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Intermittent fasting: A "new" historical strategy for controlling seizures?
Abstract
In antiquity, fasting was a treatment for epilepsy and a rationale for the ketogenic diet (KD). Preclinical data indicate the KD and intermittent fasting do not share identical anticonvulsant mechanisms. We implemented an intermittent fasting regimen in six children with an incomplete response to a KD. Three patients adhered to the combined intermittent fasting/KD regimen for 2 months and four had transient improvement in seizure control, albeit with some hunger-related adverse reactions.
... Catabolism of fatty acids in the liver produces ketone bodies (KB), which induces urinary ketosis [4]. However, patients that are less responsive to the KD may benefit from intermittent fasting, suggesting different mechanism of intermittent fasting than KD on seizure control [5]. ...
... The present study showed significant improvement of certain seizure types by Ramadan fasting. Ramadan fasting may be similar to the KD and intermittent fasting in that they all improve focal and myoclonic seizure control [4,5]. Despite the effectiveness of the KD in improving generalized tonic-clonic seizures [4], Ramadan fasting in this study was not associated with improvements in this type of seizure. ...
Background and objectives:
Fasting is the basis for the ketogenic diet, and intermittent fasting is emerging as a treatment for epilepsy. There are no available data about the role of Islamic fasting on seizure control. This study aims to assess the effect of Ramadan fasting on the frequency of different seizure types.
Methods:
This was a prospective observational study on Muslim patients with active epilepsy intending to fast during Ramadan in the year 2019, with an average of 16 fasting hours per day. Seizure frequency for each seizure type was followed over three months, one month before (Shaaban), during Ramadan and one month after (Shawwal), after ensuring drug compliance.
Results:
Three hundred and twenty one Muslim patients with active epilepsy with median age of 33 years were included (some patients had more than one type of seizure). In Ramadan, 86 out of 224 patients with focal seizures, 17 out of 38 patients with myoclonic seizures and 6 out of 10 patients with absence seizures showed ≥ 50% reduction. In Shawaal, such improvement continued to include 83, 13 and 4 patients with focal, myoclonic and absence seizures. Focal and myoclonic seizures were significantly improved in the months of Ramadan and Shawaal compared to Shaaban. However, absence seizures were significantly improved only in Ramadan compared with Shaaban. The frequency of generalized tonic-clonic seizures did not significantly differ between the three months.
Discussion:
Ramadan fasting may have an improving effect, as well as a post-fasting effect, on active focal, myoclonic and absence seizures.
... Study done on 6 children from age group 2 to 7 years old at Johns Hopkins Hospital [70] who were diagnosed with Lennox-Gastaut syndrome (two patients), Doose syndrome (two patients), and one child each with idiopathic generalized epilepsy and multifocal epilepsy. From the past 4 months they all were on a Ketogenic diet (KD) but showed no good results. ...
... ADF protocol was followed (fasting on Monday and Thursday) and no changes were made on KD. IF+KD was followed for 2 months and it was found that out of 6, 4 children showed positive effect for IF+KD but complete freedom from seizure was not seen, they possessed atonic seizures as part of their semiology [70]. ...
Fasting helps the vital energy to remove the toxic matter from the blood and purify the system. Fasting awakens the mind and enhances inner tranquility. In today's world many people are living a very unhealthy, sedentary lifestyle where no such physical activities are involved. Sedentary lifestyle and meals three times per day (breakfast, lunch, dinner and snacks in between) often leads to metabolic morbidities that lead to many diseases that they are unaware of. In these situations, the concept of Intermittent Fasting gained much popularity globally. Intermittent fasting (IF) is basically a banqueting mosaic and not a diet, one has to follow. IF in general is a regimen where one can refrain themselves from eating for some fixed consecutive hours mainly more than 12 hours fasting and rest is eating time period. The objective of this review paper is to summarize and bring out the fruitful wellness benefits of Intermittent Fasting that have shown clinical results from human studies as well as from animal studies. IF can counteract many diseases and functional improvement was shown in various experimental models with a wide range of diseases and disorders. IF can be paradigmatic in developing new approach to weight loss, reduction in inflammation, deduction and prevention in skin disease, decrease in Hypertension, metabolic switching, diabetes prevention and maintenance, maintaining insulin level and increase insulin sensitivity, prevention and help in cardiovascular disease and stroke, increase in wound healing process, boosting immune system, promoting autophagy, help in treating neurodegenerative disease like Alzheimer disease and Vascular Dementia and Seizures.
... Interestingly, different ways of dietary treatment has been used since ancient times for epilepsy treatment, and nowadays, this alternative is an effective way to diminish seizures in patients with refractory epilepsy [5]. In spite of this, the precise mechanisms by which these kinds of treatments exert its beneficial effects are far away to be fully elucidated [6]. ...
... Currently, the dietary treatments that have proven efficacy on epilepsy include a wide variety of dietary interventions, such as ketogenic diets, intermittent fasting, and calorie restriction [5,6,11] (Fig. 1). Specifically, these kinds of treatments are characterized by a metabolic shift in which the restriction of glycolysis and the increase of fatty acid oxidation may result in ketosis, replenishment of tricarboxylic acid cycle (TCA), and restoration of neurotransmitter and ion channel [12]. ...
Purpose of Review
Seizures are able to induce a wide range of complex alterations that may be due to abnormalities in gene expression patterns. In recent years, there has been resurgence regarding the use of dietary therapies for seizure treatment. Unfortunately, the precise mechanisms by which these therapies exert its effects remain unknown.
Recent Findings
Recent evidence suggest that dietary treatment, throughout a metabolic shift, could impact the concentration of some metabolites, such as beta-hydroxybutyrate (B-HB) or S-adenosyl methionine (SAM), which are able to modulate the activity of enzymes involved in regulatory processes that control gene expression. Despite of this evidence, only a few studies have fully explored this emerging field.
Summary
The purpose of this article is to discuss how dietary treatment, throughout these molecules, could influence epigenetic modifications that may be able to restore aberrant patterns of gene expression produced by seizures, having an impact on this complex disease, such as seizures or even in epileptogenesis.
... Recently, a small study investigated the effects of a two-month modified TRF regimen in six epileptic children with an incomplete response to a ketogenic diet, reporting that four of the six children experienced modest improvements in seizure control [157]. These results are not surprising, as fasting and ketogenic diets share many similar mechanisms; for example, both increase BHB, which in some studies has correlated with improved seizure control [158,159], and both induce additional mechanisms that collectively stabilize synaptic function. ...
Fasting is deeply entrenched in evolution, yet its potential applications to today’s most common, disabling neurological diseases remain relatively unexplored. Fasting induces an altered metabolic state that optimizes neuron bioenergetics, plasticity, and resilience in a way that may counteract a broad array of neurological disorders. In both animals and humans, fasting prevents and treats the metabolic syndrome, a major risk factor for many neurological diseases. In animals, fasting probably prevents the formation of tumors, possibly treats established tumors, and improves tumor responses to chemotherapy. In human cancers, including cancers that involve the brain, fasting ameliorates chemotherapy-related adverse effects and may protect normal cells from chemotherapy. Fasting improves cognition, stalls age-related cognitive decline, usually slows neurodegeneration, reduces brain damage and enhances functional recovery after stroke, and mitigates the pathological and clinical features of epilepsy and multiple sclerosis in animal models. Primarily due to a lack of research, the evidence supporting fasting as a treatment in human neurological disorders, including neurodegeneration, stroke, epilepsy, and multiple sclerosis, is indirect or non-existent. Given the strength of the animal evidence, many exciting discoveries may lie ahead, awaiting future investigations into the viability of fasting as a therapy in neurological disease.
... Excitatory and inhibitory amino acids, beyond glutamate and GABA, must also be investigated further (Dahlin et al. 2005). Even the genetic differences between CR, IF, and the KD must be investigated as they seem to have different effects on epilepsy (Hartman et al. 2010(Hartman et al. , 2013Cheng et al. 2003). Finally, a combination or rotation of all three dietary interventions, even though most difficult to sustain, may be the most effective treatment for patients with chronic seizures. ...
Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by seizures, which can be caused by a diverse array of afflictions. As such, drug interventions that target a single biological pathway will only help the specific individuals where that drug?s mechanism of action is relevant to their disorder. Most likely, this will not alleviate all forms of epilepsy nor the potential biological pathways causing the seizures, such as glucose/amino acid transport, mitochondrial dysfunction, or neuronal myelination. Considering our current inability to test every individual effectively for the true causes of their epilepsy and the alarming number of misdiagnoses observed, we propose the use of the ketogenic diet (KD) as an effective and efficient preliminary/long-term treatment. The KD mimics fasting by altering substrate metabolism from carbohydrates to fatty acids and ketone bodies (KBs). Here, we underscore the need to understand the underlying cellular mechanisms governing the KD?s modulation of various forms of epilepsy and how a diverse array of metabolites including soluble fibers, specific fatty acids, and functional amino acids (e.g., leucine, d-serine, glycine, arginine metabolites, and N-acetyl-cysteine) may potentially enhance the KD?s ability to treat and reverse, not mask, these neurological disorders that lead to epilepsy.
... Significant reductions in BDNF were also reported in women after a 12-week CR intervention (8-week VLCD + 4-week weight maintenance) [63], but this was not associated with changes in cognitive function. To our knowledge, only one pilot study has tested the effect of a combination of IF and ketogenic diet in children who underwent seizure control [64]. Improved seizure control compared to baseline was reported by four families but only three children adhered to the combined diet for two months or longer. ...
Obesity and overweight are contributing factors to chronic disease. Lifestyle management, which incorporates advice on moderate daily caloric restriction (CR) and physical activity to reduce body weight, is the cornerstone treatment in practice. Intermittent fasting (IF) is a popular alternative that cycles fasting with unrestricted eating periods. IF appears to be an equivalent approach to CR to induce weight loss, although as yet there is limited long-term evidence. Some controversy exists as to whether IF yields superior health benefits to CR. Discrepancies between studies may be due to the heterogeneity in the design of IF protocols. There is also still some concerns around the safety and feasibility of IF compared to CR, which has not been well-studied to date. Moreover, the underlying cellular pathways that are differentially activated in IF in comparison to CR requires further investigation in humans. This review summarises trials that have compared IF with CR, and discusses evidence from animal studies to raise questions for future research in humans.
