beyond reason
미량원소 치유의학의 세계
케톤체 식사
- 고지방 식이, 단백질, 저탄수화물 식이를 하면 미토콘드리아는 지방을 에너지로 사용하고 케톤체가 생성됨
- 설탕을 에너지원으로 사용하는 암세포는 기아상태에 빠짐.
- 설탕, 탄수화물 식사로 인한 인슐린 저항성이 떨어짐. 염증이 줄어듬.
The KD has a high fat content (90%) and low protein and carbohydrate
Ketogenic Diet and Epilepsy: What We Know So Far
,1,2,* ,2 ,1,2 ,1 ,1 and 3
Isabella D’Andrea Meira
1Epilepsy Department, Paulo Niemeyer State Brain Institute, Rio de Janeiro, Brazil
2Neurology Department, Federal Fluminense University, Rio de Janeiro, Brazil
Tayla Taynan Romão
2Neurology Department, Federal Fluminense University, Rio de Janeiro, Brazil
Henrique Jannuzzelli Pires do Prado
1Epilepsy Department, Paulo Niemeyer State Brain Institute, Rio de Janeiro, Brazil
2Neurology Department, Federal Fluminense University, Rio de Janeiro, Brazil
Lia Theophilo Krüger
1Epilepsy Department, Paulo Niemeyer State Brain Institute, Rio de Janeiro, Brazil
Maria Elisa Paiva Pires
1Epilepsy Department, Paulo Niemeyer State Brain Institute, Rio de Janeiro, Brazil
Priscila Oliveira da Conceição
3Neurology Department, Rio de Janeiro State University, Rio de Janeiro, Brazil
1Epilepsy Department, Paulo Niemeyer State Brain Institute, Rio de Janeiro, Brazil
2Neurology Department, Federal Fluminense University, Rio de Janeiro, Brazil
3Neurology Department, Rio de Janeiro State University, Rio de Janeiro, Brazil
Edited by: Rubem C. A. Guedes, Federal University of Pernambuco, Brazil
Reviewed by: Xuefeng Wang, The First Affiliated Hospital of Chongqing Medical University, China; Sergei V. Fedorovich, Institute of Biophysics and Cell Engineering (NASB), Belarus
This article was submitted to Neuroenergetics, Nutrition and Brain Health, a section of the journal Frontiers in Neuroscience
Received 2018 Oct 31; Accepted 2019 Jan 4.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Abstract
The Ketogenic Diet (KD) is a modality of treatment used since the 1920s as a treatment for intractable epilepsy. It has been proposed as a dietary treatment that would produce similar benefits to fasting, which is already recorded in the Hippocratic collection. The KD has a high fat content (90%) and low protein and carbohydrate. Evidence shows that KD and its variants are a good alternative for non-surgical pharmacoresistant patients with epilepsy of any age, taking into account that the type of diet should be designed individually and that less-restrictive and more-palatable diets are usually better options for adults and adolescents. This review discusses the KD, including the possible mechanisms of action, applicability, side effects, and evidence for its efficacy, and for the more-palatable diets such as the Modified Atkins Diet (MAD) and the Low Glycemic Index Diet (LGID) in children and adults.
