the ketogenic diet objectives epilepsy center epilepsy statistics

November 14

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© The Children's Mercy Hospital, 2014. 03/14

Lindsey Thompson, MS, RD, CSP, LD

The Ketogenic Dietfor the treatment of epilepsy


Objectives• Define ketogenic diet, history,

possible mechanism of action

• Identify appropriate ketogenic diet candidates

• Review ketogenic diet induction process

• Describe monitoring of the ketogenic diet, potential complications and troubleshooting New York Times, www.nytimes.com


Epilepsy Center

• Level IV Epilepsy Center- National Association of Epilepsy Centers

• Multidisciplinary team

• Epilepsy Clinic

• Epilepsy Monitoring Unit 24/7

• 4 beds


Epilepsy Statistics

• Epilepsy is the 4th most common neurological disorder after migraine, stroke and Alzheimer's

• 200,000 new cases of epilepsy are diagnosed in the United States every year

• About 326,000 children under the age of 15 have epilepsy in the United States


Epilepsy DefinitionsInternational League Against Epilepsy

• Epilepsy– 2 or more unprovoked seizures occurring greater than 24 hours apart

– One or more unprovoked seizure(s) with a probability to have more

• Seizure– The physical findings or changes in behavior that occur after an episode of

abnormal electrical activity in the brain

– A seizure is a symptom, not a disease

• Intractable / Refractory Epilepsy– Occurs when a person has failed to become (and stay) seizure free with

adequate trials of two seizure medications

– These seizure medications must have been chosen appropriately for the person’s seizure type and tolerated by the person

– For some, medications cause unacceptable side effects


Seizure Free Rates with Different Strategies

Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

Seizure-free monotherapy

1st AED

47%

Not seizure-freeafter polytherapy

36%

Seizure-free polytherapy

3%Seizure-free

monotherapy 3rd AED

1%

Seizure-freemonotherapy 2nd AED

13%

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Treatment Options for Intractable Epilepsy - AEDs

• Bromides- 1800s• Phenobarbital-1912• Phenytoin- 1938• Primidone- 1949• Ethosuximide- 1958• Carbamazepine- 1968• Valproate– 1978

• Felbamate - 1993• Gabapentin - 1993• Lamotrigine - 1994• Topiramate - 1996• Tiagabine - 1997• Levetiracetam - 1999• Oxcarbazepine - 2000• Zonisamide - 2000• Pregabalin - 2005• Rufinamide- 2008• Lacosamide- 2008/2009• Vigabatrin - 2009• Ezogabine - 2011• Clobazam - 2011• Perampanel - 2013


Drug Development and Refractory Epilepsy (Adults)

1951 Refractory Epilepsy: ~21-25% (Walker, J Pediatr)

2014 Refractory Epilepsy: ~21.5% (Kong, Epilepsy Res)


Wheless JW. Neurostimulation Therapy for Epilepsy. In: Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc. 2008.

AED Trial 1 Monotherapy

Treatment Goal

• Seizure freedom

Treatment Goal• Maximize quality of life

• Optimize Long-term seizure control

• Minimize AED side effects

• Maximize adherence

AED Trial 2 Monotherapy or Polytherapy

Newly Diagnosed Refractory Epilepsy

Epilepsy Surgery

Surgical Evaluation

VNS Therapy AEDs (Polytherapy)

Ketogenic Diet

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Treatment Goals for Epilepsy


Treatment Options for Intractable Epilepsy

• Resection Surgery

– Focal epilepsy

– Remove part of the brain (non-eloquent cortex) where the seizures are known to originate

– Callosotomy – separate the hemispheres to stop the spread of seizure activity from one side of the brain to the other



• Vagal Nerve Stimulator (VNS)

– Surgical intervention

– An implanted device prevents or interrupts seizures by sending small pulses of electrical energy to the Vagus Nerve

– Interval period of 12-18 months

– FDA labeling (VNS>14 years)



• Diet Therapies

– Ketogenic Diet (KD)

– Medium Chain Triglyceride (MCT) Oil Diet

– Modified Atkins Diet (MAD)

– Low Glycemic Index Treatment (LGIT)

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Historical References to Epilepsy and Diet

•Physicians of ancient Greece treated diseases, including epilepsy, by altering their patients’ diet

•Hippocrates described a “man whose epilepsy is cured as quickly as it had appeared, through complete abstinence of food and drink”.

