Ketogenic Diet in the Treatment of Epilepsy.

Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Telemedicine for Ketogenic Dietary Treatment in Refractory Epilepsy and Inherited Metabolic Disease: State of Play and Future Perspectives.

Ketogenic dietary therapies (KDT) are diets that induce a metabolic condition comparable to fasting. All types of KDT comprise a reduction in carbohydrates whilst dietary fat is increased up to 90% of daily energy expenditure. The amount of protein is normal or slightly increased. KDT are effective, well studied and established as non-pharmacological treatments for pediatric patients with refractory epilepsy and specific inherited metabolic diseases such as Glucose Transporter Type 1 Deficiency Syndrome. Patients and caregivers have to contribute actively to their day-to-day care especially in terms of (self-) calculation and (self-) provision of dietary treatment as well as (self-) measurement of blood glucose and ketones for therapy monitoring. In addition, patients often have to deal with ever-changing drug treatment plans and need to document occurring seizures on a regular basis. With this review, we aim to identify existing tools and features of telemedicine used in the KDT context and further aim to derive implications for further research and development.

[Fourteenth Jesús Culebras Lecture. Ketogenic diet, a half-discovered treatment]. / Decimocuarta Lección Jesús Culebras. Dieta cetogénica, un tratamiento a medio descubrir.

Introduction: The ketogenic diet was an amazing approach to treating epilepsy from its beginning. The body undergoes a change in obtaining energy, going from depending on carbohydrates to depending on fats, and then a whole series of biochemical routes are launched that, independently but also complementary, give rise to a set of effects that benefit the patient. This search for its mechanism of action, of devising how to improve compliance and take advantage of it for other diseases has marked its trajectory. This article briefly reviews these aspects, emphasizing the importance of continuing to carry out basic and clinical research so that this treatment can be applied with solid scientific bases.

Introducción: La dieta cetogénica constituyó desde su inicio un planteamiento sorprendente para el tratamiento de la epilepsia. Someter al organismo a un cambio en la obtención de energía, pasando de depender de los carbohidratos a hacerlo de las grasas, pone en marcha toda una serie de rutas bioquímicas que, de forma independiente pero también complementaria, dan lugar a un conjunto de efectos que benefician al paciente. Esta búsqueda de su mecanismo de acción, de idear cómo mejorar el cumplimiento y de aprovecharla para otras enfermedades ha marcado su trayectoria. En este artículo se revisan someramente estos aspectos, haciendo hincapié en la importancia de seguir realizando investigación básica y clínica para que este tratamiento pueda aplicarse con bases científicas sólidas.

The efficacy of low glycemic index diet on seizure frequency in pediatric patients with epilepsy: A systematic review and meta-analysis.

BACKGROUND: Despite extensive research examining the effect of a low glycemic index (LGI) diet on the frequency of seizures in patients with epilepsy, the findings are inconclusive. Hence, we performed a systematic review and meta-analysis in order to clarify the potential effect of a low glycemic index (LGI) diet on the frequency of seizures in children. METHODS: A systematic review and meta-analysis written in accordance with the PRISMA checklist was realized using a comprehensive systematic search in four electronic databases until October 2023 without time or language restrictions. A random effects model was employed to combine the data. The main outcomes were analyzed using weight mean difference (WMD) and 95 % confidence interval (95 % CI). In total, 13 studies met the eligible criteria and were included. RESULTS: The publications included in this study were published between 2005 and 2021. The duration of the interventions in the studies included in this analysis ranged from 6 to 58 weeks. Our findings indicated that the pooled efficacy rate for < 50 %, ≥ 50 %, > 90 % seizure reduction in patients with epilepsy receiving a low glycemic index diet was 39 % (95 % CI: 26, 52), 34 % (95 % CI: 23, 45), and 19 % (95 % CI: 13, 25), respectively. It seems that the efficacy of this ketogenic diet in reducing seizures is greater during a shorter intervention period than 12 weeks. CONCLUSION: This systematic review and meta-analysis suggests that the low glycemia index diet can be beneficial as a treatment for epilepsy in pediatric patients.

ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet.

BACKGROUND: Research has shown gene ATN1 to be associated with the nuclear receptor signaling. Its mutations in an evolutionarily conserved histidine-rich motif may cause CHEDDA, short for congenital hypotonia, epilepsy, developmental delay and digital anomalies, a recently identified neurodevelopmental syndrome that could evolve into developmental and epileptic encephalopathy (DEE). Up to date, there have been reported less than 20 cases, whose clinical features and treatment are worth in-depth exploring. METHODS: The clinical characteristics and genetic data of an infant with CHEDDA and further DEE were analyzed, who carried a de novo ATN1 variant identified by trio whole-exome sequencing. The alike patients with such a neurodevelopmental syndrome and epileptic seizures were reviewed on the literature. RESULTS: The infant harboring a de novo missense mutation in ATN1 (c.3155A>C; p.His1052Pro) held almost all features of CHEDDA and presented with drug-resistant epileptic spasms, differing from one case previously reported with the same gene variant exhibiting milder seizures controlled easily. We further reviewed 11 CHEDDA patients with epileptic seizures in the literature and compared the correlation between abnormal cerebral structure and the incidence of intractable epilepsy among CHEDDA patients. Fortunately, this patient's seizures decreased remarkably after administering ketogenic diet (KD). CONCLUSION: CHEDDA patients have significant phenotypic differences, especially in the epilepsy severity and their drug resistance, even if they carry the same mutation hotspot. Ketogenic diet and other treatments like Topiramate should be recommended for ATN1-related refractory epilepsy based on their regulation on expression of cation-chloride cotransporters and cellular hyperpolarization.

The Modified Atkins Diet for Epilepsy: Two Decades of an "Alternative" Ketogenic Diet Therapy.

In 2003, the first case series of six patients treated with an Atkins diet for epilepsy was published in the journal Neurology. The concept was a simple, outpatient-initiated diet in which ketosis could be maintained by eating high-fat foods while tracking and limiting daily carbohydrate counts based on food ingredient labels. Twenty years later, after dozens of studies encompassing hundreds of patients, including several randomized controlled trials, the Modified Atkins Diet is a proven method of providing ketogenic dietary therapy for epilepsy. It is a diet therapy of choice for adolescents and adults, is being investigated for new-onset epilepsy, and is researched for neurological conditions other than epilepsy. Adverse effects do exist but may be less common than the classic ketogenic diet. This review will cover the history, clinical trials, implementation, current utilization, and future directions of this "alternative" ketogenic diet therapy on its 20-year anniversary.

Effect of a Ketogenic Diet on Oxidative Posttranslational Protein Modifications and Brain Homogenate Denaturation in the Kindling Model of Epilepsy in Mice.

This study focused on the ketogenic diet (KD) effects on oxidative posttranslational protein modification (PPM) as presumptive factors implicated in epileptogenesis. A 28-day of KD treatment was performed. The corneal kindling model of epileptogenesis was used. Four groups of adult male ICR mice (25-30 g) were randomized in standard rodent chow (SRC) group, KD-treatment group; SRC + kindling group; KD + kindling group (n = 10 each). Advanced oxidation protein products (AOPP) and protein carbonyl contents of brain homogenates together with differential scanning calorimetry (DSC) were evaluated. Two exothermic transitions (Exo1 and Exo2) were explored after deconvolution of the thermograms. Factor analysis was applied. The protective effect of KD in the kindling model was demonstrated with both decreased seizure score and increased seizure latency. KD significantly decreased glucose and increased ketone bodies (KB) in blood. Despite its antiseizure effect, the KD increased the AOPP level and the brain proteome's exothermic transitions, suggestive for qualitative modifications. The ratio of the two exothermic peaks (Exo2/Exo1) of the thermograms from the KD vs. SRC treated group differed more than twice (3.7 vs. 1.6). Kindling introduced the opposite effect, changing this ratio to 2.7 for the KD + kindling group. Kindling significantly increased glucose and KB in the blood whereas decreased the BW under the SRC treatment. Kindling decreased carbonyl proteins in the brain irrespectively of the diet. Further evaluations are needed to assess the nature of correspondence of calorimetric images of the brain homogenates with PPM.