Keywords: refractory epilepsy, ketogenic diet, modified Atkins diet, low glycemic index, diet therapy
Introduction
Epilepsy is a disabling and common neurological disease, which can be controlled successfully in most patients with one or more antiepileptic drugs. Approximately 30% of patients with epilepsy have refractory epilepsy, that is, have a failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules to achieve sustained relief of seizures (Picot et al., 2008; Kwan et al., 2009
The classic ketogenic diet (CKD) consists of a high-fat and low-protein and carbohydrate diet, with restricted calories and fluids. The diet mimics the fasting state, altering the metabolism to use fats as a primary fuel source; catabolism of fatty acids in the liver produces ketone bodies (KB), which induces urinary ketosis (Rho, 2017
Recent studies have found a significantly positive outcome with the use of the KD for treatment of refractory epilepsy in children and adults (Barborka, 1928; Neal et al., 2008; Kverneland et al., 2015; Liu et al., 2018
Regardless of the efficacy of the KD, most patients discontinue the diet because of its unpalatable and restrictive features. In the last 20 years, new variants of the KD diet have emerged, including the Modified Atkins diet (MAD), a low-glycemic-index diet, which although it has a high fat content, allows more protein and does not restrict calories and fluids. Several studies have shown that the new variants of the KD have a similar efficacy to the CKD (Kossoff et al., 2006; Tonekaboni et al., 2010; Coppola et al., 2011; Miranda et al., 2012; El-Rashidy et al., 2013Bough and Rho, 2007; Lutas and Yellen, 2013; Rho, 2017; Youngson et al., 2017
Because epilepsy is a metabolic disease (Clanton et al., 2017
Ketogenic Diet Past to Present
Dietary treatments for diseases have probably been used for over 2000 years (Yuen and Sander, 2014Wheless, 2008Lima et al., 2014; Yuen and Sander, 2014Wheless, 2008Wilder, 1921
In 1970, Robert C. Atkins developed a weight-loss diet that restricted the intake of carbohydrates (Sharma and Jain, 2014Kossoff et al., 2013Kossoff et al., 2013Atkins, 2002; Sharma and Jain, 2014
Nowadays, despite the new generation of anti-epileptic drugs, 35% of patients remain refractory. Interest in dietary therapy continues as a means of treatment for this group, even more with advances in knowledge regarding the association of gut microbiota and neurological diseases.
Classic Ketogenic Diet
What Is Classic KD?
The CKD is rich in lipids (90%) and low in carbohydrates and protein, in order to produce ketosis, and simulates a starvation state. It is a rigid diet, mathematically and individually calculated, and medically monitored (Armeno et al., 2014Bough, 2008; Liu et al., 2018
Indication and Contraindications
Traditionally, the KD has been considered the gold standard for the treatment of metabolic diseases such as Glucose Transporter Protein 1 (GLUT-1) deficiency syndrome and Pyruvate Dehydrogenase Deficiency. At present, the KD has been consistently reported as more beneficial, with more than 70% patients showing positive responses, as opposed to the average 50% response in several conditions such as infantile spasms () (Kossoff et al., 2018Rho, 2017
Table 1
Epilepsy syndromes and some conditions in which the KD therapies has been reported probable benefit∗.
Angelman syndrome |
Complex 1 mitochondrial disorders |
Dravet syndrome |
Epilepsy with myoclonic–atonic seizures (Doose syndrome) |
Glucose transporter protein 1 (Glut-1) deficiency syndrome (Glut1DS) |
Febrile infection–related epilepsy syndrome (FIRES) |
Formula-fed (solely) children or infants |
Infantile spasms |
Ohtahara syndrome |
Pyruvate dehydrogenase deficiency (PDHD) |
Super-refractory status epilepticus |
Tuberous sclerosis complex |
|
Table 2
Epilepsy syndromes and some conditions in which the KD therapies has been reported possible benefit (one case report or series)∗.
Adenylosuccinate lyase deficiency |
CDKL5 encephalopathy |
Childhood absence epilepsy |
Cortical malformations |
Epilepsy of infancy with migrating focal seizures |
Epileptic encephalopathy with continuous spike-and-wave during sleep |
Glycogenosis type V65 Juvenile myoclonic epilepsy |
Lafora body disease |
Landau-Kleffner syndrome |
Lennox-Gastaut syndrome |
Phosphofructokinase deficiency |
Rett syndrome |
Subacute sclerosing panencephalitis (SSPE) |
|
Kossoff et al. (2018) proposed that dietary therapy should be considered earlier as an option for treatment of intractable epilepsy, because of its proven efficacy, the poor chance of improvement with further anticonvulsant administration, and the possibility of using the MAD (Kossoff et al., 2006Pfeifer and Thiele, 2005
In contrast, some pathologies are considered contra-indicated for KD. Absolute contraindications have been described and summarized by Kossoff et al. (2018) () (Kossoff et al., 2018
Table 3
Absolute contraindications for the use of KD therapies∗.
