with placebo
 Responder rates reported as
 Subjective recording of seizures and adverse effects
intention-to-treat
 No details on failed AEDs
 Results robust after accounting
 Per-protocol with high drop-out rate
for outliers
 Cultural diet differences
 Lacked clear analysis of baseline characteristics
 First randomized, controlled trial of KD
 High number of drop-outs and non-starters
 Effective in reducing seizures but not without adverse effects/intolerability
 No data on number of failed AEDs
 Cultural diet differences
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Sharma S et al. Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized
controlled trial. Epilepsia. 2013;54(3):481-486.43
Overview
To evaluate the efficacy of the modified Atkins diet in a randomized controlled trial in children with
Objective
refractory epilepsy
Trial Design
Open-label, parallel-group, randomized-controlled trial in India
Inclusion Criteria
Exclusion Criteria
 Age between 2-14 years
 Known/suspected inborn errors of metabolism
Patients
 Daily seizures or > 7 seizures per week
 Systemic illness
 Failure of > 3 AEDs
 Motivational issues with family
Primary
Secondary
 % change in seizure frequency compared  Tolerability of diet
to baseline
 Adverse effects
Outcomes
 Proportion of children with:
o Seizure freedom
o >90% reduction in seizures
o >50% reduction in seizures
 Assigned to modified Atkins diet group or control group (no diet changes)
 4-week baseline observation period followed by study period
o Recorded daily seizure log by parents (seizure type, duration, and frequency)
 Both groups remained on same AEDs during 3 month trial period and throughout the study,
unless medically indicated
 Intervention arm began modified Atkins diet as outpatients at end of baseline period
o Carbohydrate intake of 10 grams/day
o Intake of fats encouraged
Interventions
o Calories and protein intake not restricted
o Received sugar-free, fat-soluble vitamin supplement and calcium supplement
o Recipes provided, based on patient’s dietary habits (e.g. vegetarian)
o Urine ketones checked by parents daily during the first week and twice weekly thereafter
 Reviewed as outpatients at 1, 2, and 3 months
 Three-day dietary intake chart reviewed at each visit in diet group to calculate carbohydrate
and calorie intake, and to reinforce compliance
 Tolerability and adverse effects evaluated by parental interview
 Calculated sample size of 48 in each group to detect 25% difference in primary outcome at 5%
with 90% power
 All analysis intention-to-treat
Statistical
 Drop outs were treated as worst case scenario in the treatment group (0% seizure control) and
Analysis
as best case scenario in the control group (100% seizure control)
 Mean % of seizures compared with unpaired t-test/Mann-Whitney U test
 Responder rates (seizure freedom, >50% and >90% seizure reduction) compared using Fisher’s
exact test
Results
 102 children enrolled (diet group=50, control group=52)
 No significant differences in baseline characteristics between groups
Baseline
 Average age of 4.7 years in diet group and 5.2 years in control group
characteristics
 Median of 5 (range 3-9) AEDs tried in diet group; median of 4 (range 3-9) tried in control group)
 Median of 3 ongoing AEDs (range 2-4) in both groups during study period
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
No significant differences in response between epilepsy syndromes
Table 6. Seizure outcome at 3 months
Diet group
(N=50)
Mean % of seizures compared to baseline
59 ± 54
(95% CI 44-74.5)
Median % of seizures as compared to baseline (IQR)
37
>90 % responder rate
30%
>50% responder rate
52%
Proportion of children seizure free
10%
Primary
outcomes
Control group
(N=52)
95.5
(95% CI, 82-109)
100
7.7%
11.5%
5.8% (drop-outs)
p-value
0.003
0.003
0.003
0.001
-----

Secondary
outcomes
Author’s
conclusions
Critique
Take-home
points
Adverse effects in the diet group included constipation (46%), anorexia (18%), vomiting (10%),
lethargy (6%), lower respiratory tract infections (4%), hyperammonemic encephalopathy (2%)
 4 patients discontinued the diet
o 3 due to adverse effects (2 with frequent chest infections, 1 for hyperammonemic
encephalopathy 1 week after starting the diet)
o 1 child discontinued because family found diet too restrictive
 Older children complained that diet was too restrictive and difficult
 Diet more difficult to tolerate in patients with dietary restrictions (vegetarians)
Conclusions
The modified Atkins diet was found to be effective and well tolerated in children with refractory
epilepsy. However, the diet does have adverse effects, and careful medical supervision is
warranted.