•In 1911, American Dr. Hugh Conklin began to treat his epilepsy patients with a fast for18-25 days. His case records showed:

–20% of his patients achieved freedom from seizures and

–50% had some improvement.

•His fasting therapy was adopted by neurologists and widely used

•First described in the literature in 1921 after 2 pivotal observations:

–Woodyatt noted that acetone and betahydroxybutyric acid appear by starvation or a diet containing low carb and high fat

–Dr. Wlider at Mayo Clinic proposed that benefits of fasting could be obtained if ketonemia was produced by other means

•1 gm of protein per kg/day and 10-15 g of carbohydrate /day and the remainder of the calories from fat


Anticonvulsants and Decline of the Diet

• In 1938, H. Houston Merritt and Tracy Putnam discovered phenytoin (Dilantin)

• Focus of research shifted to discovering new drugs

• In the 1970s- introduction of sodium valproate

• Drugs were available to neurologists that were effective across a broad range of epileptic syndromes and seizures types

• The ketogenic diet restricted to mainly difficult cases


Revival of the Ketogenic Diet

• In October 1994, NBC’s Dateline reported the case of Charlie Abrahams

• 2-year-old son of Hollywood producer Jim Abrahams

• Charlie’s epilepsy had remained uncontrolled by mainstream therapies

• His parents brought Charlie to the Johns Hopkins Hospital, which had continued to offer the diet

• Charlie’s epilepsy was quickly controlled and his developmental progress resumed

• Abrahams created the Charlie Foundation in 1994 to the promote the ketogenic diet and fund research


The Ketogenic Diet in more than 45 countries

Kossoff et al., Epilepsia 2005 (updated 2014)


Ketogenic Diet Studies Published

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1965 19801975 19851970 20101990 1995 20052000


Timeline of the Ketogenic Diet

Hippocrates

H. Houston Merritt and Tracy

Putnam discovered phenytoin(Dilantin)

Publish in 1998 in the American

Epilepsy Society. There followed an explosion of

scientific interest in the diet.

Ketogenic Diet is mainstream

With the introduction

sodium valproate, the

use of the ketogenic diet is

restricted to mainly difficult

cases.

AEDs are 1st line therapy

The diet regains interest by the medical

community

400 BC

1911 1938 1970 1994 1997 1998

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Increasing Interest in the Ketogenic Diet

• Cancer• Aft et al., 2002; Pelicano et al., 2006; Otto et al., 2008, Seyfried et al.,

2011); Stafford et al., 2010; Zuccoli et al., 2010

• Alzheimer's • Roberson et al., 2011; Kapogiannis and Mattson, 2011; Henderson et

al.,2009

• Amyotrophic lateral sclerosis (ALS)• Zhao et al., 2006, Siva, 2006, Cardinali et al., 2006

• Concussions / Brain Injury• Appelberg et al., 2009; Prins et al., 2005 ; Hu et al., 2009

• Autism Spectrum Disorders• Evangeliou et al., 2003; Masino et al., 2011


What is the Ketogenic Diet?

• Medical diet for the treatment of intractable epilepsy

– 20-30% of patients are resistant to traditional/medicinal therapies

• High in fat, moderate in protein

and limited in carbohydratesFat

Carbs

Protein

Fat

Carbs

Protein

Ketogenic Diet

“Western” Diet


How Does it Work?

• Under conditions of reduced serum glucose, ketone bodies are formed in the liver from metabolism of fatty acids

• Ketone bodies can provide nearly 70% of the brain’s energy requirements


Mechanism of Action• Hallmark features of KD treatment: rise in ketone body production

and reduction in blood glucose levels

• Elevation of ketones is largely a consequence of fatty acid oxidation

• PUFAs (such as AA, DHA, and EPA), may regulate neuronal membrane excitability

– blocking voltage-gated Na and Ca channels (Voskuyl and Vreugdenhil, 2001)

– reducing inflammation through activation of PPARs (Jeong et al., 2011)

– inducing expression of mitochondrial uncoupling proteins which reduce ROS production (Bough et al., 2006; Kim do and Rho, 2008)

• Ketone bodies possess neuroprotective properties

– raising ATP levels and reducing ROS production through ↑NADH oxidation and inhibition of mitochondrial permeability transition (Kim do et al., 2007)


Mechanism of action

• KD treatment results in reduction of blood glucose, likely involving reduced glycolytic flux

– Reduction of glycolysis is an essential feature of calorie restriction, which has been shown to suppress seizures (Greeneetal.,2001)