Carnitine deficiency (primary) |
Carnitine palmitoyltransferase (CPT) I or II deficiency |
Carnitine translocase deficiency |
β-oxidation defects |
Medium-chain acyl dehydrogenase deficiency (MCAD) |
Long-chain acyl dehydrogenase deficiency (LCAD) |
Short-chain acyl dehydrogenase deficiency (SCAD) |
Long-chain 3-hydroxyacyl-CoA deficiency |
Medium-chain 3-hydroxyacyl-CoA deficiency |
Pyruvate carboxylase deficiency |
Porphyria |
|
Table 4
Relative contraindications for the use of KD therapies∗.
Inability to maintain adequate nutrition |
Surgical focus identified by neuroimaging and video-EEG monitoring |
Parent or caregiver noncompliance |
Propofol concurrent use (risk of propofol infusion syndrome may be higher) |
|
Pre-KD Counseling and Evaluation
To obtain the optimum engagement of the family and the patients, providing information and training is essential because the diet is difficult to maintain. Counselors should talk with the family about their expectations and make clear the efficacy rate and adverse events (AE), to reduce the abandonment of the diet. Websites, videos and publications, especially from support groups, can be very helpful and should be encouraged. It is also important to review the medications and change from oral solutions (carbohydrate content) to tablets (Armeno et al., 2014
Before starting the diet, the patient should maintain a seizure diary to establish a frequency parameter. Also needed are a laboratory evaluation including selenium and carnitine levels (Kossoff et al., 2018Kossoff et al., 2009
Table 5
Complete blood count with platelets |
Electrolytes to include serum bicarbonate, total protein, calcium, zinc, selenium, magnesium, and phosphate serum |
Liver and kidney tests (including albumin, blood urea nitrogen and creatinine |
Fasting lipid profile |
Serum acylcarnitine profile |
Urinalysis |
Urine calcium and creatinine |
Anticonvulsant drug levels a |
Urine organic acids b |
Serum amino acids b |
Vitamin D level |
|
Diet Initiation
The goal is to reach a ratio of four portion of fat to one portion of protein plus carbohydrate, described as “4:1.” To achieve this level, one of two approaches, with or without fasting, may be used. In the former approach, the patient must be hospitalized for 12–48 h, or when ketones are present in the urine (Rubenstein, 2008Armeno et al., 2014Kossoff et al., 2009Bergqvist et al., 2005Kim et al., 2004
Taking into account that the KD provides only small amounts of fruits, vegetables, grains, milk and cheese, supplementation is essential. Low-carbohydrate multivitamin and mineral supplements should be taken daily.
Follow Up
Patients on the KD should be seen regularly every 3 months, and the family should be able to easily contact the diet team to resolve possible doubts and discuss adverse effects. In each evaluation, the seizure dairy and the child’s cognitive development and behavior should be observed (Auvin and Nabbout, 2011Kossoff et al., 2009
For efficacy, the KD requires a period of at least 3 months from the time that the patient reaches ketosis, so it is important to encourage the patient and the family to continue with the diet for this period without changing the medication.
Adverse Effects
Because KD is not a physiological diet, it is necessary to recognize and closely manage AE (Kossoff et al., 2009Liu et al., 2018
The family should also be informed about how to recognize the symptoms of hypoglycemia and be advised to administer a small amount of juice or other forms of dextrose (Kossoff et al., 2018
Mechanism of Action
The understanding of the mechanisms of action of KD is incomplete; however, some theories have been advanced about how it modifies the neuronal metabolism and excitability in order to reduce the seizure frequency. Possibly, the real mechanism of reduction of cortical hyperexcitability involves multiple factors. Some of the systems involved in seizure reduction are related to metabolic changes in the blood and cerebrospinal fluid (CSF), including a decrease in glucose levels and an increase in KB. The mitochondria function and energy reserve may also play a role in the KD mechanisms, resulting in synapse stabilization and excitatory decrease.
