or slow release of glucose intervention: A review

Clinical Nutrition xxx (xxxx) xxx

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Review

The ‘epileptic diet’- ketogenic and/or slow release of glucose intervention: A review Xin Qi*, Richard F. Tester Glycologic Limited, Glasgow, G4 0BA, UK

a r t i c l e i n f o

s u m m a r y

Article history: Received 11 January 2019 Accepted 30 May 2019

Background & aims: The ketogenic diet is high in fat content, adequate with respect to protein but low in carbohydrate and designed to provide brain energy as ketone bodies rather than glucose. The consequence is that epilepsy can be managed and endurance (sport) related energy be derived from fat rather than ingested or stored (glycogen) carbohydrate. This review aims to set the diet in context for seizure related intervention, sport and potential modern variants with respect to glucose management e which have many medical (including epilepsy potentially) and activity related applications. Methods: The literature was reviewed using relevant data bases (e.g. Pubmed, Science Direct, Web of Science, Wiley on Line Library) and relevant articles were selected to provide historic and contemporary data for the text and associated Tables. Results: It is clear great health related benefits have been achieved by feeding the ketogenic to individuals subject to seizures where it helps manage the malaise. Sports applications are evident to. Glucose control diets provide health benefits of the ketogenic diet potentially and there is some evidence they are/can be very effective. Conclusions: Key to epilepsy and sport performance is the control of blood glucose. The ketogenic diet has proven to be very effective in this regard but now other approaches to control blood glucose ae being evaluated which have advantages over the ketogenic diet. This therapeutic approach of clinical nutrition will undoubtedly move forwards over the next few years in view of the negative aspects of the ketogenic diet. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Epilepsy Ketogenic diet Ketone bodies Glucose

1. Introduction

although the low glycaemic index diet and low dose fish oil diet for the same therapeutic purpose had fewer side effects.

1.1. Epidemiology The epidemiology associated with the use of the ketogenic diet to manage epilepsy/seizure in children especially has been discussed in some detail elsewhere [1e8]. Using this approach Keene [1] reported that 10% or 16% of children exhibit complete seizure control with 33% reporting more than a 50% reduction in seizures. Figures reported by Zupec-Kania and Spellman [2] indicate that using this approach 16% became seizure free, 32% had a greater than 90% reduction with 56% had a more than 50% reduction. Similar data has been reported by Liu et al. [8]. These authors indicated also that the diet produced only mild adverse effects -

* Corresponding author. E-mail addresses: [email protected] (X. Qi), [email protected] (R.F. Tester).

1.2. General Manford [9] has highlighted the issues faced when defining epilepsy symptomatically. Specifically, the author indicates: ‘Definitions in epilepsy have always been problematic. The disorder is characterised by seizures but not all seizures are due to epilepsy febrile seizures or drug induced seizures, for example. Earlier classifications sought to reconcile these difficulties by describing different electro-clinical syndromes but new data from modern imaging and genetics need to be incorporated.’ The authors discussed also in some detail the International League Against Epilepsy review of the condition published by Trinka et al. [10] where these authors described the condition as: ‘a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to

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Please cite this article as: Qi X, Tester RF, The ‘epileptic diet’- ketogenic and/or slow release of glucose intervention: A review, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.05.026