Strengths
Limitations
 Randomized, controlled
 Non-blinded
 Enrollment achieved power
 Compared with placebo
 Intention-to-treat analysis
 Excluded families with “motivational issues”
 Cultural diet differences
 Subjective recording of seizures and adverse effects
 Diet effective in reducing seizures, though not without adverse effects
 50% responder rate = 52%
 Average of 4-5 failed AEDs before starting treatment
 Difficult to tolerate in older children and patients with diet restrictions
 Cultural dietary differences
Espiritu | 13
Kossoff EH et al. A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins diet.
Epilepsy Behav. 2007;10(3):432-6.44
Overview
To identify the ideal starting limit of carbohydrates on the modified Atkins diet to maximize efficacy,
Objective
ketosis, and tolerability
Trial Design
Prospective, randomized, crossover study in the United States (US)
Inclusion Criteria
Exclusion Criteria
 Age between 3-18 years
 Use of Atkins diet < 7 days previously
 Failure of > 2 AEDs
 Known hypercholesterolemia, kidney dysfunction,
Patients
or heart disease
 At least daily, countable seizures
 Recent (<1 year)/current use of KD
 BMI <3% for age
Primary
Secondary
 Proportion of children with:
 Ketosis
Outcomes
o Seizure freedom
 Tolerability of diet
o >90% reduction in seizures
 Adverse effects
o >50% reduction in seizures
 Patients randomized to begin diet with 10 grams or 20 grams per day
o Baseline blood counts, fasting lipid profile, comprehensive metabolic profile, urine calcium
and creatinine levels obtained
o 3-day pre-diet food record analyzed
o Diet explained to families in hour long visit
o Monthly calendar to record seizures daily, ketones semi-weekly, and weight weekly
o Frequent contact with physician and dietitians via phone and e-mail
o Each patient received multivitamin and calcium supplement
Interventions
o At 3 months, patients were crossed over to opposite amount (i.e. 10 gram  20 gram, 20
gram  10 gram)
 Children evaluated at baseline, 3 months and 6 months
o Urine ketones checked semi-weekly and urine/laboratory tests repeated at 3 months and 6
months
o Medication changes allowed after 2 weeks if requested by families
o Families given the option to continue diet with carbohydrate limit of their choice, or
discontinue diet after 6 months
 Calculated total number of 20 patients needed to show difference of 20% between group
assuming a 40% dropout rate
 Categorical data analyzed with Fisher’s exact test
Statistical
Analysis
 Medians compared using Wilcoxon two-sample test; means with paired two-sample t test
 Significance level set at P=0.05
 Intention-to-treat analysis
Results
 N=20 (10 patients in each carbohydrate group)
 No differences in baseline characteristics between groups
 Average age of 7.5 years in 10 gram group and 9.8 years in 20 gram group
Baseline
 Average number of 6 AEDs previously tried in each group
characteristics
 Average of 2 concurrent AEDs in each group
 4 patients previously attempted on KD with no reported improvement (randomized 2 patients
to each group)
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Primary
outcomes
Secondary
outcomes
Author’s
conclusions
Critique
Take-home
points
Table 7. Seizure outcomes at 1, 3, and 6 months
10 gram group (N=10)
20 gram group (N=10)
p-value
>50% seizure reduction
6 (60%)
4 (40%)
0.33
1 month
>90% seizure reduction
0 (0%)
1 (10%)
0.50
>50% seizure reduction
6 (60%)
1 (10%)
0.03
3 months
>90% seizure reduction
3 (30%)
0 (0%)
0.10
>50% seizure reduction
5 (50%)
5 (50%)
0.67
6 months
>90% seizure reduction
3 (30%)
4 (40%)
0.50
Table 8. Tolerability outcomes in diet group
10 gram group (N=10)
20 gram group (N=10)
p-value
Diet duration (in months)
9.0 (3-22)
4.5 (0-19)
0.12
Number completing 6-month study
7 (70%)
5 (50%)
0.33

Of the 12 patients who completed the study, 9 decided to continue on modified Atkins diet
after 6 months
 4 patients reported significant constipation while on diet
Conclusions
A starting carbohydrate limit of 10 grams/day for children starting the modified Atkins diet may be
ideal, with a planned increase to 20 grams/day after 3 months. The study adds further prospective
evidence for the efficacy and safety of the modified Atkins diet for refractory pediatric seizures.