– Reduced glycolytic flux blocks epileptogenesis in the rat kindling model by decreasing the expression of brain derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase B (Garriga-Canutetal.,2006)

• Neuroprotective mechanisms of calorie restriction

– mitochondrial function and decreased oxidative stress

– decreased activity of pro-apoptotic factors

– inhibition of inflammatory mediators such as interleukins and tumor necrosis factor alpha (Maalouf et al.,2009)


Ketogenic Diet- Efficacy in Intractable Epilepsy

• Hundreds of studies in the past 20 years show similar efficacy in intractable epilepsy

– 50-60% have a >50% reduction in seizures

– 33% have a >90% reduction in seizures

• 2008: Neal et al, First randomized controlled trial

• 2012: Cohrane Review- “in children, the ketogenic diet results in short to medium term benefits in seizure control, the effects of which are comparable to modern antiepileptic drugs”

Levy, R.G., Cochrane Database Syst Rev, 2012. 3: p. CD001903.Kossoff, E.H. Epilepsia, 2009. 50(2): p. 304-17.Neal, E.G., et al. Lancet Neurol, 2008. 7(6): p. 500-6.Freeman, J.M., et al. Epilepsia, 2009. 50(2): p. 322-5

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Efficacy

• Children 2-16 years

• > 7 seizures/ week

• Failed 2 AEDs

• Had not been treated with the ketogenic diet

Neal EG, Chaffe H, Schwartz RH et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 2008; 7:500-506


CMH: KGD in Intractable Epileptic Spasms

N=20 Seizure onset 4.5 mos Diet onset 1.2 years At 3 months, 70% of

patients had >50% reduction in seizures

>90% reduction in seizures in 20% of patients

63% reported reduction in spasms at one month

QOL improvement


Epilepsy syndromes helped by KD

•

Kossoff et al. 2008 Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group by


Epilepsy Program at CMH• 91 patients

• 50 (55%) males

• Age of seizure onset: 1.39 years ± 2.02

• Age of diet onset: 3.45 years ± 2.83

• Time on diet: 2.52 years ±1.23

• 40 (44%) tube fed

– 1 blenderized tube feeding

• 9 (10%) on Modified Atkins Diet

Epileptic Spasms, 19%

Generalized Epilepsy of

Unknown Etiology, 19%

Doose Syndrome/ Myoclonic Astatic

Epilepsy, 15%

Focal Epilepsy of Unknown Etiology,

12%

Hypoxic Ischemic Encephalopathy,

12%

Glut 1 Deficiency , 7%

Lennox Gastaut Syndrome, 3%

Lissencephaly, 3%Rett Syndrome,

3%

Other , 5%

Diagnoses of Patients on KGD (n=91)


Ketogenic Diet


• Inpatient initiation• All food is weighed using a gram scale• Calculated according to a ketogenic ratio• Most commonly prescribed as a 4:1 or 3:1 ketogenic ratio

Classic

• Inpatient/Outpatient initiation• Household measurements or gram scale can be used• Calculated according to the percentage of calories coming

from MCT oil

MCT

• Outpatient initiation• Household measurements used; no gram scale needed• Only carbs are restricted; Protein and calories are liberal• Although not calculated as a ratio, typically ~ 1:1 ratio

Modified Atkins Diet

• Outpatient initiation• Household measurements used; no gram scale needed• Restricts carbs according to GI scale to allow for more

total carbs• Carbs, protein and calories are restricted for LGIT

Low Glycemic Index Treatment

Alternatives to the Ketogenic Diet

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Diet Comparison


Ketogenic Diet Team and Roles

• Epilespy Coordinator

• Physicians

• Nurse Practitioners

• Dietitians

• Social Worker

• Chef Educator

• Neuropsychologist


Ketogenic Diet Baseline Screening Process

• EKG

• Bone Scan

• Nutrition

– Concerns with child's ability to safely eat/swallow

– Fluid intake

• Labs• Complete blood count with differential• Basal metabolic panel• Magnesium• Zinc• Selenium• Hepatic function test• Lipid profile• Beta-hydroxybutyrate• Urine organic acids• Serum amino acids• Vitamin D• Lactic acid• Acetylcarnitine• Urinalysis • Ammonia• PTH