The gut microbiota as a biomarker in epilepsy.

Biomarkers are defined as objectively measurable variables of a biologic process, either physiologic or pathologic, that provide reliable information on the status of that specific process in a specific moment. Validated biomarkers in epilepsy research represent an urgent unmet need being essential to improve research quality; as an example, biomarkers in epileptogenesis identifying these subjects at risk to develop epilepsy after an initial insult definitively would lead to an improvement in clinical studies to find antiepileptogenic drugs. The gut microbiota (GM) has recently encountered the interest of neuroscience which confirmed its clear involvement in several neurological disorders. GM's role in epilepsy has only recently been studied, however, interesting results are already available. Besides the interest in GM as a suitable therapeutic target and a few preclinical and clinical studies indicating the potential antiseizure effects of GM manipulation, microbiota composition has been found altered in patients with epilepsy as well as some animal models. Only few studies have tried to analyse GM composition as a suitable biomarker and, despite very promising, several drawbacks limit our understanding. On the other hand, GM composition may be useful in discriminating drug-resistant from drug-responsive patients at any stage or patients at risk of developing epilepsy after an insult. The main limitation in the area is the lack of large studies in homogeneous patients and standardization is a must for a proper understanding. Finally, considering the number of variables coming both from epilepsy and GM, big data analysis as in the case of genetics should be considered.

Dietary-Induced Ketogenesis: Adults Are Not Children.

There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. METHODS: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009-2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (ß-hydroxybutyrate) were measured in blood and/or urine. RESULTS: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. CONCLUSIONS: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.

Graph Theory-Based Electroencephalographic Connectivity and Its Association with Ketogenic Diet Effectiveness in Epileptic Children.

Ketogenic diet therapies (KDTs) are widely used treatments for epilepsy, but the factors influencing their responsiveness remain unknown. This study aimed to explore the predictors or associated factors for KDTs effectiveness by evaluating the subtle changes in brain functional connectivity (FC) before and after KDTs. Segments of interictal sleep electroencephalography (EEG) were acquired before and after six months of KDTs. Analyses of FC were based on network-based statistics and graph theory, with a focus on different frequency bands. Seventeen responders and 14 non-responders were enrolled. After six months of KDTs, the responders exhibited a significant functional connectivity strength decrease compared with the non-responders; reductions in global efficiency, clustering coefficient, and nodal strength in the beta frequency band for a consecutive range of weighted proportional thresholds were observed in the responders. The alteration of betweenness centrality was significantly and positively correlated with seizure reduction rate in alpha, beta, and theta frequency bands in weighted adjacency matrices with densities of 90%. We conclude that KDTs tended to modify minor-to-moderate-intensity brain connections; the reduction of global connectivity and the increment of betweenness centrality after six months of KDTs were associated with better KD effectiveness.

Ketogenic Diet Therapy for Epilepsy Associated With Aicardi Syndrome.

INTRODUCTION: Aicardi syndrome is a rare neurodevelopmental disorder associated with epilepsy in females. Ketogenic diet therapy represents a possible nonpharmacologic treatment in Aicardi syndrome patients. METHODS: All patients with Aicardi syndrome seen at Johns Hopkins Hospital (Baltimore, MD) and Johns Hopkins All Children's Hospital (St Petersburg, FL) treated with ketogenic diet therapy since 1994 were evaluated retrospectively. RESULTS: Fifteen patients, ages 4 months to 34 years, were identified. Ten (67%) patients experienced a ≥50% seizure reduction after 3 months, with 3 (20%) having a ≥90% reduction. Only 1 patient was seizure-free for a short period of time. The number of drugs tried prior to ketogenic diet therapy initiation was correlated with ≥50% seizure reduction at 3 months, 5.8 vs 2.6 in responders versus nonresponders (P = .01). In addition, the mean number of drugs actively received also correlated, 3.0 vs 1.2, P = .005. Ketogenic diet therapy was slightly more successful in those without infantile spasms, 78% vs 50%, P = .33. CONCLUSION: Ketogenic diet therapy was helpful in Aicardi syndrome, although seizure freedom was rare. It was especially helpful for those who were more drug-resistant and did not have infantile spasms at ketogenic diet therapy onset.

