Revisiting the Ketogenic Diet and Related Therapies in the Modern Era
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1 Revisiting the Ketogenic Diet and Related Therapies in the Modern Era Heung Dong Kim M.D., Ph.D. Pediatric Epilepsy Clinic, Division of Pediatric Neurology Severance Children s Hospital Yonsei University College of Medicine
2 Ketogenic Diet Most potent antiepileptic treatment among non-surgical modalities Benefits to prevent major cognitive side effects from multiple medications Most difficult treatment for prolonged maintenance Hazards from many early and late complications
3 Seizure Free Rate of Ketogenic Diet Compared with New AED s for Intractable Epilepsy Drugs Seizure type Follow-up Seizure-free rate Felbamate LGS 8 wks 8% Gabapentin PS 12 wks 1% Topiramate PS 12 wks 12% LGS 8 wks 2% GS 12 wks 4% Levetiracetam PS 12 wks 8.2% Vigabatrin PS 12 wks 6% Ketogenic diet Total 12 wks 35% LGS 12 wks 26% PS 12 wks 42%
4 History of Ketogenic Diet Sustained fasting used to control seizure in the time of Hippocrates The Middle Ages: Preying with fasting in Monastery Guelpa & Marie (1911): first scientific report of anticonvulsive effect from fasting Geylin (1921): seizure control by cyclic fasting Wilder (1921): develop ketogenic diet for maintaining prolonged anti-epileptic efficacy of fasting World wide spread from 1994 after broadcasting from NBC dateline introducing Charlie foundation In Korea: First application in 1995
5 History of Ketogenic Diet NBC dateline video
6 History of Ketogenic Diet NBC dateline video
7 History of Ketogenic Diet NBC dateline video
8 Publications for Ketogenic Diet in the Past 24 Years
9 Advances of Ketogenic Diet Scientific evidences Mechanism of action Standardization Widening of usability and indication Protocol modification Enhancing tolerability and safety
10 Advances of Ketogenic Diet Scientific evidences Mechanism of action Standardization Widening of usability and indication Protocol modification Enhancing tolerability and safety
11 Class I Evidence for Ketogenic Diet Neal EG, et al. Lancet Neurol 2008;7:500-6
12 Advances of Ketogenic Diet Scientific evidences Mechanism of action Standardization Widening of usability and indication Protocol modification Enhancing tolerability and safety
13 Anticonvulsive Mechanism of Ketogenic Diet Bough & Rho. Epilepsia, 48(1):43 58, 2007
14 Anticonvulsive Mechanism of Ketogenic Diet Bough & Rho. Epilepsia, 48(1):43 58, 2007
15 Ketogenic Diet: Mechanism of Action Gano, LB, M Patel, and JM Rho. J. Lipid Res :
16 Advances of Ketogenic Diet Scientific evidences Mechanism of action Standardization Widening of usability and indication Protocol modification Enhancing tolerability and safety
17 International Consensus Statement Kossoff, E, et al. Epilepsia, 50(2): , 2009/Epiepsia Open, 3(2): ,2018
18 Indication of Ketogenic Diet Kossoff, E, et al. Epilepsia, 50(2): , 2009/Epiepsia Open, 3(2): ,2018
19 Contraindications to the diet? Kossoff, E, et al. Epilepsia, 50(2): , 2009/Epiepsia Open, 3(2): ,2018
20 Surgery or the Diet in Focal Epilepsy? 45 children with surgically approachable lesions 25 underwent surgery More likely to have a >90% (71% versus 17%) or seizure-free (63% versus 0%) response with surgery (p<0.0001) Stainman Seizure 2007
21 Case: Late Onset Infantile Spasm Seizure: frequent tonic spasms Onset: 22 mo. of age Development: well until seizure onset, and subsequent profound regression Intractable to all AEDs
22 Case: Late Onset Infantile Spasm Seizure: frequent tonic spasms Onset: 22 mo. of age Development: well until seizure onset, and subsequent profound regression Intractable to all AEDs Ketogenic diet started at 36 mo. and became seizure free Progressive regaining of cognitive function: DQ below 40 at 36 mo., over 100 at 7 yrs. 2 mo.