Ketogenic Diet Induction

• Involves a 3-5 day inpatient admission

– Monday start day

– Admission ~9-10AM after regular breakfast

• Gradual induction of the diet each day

• 1:1 2:1 3:1

• Monitor for tolerability and side effects

• Parent education


Ketogenic Ratio

The ketogenic ratio is the ratio of grams of fat to grams of protein and carbohydrates

4:1

3:1 ratio used most frequently due to tolerability Ample protein and sufficient calories for growth Supplementation of vitamins and minerals at

100% of the DRI

grams of carbohydrate + protein

grams of fat


Sample Menu

Meals for: KSR KSR KSR Calorie Level: 1200Ratio: 3:1Meals Per Day: 4

13-Chicken Breast/Fruit/Mayo

Grams

30 Cream, 36%

34 10%Fruit

14 Chicken Breast, no skin – cooked

9 Oil, Canola

11 Mayonnaise, Hellmann's/Best Foods

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Ketogenic Diet- Medications

• All medications changed to tablets (or lowest carbohydrate form)

– Any suspension or syrup likely contains carb

– Looking for "carbohydrate-free" not just "sugar-free"

– Goal is <1 gram (1000 mg) carb for all medications and supplements

• No IV solutions with dextrose added

– If IV fluid needed use Normal Saline


“Normal Labs” for the Ketogenic Patient

• Blood Glucose: 40-100 mg/dl

– Typically checking q 6 hours when diet is being initiated, q 12-24 thereafter

– Typically if <40 mg/dl, treated with a bolus of apple juice

• 10 ml D10 or 10 ml apple juice contain 1 gram carbohydrate

• CO2: >15 mmol/L

– Typically checked daily during initiation

– If falls <15, treated with IV bicarb (1 mg/kg)


“Normal Labs” for the Ketogenic Patient

• Betahydroxybutyrate: >2,000 mcmol/ml

– Serum level of ketones

– Typically checked daily during initiation

– Satisfactory level very individualized (2-10,000 mcmo/ml)

• Urinary Ketones: moderate-large

– Typically checked q void during initiation

– Urine ketones are very weak in infants and may not be as accurate as serum ketones


Ketogenic Diet Supplements

• Multivitamin

• Calcium with Vitamin D

• Salt substitute/ table salt

• Polycitra K or Sodium Bicarb (optional)

• Carnitor (optional)


Patient identified as needing thickener and ketogenic diet

<12 months of age and/or history of NEC?

Consider Tube Feeding

Simply Thick

Ketogenic Diet- Thickeners

NO

YES

What is most important and realistic for the

patient? seizure control vs. feeding /

quality of life

• Simply Thick is the only approved thickener for patients on the ketogenic diet (xanthum gum based)

• FDA issued a warning for patients < 12 months of age or with a history of NEC


Ketogenic Diet- OTC Products

• Increased seizures have been documented in children on the ketogenic diet after use of topical products containing carbohydrates

• Charlie Foundation List www.charliefoundation.org

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Potential Complications

Acute• Hypoglycemia• Acidosis (CO2 <15)• Lethargy • Nausea/ Vomiting• Irritability – “waking up”;

change in sensory experience

Long Term• Constipation – most

common• Osteopenia• Kidney stones• Growth failure


Growth on Ketogenic Diet

Thompson L, et al (2013): Growth and Energy Intake of Infants and Children treated with the Ketogenic Diet (American Epilepsy Society Annual Meeting 2013)

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Baseline 3 Month 6 Month 12 Month

Weight Percentile

Height Percentile

Weight and Height Percentile for Patients on Ketogenic Diet (n=76)

Age 5.95 years ± 3.86

Males n (%) 49 (64.5%)

Age of Seizure Onset 1.25 years ± 2.27

Age of Diet Onset 3.13 years ± 3.04

Time on Diet 2.43 years ± 1.34

Tube Fed n (%) 37 (48.7%)

Patient Demographics1

(n=76)

1Means ±SD at baseline unless otherwise noted


Discharge and Follow Up

• Needed for discharge:– Formula

– Ketone strips

– Do not usually have patients check blood sugars at home

• Follow up: Epilepsy Clinic– Typically 2 weeks – 1 month after discharge

– Every 3 months thereafter


Ketogenic Diet Monitoring

Every 3 months

Growth assessment

Labs

CBC with differential

Serum BMP

Hepatic function tests

Serum lipid panel

Annually

Serum selenium and vitamin D levels

Bone Scan (DXA)


Troubleshooting Increased seizures

Constipation

Teething

Illness/infection (increases serum glucose)

