The Ketogenic diet: from molecular mechanisms to clinical effects
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Is ketogenic diet a ‘precision medicine’? Recent developments and future challenges
2024, European Journal of Paediatric NeurologyRecently, precision medicine has attracted much attention in the management of epilepsies, but it remains unclear if the increasingly utilized ketogenic diet approaches can truly be considered precision medicine in all epilepsy treatment. Currently, it is the standard treatment for patients with GLUT1 deficiency and the latest NICE guidelines highlight ketogenic diet as a therapeutic option for multi-drug resistant epilepsy patients. Ketogenic diet is presumed to be a precision medicine tool when applied to the treatment of seizures secondary to GLUT1 transporter deficiency. In contrast, the genetic and epigenetic mechanisms modulated by ketogenic diet and underlying its efficacy in other epilepsy types can only be hypothesized to relate to mechanisms of neuroprotection, neuromodulation, and reduction of neuroinflammation. Early ketogenic diet initiation in well-selected patients, would allow immediate action in the direction of neuroprotection and modulation of neuroinflammation, ensuring higher success rates and lower “cost” to the patient in terms of quality of life and comorbidities. These considerations have fueled an increasing interest in investigating the efficacy, side effects, and adherence to long-term use of the ketogenic diet in epilepsy treatment in large contemporary cohorts, available within the scope of multicentric collaborations, such as the European Network for Therapy in Rare Epilepsies (NETRE). Future directions should involve the use of precision medicine, applied to each patient with the help of “omics”, whose use should be expanded and inclusive.
Prospective study of the modified Atkins diet in adult drug-resistant epilepsy: Effectiveness, tolerability, and adherence
2022, NeurologiaLa epilepsia farmacorresistente (EFR) tiene una elevada prevalencia mundial y presenta una gran dificultad en su control, pese a una gran variedad de fármacos antiepilépticos (FAE). La dieta Atkins modificada (DAM) constituye una alternativa favorable adicional. Existen varios estudios sobre niños con EFR y uso de dieta cetogénica o DAM, pero no son suficientes en adultos con la misma condición.
Evaluar la efectividad, tolerabilidad y adherencia de la DAM en adultos con EFR.
Estudio prospectivo, antes-después, aplicado durante 6 meses en un hospital de referencia. Se instauró DAM con limitación de hidratos de carbono y libertad de dieta grasa. Se realizó un seguimiento clínico y electroencefalográfico con guías relacionadas, además de valorar los efectos adversos, las modificaciones laboratoriales y aplicar un test de adherencia.
Se incluyó a 32 pacientes con EFR. La edad media fue de 30 años, el tiempo promedio de evolución fue de 22 años y todos tenían epilepsia focal o multifocal. La disminución global de crisis epilépticas superior al 50% se presentó en el 34% de los casos (p = 0,001); el control fue mayor en el primer mes y decayó posteriormente. Dichos pacientes manifestaron pérdida ponderal (RR 7,2; IC 95%: 1,3-39,5; p = 0,02), adherencia de buena a regular solo en los meses primero y tercero (RR 9,4; IC 95%: 0,9-93,6; p = 0,04; RR 0,4; IC 95%: 0,30-0,69; p = 0,02, respectivamente). La tolerabilidad de DAM se mostró como un tratamiento seguro, dados los efectos adversos menores y de corta duración en la mayoría, salvo la presencia de hiperlipidemia de leve a moderada en un tercio de los casos. El test de adherencia mostró un 50% de cumplimiento al final del estudio.
La DAM demuestra en adultos con EFR focal una tolerabilidad adecuada, una efectividad y adherencia moderadas, pero decrecientes, que se atribuyen probablemente a la preferencia por una dieta basada en los hidratos de carbono.
Drug-resistant epilepsy presents high worldwide prevalence and is difficult to control despite the wide variety of available antiepileptic drugs (AED). Modified Atkins diet (MAD) is an additional treatment alternative. Several studies have addressed the use of ketogenic diet and MAD in children with drug-resistant epilepsy, but insufficient research has been conducted into adults with the same condition.