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abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures’. A number of authors have attempted to define the epileptic condition in terms of biochemistry or biochemical causes [8,9,11e13]. Despite the fact that research based progress is being made in this respect, the key underlying biochemical process aberrations creating the condition(s) are still uncertain in many respects. Seizures may be generalised or focal and do take different forms [14]. The epilepsy may be genetic or have a structural or metabolic cause. About one third of epilepsies have a genetic element [15]. Glucose transporter 1 (GLUT1) deficiency syndrome for example, is a disorder of glucose transport into the brain due to a variety of mutations in the solute carrier family 2 member 1 (SLC2A1) gene, which are the cause of different neurological disorders - including types of epilepsy [16]. The gene directs the production of GLUT 1 e where numerous mutations have been reported in people with GLUT1 deficiency. Glucose consumption increases during seizure [17]. According to Kalser and Cross [18], from 0.35 to 0.5% of children are affected with epilepsy. The condition affects about 50 million people worldwide (about 1% of the USA population) according to McNally and Hartman [19] and Schauwecker [20]. Similar figures (0.5e1%) have been reported by Hart [21] for developed countries. Infancy and old age are key demographic groups which are affected by the conditions. There is a distinct neuropsychological profile difference between patients with epilepsy and healthy subjects [22]. According to these authors, an accurate understanding of the relationship between epilepsy and psychiatric problems is essential. 2. Dietary treatments for epilepsy 2.1. Ketogenic diet A dietary therapy - a high fat-low carbohydrate diet known as the ketogenic diet - was developed in the 1920s to control (epileptic) seizures [perhaps centuries before if one considers broader historic approaches to diet intervention for the morbidity] without surgical intervention [1,8,11,23e36]. This diet consists typically of a ratio of 3:1 or 4:1 of fats to carbohydrates and proteins (w/w) [25,26,29,35,37,38]. This relative decrease in carbohydrate intake reduces the amount of glucose available for utilisation throughout the body. Instead, fatty acids are used by the liver to produce the ketone bodies, which fuel cellular metabolism in lieu of glucose. As neurons have a high rate of energy expenditure, much of the energy production of the body goes into fuelling them. Overall, when consuming a ketogenic diet, ketone bodies replace glucose as the major fuel source for the brain [39]. The mechanism(s) underlying the effects of the ketogenic diet on seizures is not well understood. However, the two major areas of focus in research on the ketogenic diet have been (i) the ketone bodies themselves and (ii) the metabolic changes associated with decreased glucose oxidation. 2.1.1. Ketone bodies and their functionality in the body Ketone bodies are represented in the nutritional context by acetoacetate, acetone and b-hydroxybutyrate. Acetone is actually generated as a breakdown product of the other two molecules. These molecules are produced in the liver from lipids (fatty acids) during fasting, due to the consumption of low carbohydrate diets, extreme exercise, excess consumption of alcohol and due to

unmanaged type 1 diabetes. Multiple roles of ketone bodies in the body (especially b-hydroxybutyrate) have been reported by for example Simeone et al. [13]. These include interactions with histone deacetylases, hydroxycarboxylic acid receptors on immune cells and the innate immune sensor nucleotide-binding oligomerisation domain (NOD)-like receptor protein (3NLRP3) inflammasome (a multiprotein oligomer responsible for the activation of inflammatory responses). In the brain, ketone bodies are used for energy when glucose is deficient. This state is induced for people with seizure deliberately by the medical profession to control the condition. Directly administered acetone or acetoacetate therapies/nutrients in animals have been proven to have anticonvulsant properties by some authors [19]. However, not all studies are so conclusive. Kosinski and Jornayvaz [6] discussed ketogenic diets in the context of both animal and human studies. They made only one really unambiguous conclusion in that for rodents and humans the diet is (i) beneficial for weight loss due to increased energy expenditure in animals and (ii) decreased food intake in man. Lutas and Yellen [38] discussed the role of the ketogenic diet in biochemical - mechanistic detail where they reported that ‘multiple mechanisms are likely [to be] at play’. Ketone bodies may inhibit vesicular glutamate transport and also produce changes in cellular metabolism that reduce seizures. The ketone bodies bypass glycolysis and increase (mitochondrial) oxidation. This metabolic flow may lead to activation of adenosine triphosphatesensitive potassium channels and thus reduce neuronal excitability. Other authors discussing the metabolic impact of ketone bodies [11,26,30] have reported that two potential biochemical mechanisms are operational in the body: reflected in blood arachidonate concentrations and cerebrospinal fluid gamma-aminobutyric acid concentrations. The glutamate related activity of ketone bodies has been discussed in detail by Daikhin and Yudkoff [40] (and in their previous papers) where they indicate that the ketogenic diet increases the synthesis of g-amino butyric (GABA) - an ‘inhibitory and antiepileptic neuro transmitter’. The brain converts ketone bodies rapidly into acetyl CoA which condenses with oxaloacetate (citrate synthase) to generate citric acid. Less oxaloacetate is thus available for aspartate aminotransferase conversion. Since the rate of glutamate transamination is reduced, glutamate is made available for the glutamate decarboxylase pathway and thus the synthesis of gamino butyric. See Fig. 1 (glutamine conversions) and Fig. 2 (representing ketone bodies interaction with glutamate interconversions according to Daikhin and Yudkoff [40]). Stafstrom [11] discussed g-amino butyric acid potential impacts of ketone bodies in some detail and reported that the physiological effects may be caused by:
Glial (cell) conversion of glutamate to glutamine (g-amino butyric acid precursor) enhancement;
Interacting with g-amino butyric acid receptors directly;
Increased expression of glutamic acid decarboxylase and hence g-amino butyric acid production. Yudkoff et al. [41] discussed the relationship between ketogenic diets, glutamine, glutamate and g-amino butyrate in a very clear and precise review. They discussed the glutamateeglutamine cycle (Fig. 3) in some detail which shuttles glutamate and glutamine between astrocytes and neurons. A ketogenic diet could, the authors believe, affect this shuttle. In a general sense, ketosis (ketogenic diets) may cause a number of metabolic changes and in particular:

Please cite this article as: Qi X, Tester RF, The ‘epileptic diet’- ketogenic and/or slow release of glucose intervention: A review, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.05.026

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O

O

OH

H2N

Glutaminase

OH

HO

Glutamate decaboxylase

O H2N

OH

NH2

NH2 Glutamine

O

O

3

Glutamate

γ-Amino-butyric acid

Fig. 1. Glutamine to g-amino-butyric acid enzymatic conversion steps.


Flux through the astrocytic glutamine synthetase pathway increases; favouring ‘buffering’ of synaptic glutamate which is taken up by the glia;
Extra glutamine is accessible to g-amino butyric acid-ergic neurons; thus, creating a greater precursor source for the synthesis of g-amino butyric acid;


As discussed above, glutamate derived from glutamine by the action of phosphate dependent glutaminase may be converted by transamination to aspartate using aspartate aminotransferase - where in ketosis, less glutamate is metabolised creating availability to glutamate decarboxylase and hence g-amino butyric acid synthesis. Barry et al. [42] focussed on the neural glutamate directed role of the ketogenic diet in epilepsy management in their review's conclusion. Indicating overall that ‘glutamatergic inhibitory actions represent a promising alternative to medication for those suffering from pharmaco-resistant epilepsy’. Some attention has been focussed towards ketone body interactions with neural mitochondria. From seizure control studies in mice (kcna1-null) it has been reported [43] that ketone bodies can:
Exert anti-seizure effects;
Restore intrinsic impairment of hippocampal long-term potentiation and spatial learning-memory defects and;
Raise the threshold for calcium-induced mitochondrial permeability transition in acutely prepared mitochondria from hippocampi of the animals. Rho [44] provided an interesting slant on how the ketone diet may work for seizure control and discussed how the disease might be referred to as metabolic where it ‘works through multiple mechanisms that target fundamental biochemical pathways linked to cellular substrates (e.g. ion channels) and mediators responsible for neuronal hyper-excitability’. As an alternative theory, it works by reducing glycolysis, thus shifting glucose metabolism to the pentose phosphate pathway - possibly acting through improved reactive oxygen species handling. Liu et al. [8] reported that the high-fat, low-protein/low-carbohydrate ketogenic diet reflects a physiological starvation state, with a shift away from glycolytic energy production from carbohydrates to energy generation via oxidative phosphorylation as a

Fig. 2. Representing the Daikhin and Yudkoff [40] theory for the elevation of g-amino butyric acid due to ketone body elevation.

Fig. 3. The glutamateeglutamine cycle - see Yudkoff et al. [41] for more details.