... One hundred years ago, Dr Russell Wilder at the Mayo Clinic in Rochester, Minnesota, theorized that a low-carbohydrate, high-fat diet could mimic the beneficial effects of fasting, which had been recognized as helpful in suppressing seizures for over a decade. 1 He was partially correct -the "ketogenic" diet, as he named it, did reduce seizures, but as recent research has demonstrated, its effects are vastly different from fasting mechanistically. 2,3 For the next 20 to 30 years, the classic ketogenic diet was one of the most popular epilepsy treatments for children and adults with few options other than phenobarbital and bromides available. The period from 1940 to 1980 saw a gradual, steady decline in ketogenic diet use, likely due to a combination of new antiseizure drugs such as phenytoin, carbamazepine, and valproate, but also an abrupt drop-off in published clinical research for unclear reasons. ...
As the ketogenic diet approaches 100 years of continuous use, we reflect on its successes and consider new avenues of research for the next century. One controversial question is regarding whether ketogenic dietary therapies could be successful first-line treatments for epilepsy. Second, is it possible to mimic the mechanisms of action of ketogenic dietary therapy with a drug (eg, a tablet formulation)? A third controversy worthy of future study involves its expanded usage in adults with refractory epilepsy and its role in treating women of childbearing age. Finally, as flexible, alternative diets have recently become widely available, is it feasible and safe to have families and patients start ketogenic dietary therapy successfully on their own with limited medical supervision?
... A meta-analysis of seven studies of the classic ketogenic diet in both adolescents and adults found that the diet was associated with >50% seizure reduction in half of the patients treated, and 13% of the responsive patients were seizure-free (Payne et al., 2011). Fasting produces similar metabolic shifts and its antiepileptic properties have been recognized for millennia (Hartman et al., 2013). ...
Ketogenic diets are effective therapies for refractory epilepsy, yet the underlying mechanisms are incompletely understood. The anticonvulsant efficacy of ketogenic diets correlates positively to the serum concentration of β-hydroxybutyrate (BHB), the primary ketone body generated by ketosis. Voltage-gated potassium channels generated by KCNQ2-5 subunits, especially KCNQ2/3 heteromers, generate the M-current, a therapeutic target for synthetic anticonvulsants. Here, we report that BHB directly activates KCNQ2/3 channels (EC50, 0.7 µM), via a highly conserved S5 tryptophan (W265) on KCNQ3. BHB was also acutely effective as an anticonvulsant in the pentylene tetrazole (PTZ) seizure assay in mice. Strikingly, co-administration of γ-amino-β-hydroxybutyric acid (GABOB), a high-affinity KCNQ2/3 partial agonist that also acts via KCNQ3-W265, similarly reduced the efficacy of BHB in KCNQ2/3 channel activation in vitro and in the PTZ seizure assay in vivo. Our results uncover a novel, unexpected molecular basis for anticonvulsant effects of the major ketone body induced by ketosis. SIGNIFICANCE STATEMENT: Ketogenic diets are used to treat refractory epilepsy but the therapeutic mechanism is not fully understood. Here, we show that clinically relevant concentrations of β-hydroxybutyrate, the primary ketone body generated during ketogenesis, activates KCNQ2/3 potassium channels by binding to a specific site on KCNQ3, an effect known to reduce neuronal excitability. We provide evidence using a mouse chemoconvulsant model that KCNQ2/3 activation contributes to the antiepileptic action of β-hydroxybutyrate.
... The ketogenic diet has also demonstrated efficacy in the prevention of migraine [128]. In individuals with epilepsy, IF has produced a therapeutic response [129]. ...
Dietary behavior can have a consequential and wide-ranging influence on human health. Intermittent fasting, which involves intermittent restriction in energy intake, has been shown to have beneficial cellular, physiological, and system-wide effects in animal and human studies. Despite the potential utility in preventing, slowing, and reversing disease processes, the clinical application of intermittent fasting remains limited. The health benefits associated with the simple implementation of a 12 to 16 h fast suggest a promising role in the treatment of chronic pain. A literature review was completed to characterize the physiologic benefits of intermittent fasting and to relate the evidence to the mechanisms underlying chronic pain. Research on different fasting regimens is outlined and an overview of research demonstrating the benefits of intermittent fasting across diverse health conditions is provided. Data on the physiologic effects of intermittent fasting are summarized. The physiology of different pain states is reviewed and the possible implications for intermittent fasting in the treatment of chronic pain through non-invasive management, prehabilitation, and rehabilitation following injury and invasive procedures are presented. Evidence indicates the potential utility of intermittent fasting in the comprehensive management of chronic pain and warrants further investigation.
... During the past 50 years, it was established that ketones can constrain neuronal network activity and ketogenic diets can benefit many patients with epilepsy 24 . More recently, it was shown that rats maintained on ADF exhibit resistance to seizure-induced hippocampal damage and associated cognitive impairment 25 and that IF can reduce seizure frequency in children who do not fully respond to a ketogenic diet 26 . ...
During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.
... Affecting 47 million Americans (2), it is associated with a major increase in the risk of cardiovascular disease (CVD) and all-cause mortality (3). Although prolonged fasting or very low calorie fasting-mimicking diets (FMDs) can ameliorate the incidence of diseases such as cancer and multiple sclerosis in mice (4)(5)(6), randomized trials to assess fasting's ability to reduce markers/risk factors for aging and major age-related diseases have not been carried out (7)(8)(9). Prolonged fasting, in which only water is consumed for 2 or more days, reduces pro-growth signaling and activates cellular protection mechanisms in organisms ranging from single-cell yeast to mammals (10). In mammals, this is achieved in part by temporarily reducing glucose and circulating insulin-like growth factor 1 (IGF-1), a hormone well studied for its role in metabolism, growth, and development, as well as for its association with aging and cancer (11)(12)(13)(14)(15)(16). ...
Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)—low in calories, sugars, and protein but high in unsaturated fats—on markers/risk factors associated with aging and age-related diseases. We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months. Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles. A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk. Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment.
... In mammals, diet restriction rapidly and robustly enhances brain mitochondrial function (Davis et al., 2008;Hartman et al., 2013). We found that diet restriction increases aggressive tendency in the honey bee, but only over a prolonged time period. ...
Neuronal function demands high-level energy production, and as such, a decline in mitochondrial respiration characterizes brain injury and disease. A growing number of studies, however, link brain mitochondrial function to behavioral modulation in non-diseased contexts. In the honey bee, we show for the first time that an acute social interaction, which invokes an aggressive response, may also cause a rapid decline in brain mitochondrial bioenergetics. The degree and speed of this decline has only been previously observed in the context of brain injury. Furthermore, in the honey bee, age-related increases in aggressive tendency are associated with increased baseline brain mitochondrial respiration, as well as increased plasticity in response to metabolic fuel typein vitroSimilarly, diet restriction and ketone body feeding, which commonly enhance mammalian brain mitochondrial functionin vivo, cause increased aggression. Thus, even in normal behavioral contexts, brain mitochondria show a surprising degree of variation in function over both rapid and prolonged timescales, with age predicting both baseline function and plasticity in function. These results suggest that mitochondrial function is integral to modulating aggression-related neuronal signaling. We hypothesize that variation in function reflects mitochondrial calcium buffering activity, and that shifts in mitochondrial function signal to the neuronal soma to regulate gene expression and neural energetic state. Modulating brain energetic state is emerging as a critical component of the regulation of behavior in non-diseased contexts.
... Starvation is a chronic nutritional insufficiency usually meaning extreme fasting, causing deterioration and death. On the other hand, fasting was shown to optimize general health and stress resistance and prevent many agerelated diseases through ketogenesis and changes in metabolic signaling pathways (Muller et al. 2001;Hartman et al. 2013). ...
... It combined KD with intermittent fasting as a new regimen for epilepsy therapy. Our previous study discovered that EODKD led to a higher ketone level than KD in both serum and cerebrospinal fluid of rats [33], and researchers also found improved seizure control in pediatric patients by additional intermittent fasting during clinical KD treatment [13]. ...
Ketogenic diet (KD) has been used in epilepsy for decades, but previous studies found it may cause severe bone loss. Every-other-day ketogenic diet (EODKD), the combination of KD with intermittent fasting, showed better potential for seizure control recently, while its effects on bone remain unknown. This study aims to establish different ketogenic rat models and compare the influence of EODKD with KD on bone microstructure and metabolism. Thirty male Sprague-Dawley rats were divided into Control, KD and EODKD groups, fed with standard diet, continuous and intermittent ketogenic diet respectively. After 12 weeks, bone mineral density (BMD) and body fat percentage were obtained by dual energy X-ray absorptiometry. Micro-CT and three-point bending test were used to evaluate the bone microstructure and mechanical properties. Activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) were measured, together with the osteogenic capabilities of bone marrow stromal cells (BMSCs) tested by ALP activities and alizarin red stain in different osteogenic stage. Both EODKD and KD induced higher ketone and more fat percentage, but led to lower body weight compared with Control group. They both compromised bone mass and mechanical properties. Compared with KD, EODKD demonstrated higher ketone levels, but it also inhibited osteoclastic process as well as early osteogenic differentiation. In general, EODKD accelerated ketosis, but may not deteriorate bone microstructure and strength than KD.
... These include calorie restriction, a low glycemic index treatment (LGIT), and an anaplerotic diet, each of which acts at a different target within metabolism ( Figure 2D). Calorie restriction mimics the KD by limiting energy availability [60]. The LGIT provides carbohydrates with low glycemic indices, smoothing out the acute elevations in blood glucose levels caused by foods with high glycemic indices [61]. ...
Mechanisms underlying seizures and epilepsy have traditionally been considered to involve abnormalities of ion channels or synaptic function. Those considerations gave rise to the excitation/inhibition (E/I) imbalance theory, whereby increased excitation, decreased inhibition, or both favor a hyperexcitable state and an increased propensity for seizure generation and epileptogenesis. Several recent findings warrant reconsideration and expansion of the E/I hypothesis: novel genetic mutations have been identified that do not overtly affect E/I balance; neurotransmitters may exert paradoxical effects, especially during development; anti-seizure medications do not necessarily work by decreasing excitation or increasing inhibition; and metabolic factors participate in the regulation of neuronal and network excitability. These novel conceptual and experimental advances mandate expansion of the E/I paradigm, with the expectation that new and exciting therapies will emerge from this broadened understanding of how seizures and epilepsy arise and progress.
