Disease-Modifying, Anti-Epileptogenic, and Neuroprotective Effects of the Ketogenic Diet: Clinical Implications

Transcription

1 Disease-Modifying, Anti-Epileptogenic, and Neuroprotective Effects of the Ketogenic Diet: Clinical Implications Special Lecture 6 th Global Symposium on Ketogenic Therapies for Neurological Disorders Jeju, Korea October 8, 2018 Michael Wong, MD, PhD Allen P and Josephine B Green Professor of Pediatric Neurology Department of Neurology, Pediatrics, and Neuroscience Washington University School of Medicine Saint Louis, MO

2 Symptomatic versus Disease-Modifying Treatments Symptomatic treatment: a treatment or intervention that improves the symptoms of a disease without addressing the underlying cause or progression of the disease. Disease-modifying treatment: a treatment or intervention that affects the underlying pathophysiology of a disease and has a beneficial effect on long-term natural history and prognosis of the disease. - Early treatment (before symptom onset): prevention - Late treatment (after symptom onset): improved outcome - Neuroprotective treatment: a treatment or intervention that prevents neuronal death

3 Symptomatic versus Disease-Modifying Treatments of the Ketogenic Diet for Neurological disease Epilepsy: Anti-seizure vs. Anti-epileptogenic effects? Neuroprotective effects? Metabolic Disorders (Glut1 deficiency) Stroke Traumatic Brain Injury Neurodegenerative Diseases (e.g., Alzheimer s Disease) Autism Spectrum Disorder Other Neurocognitive Disorders Cancer/Tumors

4 History of Antiseizure ( Antiepileptic ) Drug Development 1857 Bromide 1912 Phenobarbital 1938 Phenytoin 1952 Primidone 1957 Methsuximide 1960 Ethosuximide 1968 Diazepam 1974 Carbamazepine 1975 Clonazepam 1978 Valproate 1993 Felbamate 1993 Gabapentin 1994 Lamotrigine 1996 Topiramate 1997 Tiagabine 1999 Levetiracetam 2000 Oxcarbazepine 2000 Zonisamide 2004 Pregabalin 2008 Rufinamide 2009 Lacosamide 2009 Vigabatrin 2011 Ezogabine 2011 Clobazam 2012 Perampanel 2013 Eslicarbazepine 2016 Brivaracetam 2018 Everolimus 2018 Cannabidiol Old ASDs/AEDs (1 st generation) New ASDs/AEDs (2 nd generation) Really New ASDs/AEDs (3 rd generation)

5 Limitations of Current Antiseizure Drugs 1. Medical Intractability/Drug Resistance - Approximately one-third of patients with epilepsy are intractable to available seizure medications. - With a few exceptions, overall all ASDs have relatively similar rates of responsiveness (and unresponsiveness). - There appears to be no significant difference in seizure-free rates between patients treated with old versus new ASDs (Kwan and Brodie, 2000); i.e. the new ASDs have not significantly decreased the number of patients with intractable epilepsy.

6 Limitations of Current Antiseizure Drugs 1. Medical Intractability/Drug Resistance - In newly-treated epilepsy patients, about 47% will become seizure-free with the first ASD, 13% with the second ASD, and only 4% with the third ASD (Kwan and Brodie, 2000); i.e. medical intractability can be predicted after failure of just 2 or 3 ASDs.

7 Limitations of Current Antiseizure Drugs 2. Lack of Documented Antiepileptogenic Properties of Current ASDs - Prophylaxis of Posttraumatic Epilepsy: In randomized, controlled trials, standard ASDs, such as phenytoin or valproate, suppress seizures in the immediate period following head trauma, but do not decrease the long-term risk of developing posttraumatic epilepsy.

8 Mechanistic Stages of Epileptogenesis Initial Precipitating Brain Injury (Etiology) Causes Traumatic brain injury Brain Tumor Cortical malformation Stroke/Hypoxia-ischemia Infection Prolonged febrile seizure Genetic disease Primary Prevention Latent Period (Epileptogenesis) Epileptogenic Mechanisms Cell signaling pathways Gene regulation/transcription Protein synthesis Metabolism/mitochondrial function Synaptic reorganization Neuronal death Neurogenesis Inflammation Vascular changes Disease-Modifying Strategies Seizures (Epilepsy) Ictogenic Mechanisms Excitatory/Inhibitory Circuits Neurotransmitters/Receptors Ion Channels Current Antiseizure Drugs