23 Ketogenic Diet in Surgically Remediable Focal MCD DE Jung, et al. Pediatrics, 2008: 122: e330-
24 DE Jung, et al. Pediatrics, 2008: 122: e330- Ketogenic Diet in Surgically Remediable Focal MCD
25 Ketogenic Diet in Surgically Remediable Focal MCD Seizure free outcome at 3 months: 44.7% (21/47) Seizure free outcome at 24 months: 34.0% (16/47) Successful seizure free maintenance from 3 months at 24 months: 76.2% (16/21) Long-term seizure free outcome after DC of KD in initial remission patients: 47.6% (10/21) Long-term seizure free outcome after surgery: 59.1% (13/22) DE Jung, et al. Pediatrics, 2008: 122: e330-
26 mtor Activation in Focal Cortical Dysplasia JS Lim, WI Kim, HC Kang, et. a.l. Nature Med
27 mtor Activation in Focal Cortical Dysplasia JS Lim, WI Kim, HC Kang, et. a.l. Nature Med
28 mtor Activation in Focal Cortical Dysplasia JS Lim, WI Kim, HC Kang, et. a.l. Nature Med
29 mtor Activation in Focal Cortical Dysplasia M. Wong / Experimental Neurology 244 (2013) 2
30 mtor Activation in Focal Cortical Dysplasia M. Wong / Experimental Neurology 244 (2013) 22 2
31 Advances of Ketogenic Diet Scientific evidences Mechanism of action Standardization Widening of usability and indication Protocol modification Enhancing tolerability and safety
32 Case: Landau-Kleffner Syndrome Fluctuating sensory aphasia in previous complete normal child at 5 years of age No presenting clinical seizure EEG: ESES MRI: normal Intractable to multiple AED s Serum lactate: increased Lactate/pyruvate ratio: high Serum amino acid: normal Urine organic acid: increased lactate MELAS/MERRF gene study: normal WISC: not checkable
33 Case: Landau-Kleffner Syndrome Started KGD at 7 years of age: improving mental function and no more seizure Normalization of EEG s Skin fibroblast culture: decrease of MRC I activity Started mitochondrial cocktail IQ: not checkable at onset of KD, 105 1year later, years later
34 Landau-Kleffner Syndrome Fluctuating sensory aphasia in previous complete normal child at 5 years of age EEG: ESES KGD at 7 years of age: improving mental function and no more seizure Normalization of EEG s Skin fibroblast culture: decrease of enzyme complex I activity Started mitochondrial cocktail IQ: not checkable at onset of KD, 105 1year later, 116 2years later
35 Ketogenic Diet in Intractable Epilepsy from MRC Deficiency
36 Ketogenic Diet in Intractable Epilepsy from MRC Deficiency Kang et al. / Epilepsia 2007, 48 (1);82-8
37 Ketogenic Diet in MRC Deficiency MRC defect is a contraindication for KD because of the metabolic burden - Vinning EPG. Ketogenic diet. In Engel J Jr, Pedley TA, eds. Epilepsy, a Comprehensive Textbook., 1998: Nordli DR Jr, DeVivo DC The ketogenic diet. In Wyllie E, ed. The Treatment of Epilepsy, Principles and Practice, 3 rd ed. 2001: Although we used to avoid the diet in certain respiratory chain abnormalities, recently a group from South Korea showed that the diet can be used successfully in some patients with respiratory chain abnormalities (Kang et al., 2005) - Nordli, DR Jr., The role of the ketogenic diet in the modern treatment of epilepsy. In Conference review, John Freeman et al. Epilepsy Research 68 (2006)
38 Indication of Ketogenic Diet Kossoff, E, et al. Epilepsia, 50(2): , 2009/Epiepsia Open, 3(2): ,2018
39 Advances of Ketogenic Diet Scientific evidences Mechanism of action Standardization Widening of usability and indication Protocol modification Enhancing tolerability and safety
40 Benefits of Nonfasting Ketogenic Diet
41 Benefits of Nonfasting Ketogenic Diet Kossoff, E, et al. Epiepsia Open, 3(2): ,2018
42 Protocol Modification to Shorten Duration
43 Advances of Ketogenic Diet Scientific evidences Mechanism of action Standardization Widening of usability and indication Protocol modification Enhancing tolerability and safety