... циальных монокарбоксилатных транспортеров [5] и становятся источником энергии для клеток головного мозга -наиболее глюкозозависимого органа. Уже давно было показано, что голодание имеет терапевтическую ценность в лечении эпилепсии [6]. А поскольку кетоны являются продуктами метаболизма липидов, была предложена концепция кетогенной диеты, которая заключается в уменьшении плазменного уровня глюкозы и повышении кетоновых тел путем увеличения содержания в пище липидов и снижения содержания углеводов [7]. ...
The paper considers the necessity of using ketogenic diet and its efficacy in epilepsy. Direct and indirect effects of ketones on brain cells and molecular mechanisms of their action are discussed in detail.
... The disadvantages of fasting are physiologic stress, risk of hypoglycemia and dehydration, improper hospital conditions, increased expenses, and repeated blood tests. 'Intermittent fasting' was used with KD in pediatric patients in whom seizures were not well controlled and a temporary improvement in the frequency of seizures was reported (42). ...
Epilepsy is an important health issue. The interest in ketogenic diet (KD) treatment in children and adolescents with drug-resistant epilepsy has increased in recent years. It was thought that KD was a last option of treatment in patients who were unresponsive to 2 or 3 anticonvulsant drugs. KD with limited protein, low carbohydrate, and high fat content was thought as a last option of treatment, previously. However, nowadays it is the most selected therapy worldwide in epileptic children and adolescents. Ketone bodies are elevated in the blood due to low carbohydrate and high lipid content of KD. Through the elevation of ketone bodies, the brain uses ketone bodies as energy sources, which results in decreased in epileptic seizures. Medical nutritional therapy during treatment of childhood epilepsies should also provide normal growth and development. For this reason, full compliance with the diet is important. The effect, place, and importance of ketogenic nutrition therapy in drug-resistant epilepsies of childhood are discussed in this review. © 2018 by Turkish Neurological Society Turkish Journal of Neurology published by Galenos Publishing House.
... We now know that fasting results in ketogenesis, promotes potent changes in metabolic pathways and cellular processes such as stress resistance, lipolysis and autophagy, and can have medical applications that in some cases can become an alternative strategy to medication [11,12]. RCF may alter the circadian consumption and distribution of energy and other nutrients for the fulfilment of daily requirements [13,14]. ...
Background:
The effects of fasting on health in non-human models have been widely publicised for a long time and emerging evidence support the idea that these effects can be applicable to human practice.
Methods:
In an open label longitudinal follow-up, a cohort of 78 adult men (aged 20 to 85 years) who fasted for 29 consecutive days from sunrise to sunset (16 h fasting-referred to as recurrent circadian fasting) in Pakistan, were studied. The primary outcomes of the fasting study was weight loss/recovery and the associated changes in blood pressure and circulating levels of surrogate markers linked to organ and system functions-including cardiovascular, metabolic and inflammation. Post-fasting outcomes include the regulation of physiological biomarkers.
Results:
Recurrent circadian fasting with weight loss reduced blood pressure (140.6 vs. 124.2 mmHg) and markers of cardiovascular risk (~ 4-fold for resistin; triglycerides: p < 0.0001). Reduced glycemia (p < 0.0001) and the associated changes in the regulation of ketosis (β-hydroxybutyrate) were accompanied by a metabolic shift (PPARβ, osteoprotegerin), suggesting the involvement of the different physiological systems tested. Elevated orexin-A levels (p = 0.0183) in participants indicate sleep disturbance and circadian adaptation. All participants had CRP level < 2 mg/l during the fasting period and a similar trend was observed for TNFα. While most SASP molecules were decreased after the fasting period, heightened levels of IL-8 and IL-6 suggest that some inflammatory markers may be elevated by recurrent circadian fasting. Importantly, older adults reveal similar or more substantial benefits from fasting.
Conclusions:
Recurrent circadian fasting is beneficial at the cardiometabolic and inflammatory levels, especially for at-risk individuals-this is contingent on compliance towards the recommended dietary behaviour, which controls carbohydrate and caloric intake. These benefits from fasting may be particularly beneficial to older adults as they often exhibit abnormal cardiovascular, metabolic and inflammatory signatures.
... In mammals, diet restriction rapidly and robustly enhances brain mitochondrial function (Davis et al., 2008;Hartman et al., 2013). We found that diet restriction increases aggressive tendency in the honey bee, but only over a prolonged time period. ...
... Interestingly, fasting has been shown to have similar mitigating effects in treating seizures, seizure-associated brain damage, and rheumatoid arthritis compared to currently approved drugs. [89][90][91] Various fasting regimes have also been shown to improve healthspan and lifespan in model organisms. 75,92 For clarity, all fasting regimes will be described by fasting duration. ...
Stem cell dysfunction is a hallmark of aging, associated with the decline of physical and cognitive abilities of humans and other mammals. 1 Therefore, it has become an active area of research within the aging and stem cell fields, and various techniques have been employed to mitigate the decline of stem cell function both in vitro and in vivo. While some techniques developed in model organisms are not directly translatable to humans, others show promise in becoming clinically relevant to delay or even mitigate negative phenotypes associated with aging. This review focuses on diet, treatment, and small molecule interventions that provide evidence of functional improvement in at least one type of aged adult stem cell. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: We present the current status of interventions to improve aging phenotypes, in the context of stem cell aging. By restoring potential to aged stem cells, there will likely be a cascading beneficial effect on the entire system. However, many interventions only have reports in a few tissue-specific stem cell types, and more comprehensive analysis of potential benefits and consequences to all stem cells is necessary. We highlight overlaps between interventions and proposed considerations needed before moving some of these interventions into human trials.
... Similar results have been found for 7-10 weeks and 6 months of ADF in epilepsy-induced rats [111,112]. In children with epilepsy not responding to antiepileptic treatment, a PF regimen for two months improved seizure control in four out six children [82]. ...
The importance of diet and the gut-brain axis for brain health and cognitive function is increasingly acknowledged. Dietary interventions are tested for their potential to prevent and/or treat brain disorders. Intermittent fasting (IF), the abstinence or strong limitation of calories for 12 to 48 h, alternated with periods of regular food intake, has shown promising results on neurobiological health in animal models. In this review article, we discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of brain-related disorders in animals and humans. We do so by summarizing the effects of IF which through metabolic, cellular, and circadian mechanisms lead to anatomical and functional changes in the brain. Our review shows that there is no clear evidence of a positive short-term effect of IF on cognition in healthy subjects. Clinical studies show benefits of IF for epilepsy, Alzheimer’s disease, and multiple sclerosis on disease symptoms and progress. Findings from animal studies show mechanisms by which Parkinson’s disease, ischemic stroke, autism spectrum disorder, and mood and anxiety disorders could benefit from IF. Future research should disentangle whether positive effects of IF hold true regardless of age or the presence of obesity. Moreover, variations in fasting patterns, total caloric intake, and intake of specific nutrients may be relevant components of IF success. Longitudinal studies and randomized clinical trials (RCTs) will provide a window into the long-term effects of IF on the development and progress of brain-related diseases.
... More than 1.5 billion Muslims reportedly refrain from eating or drinking from sunrise (Sahur) to sunset (Iftar) during the holy month of Ramadan each year, which lasts between 28 and 30 days (1,2), and thus practice intermittent fasting and caloric restriction. Intermittent fasting has been shown to have various beneficial health effects, including improved immune system function (3,4), enhanced cognitive function (5), improved body composition and reduced obesity (6,7), and even reduced episodes of seizures in some patients with epilepsy (8). However, the mechanisms mediating the effects of intermittent fasting remain largely obscure, which hamper the adoption of intermittent fasting as a strategy for improving health or as a disease intervention. ...
The human gut microbiota has been proposed to serve as a multifunctional organ in host metabolism, contributing effects to nutrient acquisition, immune response, and digestive health. Fasting during Ramadan may alter the composition of gut microbiota through changes in dietary behavior, which ultimately affects the contents of various metabolites in the gut. Here, we used liquid chromatography–mass spectrometry-based metabolomics to investigate the composition of fecal metabolites in Chinese and Pakistani individuals before and after Ramadan fasting. Principal component analysis showed distinct separation of metabolite profiles among ethnic groups as well as between pre- and post-fasting samples. After Ramadan fasting, the Chinese and Pakistani groups showed significant differences in their respective contents of various fecal metabolites. In particular, L-histidine, lycofawcine, and cordycepin concentrations were higher after Ramadan fasting in the Chinese group, while brucine was enriched in the Pakistani group. The KEGG analysis suggested that metabolites related to purine metabolism, 2-oxocarboxylic acid metabolism, and lysine degradation were significantly enriched in the total subject population pre-fasting vs. post-fasting comparisons. Several bacterial taxa were significantly correlated with specific metabolites unique to each ethnic group, suggesting that changes in fecal metabolite profiles related to Ramadan fasting may be influenced by associated shifts in gut microbiota. The fasting-related differences in fecal metabolite profile, together with these group-specific correlations between taxa and metabolites, support our previous findings that ethnic differences in dietary composition also drive variation in gut microbial composition and diversity. This landscape view of interconnected dietary behaviors, microbiota, and metabolites contributes to the future development of personalized, diet-based therapeutic strategies for gut-related disorders.
... While there is extremely limited information on the combination of TRF with a KD in humans, limited data from case studies [34] and small clinical trials [35] indicate that the combination may provide therapeutic relief for uncontrollable diabetes or insulin resistance. However, there were notable differences in seizure relief in children who differed in response to the two dietary paradigms [36]. ...
Both ketogenic diets (KD) and time-restricted feeding (TRF) regimens have the ability to influence several parameters of physical health, including gut microbiome composition and circulating cytokine concentration. Moreover, both of these dietary interventions prevent common impairments associated with the aging process. However, significantly altering macronutrient intake, which is required for a KD, may be unappealing to individuals and decrease compliance to dietary treatments. In contrast to a KD, TRF allows individuals to continue eating the foods they are used to, and only requires a change in the time of day at which they eat. Therefore, we investigated both a KD and a diet with a more Western-like macronutrient profile in the context of TRF, and compared both diets to animals allowed access to standard chow ad libitum in young adult and aged rats. While limited effects on cytokine levels were observed, both methods of microbiome analysis (16S sequencing and metagenomics) indicate that TRF and KDs significantly altered the gut microbiome in aged rats. These changes were largely dependent on changes to feeding paradigm (TRF vs. ad libitum) alone regardless of macronutrient content for many gut microbiota, but there were also macronutrient-specific changes. Specifically, functional analysis indicates significant differences in several pathways, including those involved in the tricarboxylic acid (TCA) cycle, carbohydrate metabolism and neurodegenerative disease. These data indicate that age- and disease-related gut dysbiosis may be ameliorated through the use of TRF with both standard diets and KDs.