Strengths
Limitations
 Randomized
 Non-blinded, not controlled
 Enrollment achieved
 Subjective recording of seizures
 Intention-to-treat analysis
 Small sample
 Conducted in the US
 High drop-out rate
 Data on number of failed AEDs
 Diet effective in reducing seizures (50% responder rate of 10-60%)
 High drop-out rates suggest poor tolerability
 Average of 6 failed AEDs before starting diet
 Conducted in the United States
SUMMARY
I.
Summary of literature
A. Responder rate (>50% reduction in seizures)
i. Range from 10-60% in prospective, randomized trials
ii. 38-52% in prospective, randomized, controlled trials
B. Average of 4-6 AEDs tried prior to trying KD
C. Tolerability
i. Most common side effects are gastrointestinal, particularly constipation
ii. High drop-out rates, particularly in the UK and US
iii. More difficult to tolerate in older patients and those with diet restrictions
D. Lack of head-to-head trials comparing alternative AED and KD in refractory epilepsy, or
starting KD earlier in management
II. KD treatment
A. Effective treatment for pediatric refractory epilepsy
B. Requires strict compliance to achieve benefits
C. Pharmacists can play a role in the management of a child on KD
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RECOMMENDATIONS
I.
Recommendations
A. Due to availability and efficacy of alternative AEDs, KD should not be considered in most
children until failure of at least 4 AEDs
i. Difficulties with tolerability and compliance limit use of KD
ii. High drop-out rates in studies
iii. Alternative AEDs or polytherapy should be considered first in refractory epilepsy
B. Considerations of starting KD vs. AED
i. Type of seizure/epilepsy syndrome
ii. Patient age
iii. Diet preferences and cultural considerations
iv. Family compliance and motivation
v. Cost
vi. Enteral feeding
vii. Adverse effects of KD and AEDs
viii. Concurrent medications
ix. Available alternative treatment(s)
II. Future directions
A. Discovering mechanism of KD may provide targets for future AEDs
B. Head-to-head trials of KD vs. starting another AED
C. Trials of KD earlier in treatment
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APPENDICES
Appendix A. Example of Typical 4:1 KD Meal using 1100 kcal/day10
Breakfast
Lunch
Dinner
Snack
90 g ketogenic pudding 40 g 36% heavy cream
35 g 36% heavy cream
Ketogenic chocolate
44 g cream cheese
8 g MCT oil
Ground beef and cheese
3 g cocoa
13 g eggs
Dark meat chicken salad
11 g ground beef
6 g butter
29 g heavy cream
20 g dark meat chicken
10 g cheese
6 g coconut oil
8 g mayonnaise
8 g butter
20 g avocado
26 g cooked broccoli
11 g butter
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Appendix B. Carbohydrate content of antibiotics, AEDs, and over-the-counter medications28-30
Medication (Brand Name)
Dosage Unit
Grams of carbohydrate per dosage unit
Over-the-counter pain medications
Acetaminophen liquid suspension (Tylenol®)
160 mg/5 mL
5 grams/5 mL
Ibuprofen suspension (Motrin®)
100 mg/5 mL
0.63 grams/5 mL
Antibiotics
Amoxicillin oral suspension (Amoxil®)
400 mg/5 mL
1.88 grams/5 mL
Azithromycin oral suspension (Zithromax®)
100 mg/5 mL
3.86 grams/5 mL
Cephalexin oral suspension (Keflex®)
250 mg/5 mL
3.03 grams/5 mL
AEDs
Carbamazepine suspension (Tegretol®)
100 mg/5 mL
2.65 grams/5 mL
Gabapentin tablets (Neurontin®)
100 mg
0.03 grams
Lamotrigine tablets (Lamictal)
25 mg
0.03 grams
Levetiracetam oral solution (Keppra®)
100 mg/mL
0.3 grams/mL
Phenobarbital elixir
20 mg/5 mL
3.4 grams/5 mL
Phenytoin suspension (Dilantin®)
125 mg/5 mL
1.39 grams/5 mL
Topiramate tablets (Topamax®)
25 mg
0.04 grams