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consequence of fatty acid b-oxidation and ketone body production. This metabolic shift being associated with increased g-amino butyric acid synthesis and reduction of reactive oxygen species generation while boosting energy production. The B-cell lymphoma 2 (BCL-2)-associated agonist of cell death (BAD) protein is a member of the BCL-2 family of cell death/survival proteins which plays a role in cellular apoptosis and glucose metabolism - including within the brain [45]. Adenosine triphosphate sensitive potassium channels (KATP) activity in neurones can be affected by modification of the protein activity. Specific modifications reducing glucose metabolism lead to an increase in activity of metabolically sensitive KATP channels in neurons associated with a resistance to behavioural/electrographic seizures. Hence, these proteins have received attention in the medical field in terms of seizure regulation and control. Sada and Inoue [12] have discussed the regulation of neuronal activity by the ketogenic diet and indicated that:
Ketone bodies in the brain change electrical activities in neurons and consequently suppress seizures in epileptic patients;
Electrical regulators driven by the ketogenic diet include ion channels - adenosine triphosphate (ATP)-sensitive Kþ channels and voltage-dependent Ca2þ channels;
There is also impact on specific synaptic receptors (a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA)type glutamate receptors and adenosine A1 receptors);
There is associated impact on neurotransmitter transporters (vesicular glutamate transporters), in addition;
The BCL-2-associated agonist of cell death is affected too and;
There is impact on the functionality of lactate dehydrogenase. The authors proposed that neuronal inhibition occurs via the combined actions of these processes/molecules. McDonald et al. [46] discussed ketogenic diet benefits in terms of metabolism and they indicated specifically that the diet caused:
Decreased glucose transport processes within the body;
Reduced oxidative metabolism of glucose (due to for example pyruvate dehydrogenase activity) and;
Increased anaplerotic need (reflecting replenishment tricarboxylic acid cycle intermediates used for biosynthesis).

2.1.2. Health - weight loss, sport and longevity Not surprisingly, since the 1800s ketogenic diets have been popular for weight loss as reported by Lacovides and Meiring [47]. According to Paoli [48] ‘a period of a low carbohydrate ketogenic diet [consumption] may help to control hunger and may improve fat oxidative metabolism and therefore reduce body weight’. It thus depletes fat as the fat is mobilised to provide energy - in the absence of carbohydrate. The ketogenic diet approach has also been followed by some athletes for performance optimisation. According to Zinn et al. [49] ‘The appeal of low-carbohydrate high-fat eating for endurance athletes is likely [to be] due to the shift in fuel utilisation from a carbohydrate -centric modal to one that uses fat predominantly, of which stores are unlimited compared to carbohydrate (i.e. muscle glycogen). This metabolic shift, seen after a period of dietary alteration is often described as ‘fat-adapted … ’. Interestingly, it has been reported that a ketogenic diet - like a calorie restricted diet - can induce longevity [50]. This is due apparently to a number of metabolic events where key to this is ‘decreased signalling through the insulin/insulin-like growth factor receptor signalling pathway.’ Glucose control in the blood stream is a critical component of this physiological molecular interplay.