... It is widely accepted that these changes under IF positively contributes to human health in multiple areas [21][22][23][24]. Recent studies in the field of neuroscience have found scientific evidence that IF exerts protective effects against multiple neurological diseases and disorders, including Alzheimer's disease (AD) [25,26], Parkinson's disease (PD) [27,28], multiple sclerosis (MS) [29,30], epilepsy [31,32], ischemic stroke [33][34][35], and depression [36][37][38]. ...
It has widely been accepted that food restriction (FR) without malnutrition has multiple health benefits. Various calorie restriction (CR) and intermittent fasting (IF) regimens have recently been reported to exert neuroprotective effects in traumatic brain injury (TBI) through variable mechanisms. However, the evidence connecting CR or IF to neuroprotection in TBI as well as current issues remaining in this research field have yet to be reviewed in literature. The objective of our review was therefore to weigh the evidence that suggests the connection between CR/IF with recovery promotion following TBI. Medline, Google Scholar and Web of Science were searched from inception to 25 February 2022. An overwhelming number of results generated suggest that several types of CR/IF play a promising role in promoting post-TBI recovery. This recovery is believed to be achieved by alleviating mitochondrial dysfunction, promoting hippocampal neurogenesis, inhibiting glial cell responses, shaping neural cell plasticity, as well as targeting apoptosis and autophagy. Further, we represent our views on the current issues and provide thoughts on the future direction of this research field.
... In 2013, Hartman et al. evaluated retrospectively the effect of a short-course, modified time-restricted fasting (TRF) in a small group of children living with epilepsy whose manifestations were inadequately controlled by drugs and ketogenic diets. Authors noted that four out of six patients benefited from IF in terms of improved seizure control and three out of six were able to keep the regimen for at least 2 months [103]. This conclusion does not come as a surprise given the common traits between IF and ketogenic diet in terms of the effect on CNS metabolism. ...
We are facing an obesity epidemic, and obesity itself and its close companion, type 2 diabetes, are independent risk factors for neurodegeneration. While most medical treatments fail to induce a clinically meaningful improvement in neurodegenerative disorders, lifestyle interventions have emerged in the spotlight. A recently rediscovered approach is intermittent fasting (IF), which, compared to the classic caloric restriction regimens, limits only the time of eating, rather than the number of calories allowed per day. There is already a large amount of evidence from preclinical and clinical studies showing the beneficial effects of IF. In this review, we specifically focus on the effects of IF on brain metabolism. Key molecular players modified during IF and involved in its beneficial central effects (ketone bodies, BDNF, GABA, GH/IGF-1, FGF2, sirtuin-3, mTOR, and gut microbiota) are identified and discussed. Studies suggest that IF induces several molecular and cellular adaptations in neurons, which, overall, enhance cellular stress resistance, synaptic plasticity, and neurogenesis. Still, the absence of guidelines regarding the application of IF to patients hampers its broad utilization in clinical practice, and further studies are needed to improve our knowledge on the different IF protocols and long-term effects of IF on brain metabolism before it can be widely prescribed.
... Intermittent fasting is defined as the nutrition type, which causes a decrease in daily total energy intake (50-100%) due to food intake restriction in full or partial (e.g., 16-48 h) at certain times of the day, 1-3 times a week, or prolonged night time [1,2]. Since ancient times, especially in the treatment of epilepsy, mainly in ketogenic diet applications, it has been used in various ways [3]. However, its popularity increased when its effect on the potential improvement of metabolic abnormalities was determined experimentally [4]. ...
Objective:
This study was aimed at evaluating the effect of intermittent fasting of Ramadan on resting energy expenditure (REE), body composition, and nutritional status.
Methods:
The study was conducted on a total of 27 adults (16 females, 11 males) who were fasting (18 h) in the Ramadan month (May 6-June 3) of 2019. REE was measured using the indirect calorimeter. Dietary energy and nutrient intakes were evaluated by 3-day food records in baseline and post-Ramadan. Body composition and some metabolic parameters were analyzed simultaneously with REE measurements. All measurements were performed two times at baseline, and post-Ramadan.
Results:
Body weight (-2.9% vs. -1.4%), body mass index (BMI) (-3.1% vs. -2.1%), fat-free mass (-2.7% vs. -1.4%), and hydration status were decreased in both males and females after the Ramadan fasting (p < 0.05). REEs (kcal/d) of the participants were 1708.1 ± 262.50 kcal/d and 1596.5 ± 302.27 kcal/d at baseline and post-Ramadan, respectively (6.5%) (p < 0.05). This decrease in REE (kcal/d) in females was greater than that in males (-8.1% vs. -4.6%). However, no statistically significant difference was found in sleep duration (h), physical activity levels, dietary energy and nutrient intakes, and blood pressures (mm Hg) of both genders compared to baseline (p > 0.05).
Conclusion:
Intermittent circadian fasting may lead to a decreased energy expenditure and a change in fat-free mass in healthy individuals, and this effect is interpreted as gender-dependent.
... Mekanisme inilah yang menyebabkan terjadinya penurunan berat badan. Hal serupa juga disebutkan oleh studi lain yang menyatakan bahwa dengan puasa akan menstimulasi lipolisis untuk memenuhi kebutuhan energi (19). Sesuai dengan uraian tersebut, asam lemak akan memicu ketogenesis untuk menghasilkan energi yang diperlukan oleh tubuh. ...
Effect of intermittent fasting 5:2 on plasma malondialdehyde levels in adult male employees with obesity
Background: Obesity is a major risk factor for various non-communicable diseases such as type 2 diabetes mellitus and cardiovascular disease. In obesity, the free radical product will be produced, such as malondialdehyde (MDA) which plays a role in the pathogenesis of various diseases. Intermittent fasting (IF) is an alternative way to reduce free radical levels in the body therefore it can prevent complications of obesity. However, the effect of IF on MDA level in an obese adult male in Jakarta has not been reported.
Objective: The objective of this study was to determine the effect of IF on malondialdehyde levels in adult male employees with obesity in Jakarta.
Methods: This study used a randomized controlled clinical trial. The subjects were men aged 19-59 years with a body mass index (BMI) ≥ 25 kg/m2, divided into fasting and control groups, each group consists of 25 subjects. Intermittent fasting 5:2 is calorie restriction up to 20-25% was done every Monday and Thursday, and not allowed to eat and drink during 14 hours of fasting. Before the intervention, both groups were given education about balanced nutrition. Association of intermittent fasting with MDA and catalase was analyzed by means of difference formula with a significance limit of 5%.
Results: MDA levels post-intervention significantly decreased compared to the pre-intervention both in the fasting group [1,3(0,9-2) nmol/mL to 0,4(0,3-0,6) nmol/mL] and in the control groups [1,4(0,9-1,9) nmol/mL to 0,5(0,3-0,7) nmol/mL]. MDA level post-intervention in the fasting group was significantly lower (p
... In a large RCT, 145 children not responding to antiepileptic drugs were given a 3-month ketogenic diet after which they experienced significantly less seizures than a control group [109]. In children with epilepsy not responding to antiepileptic treatment, a PF regimen for two months improved seizure control in four out six children [110]. ...
The importance of diet and the gut-brain axis for brain health and cognitive function is increasingly acknowledged. Dietary interventions are tested for their potential to prevent and/or treat brain disorders. Intermittent fasting (IF), the abstinence or strong limitation of calories for 12 to 48 hours, alternated with periods of regular food intake, has shown promising results on neurobiological health in animal models. In this review article, we discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of brain-related disorders in animals and humans. We do so by summarizing the effects of IF which - through metabolic, cellular and circadian mechanisms - lead to anatomical and functional changes in the brain. Our review shows that there is no clear evidence of a positive short-term effect of IF on cognition in healthy subjects. Clinical studies show benefits of IF for epilepsy, Alzheimer’s disease and multiple sclerosis on disease symptoms and progress. Findings from animal studies show mechanisms by which Parkinson’s disease, ischaemic stroke, autism spectrum disorder and mood- and anxiety disorders could benefit from IF. Future research should disentangle whether positive effects of IF hold true regardless of age or the presence of obesity. Also, variations in fasting patterns, total caloric intake and intake of specific nutrients may be relevant components of IF success. Longitudinal studies and Randomized Clinical Trials (RCTs) will provide a window into the long-term effects of IF on the development and progress of brain-related diseases.
... [54] IF decreased proinflammatory proteins such as NLRP1 and NLRP3, NF-κB, IL-1 β, and IL-18 in the brain and periphery after cerebral ischemia in mice. [55] IF combined with a ketogenic diet (KD) in children with an incomplete response to the diet had modest or transient improvements in seizure control in four of six children in the study and was attributed to the neuroprotective effects of IF. [56] Furthermore, it has been reported that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving suppression of pro-inflammatory cytokines, activating NFκB and enhancement of neurotrophic support. In addition, it decreases lipopolysacharid-induced elevation of interleukin (IL)-1α, IL-1β and tumor necrosis factor alpha levels, and prevents the lipopolysaccharide-induced reduction of (BDNF) levels in the hippocampus. ...
Data from epidemiological and experimental studies have shown that diet and eating patterns have a major role in the pathogenesis of many age-associated diseases. Since 1935, calorie restriction (CR) has been identified as one of the most effective nongenetic dietary interventions that can increase lifespan. It involves reducing calorie intake by about 20%–40% below ad libitum, without malnutrition. Restricting food intake has been observed to increase lifespan and prevent many age-associated diseases in rats, mice, and many other species. Understanding the metabolic, molecular, and cellular mechanisms involved in the anti-aging effects of CR can help us to find dietary interventions that can mimic its effects. Recently, different studies have shown that intermittent fasting, protein restriction, and an epigenetic diet can have similar effects to those of CR. These approaches were selected because it has been indicated that they act through a similar molecular pathway and also, are safe and effective in delaying or preventing diseases. In this review, we focus on the mechanistic pathway involved in CR. Then, we review the mimicking interventions through the mechanistic approach. For this purpose, we reviewed both animal and human articles, mainly available through the PubMed online database. We then selected the most relevant full texts which are summarized in this article.