Ketone Bodies: Anticonvulsant Effects
Ketone bodies, acetoacetate, and β-hydroxybutyrate (βOHB), are byproducts of fatty acid oxidation in the mitochondrial matrix of the hepatocytes. There are many theories about the role of KB, but the existence of an anticonvulsant effect is controversial. Some authors have found no relationship between KB and synaptic transmission and seizure control.
Experimental studies in an animal model showed that in rats exposed to KD there was no change in synaptic plasticity, using paired-pulse modulation and long-term potentiation (Thio et al., 2010Likhodii et al. (2003) did not detect any anticonvulsant effects in either ketone body (Likhodii et al., 2003Kcna1-null mice, KB supplementation resulted in attenuation of electrographic seizure-like events (Kim et al., 2015Rho et al., 2002Rho (2017)Rho, 2017Gasior et al., 2008Ma et al. (2007)Juge et al., 2010
Neuronal Metabolism and Synaptic Function
Another hypothesis regarding the function of the KD is related to changes in neuronal metabolism, mitochondrial function and energy reserve, and the environment. In normal conditions, the usual substrate for the neurons is glucose. To facilitate its diffusion through the brain-blood barrier, glucose transports are present in the brain capillary endothelial layer (Greene et al., 2003Garriga-Canut et al., 2006Huttenlocher, 1976
Chronic ketosis may play a role in the KD anticonvulsant properties, since it has been shown that chronic ketosis elevates the brain energy reserve via stabilization and reduction of excitability of synapses (Devivo et al., 1978Bough et al. (2006) demonstrated an increase in mitochondria biogenesis in an experimental model of rats fed with KD, indicating an increase in the energy stores (Bough et al., 2006Li et al., 2010) and GABAB receptors (Mironov and Richter, 2000
In this process, we can postulate that modifications of the metabolism are associated with an increase of ATP, and improve mitochondrial capacity and cell energy, with an increase in metabolic resilience.
Neurotransmitter Function
The KD-induced synaptic stabilization is additionally related to changes in critical amino acids as a result of ketone metabolism. It has been proposed that KD interferes with the concentration of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter. There is evidence in clinical practice of increased GABA levels in the CSF of patients on the KD diet (Wang et al., 2003Yudkoff et al., 2008Szot et al., 2001
Gut Microbiota, Inflammation, and Genetic
The role of gut microbiota has recently been studied for its effect on several diseases, especially those with some inflammatory involvement. Several metabolic pathways are known to be modulated by the gut microbiota. Olson et al. (2018)Akkermansia muciniphila and Parabacteroides spp. This microbiota transformation leads to changes in the colonic luminal metabolome, with a decrease in gamma-glutamyl amino acids. This increases the GABA/glutamate content in the brain by decreasing gamma-glutamyl amino acids in the blood (Olson et al., 2018Kim et al., 2015
The role of inflammatory cytokines in epilepsy is well known, and there is evidence that KD also interferes with pro-inflammatory cytokines. Dupuis et al. (2015)
Notably, there is a relationship between metabolic and epigenetic modifications. Shimazu et al. (2013)
In conclusion, all the mechanisms described above lead to systemic modifications and a dynamic metabolic homeostasis, in which the interplay among KB, glucose levels, mitochondrial function, synaptic neurotransmitters, and channel modifications can lead to changes in the seizure threshold and hyperexcitability. These changes contribute to the final antiseizure mechanism of KD.