Liquid medication

Wrong brand of food/ patient sneaking food

Used a product that contains carbohydrates

High serum triglycerides

Increase MCT oil (start with 5% of fat kcal and increase up to 40% of fat kcal)

Carnitine supplementation: 330 mg TID


Constipation

• MCT Oil

– Added to formula or foods

– Start at 5% of calories, can increase up to 40% of calories as tolerated

• Miralax

• Glycerin Suppositories

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Fine Tuning the Diet Fine Tuning

– Calorie adjustments

– Ratio adjustments

– Meal plans (3 versus 4 meals, snacks)

– Liquid intake

– Medications

– Supplement adjustments


Weaning off the Diet• Wean slowly- 0.25-0.5 in ratio every 1-2 weeks

• EEG prior to weaning

• After reaching 1:1 ratio, follow the following steps:

– Step 1: 3-4 days

• Provide menus from ketogenic plan, but discontinue measuring foods


• Replace all cream with milk

• Start increasing portions of fruits, vegetables and other carbohydrates


• Begin offering 1 starch daily, such as rice, cereal, pasta or bread

• Slowly increase starch offerings until providing an age appropriate diet


The Che“Finn”ator• Rachel Finn, Chef

Educator

• Stop by her booth for samples


Creative Menu IdeasTea Party for 6 year old

Butterfly:Flaxseed Bread with

Butter tinted with food color

Flower:“Raw” Cookie Dough

Nail polish bottle:Jello/Cream roll with “raw”cookie dough lid.


Questions?

“Let food be thy medicine and medicine be thy food.”

Hippocrates


References- Epilepsy• Freeman, J.M., et al. Epilepsia, 2009. 50(2): p. 322-5

• Garriga-Canutetal., 2006. Nat Neurosci 9, 1382-1387

• Greene etal., 2001 Epilepsia 42, 1371-1378

• Henderson et al. 2006 Meta-analysis of 19 studies and a total of 1084 patients

• Kong ST. Epilepsy Res. 2014 Sep;108(7):1253-62

• Kossoff, E.H. Epilepsia, 2009. 50(2): p. 304-17.

• Kossoff et al. 2008 Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group by

• Kossoff et al., Epilepsia 2005 (updated 2014)

• Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

• Levy, R.G., Cochrane Database Syst Rev, 2012. 3: p. CD001903.

• Maalouf et al., 2009. Brain Res Rev. 59, 293-315

• Neal, E.G., et al. Lancet Neurol, 2008. 7(6): p. 500-6.

• Seo JH, Lee YM, Lee JS et al. Efficacy and Tolerability of the Ketogenic Diet According to Lipid:Nonlipid Ratios—Comparison of 3:1 with 4:1 Diet. Epilepsia, 2007;48(4):801–805.

• Stafstrom, et al 2012; Front Pharmacol. 9;3:59

• Theile, et al Epilepsia 2003, 44(suppl.7):26-29

• Walker AE. J Pediatr. 1951 Mar;38(3):285-98.

• Wheless JW. Neurostimulation Therapy for Epilepsy. In: Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc. 2008.

• Wilder RM. (1921) Mayo Clinic Bulletin 2:307.

• Woodyatt RT. (1921) Objects and method of diet adjustment in diabetics. Arch Intern Med 28:125–141.

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References- Other• Aft et al., 2002; Br J Cancer 87, 805-812.• Appelberg et al., 2009; J Neurotrauma 26, 497-506• Cardinali et al., 2006; Epilepsy Res 69, 129-134• Evangeliou et al., 2003; J Child Neurol 18; 113-118 • Henderson et al.,2009; Nutr Metab (Lond) 6, 31• Hu et al., 2009; Brain Inj. 23, 459-465• Kapogiannis and Mattson, 2011; Lancet Neurol 10, 187-198• Masino et al., 2011; Neurosci Lett. 500, 1-5• Otto et al., 2008, BMC Cancer 8, 122• Pelicano et al., 2006; Oncogene 25, 4633-4646• Prins et al., 2005; J. Neurosci. Res. 82, 413-420• Roberson et al., 2011; J Neurosci, 31, 700-714• Seyfried et al., 2011; Epilepsy Res• Siva, 2006; Lancet Neurol, 5 476. • Stafford et al., 2010; Nutr Metab (Lond) 7, 74• Zhao et al., 2006, BMC Neurosci. 7, 29.• Zuccoli et al., 2010; Nutr Metab (Lond) 7, 33.

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