... The N-Methyl-D-Aspartate (NMDA) receptor subunit 2A (GRIN2A) gene encodes Glutamate NMDA receptor subunit epsilon-1 [31][32][33][34]. This protein is found in the brain and spinal cord neurons, including the regions of the brain responsible for language [35][36][37][38]. ...
Quite few centers in the Middle East are offering the ketogenic diet therapy for the treatment of epilepsy in patients with drug refractory seizures. In King Fahad Medical City, National Neuroscience Institute, Department of Pediatric Neurology, there started the ketogenic therapy program in November 2008. Since then, interesting cases that are seldom encountered by many physicians during their medical careers as well as lab work that is unforeseen and deemed interesting, were observed, and collected. Here we try to exhibit these interesting cases and display unexpected laboratory results. We raise questions more than answers, as searching medical literature and personal communication could not bring clear answers. We quickly review results of patients’ responses and failures to the diet.
... In the brain, hippocampus neurons have an important role in learning and memory; these neurons are degenerated in Alzheimer's disease (14), stroke (15), traumatic brain injury and epilepsy (3). Brain communicates with all of the peripheral organs involved in energy metabolism, and fasting improves brain function and peripheral energy metabolism by modifying brain neurochemistry and neuronal network activity. ...
Calorie restriction through ingesting no or minimal amounts of food and caloric beverages for periods of time is called fasting. Fasting can affect body through changing in physical and metabolic adaptations, as well as mineral and hormonal status. However, psychological effects and sometimes medical complications are likely inlikely in case of inappropriate fasting. Fasting is associated with changes in expression of different genes and signaling pathways. In this brief review, physiological effects of fasting, affected pathways during fasting and potential applications of fasting are discussed.
... Further major changes as a result of nutrition restriction and lowered insulin levels in metabolic pathways and cellular processes, such as lipolysis, autophagy, and increased lifespan, have been discussed in previous reviews [1,37]. Thus, a metabolic change caused by fasting can potentially be as medically effective as approved drugs [38][39][40]. ...
Lifestyle interventions, including meal replacement, are effective in the prevention and treatment of type-2-diabetes and obesity. Since insulin is the key weight regulator, we hypothesised that the addition of meal replacement to a lifestyle intervention reduces insulin levels more effectively than lifestyle intervention alone. In the international multicentre randomised controlled ACOORH (Almased Concept against Overweight and Obesity and Related Health Risk) trial, overweight or obese persons who meet the criteria for metabolic syndrome (n = 463) were randomised into two groups. Both groups received nutritional advice focusing on carbohydrate restriction and the use of telemonitoring devices. The intervention group substituted all three main meals per day in week 1, two meals per day in weeks 2–4, and one meal per day in weeks 5–26 with a protein-rich, low-glycaemic meal replacement. Data were collected at baseline and after 1, 3, 6 and 12 months. All datasets providing insulin data (n = 446) were included in this predefined subanalysis. Significantly higher reductions in insulin (−3.3 ± 8.7 µU/mL vs. −1.6 ± 9.8 µU/mL), weight (−6.1 ± 5.2 kg vs. −3.2 ± 4.6 kg), and inflammation markers were observed in the intervention group. Insulin reduction correlated with weight reduction and the highest amount of weight loss (−7.6 ± 4.9 kg) was observed in those participants with an insulin decrease > 2 µU/mL. These results underline the potential for meal replacement-based lifestyle interventions in diabetes prevention, and measurement of insulin levels may serve as an indicator for adherence to carbohydrate restriction.
... Subsequently, increasing efforts on the studies in multiple fields revealed positive effects of fasting. Evidences have consistently shown that robust efficacy of caloric restriction in cancers, neurodegenerative disease, epilepsy, ischemic injury, cardiovascular disease, ageing, obesity and its related chronic disorders, etc [25][26][27][28]. Among different fasting regimens, the IF was intensely studied recently. ...
Interventions for preventing cognitive dysfunction post traumatic brain injury (TBI) is limited. Given that adult hippocampal neurogenesis (AHN) after brain injury contributes to cognitive recovery, and that the AHN is potentially affected by nutritional factors, we asked whether fasting could promote AHN and thus ameliorates cognitive defects after TBI. Here we show that a one-month intermittent fasting (IF) regimen enhanced proliferation of neural stem cells (NSCs) in the subgranular zone (SGZ) of hippocampus 3 days post TBI, as well as improved cognitive performance in Morris water maze (MWM) test. Furthermore, an increase in hippocampal Npy expression was detected in IF group after injury, compared to the mice fed ad libitum (AL), and locally knock-down of Npy in vivo attenuated the aforementioned effects of IF in TBI. These findings suggest that IF promotes AHN following TBI by a mechanism involving enhancement of Npy expression, which may offer novel interventions that might prevent cognitive dysfunction caused by injury.
... Nevertheless, the strategy of adding a third ASM was associated with increasing the odds of increasing seizure frequency by only 6 times while the odds were increased to 16 times by maintaining the same dual ASMs. For the expected second wave, some bridge therapies that do not necessitate hospitalization must be raised as options for patients with DRE, as ketogenic diet (Williams and Cervenka, 2017) and intermittent fasting (Hartman et al., 2013). However, the real risk of proceeding and the real risk of deferral on epilepsy surgery should be considered case by case. ...
Objective
No data exist regarding the impact of the lockdown due to the COVID-19 pandemic on the risk factors of sudden unexpected death in epilepsy (SUDEP). This study aimed to stratify risk factors of SUDEP in relation to COVID-19 lockdown, among patients with epilepsy (PWE) in Cairo University epilepsy unit (CUEU). Therefore, we can detect risk factors and mitigate such factors in the second wave of the virus.
Methods
an observational, cross-sectional study carried on 340 Egyptian patients with active epilepsy. Individual risk identification and stratification was done by using The SUDEP and seizure Safety Checklist, after which sharing risk knowledge to PWE and their caregivers was undertaken.
Results
The mean age of patients was 29.72 ± 12.12. The median of the static factors was 4 (IQR 3-5) whereas, the median of the modifiable factors was 2 (IQR 1-3). Epilepsy emergencies (serial seizures or status epilepticus) were reported in 24.1% of patients, for which non-compliance was the commonest cause, followed by deferral of epilepsy surgery for patients with drug resistant epilepsy (DRE). Stepwise logistic regression analysis showed that use of anxiolytic medications, non-compliance, keeping patients with DRE on dual anti-seizure medications (ASMs), or adding third medication increased the odds of increased seizure frequency by 2.7, 3.5, 16.6 and 6.1 times, respectively.
Conclusion
Some COVID-19 related issues had influenced the risk of seizure worsening including postponing epilepsy surgery for patients with DRE, non-compliance, and psychiatric comorbidities. Special attention should be paid to these issues to mitigate the risk of SUDEP.
... Low BMD, abnormal cancellous and cortical bone mass have been described in mice under KD treatment [103]. Quite recently, an every other-day ketogenic diet (EODKD) and a combination of KD with intermittent fasting has been introduced in order to combine KD with intermittent fasting as a new regimen for epilepsy therapy, with a better potential for seizure control [104]. In rats, EODKD determines higher ketone levels in both serum and cerebrospinal fluid than KD [105]. ...
The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a "poor" quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included.
... 8 In addition to limiting carbohydrate intake, restricting total calorie intake also suppresses seizures and affords neuroprotection. [8][9][10][11] In fact, the original idea behind the KD was to mimic the physiologic effects of fasting, and some data support intermittent fasting for seizure control, 12 but this strategy is not a pragmatic long-term treatment option. ...
Conventional antiseizure medications reduce neuronal excitability through effects on ion channels or synaptic function. In recent years, it has become clear that metabolic factors also play a crucial role in the modulation of neuronal excitability. Indeed, metabolic regulation of neuronal excitability is pivotal in seizure pathogenesis and control. The clinical effectiveness of a variety of metabolism‐based diets, especially for children with medication‐refractory epilepsy, underscores the applicability of metabolic approaches to the control of seizures and epilepsy. Such diets include the ketogenic diet, the modified Atkins diet, and the low‐glycemic index treatment (among others). A promising avenue to alter cellular metabolism, and hence excitability, is by partial inhibition of glycolysis, which has been shown to reduce seizure susceptibility in a variety of animal models as well as in cellular systems in vitro. One such glycolytic inhibitor, 2‐deoxy‐d‐glucose (2DG), increases seizure threshold in vivo and reduces interictal and ictal epileptiform discharges in hippocampal slices. Here, we review the role of glucose metabolism and glycolysis on neuronal excitability, with specific reference to 2DG, and discuss the potential use of 2DG and similar agents in the clinical arena for seizure management.
Introduction: Fasting is defined as a period of voluntary abstinence from eating food for religious, therapeutic or political reasons, which is associated with a reduction in the supply of sources (kilocalories) to the body. There are different types of fasting, including short, long or intermittent fasting. It has been shown that the use of different types of fasting can influence the occurrence of mood disorders. The aim of this review was to search for the relationship between the use of fasting and mood disorders and its potential use as a therapeutic method.
Material and method: The available literature was reviewed by searching the PubMed and Google Scholar databases using the following keywords: fasting, intermittent fasting, mood disorders, depression, Ramadan, for studies listed from database inception to November 2021.
Results: A review of the collected scientific articles indicates that the dietary restrictions, including both daily restriction of caloric consumption and the use of intermittent fasting (IF), has potentially numerous health benefits in the co-treatment of mental diseases. However, due to conflicting results, further clinical trials in mentally ill people should be conducted. It is worth remembering that among patients with mental illnesses there are somatically ill. IF in these people may require additional nutritional modifications or discontinuation of therapy.
Conclusions: Dietary restriction and fasting are promising methods in co-therapy of mood disorders treatment. However, implementing therapy needs earlier individual evaluation of their benefits and risk, the same as patient’s feasibility of implementing this type of intervention.