Ketogenic diet-mediated seizure reduction preserves CA1 cell numbers in epileptic Kcna1-null mice: An unbiased stereological assessment.

There is growing evidence for the disease-modifying potential of metabolic therapies, including the ketogenic diet (KD), which is used to treat medically intractable epilepsy. However, it remains unclear whether the KD exerts direct effects on histopathological changes in epileptic brain, or whether the changes are a consequence of diet-induced reduction in seizure activity. Here, we used unbiased stereological techniques to quantify the seizure-induced reduction in cell number in the CA1 region of the hippocampus of epileptic Kcna1-null mice and compared the effects of the KD with that of phenobarbital (PB), a widely employed anti-seizure drug. Our data suggest that the anti-seizure activity of the KD or PB was similar. However, CA1 cell numbers of KD-treated hippocampi were not significantly different from those seen in wild-type (WT) mice, whereas CA1 cell counts in standard diet and PB-treated Kcna1-null mice were 23% and 31% lower than WT animals, respectively. These results support the notion that structural protection of cells may involve more than seizure attenuation, and that the KD engages mechanisms that also promote or restore hippocampal morphological integrity.

The Chemistry of the Ketogenic Diet: Updates and Opportunities in Organic Synthesis.

The high-fat, low-carbohydrate (ketogenic) diet has grown in popularity in the last decade as a weight loss tool. Research into the diet's effects on the body have revealed a variety of other health benefits. The use of exogenous ketone supplements to confer the benefits of the diet without strict adherence to it represents an exciting new area of focus. Synthetic ketogenic compounds are of particular interest that has received very little emphasis and is an untapped area of focus for chemical synthesis. In this review, we summarize the chemical basis for ketogenicity and opportunities for further advancement of the field.

Dietary medium chain triglycerides for management of epilepsy: New data from human, dog, and rodent studies.

Many studies show that glucose metabolism in epileptic brain areas can be impaired. Energy is crucial to maintain normal brain function, including ion and neurotransmitter balances. Energy deficits can lead to disruption of ion gradients, which can trigger neuronal depolarization and generation of seizures. Thus, perturbed metabolic processing of glucose in epileptogenic brain areas indicates a specific nutritional need for people and animals with epilepsy, as they are likely to benefit from auxiliary brain fuels other than glucose. Ketogenic diets provide the ketone bodies acetoacetate and ß-hydroxybutyrate, which can be used as auxiliary fuel by the brain. In approximately 50% children and adults with certain types of epilepsy, who can tolerate and maintain these dietary regimens, seizure frequency can be effectively reduced. More recent data demonstrate that addition of medium chain triglycerides (MCTs), which provide the medium chain fatty acids octanoic and decanoic acid, as well as ketone bodies as auxiliary brain energy, can be beneficial in rodent seizure models, and dogs and humans with epilepsy. Here, this evidence is reviewed, including tolerance in 65% of humans, efficacy studies in dogs, possible anticonvulsant mechanisms of actions of MCTs, and specifically decanoic acid as well as metabolic and antioxidant mechanisms. In conclusion, MCTs are a promising adjunct to standard pharmacological treatment for both humans and dogs with epilepsy, as they lack central nervous system side effects found with current antiepileptic drugs. There is now a need for larger clinical trials in children, adults, and dogs to find the ideal composition and doses of MCTs and the types of epilepsy that respond best.

Diet in the Treatment of Epilepsy.

This Special Issue for Nutrients focuses on the effects of diet on brain function with a special emphasis on epileptic disorders [...].

Neutropenia in Children Treated With Ketogenic Diet Therapy.