Multiple mechanisms of action may explain why the modification of the KD can be effective even without ketosis. Importantly, the KD systemic action can have a broad spectrum of effects that may be beneficial in the treatment of different types of epilepsy and associated comorbidities such as cognition impairment, psychiatric disturbance, and sudden unexplained death.
Modified Atkins Diet in Patients With Refractory Epilepsy
Definition and Diet Composition
The MAD aims to provide increased flexibility and palatability, with a 1:1 ratio of fat to carbohydrates and protein, and contains around 65% fat, 25% protein, and 10% carbohydrate (Payne et al., 2018Kossoff, 2004; Kossoff and Dorward, 2008Carrette et al., 2008Cervenka et al., 2012Kossoff et al., 2009
Efficacy in Children
Several studies have shown that the MAD, besides being more palatable, is as effective as the KD in the treatment of drug-resistant epilepsy in children (Miranda et al., 2011; Martin et al., 2016Kossoff et al., 2006Kang et al., 2007Rezaei et al., 2017Park et al., 2018
Treatment with MAD was shown to be more effective in seizure control when the MAD was started with lower carbohydrate limits (Kossoff et al., 2010p = 0.03). In the same study, after 3 months, an increase in carbohydrate intake to 20 g/day, maintained seizure control and improved tolerability, suggesting that a lower carbohydrate limit is important only in the first 3 months (Kossoff et al., 2007; Kossoff and Dorward, 2008
Efficacy in Adolescents and Adults
The efficacy of the MAD is also proven for the treatment of drug-resistant epilepsy in adults and adolescents. In this patient group, carbohydrate intake is generally around 15–20 g/day and the rates of seizure reduction and adherence are lower compared to those of the child population (Kossoff et al., 2008; Zare et al., 2017; Payne et al., 2018
In a recent meta-analysis, eight studies were identified that used the MAD in adult patients with refractory epilepsy, aged between 15 and 86 years, with treatment times ranging from 3 to 36 months. In these studies, the proportion of patients who showed >50% seizure reduction ranged from 20 to 70% and the rate of seizure freedom ranged from 7 to 30%. The rate of abandonment of the diet varied between 12.5 and 82% of the patients (Liu et al., 2018
Side Effects
The MAD has been shown to be better tolerated than the classical KD, but some typical side effects such as gastrointestinal complaints, dyslipidemia and weight loss are reported (Zare et al., 2017Carrette et al., 2008
Low Glycemic Index Diet in Patients With Refractory Epilepsy
Efficacy
The LGIT has proven to be effective in the treatment of focal and generalized epilepsies, with a reduction in seizure frequency occurring at 3–14 months and seizure control continuing for at least 1 year after the end of treatment (Pfeifer et al., 2008; Kim et al., 2017; Rezaei et al., 2018Pfeifer and Thiele (2005)Coppola et al. (2011)Muzykewicz et al. (2009)
However, according to a recent systematic review, the positive results for LGIT efficacy in epileptic patients are doubtful because of the low number of high-quality studies. In this review, which included all electronic literature databases until July 2017, the authors found only eight studies with good or fair quality (69).
Side Effects
Constipation and vomiting are the most common adverse effects reported in patients on the LGIT (Rezaei et al., 2018
Conclusion
The CKD and its variants should be considered as an alternative for non-surgical pharmacoresistant patients with epilepsy, of any age. Each patient must have an individually designed diet; however, adult patients have more difficulty in maintaining the CKD. It is essential to inform the patient and the family about the efficacy and AE related to the KD, and the use of websites and videos may help in this education. Although several theories exist regarding the mechanisms of action, further study is needed nevertheless the positive results are probably due to several mechanisms.
Author Contributions
All the authors contributed substantially to the writing and revising of the manuscript. ID’A, HP, TR, MP, PC, and LK participated in the conception and design of the study, collected the literature, prepared the tables, and wrote the manuscript. ID’A, TR, and HP reviewed and edited the manuscript and approved the final version.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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