A high-fat, low-carbohydrate diet (KD) or calorie restriction in the form of every-other-day fasting (EODF) results in ketone body metabolism with an increasing β-hydroxybutyrate (βOHB) level. Previous studies have supported that a KD and EODF have a neuroprotective effect. However, the βOHB levels in the cerebrospinal fluid (CSF) resulting from a KD and EODF remain unknown. The aim of this study was to detect βOHB levels in rats fed a KD, EODF diet, and every-other-day ketogenic diet (EODKD) and to compare the serum βOHB level with the CSF βOHB level. Twenty-four male Sprague-Dawley rats were randomly divided into KD, EODF, EODKD, and standard diet (SD) groups. A customized food with a ratio of carbohydrates to fats of 1:4 was used in the KD and EODKD groups. The βOHB level was measured using ELISA kits in 200 µl serum and 100 µl CSF samples for each rat after feeding for 2 weeks. The KD, EODF, and EODKD resulted in a significant increase in βOHB levels in both the serum and CSF. The βOHB levels in the EODKD group were the highest. The CSF βOHB level was, on average, 69% of the serum βOHB level. There was a positive correlation between the overall βOHB levels in serum and that in cerebrospinal fluid. This study demonstrated that the KD, EODF, and EODKD resulted in ketone body metabolism, as the βOHB levels increased significantly compared with those resulting from the standard diet. Our results suggested that the serum βOHB level was an indicator of the CSF βOHB level, and that the EODKD was an effective diet to enhance ketogenic metabolism.
Based on the observation that fasting reduces the number and severity of convulsive seizures, a few different eating regimes have emerged to treat epilepsy. These are the ketogenic diet, medium-chain triglyceride regime, modified Atkins diet and low glycemic index treatment, all of which have been used clinically. These nutritional procedures are effective and have few adverse collateral actions. A related diet is caloric restriction, which can be accomplished by several methods. Caloric restriction has been shown to possess anticonvulsive and, most importantly, antiepileptogenic properties. But there are no clinical studies exploring if caloric restriction by itself reduces the number and severity of seizures. However, there is some data suggesting that caloric restriction improves the efficacy of the ketogenic and modified Atkins diets. Its mechanism(s) of action remain(s) mysterious, although several possibilities have been suggested. Each of its proposed mechanisms of action can be targeted for the discovery of drugs that prevent or modify epilepsy. This chapter briefly describes every one of the food modifications in current clinical use or that has been studied using animal models. Much evidence indicating that caloric restriction induced by food restriction or intermittent fasting is antiepileptic or antiepileptogenic is discussed. The possible mechanisms of action of the ketogenic diet and caloric restriction are presented in short. Lastly, a brief method for performing a type of caloric restriction is detailed.
Conclusions:
The aim of this review is to revisit ketogenic diet effectiveness and safety in order to highlight its importance in drug-resistant epilepsy and other neurological disorders.
What is known:
• Ketogenic diet efficacy is now described in large case series, with adequate diet compliance and side effects control. • Ketogenic diet is far from being attempted as a first line therapy. Its availability varies worldwide. What is New: • New pharmacological targets such as mitochondrial permeability transition and new epileptic syndromes and etiologies responding to the diet such as refractory status epilepticus are being pointed out. • Ketogenic diet can function at its best when used as a tailor-made therapy. Fine tuning is crucial.
Ketogenic diet (KD) therapy is an established form of treatment for both pediatric and adult patients with intractable epilepsy. Ketogenic diet is a term that refers to any diet therapy in which dietary composition would be expected to result in a ketogenic state of human metabolism. While historically considered a last-resort therapy, classic KDs and their modified counterparts, including the modified Atkins diet and low glycemic index treatment, are gaining ground for use across the spectrum of seizure disorders. Registered dietitian nutritionists are often the first line and the most influential team members when it comes to treating those on KD therapy. This paper offers registered dietitian nutritionists insight into the history of KD therapy, an overview of the various diets, and a brief review of the literature with regard to efficacy; provides basic guidelines for practical implementation and coordination of care across multiple health care and community settings; and describes the role of registered dietitian nutritionists in achieving successful KD therapy.
This review focuses on the role of mental and cognitive disorders in the prognosis for surgical treatment of pharmacoresistant epilepsy. The authors analyze historical aspects of the surgical treatment of epilepsy and present current data on the prognosis of operative intervention with respect to seizure control, cognitive functioning, and psychiatric disorders. The psychiatrist's role in the structure of preoperative and postoperative management of patients is considered.
We analyzed the article of Guelpa & Marie, published in 1911 and often quoted in the history of dietary treatment, as the basis for the use of ketogenic diet to mimic fasting. In this paper, the authors treated 21 patients with a diet consisting of daily administration of 30 g of sodium sulphate for 4 days, with unlimited aqueous beverage and no food, followed by a vegetarian diet restricted to half of the ordinary intake. This is the first report of intermittent fasting as treatment strategy for epilepsy. In this case series, 15 patients did not follow properly the diet while 2 improved temporary before they quitted the diet and 4 presented an improvement.
Try to collect information on fasting ketogenic diets and medicinal plants, and its possible usefulness in preventing epilepticseizures.
This is a commentary on the details of the increasing flexibility of the original classic ketogenic diet, a well-known evidence-based treatment option for intractable epilepsy. The variety of ketogenic diet therapies (KDT) have shown similar efficacy to the classic version. Initiation protocols, outpatient diet starts, hospital teaching kitchens, premade ketogenic foods and ways to calculate and administer the diet are readily available for ketogenic professionals and their patients. This approach to a more flexible diet management may help to make KDTs easier in compliance, palatability and reducing the risk of side effects.
Interest in exploring nutritional interventions, including therapeutic ketogenic diets, has recently intensified in both the research community and private sector, driven in part by the failure of mainstream policies to prevent or treat the unprecedented surge in metabolic diseases. Also, movement toward the development of new guidelines has not kept pace with research findings, due in part to a deficiency in the education of the next generation of health and nutrition practitioners. At the heart of this problem lies a pervasive belief, even among integrative practitioners, that ketogenic plans are inherently inferior to those that stress the importance of a “balanced diet.” This current nutrition paradigm should be re-evaluated within the context of the body of evidence pointing to an underlying mechanism common to most disease states: specifically, that epigenetic changes in gene expression induced by an overabundant supply of glucose contribute to a broad spectrum of conditions, including obesity, diabetes, cancer, and neurodegenerative disease. This chapter describes the major metabolic alterations to glucose, insulin, and ketone regulation that accompany a sustained shift to ketosis. Beyond the science, readers will come to understand the history, rationale, and limitations of therapeutic ketosis. This foundational knowledge is crucial to building a network of integrative practitioners that can guide and support patients/clients during what is often a challenging transition. To that end, readers will gain the skills essential to developing individualized nutrition plans as well as guidance in troubleshooting the most common dietary issues. Tools that improve compliance and accountability are introduced with full knowledge that this rapidly changing landscape will evolve in response to technological advances.
The study aimed to evaluate the effect of Ramadan fasting on seizure control in epileptic adolescents. A prospective cohort study that included 56 epileptic patients aged 11 to 18 years. Patients were followed-up in the pediatric neurology clinic at Tanta University Children's Hospital during Ramadan 2019. Seizures frequency and severity, measured by Chalfont seizure severity scale, during Ramadan fasting were compared with those in the month before Ramadan. Before Ramadan, 43/56 patients were controlled and seizure free. Meanwhile, 13/56 patients were uncontrolled and had seizure frequency of one to six seizures in the month before Ramadan. There was no significant difference in seizure frequency during Ramadan compared with before Ramadan (p = 0.132), whereas seizure severity was significantly reduced during Ramadan (p = 0.028). Both seizure frequency and severity were significantly lower during Ramadan in uncontrolled epileptic patients compared with before Ramadan (p = 0.02 and 0.005). Ramadan fasting is safe in adolescents with epilepsy. Fasting is not a precipitating factor for seizures in epileptic adolescents, provided compliance to antiepileptic drugs, and could be beneficial for seizure control in uncontrolled epilepsy.
OBJECTIVE
To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma.
METHODS
25 patients with biopsy-confirmed WHO Grade 2-4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories<20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates≤20 gm/day) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, IGF-1, and MR spectroscopy at baseline and week 8.
RESULTS
21 patients completed the study (84%). 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s 0.52, p=0.05). Sub-group analysis of IDH-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria.
CONCLUSIONS
The GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appear to be a better indicator of systemic activity than patient-reported food records.
Résumé
Diverses formules de jeûne légitimées par des études expérimentales ont connu récemment un certain succès auprès du grand public. Le jeûne entraine une diminution du stress oxydatif et de l’inflammation, accroit la protection et la résistance cellulaire aux agressions, augmente la sensibilité à l’insuline, et modifie la régulation hormonale du métabolisme cellulaire. Chez l’animal, le jeûne est à même de retarder le vieillissement et de prévenir les maladies chroniques liées à l’âge. Chez l’homme, le jeûne intermittent ou périodique améliore les anomalies du syndrome métabolique et détermine une perte de poids significative. Toutefois, le jeûne intermittent n’est pas plus efficace que la restriction calorique continue dans le traitement de l’obésité ou la lutte contre l’insulinorésistance. Le jeûne a des effets intéressants dans la prévention et le traitement du cancer. Appliqué à des modèles animaux de tumeur, il ralentit la prolifération et optimise l’efficacité de la chimiothérapie, tout en améliorant sa tolérance, à condition d’éviter l’installation d’une dénutrition. Fondé sur un argumentaire scientifique expérimental et sur quelques rares études chez l’homme, le jeûne intermittent ou périodique intégré semble à même de promouvoir un état de santé optimal et de retarder les maladies chroniques métaboliques et dégénératives. Ces vertus avaient déjà été décrites dans le cadre d’une restriction énergétique chronique modérée, et ne font que souligner les méfaits bien connus d’une alimentation hypercalorique. Toutefois, à ce jour, le jeûne intermittent n’a pas d’intérêt médical démontré comme alternative à la restriction calorique chronique chez l’homme sain ou malade.
The ketogenic diet (KD) is a 90% fat diet that is an effective treatment for intractable epilepsy. Rapid initiation of the KD requires hospital admission because of the complexity of the protocol and frequent mild and moderate adverse events. The purpose of the study was to compare the efficacy of a gradual KD initiation with the standard KD initiation preceded by a 24- to 48-h fast.