Valproic acid syrup (Depakene®)
250 mg/5 mL
4.5 grams/5 mL
Multivitamins
Poly-vi-sol®
---4.25 grams/5 mL
8
Appendix C. Recommended AEDs according to epilepsy syndrome
Epilepsy Syndrome
First-line AEDs
Alternative AEDs
Do not use (may worsen)
Ethosuximide
Levetiracetam
Childhood absence epilepsy
Lamotrigine
Topiramate
Valproate
Carbamezepine
Lamotrigine
Levetiracitam
Oxcarbazepine
Juvenile absence epilepsy
Valproate
Topiramate
Phenytoin
Tiagabine
Clobazam
Vigabatrin
Lamotrigine
Clonazepam
Juvenile myoclonic epilepsy
Valproate
Levetiracitam
Topiramate
Levetiracetam
Carbamazepine
Clobazam
Epilepsy with generalized tonic-clonic
Lamotrigine
Oxcarbazepine
Tiagabine
seizures
Topiramate
Phenobarbital
Vigabatrin
Valproate
Phenytoin
Primidone
Clobazam
Gabapentin
Carbamazepine
Levetiracetam
Lamotrigine
Focal epilepsies: cryptogenic or
Phenytoin
Oxcarbazepine
symptomatic
Tiagabine
Valproate
Clonazepam
Topiramate
Phenobarbital
Primidone
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8
Appendix C (continued). Recommended AEDs according to epilepsy syndrome
Clobazam
Clonazepam
Carbamezapine
Infantile spasms
Vigabatrin
Valproate
Oxcarbazepine
Topiramate
Carbamazepine
Benign epilepsy with centrotemoral
Lamotrigine
Levetiracetam
spikes or occipital paroxysms
Oxcarbazepine
Topiramate
Valproate
Clobazam
Carbamazpeine
Clonazepam
Levetiracetam
Lamotrigine
Dravet syndrome
Valproate
Phenobarbital
Oxcarbazepine
Topiramate
Vigabatrin
Clobazam
Clonazepam
Carbamazepine
Levetiracetam
Continuous spike wave of slow sleep
Ethosuximide
Oxcarbazepine
Topiramate
Lamotrigine
Vigabatrin
Valproate
Clobazam
Lamotrigine
Clonazepam
Carbamazepine
Lennox-Gastaut syndrome
Valproate
Ethosuximide
Oxcarbazepine
Topiramate
Levetiracetam
Felbamate
Lamotrigine
Levetiracetam
Carbamazepine
Landau-Kleffner syndrome
Valproate
Topiramate
Oxcarbazepine
Clobazam
Clonazepam
Lamotrigine
Carbamazepine
Myoclonic astatic epilepsy
Valproate
Levetiracetam
Oxcarbazepine
Topiramate
38,40,42,45
AED
Clobazam
Felbamate
Gabapentin
Lamotrigine
Lacosamide
Levetiracitam
Oxcarbazepine
Pregabalin
Rufinamide
Tiagabine
Topiramate
Valproic Acid
Vigabatrin
Zonisamide
Appendix D. Adverse reactions in AEDs for refractory epilepsy
Adverse Reactions
Sedation, hyperactivity, behavioral problems, irritability, fatigue, salivation, weight gain, sleep
disturbances
Anorexia, weight loss, insomnia, gait disturbance, aplastic anemia, hepatotoxicity
Emotional lability, aggression, hyperactivity, weight gain, somnolence, dizziness, dyspepsia,
constipation, nausea, fatigue, ataxia
Dizziness, sedation, headache, diplopia, ataxia, skin rash
Dizziness, headache, nausea, diplopia
Somnolence, asthenia, headache, anorexia, noninvasive infections, hostility, emotional
lability, nervousness, depersonalization, psychotic behavior
Dizziness, diplopia, nausea, ataxia, hyponatremia
Dizziness, somnolence, ataxia, weight gain, euphoric effects
Dizziness, fatigue, headache, somnolence, nausea
Dizziness, asthenia, tremor, fatigue, nervousness
Somnolence, fatigue, problems with concentration and word finding, difficulty with memory,
decreased appetite and weight loss, nervousness, headache, asthenia
Weight gain, vomiting, tremor, nausea, thrombocytopenia, impaired coagulation, drowsiness
alopecia, encephalopathy, hyperammonemia
Peripheral visual-field defect, hyperactivity, irritability, aggression, self-injurious behavior, selfdefiance, weight gain, facial edema, headache, drowsiness, insomnia, ataxia, somnolence,
stupor
Sleepiness, loss of appetite, weight loss, ataxia, oligohydrosis, hyperthermia
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