OBJECTIVES: The objectives were to investigate the relationship between ketogenic diet therapy and neutropenia in children with epilepsy. METHODS: A retrospective chart review of children who initiated ketogenic diet at the Hospital for Sick Children between January 1, 2000, and May 1, 2018 was performed. Factors associated with the development of neutropenia during ketogenic diet therapy were evaluated and the relationship between development of a significant or suspected infection and neutrophil count was analyzed. RESULTS: One hundred two children met inclusion criteria and were followed on the diet for up to 24 months. Thirteen of 102 (13%) children were neutropenic at diet initiation. In the remaining 89 children, 27 developed neutropenia. Developing neutropenia was significantly associated with the ketogenic diet at 6 (13%), 12 (23%), and 24 (25%) months follow-up. Developing neutropenia was associated with higher urinary ketones (OR = 4.26, 95% CI: 1.27, 14.15) and longer duration of ketogenic diet therapy (OR = 3.29, 95% CI: 1.42, 7.96). There was no significant association between development of a clinically significant infection and neutropenia. CONCLUSION: Ketogenic diet therapy is associated with neutropenia in children with epilepsy, however, it does not have a significant clinical impact. Concern regarding neutropenia should not discourage the use of the ketogenic diet in children.

Ketogenic Diet Therapy for Intractable Epilepsy in Infantile Alexander Disease: A Small Case Series and Analyses of Astroglial Chemokines and Proinflammatory Cytokines.

In infantile Alexander disease (iAxD), one of the serious symptoms is intractable epilepsy, and some reports have suggested that neuroinflammation may be involved in the pathophysiology of the disease. Drug-resistant seizures adversely affect not only the quality of life of the caregivers and patients, but also patients' lifespan. Thus, controlling epilepsy is clinically important. For intractable childhood epilepsy, ketogenic diet therapy (KDT) is well-established, but its effects on iAxD have not been characterized. Here, we describe the use of KDT in three iAxD patients experiencing drug-resistant seizures. In all three cases, the formerly intractable epilepsies were well controlled by KDT. However, the brain magnetic resonance imaging findings deteriorated even after the epilepsy was controlled. In addition, the concentrations of monocyte chemotactic protein-1 and proinflammatory cytokines in the cerebrospinal fluid of the patients remained still high. KDT is effective in controlling epilepsy in iAxD. Our results clinically support previous reports arguing the involvement of neuroinflammation in the pathophysiology of iAxD.　Although KDT cannot prevent disease progression, earlier initiation might contribute to a better prognosis.

Metabolic epilepsies amenable to ketogenic therapies: Indications, contraindications, and underlying mechanisms.

Metabolic epilepsies arise in the context of rare inborn errors of metabolism (IEM), notably glucose transporter type 1 deficiency syndrome, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency, nonketotic hyperglycinemia, and mitochondrial cytopathies. A common feature of these disorders is impaired bioenergetics, which through incompletely defined mechanisms result in a wide spectrum of neurological symptoms, such as epileptic seizures, developmental delay, and movement disorders. The ketogenic diet (KD) has been successfully utilized to treat such conditions to varying degrees. While the mechanisms underlying the clinical efficacy of the KD in IEM remain unclear, it is likely that the proposed heterogeneous targets influenced by the KD work in concert to rectify or ameliorate the downstream negative consequences of genetic mutations affecting key metabolic enzymes and substrates-such as oxidative stress and cell death. These beneficial effects can be broadly grouped into restoration of impaired bioenergetics and synaptic dysfunction, improved redox homeostasis, anti-inflammatory, and epigenetic activity. Hence, it is conceivable that the KD might prove useful in other metabolic disorders that present with epileptic seizures. At the same time, however, there are notable contraindications to KD use, such as fatty acid oxidation disorders. Clearly, more research is needed to better characterize those metabolic epilepsies that would be amenable to ketogenic therapies, both experimentally and clinically. In the end, the expanded knowledge base will be critical to designing metabolism-based treatments that can afford greater clinical efficacy and tolerability compared to current KD approaches, and improved long-term outcomes for patients.