44 Development of Palatable, Individualized and Diverse Menus
45 Formulas for Ketogenic Diet VS.
46 Expanding Dietary Variability Kossoff,, EH, et. al. NEUROLOGY 2003;61:
47 Expanding Dietary Variability Random controlled trial between KD (N=51) and MAD (N=53) KD group had a lower mean percentage of baseline seizures compared with the MAD group at 3 months (38.6% for KD, 47.9% for MAD) and 6 months (33.8% for KD, 44.6% for MAD), without statistically significance (p = 0.291) Seizure free rate at 3 months was significantly higher (53% for KD, 20% for MAD, p = 0.047) in patients aged 1 2 years
48 Expanding Dietary Variability SH Kim, HC Kang, EJ Lee, et. a.l. Brain & Dev, 39:687 92, 2017
49 Clinical Application Cases of Dietary Treatment in the Past 22 Years at SCH LGI diet KD + MAD
50 Complications of Ketogenic Diet b Nausea/vomiting, constipation, food refusal, diarrhea Kang HC, Chung DE, Kim DW, Kim HD. Epilepsia 45(9): , 2004
51 Esophageal Erosion with Fungal Infection
52 Lipoid Pneumonia
53 Osteoporosis and Pathologic Fracture
54
55 Precision Medicine: Treatment in Genetic Epielpsy Gene Effect of mutation Epilepsy syndrome Therapy DEPDCS, NPRL2/3 mtor disinhibition Familial focal epilepsy mtor inhibitors/hypothetical GRIN2A/2B Gain of function BRE, LKS, ECSWS Memantine/Hypothetical KCNA2 Gain of function Epileptic encephalopathy 4-aminopyridine/Hypothetical KCNQ2 Loss of function Epileptic encephalopathy Sodium channel blockers/established Retigabine/Potential KCNT1 Gain of function EIMFS, NFLE Quinidine/Potential Beripril/Hypothetical SCN1A Gain of function Dravet syndrome Avoid sodium channel blockers/established Stiripentol/Established Fenfluramine/Potential SCN2A Gain of function Various Na+ channel blockers/potential SCN8A Gain of function Epileptic encephalopathy Na+ channel blockers/potential SLC2A1 (GLUT1) Loss of function Various Ketogenic diet /Established TSC1, TSC2 mtor disinhibition Tuberous sclerosis mtor inhibitors /Established
56 Efficacy of Ketogenic Diet According to Pathogenic Genetic Mutation in EE Ko, A et. al. Frontiers Neurol. July 2018/Volume 9/Article 530
57 Efficacy of Ketogenic Diet According to Pathogenic Genetic Mutation in DEE Ko, A et. al. Frontiers Neurol. July 2018/Volume 9/Article 530
58 Efficacy of Ketogenic Diet According to Pathogenic Genetic Mutation in DEE Ko, A et. al. Frontiers Neurol. July 2018/Volume 9/Article 530
59 Efficacy of Ketogenic Diet According to Pathogenic Genetic Mutation in EE Ko, A et. al. Frontiers Neurol. July 2018/Volume 9/Article 530
60 Global Implementation Countries providing the ketogenic diet (highlighted in grey) as identified. Kossoff & McGrogan. Epilepsia (2005) 46:280 9
61 Sixth Global Symposium of Ketogenic Therapies in Jeju Embracing Diversity, Global Implementation, and Individualized Care
62 Embracing Diversity, Global Implementation and Individualized Care of Ketogenic Therapy
63 Embracing Diversity, Global Implementation and Individualized Care of Ketogenic Therapy
64 Embracing Diversity, Global Implementation and Individualized Care of Ketogenic Therapy
65 Embracing Diversity, Global Implementation and Individualized Care of Ketogenic Therapy
66 Pediatric Epilepsy Clinic, Severance Children s Hospital, Yonsei University College of Medicine Thank you for your attention!!!
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