Minnesota Epilepsy Group, P.A. Ketogenic diet Jason Doescher, MD Pediatric Neurology & Epilepsy Minnesota Epilepsy Group, PA Saint Paul, Minnesota 651.241.5290
Ketogenic diet ADK (adenosine kinase stain) Li et al. J Clin Invest. 2008;118(2):571–582. Discussion goals: • Why: ketogenic diet in epilepsy therapy • What: ketogenic diet mechanism • Who: syndrome & seizure types • Where does it get you: results • How: strategy for tolerance & goals
Understand pathology / understand diverse therapy Seizure: abnormal neuronal & inter-neuron connections leading to recurrent imbalance in excitation & inhibition altering normal function & signaling Molecular: Genes proteins, neurotransmitters; toxins, electrolytes, energy/metabolism Cellular: Channels, receptors; neurons, astroglia Neuronal networks: Malformations of cortical development, inflammation, neoplasia, mesial temporal sclerosis/gliosis, trauma
Minnesota Epilepsy Group, P.A. Therapeutic strategy:think pathology & review results
Minnesota Epilepsy Group, P.A. AED efficacy: 64% total seizure free (301/470)Ref: Brodie & Kwan, NeurologyVol 58, Number 8, April 23, 2002 Monotherapy 1st AED Monotherapy 2nd AED Monotherapy 3rd AED Adjunctive Therapy Seizure-free 47% (n=221) Newly Diagnosed Epilepsy (n=470) Seizure-free 13% (n=32) Seizure-free 1% (n=1) Seizure-free 3% (n=1) Uncontrolled Seizures 53% (n=245) Uncontrolled Seizures 40% (n=100) Uncontrolled Seizures 39% (n=39) Uncontrolled Seizures 36% (n=14)
Minnesota Epilepsy Group, P.A. Ketogenic diet: place in therapy • Anti-epileptic medications provide approximately 60-75% of patient’s with seizure control • If patient fails 3 medication trials, only 1-15% will achieve seizure control with additional medication combinations • Surgery: 50-90% of appropriate epileptogenic zone resection candidates attain seizure control, but only 5-15% total qualify
KETOGENIC DIET
Metabolism map
Metabolism review:Typical diet: glucose pyruvate acetyl CoA Ketogenic diet: fatty acid acetyl CoA
Minnesota Epilepsy Group, P.A. Mitochondria uses ‘citric acid cycle’ to make ATP. Acetyl CoA is common substrate of both fatty acid & glucose metabolism.
Minnesota Epilepsy Group, P.A. Ketogenic diet • ‘transition of energy production from carbohydrates to fats’ • Effectiveness depends on the degree of carbohydrate restriction & maintenance of ketone level (BHB goal 3-4) • Fat: carbohydrate + protein ratio of 3:1 - 4:1 • 3:1 diet has long-chain saturated fat (87% calories), carbohydrate (6%), protein (7%)
Ketogenic diet • Mechanism of action: metabolism v anti-epileptic properties of ketones/fatty acid metabolites • Ex. Neurosteroids on GABA-a receptors • Ref: Benaroch EE. Neurology 2007;68(8):612-614.
Ketogenic diet: therapy
Minnesota Epilepsy Group, P.A. Seizure & syndrome types:typically responsive to ketogenic diet Seizure types: Syndromes: Myoclonic atonic epilepsy Doose syndrome Lennox-Gastaut syndrome Glucose transporter deficiency syndrome Pyruvate dehydrogenase deficiency Metabolic/mitochondrial encephalopathies Caution to exclude fatty oxidation disorder Intractable focal or generalized epilepsy Dravet syndrome • Atypical absence (refractory) • Atonic • myoclonic atonic * • Tonic • Myoclonic
Ketogenic diet: results
Minnesota Epilepsy Group, P.A. Ketogenic diet: results • In 1923, Conklin treated epilepsy by prescribing “rest of gastrointestinal system” for 25 days. He reported 90% ‘success’ rate in children and 50% in adults. • In 1921, Wilder introduced the ketogenic diet. Later reported 95% of patients showing improvement through treatment.
Minnesota Epilepsy Group, P.A. Ketogenic diet: results • Maydell (2001 USA): classic diet 4:1 ratio over 12 months, 143 patients • Seizure free: 16% • >90% seizure reduction: 27% • >50% seizure reduction: 38% • Kang (2005 Korea): 199 patients • Seizure free: 25% • >50% seizure reduction: 41%
Minnesota Epilepsy Group, P.A. Ketogenic diet: results • In children, composite of many studies… Seizure free at 6 months 15% >90% seizure control: 37% 90-50% seizure control: 30% <50% seizure control: 33% • Keene 2006 meta-analysis
EEG : before ketogenic diet
EEG : before ketogenic diet
Normal EEG : after ketogenic diet
Minnesota Epilepsy Group, P.A. Keys to success: patience, consistency & teamwork Team • Dietician • Parent/Caregiver • Patient • G-Tube possible • Physician/Nurse
Minnesota Epilepsy Group, P.A. Ketogenic Diet: application • Careful patient selection: exclude fatty acid oxidation disorder • Lab: Carnitine & acyl-carnitine profiles; urine organic acids • Gradual introduction (5-7 days), no fasting, no fluid restriction • Ensure energy & growth • Follow acidosis, glucose, & electrolytes (Na) • Supplements: vitamins (D, B) & minerals (Calcium, Selenium, Zinc) • Caution: • Depakote (follow liver function & carnitine stores) • Acetazolamide, topiramate & zonisamide (acidosis & kidney stones) • “Syrups & Elixirs” – sugar/carbohydrates • KNOW THE CARBOHYDRATE CONTENT!! • ‘2 week honeymoon’ then advance ratio
Minnesota Epilepsy Group, P.A. Risks & complications • Growth delay & reduction • Hyperlipidemia • Cardiac dysfunction • Kidney stones • Disordered bone metabolism • Bone marrow dysfunction • Liver dysfunction
Minnesota Epilepsy Group, P.A. Alternatives • Modified atkins diet • Low glycemic index diet
Minnesota Epilepsy Group, P.A. Ketogenic diet • Why: role ketogenic diet in epilepsy therapy • Roughly 1 in 4 patients need new strategy beyond medications & surgery • What: ketogenic diet mechanism • Shift in energy metabolism with direct or indirect anti-epileptogenic properties • Who: syndrome & seizure types • Select patients & others who fail medication trials or who are not surgical candidates • Where does it get you: results • 15% seizure freedom, 30% excellent results, 30% modest improvement • How: strategy for tolerance & goals • Patience, consistency & teamwork
Thank You Jason Doescher, MD Pediatric Neurology & Epilepsy Minnesota Epilepsy Group, PA Saint Paul, Minnesota 651.241.5290 Minnesota Epilepsy Group