Children ages 1 to 14 years with intractable epilepsy were randomized to a fasting initiation (FAST-KD) or gradual initiation (GRAD-KD). Baseline seizure activity was recorded daily for 28 days before admission and continued for the 3-month duration of the study. Effectiveness was measured in two ways: (a) the proportion of subjects with >50% reduction in target seizure type from baseline to 3-month evaluation, and (b) percentage reduction in the frequency of the target seizure type from baseline to 3-month evaluation. Blood glucose was assessed q4 to 6h, and weights, electrolytes, hydration status, vomiting, acid balance, need for interventions (citric acid and sodium citrates (Bicitra) and IV fluids) were assessed daily. Fisher's exact tests were used to examine the association between protocol and occurrence of adverse events, and longitudinal mixed-effects models were used to look for trends in tolerability data over time.
Forty-eight subjects, 24 in each arm, were randomized. In the FAST-KD protocol, 58% of the children had >50% reduction in the target seizure type at 3 months, and 21% were seizure free. In the GRAD-KD protocol, 67% had a >50% reduction at 3 months, and 21% were seizure free. The two protocols were equivalent in efficacy (p = 0.033). At 3 months, the FAST-KD median percentage seizure reduction rate was 78% (ranging from 100% reduction to 73% increase in seizures per week) and was 94% (ranging from 100% reduction to 161% increase in seizures per week) for the GRAD-KD protocol. By using a logarithmic transformed percentage reduction rate and an equivalence limit difference of 20%, the efficacy of the two protocols was equivalent (p = 0.0002). Children in the GRAD protocol lost significantly less weight (p = 0.006), and had fewer and less-severe episodes of hypoglycemia (p < 0.001), fewer treatments for acidosis (citric acid and sodium citrates) (p < 0.04) and dehydration (IV fluids) (p < 0.04), but no difference in vomiting was noted.
These data suggest that in children with intractable epilepsy, a gradual initiation results in fewer adverse events and is tolerated better overall while maintaining the efficacy of the KD.
The ketogenic diet is carefully calculated by dietitians in an effort to achieve the child's ideal body weight, theoretically to improve seizure control. This study researched whether achieving a stable body mass index or ideal body mass index-for-age correlates with efficacy with the traditional ketogenic diet. The outcomes of 123 children started on the ketogenic diet were analyzed at clinic visits 3, 6, 9, and 12 months after diet onset. Children who were at 40% to 59% body mass index-for-age did not have higher efficacy than those at a higher or lower body mass index-for-age, except at the 12-month clinic visit (81% versus 48%; P = .02). No clear link was demonstrated between either an ideal body mass index or changes in the body mass index and seizure control in the management of children receiving a ketogenic diet. Attributing changes in seizure control to a rapid weight gain or loss may be unjustified.
Food restriction (FR) in rodents is known to extend life span, reduce the incidence of age-related tumors, and suppress oxidative damage to proteins, lipids, and DNA in several organ systems. Excitotoxicity and mitochondrial impairment are believed to play major roles in the neuronal degeneration and death that occurs in the brains of patients suffering from both acute brain insults such as stroke and seizures, and chronic neurodegenerative conditions such as Alzheimer's, Parkinson's, and Huntington's diseases. We now report that FR (alternate-day feeding regimen for 2–4 months) in adult rats results in resistance of hippocampal neurons to excitotoxin-induced degeneration, and of striatal neurons to degeneration induced by the mitochondrial toxins 3-nitropropionic acid and malonate. FR greatly increased the resistance of rats to kainate-induced deficits in performance in water-maze learning and memory tasks, and to 3-nitropropionic acid–induced impairment of motor function. These findings suggest that FR not only extends life span, but increases resistance of the brain to insults that involve metabolic compromise and excitotoxicity. Ann Neurol 1999;45:8–15
Dietary restriction (DR; reduced calorie intake) increases the lifespan of rodents and increases their resistance to cancer, diabetes and other age-related diseases. DR also exerts beneficial effects on the brain including enhanced learning and memory and increased resistance of neurons to excitotoxic, oxidative and metabolic insults. The mechanisms underlying the effects of DR on neuronal plasticity and survival are unknown. In the present study we show that levels of brain-derived neurotrophic factor (BDNF) are significantly increased in the hippocampus, cerebral cortex and striatum of mice maintained on an alternate day feeding DR regimen compared to animals fed ad libitum. Damage to hippocampal neurons induced by the excitotoxin kainic acid was significantly reduced in mice maintained on DR, and this neuroprotective effect was attenuated by intraventricular administration of a BDNF-blocking antibody. Our findings show that simply reducing food intake results in increased levels of BDNF in brain cells, and suggest that the resulting activation of BDNF signaling pathways plays a key role in the neuroprotective effect of DR. These results bolster accumulating evidence that DR may be an effective approach for increasing the resistance of the brain to damage and enhancing brain neuronal plasticity.
Despite myriad anticonvulsants available and in various stages of development, there are thousands of children and adults with epilepsy worldwide still refractory to treatment and not candidates for epilepsy surgery. Many of these patients will now turn to dietary therapies such as the ketogenic diet, medium-chain triglyceride diet, modified Atkins diet, and low glycemic index treatment.
In the past several years, neurologists are finding new indications to use these dietary treatments, perhaps even as first-line therapy, including infantile spasms, myoclonic-astatic epilepsy (Doose syndrome), Dravet syndrome, and status epilepticus (including FIRES syndrome). Adults are also one of the most rapidly growing populations being treated nowadays; this group of patients previously was not typically offered these treatments. In 2009, two controlled trials of the ketogenic diet were published, as well as an International Expert Consensus Statement on dietary treatment of epilepsy. Ketogenic diets are also now being increasingly studied for neurological conditions other than epilepsy, including Alzheimer's disease and cancer. Insights from basic science research have helped elucidate the mechanisms by which metabolism-based therapy may be helpful, in terms of both an anticonvulsant and possibly a neuroprotective effect.
Dietary therapy for epilepsy continues to grow in popularity worldwide, with expanding use for adults and conditions other than epilepsy.
Calorie restriction can be anticonvulsant in animal models. The ketogenic diet was designed to mimic calorie restriction and has been assumed to work by the same mechanisms. We challenged this assumption by profiling the effects of these dietary regimens in mice subjected to a battery of acute seizure tests.
Juvenile male NIH Swiss mice received ketogenic diet or a normal diet fed in restricted quantities (continuously or intermittently) for ∼12 days, starting at 3-4 weeks of age. Seizures were induced by the 6 Hz test, kainic acid, maximal electroshock, or pentylenetetrazol.
The ketogenic and calorie-restricted diets often had opposite effects depending on the seizure test. The ketogenic diet protected from 6 Hz-induced seizures, whereas calorie restriction (daily and intermittent) increased seizure activity. Conversely, calorie restriction protected juvenile mice against seizures induced by kainic acid, whereas the ketogenic diet failed to protect. Intermittent caloric restriction worsened seizures induced by maximal electroshock but had no effect on those induced by pentylenetetrazol.
In contrast to a longstanding hypothesis, calorie restriction and the ketogenic diet differ in their acute seizure test profiles, suggesting that they have different underlying anticonvulsant mechanisms. These findings highlight the importance of the 6 Hz test and its ability to reflect the benefits of ketosis and fat consumption.
Food restriction (FR) in rodents is known to extend life span, reduce the incidence of age-related tumors, and suppress oxidative damage to proteins, lipids, and DNA in several organ systems. Excitotoxicity and mitochondrial impairment are believed to play major roles in the neuronal degeneration and death that occurs in the brains of patients suffering from both acute brain insults such as stroke and seizures, and chronic neurodegenerative conditions such as Alzheimer's, Parkinson's, and Huntington's diseases. We now report that FR (alternate-day feeding regimen for 2-4 months) in adult rats results in resistance of hippocampal neurons to excitotoxin-induced degeneration, and of striatal neurons to degeneration induced by the mitochondrial toxins 3-nitropropionic acid and malonate. FR greatly increased the resistance of rats to kainate-induced deficits in performance in water-maze learning and memory tasks, and to 3-nitropropionic acid-induced impairment of motor function. These findings suggest that FR not only extends life span, but increases resistance of the brain to insults that involve metabolic compromise and excitotoxicity.
More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown. We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures.
We prospectively studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed genetic basis), symptomatic (resulting from a structural abnormality), or cryptogenic (resulting from an unknown underlying cause). Patients were considered to be seizure-free if they had not had any seizures for at least one year.
Among the 525 patients, 333 (63 percent) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped. The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001). The seizure-free rate was similar in patients who were treated with a single established drug (67 percent) and patients who were treated with a single new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent).
Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.
The ketogenic diet (KD) is a high-fat, low-carbohydrate and -protein diet that has been used to treat refractory seizures in children for more than 75 years. However, little is known about how the KD inhibits seizures or its effects on epileptogenesis. Several animal models of epilepsy have responded favorably to KD treatment, but the KD has not been studied in animals with a genetic predisposition to seizures. Here we studied the antiepileptogenic effect of the KD in EL mice, an animal model for human idiopathic epilepsy.
Young male EL mice (postnatal day 30) were randomly separated into two groups fed ad libitum with either the KD (treated, n = 21) or Agway chow (control, n = 19). The mice were weighed and tested for seizures once per week for a total of 10 weeks. The effects of the KD on plasma levels of ketone bodies and glucose were analyzed at several time points throughout the study. Associative learning was compared between treated and control animals using a water maze.
KD treatment delayed seizure onset in young male EL mice by 1 month; however, seizure protection was transient, inasmuch as the treated and control mice experienced a similar number and intensity of seizures after 6 weeks on the diet. Plasma glucose levels and associative learning were similar in the treated and control groups, but the plasma beta-hydroxybutyrate levels were significantly higher in mice on the KD. The level of ketosis, however, was not predictive of seizure protection in EL mice.
The KD delayed seizure onset in EL mice, suggesting a transient protection against epileptogenesis. The KD did not influence plasma glucose levels or associative learning. Therefore, the EL mouse may serve as a good model to study the antiepileptogenic mechanisms of the KD.
To document the long-term outcome of the 83 children with difficult-to-control seizures who were enrolled prospectively in a study of the efficacy of the ketogenic diet and who had remained on the diet for 1 year.