2.1.3. Benign therapy? The ketogenic diet is not a benign therapy, having a number of side effects such as an association with cardiovascular disease, constipation, dehydration, diarrhoea, food refusal, hypoglycaemia, lack of energy, nutritional inadequacies and weight loss [26,35,38,51e56]. Symptoms associated with the diet can be especially marked in children. In terms of blood lipid profiles themselves, the ketogenic diet can (even if rich in ‘healthy’ vegetable oils such as olive oil) increase blood concentrations of low density lipoprotein-cholesterol and triglycerides [57]. de Lima et al. [58] reported that the ketogenic diet had a negative effect on the blood lipid profile with a more atherogenic composition associated with small low density lipoprotein sub-fractions and smaller high density lipoprotein particles. Overall cardiovascular risk is, therefore, an issue with the ketogenic diet [6]. In rodents, developments of non-alcoholic fatty liver disease and insulin resistance have been described although studies in humans are less clear cut [6]. Of potentially growing concern beyond the physical health problems associated with consuming the ketogenic diet, are cognitive associated issues. There may well be cognitive (brain) development issues associated with consumption of the ketogenic diet [59]. This is perhaps not surprising in view of the key role of glucose as a brain energy source. In animals, it has been shown that elevated blood ketone concentrations due to a ketogenic diet or exogenous ketones delay the onset of isoflurane-induced anaesthesia [60]. The authors also discussed this observation in the context of exposure to other anaesthetic gases and harmful gases (e.g. carbon monoxide, volcanic gases or chemical weapons/warfare-induced sleep-like effects). It is uncertain how anaesthetics themselves work and these observations add further mystery to anaestheticepatient interactions. 2.2. Other diets Apart from the classic ketogenic diet, recent clinical research has also shown that modified forms of the diet, such as a modified Atkins diet, low glycaemic index (GI) and oil/fish oil based treatment can also be used to manage epilepsy [8,11]. Most of the fat in the classic ketogenic diet is provided by long-chain triglycerides although (i) medium-chain triglycerides have been introduced more recently to improve palatability with (ii) higher concentrations of carbohydrates in some products - although maintaining ketosis. These nutritional modifications make the diet less stringent, which can make it easier for patients to conform to the diet which is an important condition for the efficacy of the treatment [38]. 3. Blood glucose concentrations and epilepsy Studies with rodents have indicated that there is a positive correlation between blood glucose concentration and seizure threshold - in other words, hypoglycaemia elevates the threshold and vice versa [61]. These authors indicated in their work that ‘high [blood] glucose concentrations are associated with proconvulsant effects’. Thus, blood glucose control is a critical element of seizure control. In babies, hypoglycaemia in the neonatal period is more common than in older age groups and is a possible cause of seizures in the first year of life [62]. Neonatal hyper-insulinaemic hypoglycaemic seizures have characteristics of idiopathic neonatal seizures [63]. Hypo-and hyperglycaemia can precede epileptic events after a stroke [64]. Severe hypoglycaemia may increase the risk of epilepsy

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[65]. However, the overall risk of seizures associated with hypoglycaemia generally is relatively low according to some authors [66]. Hypoglycaemia and hypoglycaemic seizures used to be common in diabetic patients treated with insulin - hypoglycaemia increases cortical excitability [67]. Hyperinsulinaemic hypoglycaemia patient management is critical to avoid the patient tendency towards epilepsy, cerebral palsy and neurological impairment [68]. Patients with the condition have an increased risk of brain injury secondary to the metabolic actions of insulin. Hyperglycaemia is a significant factor leading to epileptic seizures in individuals with diabetes and stroke [64]. After using kainite (administration of kainic acid) to induce seizures in mice, the neuropathological consequences have been investigated as a function of glycaemic control [20]. In this study glycaemic control could rescue/protect hippocampal cells from seizure-induced excitotoxic cell death. In addition, glucose dysregulation (hypo- or hyperglycaemia) increased the extent of seizureinduced cell death in a specific mouse strain. The author concluded that glucose dysfunction was therefore a key event in the pathogenesis of seizure-induced excitotoxic cell death. The author suggested further that deficiencies in insulin signalling may represent a critical factor in the susceptibility to seizure-induced cell death with important consequences for epilepsy, hypoxia, stroke and related pathologies. From epilepsy induced mice studies, it has been reported that a low glycaemic index diet may be an effective and well tolerated therapy for generalised epilepsy [69]. For the low glycaemic index diet, patients may consume 40e60 g carbohydrate per day and is thus more liberal than the low calorie (classical) ketogenic diet regime [70]. In some patients treated with this approach, a greater than 90% reduction in seizure frequency was found [71]. According to Rezaei et al. [70], this diet is useful for patients with intractable epilepsy. However, the authors did not discuss in detail the potential role of elongated glucose release profiles beyond the glycaemic index window (usually two hours post consumption). Other authors have reported positive roles for the diet for patients suffering from drug resistant epilepsy - where it was well accepted/tolerated for prolonged periods [72,73]. Paediatric benefits of the dietary approach in particular have also been discussed by others [74]. 3.1. Hypoglycaemia control specifically Hypoglycaemia control [75] for patients suffering with for example glycogen storage disease or diabetes has been achieved by the consumption of native or specially processed starch [76e78]. It is important that for seizure control blood glucose concentration are managed correctly e as discussed above. Coma is associated with hypoglycaemia, although epileptic seizures are rare [66]. However, ischaemia hypoglycaemia and epilepsy may cause similar patterns of brain damage [79]. 4. Glucose versus ketones in epilepsy management - an overview According to Greene et al. [80], epilepsy involves a disruption of brain energy homeostasis which can be manageable through brain energy metabolite availability (glucose and ketone bodies) that alter brain energy metabolism. This approach avoids extremes of starvation-associated hypoglycaemia or ketoacidosis. It appears that there are essentially three dietary approaches to epilepsy management: i. Ketogenic diet ii. Low GI diet iii. Diet with glucose control by ketogenic elements

