Ketogenic diet and other dietary therapies in epilepsy. Randa Jarrar, MD

Transcription

1 Ketogenic diet and other dietary therapies in epilepsy Randa Jarrar, MD

2 Ketogenic diet: History What is involved Efficacy Complications How does it work Variations: MCT ketogenic diet Low glycemic index diet Modified Atkins diet Dietary Therapies

3 Introduction: Epilepsy Up to 5% of the world s population will have a single seizure at some point in their life 0.5% to 2% of people will develop epilepsy during their lifetime Seizure in up to 30% of people with epilepsy do not respond to available medications

4 History Hippocrates: wrote that modification of diet is required to treat epilepsy Based on belief that epileptic patient s body was polluted and modification of diet allows purification 5 centuries later fasting was documented in biblical times in King James version of The Bible

5 History In 1911: first modern use of diet in medical literature by French physicians Guelpa and Marie: reported 20 patients, children and adults 1920s: Conklin, Mcfadden and Geyelin described the benefits of fasting on seizure control and improved cognition in patients with epilepsy

6 History 1921: two pivotal observations were made Wilder at the Mayo clinic: benefits in patients with epilepsy with low carbohydrates. As effective as starvation and can be maintained longer: coined the term Peterman at Mayo clinic: Reported calculation of KD: 1g protein per kg of body weight for children, 10-15g of CHO and the remainder from fat Reported positive effect on behavior and cognition

7 History 1927: Talbot at Harvard described the protocol still used for calculating and initiating diet: hours of fasting to hasten production of ketones 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%

8 History Bromides and phenobarbital were the only medications available at the time, there was a flurry of clinical and research activities on the ketogenic diet The diet was widely used during the 1930s, but it fell out of vogue when diphenylhydantoin was introduced in Compared with DPH treatment, the diet was viewed as difficult, rigid, and expensive

9 History Changing focus of epilepsy treatment: Talbot s Treatment of Epilepsy, 1930 One small chapter on medication Half of book focused on the ketogenic diet Lennox s Epilepsy and Related Disorders, 1960 Single paragraph on ketogenic diet For most patients, young and old, drug therapy is the kingpin of treatment

10 History Ketogenic diet in popular culture 1997: First Do No Harm (Charlie Foundation)

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12 History Ketogenic diet in medical literature Medline citations (ketogenic diet and epilepsy) in 30 years > 800 articles

13 What is involved?

14 What is involved? Ketogenic Diet American Diet Carbs Protein Carbs Protein Fats Fats

15 What is involved? Ketogenic Ratio Ratio (by grams) Fat : (Protein + Carbohydrate) i.e., 4:1 ratio implies 4 grams of fat to 1 gram combined of protein and carbohydrate Calories: Based on age, ideal body weight, and current intake: Protein: RDA or above Vitamins and minerals: RDI Fluid is not restricted

16 What is involved? Food groups Cream Fat Fruit or vegetable Protein No bread, pasta, or grains No sugar No starchy fruit or vegetable Vigilant exclusion/monitoring of extra carbohydrates e.g., in medications, lotions, toothpastes

17 The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial Inclusion criteria Referral pts; 2-16 yrs old Seizures daily or > 7 per week Failed > 2 medications ILAE syndrome classification Methods Randomized to balance in age groups Begin KD (classical or MCT) after 4 wk baseline Begin KD 3 mos after baseline, no Rx change No blinding Neal, Chaffe, Schwartz, Lawson, Fitzimmons, Whitney, Cross. Lancet Neurol 2008:7:500-06

18 The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial Methods (cont) Non fasting initiation at home Reviewed at 3 and 6 mos Primary outcome = efficacy (seizure freq) Tolerability determined by questionnaire Results 145 children participated Neal, Chaffe, Schwartz, Lawson, Fitzimmons, Whitney, Cross. Lancet Neurol 2008:7:500-06