9 Mechanistic Stages of Epileptogenesis Initial Precipitating Brain Injury (Etiology) Causes Traumatic brain injury Brain Tumor Cortical malformation Stroke/Hypoxia-ischemia Infection Prolonged febrile seizure Genetic disease Latent Period (Epileptogenesis) Epileptogenic Mechanisms Cell signaling pathways Gene regulation/transcription Protein synthesis Metabolism/mitochondrial function Synaptic reorganization Neuronal death Neurogenesis Inflammation Vascular changes Ketogenic Diet (Disease-modifying/ Anti-epileptogenic) Seizures (Epilepsy) Ictogenic Mechanisms Excitatory/Inhibitory Circuits Neurotransmitters/Receptors Ion Channels Ketogenic Diet (Anti-seizure)

10 Mechanisms of Anti-Seizure Drugs versus Ketogenic Diet Anti-Seizure Drugs Ion Channels: - Sodium channels - Potassium channels - Calcium channels Neurotransmitter Receptors - GABA receptors - Glutamate receptors Neurotransmitter Metabolism - GABA transaminase - GABA transporter Neurotransmitter Release - SV2A synaptic protein Ketogenic Diet Ion Channels/Neurotransmitter Receptors: - Katp potasium channels - GABAb receptors - Adenosine Neurotransmitter Metabolism - GABA synthesis - Glutamate metabolism Loscher et al. 2016

11 Mechanisms of Anti-Seizure Drugs versus Ketogenic Diet Anti-Seizure Drugs Ion Channels: - Sodium channels - Potassium channels - Calcium channels Neurotransmitter Receptors - GABA receptors - Glutamate receptors Neurotransmitter Metabolism - GABA transaminase - GABA transporter Neurotransmitter Release - SV2A synaptic protein Ketogenic Diet Ion Channels/Neurotransmitter Receptors: - Katp potasium channels - GABAb receptors - Adenosine Neurotransmitter Metabolism - GABA synthesis - Glutamate metabolism Cell Signaling Pathways - mtor - BDNF Transcription/Epigenetics Metabolism/Energy Processing - Glycolysis - Fatty acid oxidation - Mitochondrial function - Oxidative stress Neuroinflammation Neuronal Death

12 Clinical Studies of Long-term Outcome of Ketogenic Diet on Intractable Epilepsy: Disease-modifying effects? - A 52% responder rate (>50% reduction in seizures) was reported at the time of ketogenic diet discontinuation. - At median follow-up of six years after discontinuation of the ketogenic diet, 79% were reported to be similarly improved (p=0.0001)

13 Anti-Epileptogenic Effect of Ketogenic Diet in Animal Models Lusardi et al. 2015

14 Anti-Epileptogenic Effect of Ketogenic Diet in Animal Models Lusardi et al. 2015

15 Symptomatic versus Disease-Modifying Treatments of the Ketogenic Diet for Neurological disease Epilepsy: Anti-seizure vs. Anti-epileptogenic effects? Neuroprotective effects? Metabolic Disorders (Glut1 deficiency) Stroke Traumatic Brain Injury Neurodegenerative Diseases (e.g., Alzheimer s Disease) Autism Spectrum Disorder Other Neurocognitive Disorders Cancer/Tumors

16 Neuroprotective Effect of Ketogenic Diet in Animal Models of Stroke Pucowicz et al. 2008

17 Neuroprotective Effect of Ketogenic Diet in Animal Models of Traumatic Brain Injury Prins et al. 2005

18 Neuroprotective Effect of Ketogenic Diet in Animal Models of Alzheimer s Disease Kashiwaya et al. 2013

19 A Pilot Trial of Ketogenic Diet in Alzheimer s Disease Taylor et al. 2017

20 Summary In addition to effects on ion channels and neurotransmitter receptors, ketogenic diet has other effects on cell signaling pathways, transcription, metabolism, energy processing, neuroinflammation, and neuronal death. Ketogenic diet has antiepileptogenic effects in animal models of epilepsy. Ketogenic diet has neuroprotective effects in animal models of various neurological disorders involving acquired or genetic brain injury. Controlled clinical trials are needed to translate the potential diseasemodifying effects of the ketogenic diet to novel treatments for patients with neurological disorders.

21 Wong Lab TSC Mouse Models Linghui Zeng Brennan Beeler Ebru Altay-Erbayat Elizabeth Griffin Dongjun Guo Laura Jansen Sharon McDaniel Nicholas Rensing Yue-Shan Piao Lydia Xu Bo Zhang Jia Zou Acknowledgements Collaborators Washington University David Brody John Cirrito David Gutmann David Holtzman Erik Uhlmann David Wozniak David Kwiatkowski Harvard Support National Institutes of Health Department of Defense TSCRP Tuberous Sclerosis Alliance Citizens United for Research on Epilepsy (CURE)