5

The approaches (i) and (ii) have been discussed in detail above. Less is known about regulating blood glucose concentration via digestive control approaches. It is not clear if there would be a nutritional advantage in managing epilepsy with a diet composing/containing a slow release source of glucose with a ‘flat’ glucose release profile. This low background of glucose (and low GI) could provide glucose for the body while generating ketone bodies from fat metabolism for the brain to use as fuel and thus manage the seizures. A clue for the potential benefits of this approach have been discussed by Correia et al. [77]. These authors report: ‘The low glycaemic index is a necessary feature of an ideal food because a high insulin concentration would not only increase the risk of hypoglycaemia but would also prevent the accumulation of alternative fuels for the brain (lactate and ketones) if hypoglycaemia were to occur.’ More overtly, ‘Low levels of insulin increase the rate of ketogenesis and high levels of insulin suppress the rate of ketogenesis’ [81]. In other words, by keeping blood glucose at low levels over a long time, glucose would be provided to the body without creating surges of insulin and more generally stabilizes impacts on energy availability and utilisation by the brain and body. Further insight into this approach (slow controlled glucose release to manage seizures) has been discussed by Pfeifer et al. [82] in the context of low glycaemic index food utilisation to manage epilepsy. The authors indicate that this approach provides a viable first line dietary therapy for epilepsy. The use of a diet containing a carbohydrate:protein:fat ratio of 20:30:50 has been used to control blood glucose concentration in type 2 diabetics [83] and ameliorate hyperglycaemia - which could be usefully for seizure control too due to the glucose control. 5. Conclusions Epileptic events can be managed by a ketogenic diet although it is by no means clear how ketone bodies regulate neuronal events in the brain to control the episodes. The brain utilises ketone bodies as an energy source rather than glucose with this type of diet. Many theories have been proposed to explain how the diet works physiologically to control seizures and these are covered in this review. The ketogenic diet is very effective at seizure control but is difficult to tolerate. Hence other diets, especially the low glycaemic index diet have been developed as an alternative. The authors propose that another option for the dietary management of seizures is to consume a very slowly digestible glucose source which minimises impact on insulin response, in conjunction with a source of ketones (prefer those generated from lipid metabolism) to optimise energy for the brain and body. This approach allows for controlled amounts of a low steady supply of glucose for energy whilst reducing the negative physiological side effects of a ketogenic diet. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authorship Xin Qi and Richard Tester participated in the writing and critical revision of the article. All authors read and approved the manuscript. Conflicts of interest The authors declare no conflicts of interest.

Please cite this article as: Qi X, Tester RF, The ‘epileptic diet’- ketogenic and/or slow release of glucose intervention: A review, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.05.026

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Please cite this article as: Qi X, Tester RF, The ‘epileptic diet’- ketogenic and/or slow release of glucose intervention: A review, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.05.026