19 The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial

20 % 3-33% 12-58% Pediatric Neurology 2006;35:1-5

21 Prospective, Open label, Uncontrolled

22 Ketogenic diet efficacy by seizure type Seizure Type >90% Seizure Reduction Myoclonic 69% Atonic-drop 69% Absence 75% Atypical absence 75% Tonic-clonic 48% Tonic 33% Complex partial 53% Simple partial 100% Swink, et al

23 Ketogenic diet efficacy in status epilepticus Bodenant 2008: adult with partial status epilepticus Villeneuve 2009: 4/5 children focal status epilepticus Nam 2011: 5 patient with viral encephalitis Nabbout 2010: FIRES effective in 7/9 patients within 2-4 days Appavu /10 patients achieved resolution of SRSE with KD therapy

24 Does the ratio matter?? 76 children with intractable epilepsy 3:1 and 4:1 Efficacy higher for 4: % vs 31% seizure free at 3 months Those who switched from 4:1 to 3:1 remained seizure free Those who switched from 3:1 to 4:1 experienced modest improvement but none became seizure free Tolerability was better for 3:1 Start 4:1 and may decrease later to improve tolerability Seo et al Epilepsia 2007

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26 Ketogenic diet: benefits beyond seizures Dashti 2006: adults on KD for more than a year had significant decrease in BMI and improved lipid studies Livingston 1972: better behavior and disposition Pulsifer 2001: mean developmental quotient significantly improved. Better behavioral functioning Hallbook 2007: improved quality of life and attention

27 The Ketogenic Diet: Side Effects Elevated serum lipids: those followed into their 40s had no evidence of atherosclerosis Constipation: possibly related to fluid restriction and decrease in bulk of food intake

28 The Ketogenic Diet: Side Effects Deficiencies in water soluble vitamins supplement multivitamins with minerals, vitamin D and calcium Renal stones (5-7%): Hypercalciuria acidic urine low urinary citrate low fluid intake. Carbonic anhydrase inhibitors unlikely to contribute to this (Sampath 2007). Polycitra considered an optional supplement

29 The Ketogenic Diet: Side Effects Growth inhibition: controversial: Weight loss more likely in non-ambulatory, non-verbal and younger kids Acidosis (bone health, lethargy, vomiting) and excess ketosis during illness Low carnitine, acute pancreatitis, prolonged QT and excessive bruising

30 The Ketogenic Diet: Side Effects Contraindicated in: pyruvate carboxylase deficiency, defects in fatty acid oxidation, carnitine deficiency, porphyria

31 The Ketogenic Diet: for how long?? 28 patients treated for 6-12 years 24 had > 90% reduction in seizures 10 were below 10 th percentile for height at initiation, 22 were below 10 th percentile at follow up 7 had kidney stones 6 had skeletal fractures Dyslipidemia in all Groesbeck 2006

32 Ketogenic Diet: how long? >50%: seizure reduction: treat for two years Seizure free: treat for two years of seizure freedom. Unsuccessful: discontinue in 3 months although usually can tell by week two (75% of children respond by 14 days. Kossoff 2008)

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34 Consensus recommendations Should be offered after two AEDs have been used unsuccessfully (unless patient is a potential surgical candidate) first line for glucose transporter defect and pyruvate dehydrogenase deficiency probably very beneficial in : Doose syndrome, Dravet syndrome, infantile spasms, Rett syndrome, Tuberous sclerosis

35 Consensus recommendations Education Nutritional assessment Change medications Review supplements Fasting probably not required (no change in seizure control rates) Advantages to initiating without fast: Shorter hospitalization Better tolerated with less acidosis, hypoglycemia Less stressful for child and parents Baselines labs, possibly EEG, growth parameters

36 Consensus recommendations Follow up in one month after initiation then every three months Labs done at each follow up, monitoring of growth Ketogenic diet team crucial but frequently not available!!! Knowledgeable dietician Pediatric epileptologist Epilepsy nurse specialist