A total of 150 consecutive children were entered prospectively into a study of the ketogenic diet's efficacy and tolerability. Three to 6 years after diet initiation, all 150 families were sent a survey inquiring about their child's current health status, seizure frequency, and current anticonvulsant medications. They were asked about their experience with the diet and reasons for discontinuation. Several telephone attempts were made to contact those who did not respond to the written questionnaire. Responses were entered in an Access database and analyzed.
In 1999, 3 to 6 years after initiating the diet, 107 of 150 families responded to a questionnaire. Thirty-five additional families were interviewed by telephone, 4 were lost to follow-up, and 4 children had died, unrelated to the diet. Of the original 150 patient cohort, 20 (13%) were seizure-free and an additional 21 (14%) had a 90% to 99% decrease in their seizures. Twenty-nine were free of medications, and 28 were on only 1 medication; 15 remained on the diet. There were no known cardiac complications.
Three to 6 years after initiation, the ketogenic diet had proven to be effective in the control of difficult-to-control seizures in children. The diet often allows decrease or discontinuation of medication. It is more effective than many of the newer anticonvulsants and is well-tolerated when it is effective.
A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and 10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 +/- 1.41[mean +/- SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88 +/- 3.14[mean +/- SD]), and minor improvement (2-8 units) in eight patients (pre-Scale: 45.25 +/- 2.76 [mean +/- SD]). Although these data are very preliminary, there is some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy.
The ketogenic diet (KD) is an effective treatment for intractable epilepsy. However, little is known about its underlying mechanisms.
In this study, in vivo extracellular field responses to angular bundle stimulation were recorded in the dentate gyrus of Sprague-Dawley rats fed one of three diets: ketogenic calorie-restricted (KCR), normal calorie-restricted (NCR), or normal ad libitum (NAL). Input/output curves and paired-pulse relations were used to assess network excitability. A maximal dentate activation (MDA) protocol was used to measure electrographic seizure threshold and duration.
Animals fed calorie-restricted (CR) diets exhibited greater paired-pulse inhibition, an elevated MDA threshold, and an absence of spreading depression-like events compared with ad libitum-fed controls. In the MDA model of epileptogenesis, the rate of increase in electrographic seizure duration after repeated stimuli was markedly reduced in KCR-fed animals compared with NCR- and NAL-fed controls.
These data suggest that CR, by itself, can be anticonvulsant, and treatment with a KCR diet may be both anticonvulsant and antiepileptogenic.
Fasting and other dietary regimens have been used to treat epilepsy since biblical times. The ketogenic diet, which mimics the metabolism of fasting, was used by modern physicians to treat intractable epilepsy beginning in the 1920s. With the rising popularity of drug treatments however, the ketogenic diet lost its previous status and was used in only a handful of clinics for most of the 20th century. The diet regained widespread recognition as a viable treatment option beginning in 1992 due to the efforts of parent advocate groups. Despite challenges to implementation of the treatment, the ketogenic diet has significant potential as a powerful tool for fighting epilepsy.
The influence that dietary factors have on the nervous system and its susceptibility to disease, is an active area of biomedical research. Recent studies have shown that dietary restriction (DR) can have profound effect on brain function and vulnerability to injury and disease and can also enhance synaptic plasticity, which may increase the ability of brain to resist aging and restore function following injury. The dietary restriction may result in neuroprotection as suggested by marked reduction in neuronal cell death of the CA3 region of hippocampus after kainate administration in our study. We examined the effects of 3 months of DR (alternate day feeding regimen) on the antioxidants and antioxidant enzymes from different brain regions such as cerebral hemispheres, diencephalon, cerebellum and brain stem after kainate-induced excitotoxicity in adult male Wistar rats. The present study reports the beneficial effects of dietary restriction on different antioxidants and antioxidant enzymes against kainate-induced excitotoxicity in different brain regions of young adult male Wistar rats. The expression of stress response protein heat shock protein 70 (HSP 70) was also studied from discrete regions of rat brain under the same set of experimental conditions. DR significantly enhanced the expression of HSP 70 in kainic acid (KA)-treated rats, whereas KA treatment of ad libitum fed rats resulted in decreased HSP 70 expression. The DR was observed to exert neuroprotection by enhancing the expression of HSP 70 in kainic acid treated rats.
Reduced caloric intake obtained through long-term dietary restriction has been found beneficial in some animal models of neurodegeneration. We report here that rats maintained under dietary restriction from the second to the eighth month of age are fully protected towards degeneration of GABAergic neurons in the hippocampus and the olfactory-entorhinal cortex caused by systemic administration of the convulsant toxin, kainic acid. However, in a different model of excitotoxic neurodegeneration, injection of ibotenic acid in the forebrain magnocellular basal nucleus, the decrease of a cholinergic marker in the target areas of the cortex was only partially protected by dietary restriction. Thus, in different experimental models neurodegeneration can be differentially rescued by dietary restriction. Analysis of alterations in the expression of relevant genes in different experimental conditions, could help in better understanding these differences.
The ketogenic diet, a high fat, adequate protein, low carbohydrate diet, has, during the past decade, had a resurgence of interest for the treatment of difficult-to-control seizures in children. This review traces its history, reviews its uses and side effects, and discusses possible alternatives and the diet's possible mechanisms of action. Finally, this review looks toward possible future uses of the ketogenic diet for conditions other than epilepsy.
The ketogenic diet (KD) has been considered a highly potent antiepileptic treatment for intractable childhood epilepsy. In this study, we compared the antiepileptic efficacy and diet tolerability of two different diets with lipid:nonlipid ratios of 3:1 and 4:1.
Seventy-six patients with refractory childhood epilepsy were randomly placed into two groups and were started on KD diets with nonlipid:lipid ratios of either 3:1 or 4:1. Antiepileptic efficacy and diet tolerability were evaluated 3 months after initiating the diet. Patients showing seizure-free outcome with the 4:1 diet were changed to the 3:1 diet, and those without a seizure-free outcome on the 3:1 diet were changed to the 4:1 diet, for three more months, after which time their progress was monitored.
(1) Antiepileptic efficacy was higher for the 4:1 than the 3:1 diet (p < 0.05). Twenty-two (55.0%) of 40 patients on the 4:1 diet and 11 (30.5%) of 36 patients on the 3:1 diet became seizure free. Seizure reduction of over 90% was observed in 2 (5.0%) patients on the 4:1 diet, and 2 (5.6%) on the 3:1 diet. (2) Dietary tolerability was better for the 3:1 than the 4:1 diet. Gastrointestinal symptoms were observed in 5 (13.9%) patients with the 3:1 diet and 14 (35.0%) patients with the 4:1 diet (p < 0.05). (3) For seizure-free patients who started on the 4:1 diet, antiepileptic efficacy was maintained after changing to the 3:1 diet, while 10 (83.3%) of 12 patients who were not seizure free with the 3:1 diet showed increased seizure reduction after changing to the 4:1 diet. (4) Complications from the KD and laboratory data were not significantly different between the two groups.
The 4:1 KD showed greater antiepileptic efficacy than the 3:1 diet with higher seizure-free outcome. In most cases, seizure free outcome was maintained even after changing the ratio to 3:1. Dietary tolerability was better in the 3:1 diet than the 4:1 with less frequent gastrointestinal symptoms.
Parents often expect immediate seizure improvement after starting the ketogenic diet (KD) for their children. The purpose of this study was to determine the typical time to seizure reduction as well as the time after which it was unlikely to be helpful in those children started on the KD.
Records of all children started on the KD at Johns Hopkins Hospital, Baltimore (n = 83) and Children's Memorial Hospital, Chicago (n = 35) from November 2003 to December 2006 were examined to determine the first day in which seizures were reportedly improved.
Of the 118 children started on the KD, 99 (84%) had documented seizure reduction. The overall median time to first improvement was 5 days (range: 1-65 days). Seventy-five percent of children improved within 14 days. In those children who were fasted at KD onset, the time to improvement was quicker (median 5 vs. 14 days, p < 0.01) with a higher percentage improving within 5 days (60% vs. 31%, p = 0.01). No difference was identified between fasting and nonfasting in regards to long-term outcomes, however.
The KD works quickly when effective, typically within the first 1-2 weeks. Starting the KD after a fasting period may lead to a more rapid, but equivalent long-term seizure reduction, confirming prior reports. If the KD has not led to seizure reduction after 2 months, it can probably be discontinued.
Lifelong calorie restriction is the only known intervention that has been shown to consistently increase life span and reduce the effects of aging on the brain. Given the difficulties of replicating lifelong calorie restriction within human populations, we have sought to assess the effects of short-term adult-onset calorie restriction upon acute excitotoxic insults in the rat hippocampus. Adult animals (approximately 6 months of age) underwent calorie restriction (alternate day feeding) for 7-10 weeks. Utilizing both electrophysiological and immunocytochemical techniques, we report that calorie restriction had no effect upon long-term potentiation (LTP), a measure of neuronal function. In control animals, application of kainic acid (20 microM) resulted in only 35% recovery of CA1 population spikes post-insult. However calorie-restricted animals showed significantly improved recovery after kainic acid treatment (64%). This data was supported by immunocytochemical studies which noted widespread loss of microtubule-associated protein (MAP 2) immunoreactivity in control slices following treatment with kainic acid; however MAP 2 staining was preserved in the CA1 and CA3 regions of calorie-restricted animals. Interestingly there was no significant difference in the recovery of population spikes between groups when slices were treated with N-methyl-d-aspartate (15 microM). We conclude that short-term adult-onset calorie restriction does not alter normal neuronal function and serves to protect the hippocampus from acute kainic acid excitotoxicity.
The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial.
145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915.
73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62.0%vs 136.9%, 75% decrease, 95% CI 42.4-107.4%; p<0.0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0.0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger.
The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy.
HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council.
The keto-genic diet for the treatment of childhood epilepsy: a randomised controlled trial Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios–comparison of 3:1 with 4:1 diet
- E G Neal
- H Chaffe
- R H Schwartz
- M S Lawson
- N Edwards
- G Fitzsimmons
- A Whitney
- J H Cross
Neal, E.G., Chaffe, H., Schwartz, R.H., Lawson, M.S., Edwards, N., Fitzsimmons, G., Whitney, A., Cross, J.H., 2008. The keto-genic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7, 500—506. Seo, J.H., Lee, Y.M., Lee, J.S., Kang, H.C., Kim, H.D., 2007. Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios–comparison of 3:1 with 4:1 diet. Epilepsia 48, 801—805. Intermittent fasting for seizures 279