37 Modified Atkins Diet Reports of patients and families that a stricter version of the Atkins diet and a looser version of the KD are effective with 50% reduction in seizure frequency in half of the patients (Kossof 2003, 6 patients) Modified: fat intake is encouraged not just allowed, induction phase is maintained, weight loss is not the goal

38 Epilepsia pages 37-41, 4 NOV 2008 DOI: /j x

39 Modified Atkins for Seizures: Children Prospective open-label study of 20 patients age 3-8 years Carbs restricted to 10 g and fats encouraged 16/20 completed 6 mo study 65% had a greater than 50% reduction in seizure frequency and 35 % greater than 90% reduction Mean AED trials: 6.5 Randomized cross over comparison of daily carbohydrate limits using MAD 10 g more effective early on but may be liberalized at 3 months Kossoff, et al Kossoff et al 2007

40 Modified Atkins for Seizures Outpatient initiation No initial fast No caloric, fluid restriction No weighing of foods; no specific meal plans CHO limited to gm/day for first month; increase to gm after 1-3 mo (any CHO) Multivitamin, calcium supplementation Weekly weights Labs (CBC, electrolytes, lipid profile) q 3 mo Urinary ketones measured semiweekly

41 Low Glycemic Index Treatment: Background Anecdotes sugary treats and seizures Children on ketogenic diet can be VERY sensitive to extra carbohydrates, with adverse effects on seizure control Inadvertent D5 infusion M&M s Change in vanilla extract lot Varieties of grapes

42 Blood glucose Blood glucose Glycemic Index (GI) The two hour blood sugar response of a high-gi food versus a low-gi food Reference food (Glucose, GI=100) Test food with equal wt carbohydrate GI=40 100% 40% Time Time

43 Glycemic Index (GI) Examples of foods with various glycemic indexes Fruits Breads HIGH Melons Bagels MODERATE Apple Whole grain bread LOW Grapefruit Whole grain bread 2.5 3g fiber

44 Epilepsia pages 42-45, 4 NOV 2008 DOI: /j x

45 Low glycemic index diet 20 patients initiated on LGIT: - 9 switched over, 11 denovo Ages: 5-34 years Carbs restricted to 40-60g/day Average # of previous AED s = 7 Denovo: 73% > 50% reduction, 36% seizure free Switched over: only two experienced worsening of seizures Length of treatment: w (avg 20 w) Pfeifer and Thiele

46 Low glycemic index diet Calorie goals are based on current intake according to three day food records and food frequency questionnaires (to maintain adequate growth and development) Carbohydrates are limited to g per day from low glycemic index sources (GI<50) Food is not weighed, but based on portion sizes Fluid is not restricted, rather encouraged Vitamins and minerals are supplemented to meet individualized needs Initiation as outpatient with follow up 1 month post-diet initiation and then every 3 months for duration of treatment

47 Bough & Rho, Epilepsia 2007

48 How Do They Work? Direct action of ketone bodies: broad spectrum antiepileptic activity of acetone shown in several models but the exact mechanism is unknown Changes in brain ph: acidosis favors neuronal inhibition Glucose restriction changes in K ATP channel Polyunsaturated fatty acids: direct inhibitory action on voltage gated Na channels and L type Ca channels. Modulate voltage gated ion channels Bough & Rho, Epilepsia 2007

49 How do they work? Changes in electrolyte and water balance Mitochondrial uncoupling proteins UCPs: maybe more important to neuroprotection (decreasing Ca influx and free radical production but? antiepilpetic action: maybe seizures are provoked by oxidative stress and if you control that you control seizures)

50 How do they work? Neurotransmitters: NE increased levels Shift in aminoacid handling: increases glutamate to GABA conversion Caloric restriction increases glutamate to GABA conversion

51 Other applications Neuroprotection Alzheimer Brain tumors

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54 Thank you