To evaluate the effectiveness and tolerability of, and adherence to, the MAD in adults with drug-resistant epilepsy.
We conducted a 6-month pre-posprospective study at a reference hospital. Patients were prescribed the MAD with limited carbohydrate intake and unlimited fat intake. We conducted clinical and electroencephalographic follow-up according to the relevant guidelines, and assessed adverse effects changes in laboratory findings, and adherence.
Thirty-two patients with drug-resistant epilepsy were included in the study. Patients’ mean age was 30 years, mean disease progression time was 22 years, and all patients had focal or multifocal epilepsy. Thirty-four percent of patients presented > 50% decreases in overall seizure frequency (P = .001); seizure control was greater in the first month and subsequently declined. These patients presented weight loss (RR: 7.2; 95% CI: 1.3-39.5; P = .02), good to fair adherence only in the first and third months (RR: 9.4; 95% CI: 0.9-93.6; P = .04 and RR: 0.4; 95% CI: 0.30-0.69; P = .02, respectively). Tolerability data showed that the MAD is safe: adverse effects were minor and short-lived in most cases, with the exception of mild to moderate hyperlipidaemia in one-third of patients. The adherence rate was 50% at the end of the study.
In adults with drug-resistant focal epilepsy, the MAD showed adequate tolerability and moderate but decreasing effectiveness and adherence, probably due to a preference for a carbohydrate-based diet.
Altered cytokine levels in cerebrospinal fluid following ketogenic diet of children with refractory epilepsy
2021, Epilepsy ResearchKetogenic diet is an effective treatment which has the potential to achieve a significant seizure reduction in drug-resistant epilepsy. The mechanism behind this effect is unclear, but one hypothesis is that the mechanism is anti-inflammatory.
In this prospective study on pediatric patients we compared levels of cytokines and chemokines in the cerebrospinal fluid before and after three months on treatment to evaluate a possible anti-inflammatory effect.
We analyzed 34 cytokines and chemokines in the cerebrospinal fluid of pediatric patients (n = 21) with refractory epilepsy by a multiplex assay. Beta-hydroxybutyric acid was measured in blood and cerebrospinal fluid. Seizure frequency in relation to diet treatment was assessed.
For 9 different cytokines (CCL 7, CCL 21, CCL 22, CCL 25, CCL 27, IL-2, IL-10, CX3CL1 and MIF), a significant decrease ranging from 7 to 27% was seen after three months as compared to levels before the diet. In contrast, no cytokine displayed a significant increase during diet. A seizure reduction ≥ 50 % was seen in 15/21 patients (71 %) but no significant differences in cytokine decreases were found between responders and non-responders during treatment. A non-significant trend towards higher initial pre-treatment levels of cytokines was seen in responders, which were reduced following treatment. The levels of betahydroxybutyric acid were not related to seizure response.
We conclude that while it is not possible to state a primary anti-inflammatory effect by dietary treatment from these data, an unequivocal immunological effect is seen and may be a part of the mechanism of ketogenic dietary treatment.
Effects of the ketogenic diet in adults with refractory epilepsy
2021, Neurologia ArgentinaLa dieta cetogénica puede ser una medida terapéutica eficaz en el manejo coadyuvante de la epilepsia refractaria. Aunque su uso es más frecuente en niños, cada vez hay mayor evidencia de los beneficios en pacientes adultos.
Evaluar los efectos de la dieta cetogénica como tratamiento coadyuvante de la epilepsia refractaria en pacientes adultos atendidos por el servicio de neurología en 2 instituciones de Bogotá entre 2016 y 2020.
Se incluyeron 17 adultos con epilepsia refractaria, atendidos en 2 instituciones de Bogotá que iniciaron dieta cetogénica, 10 de ellos estuvieron en seguimiento por nutrición durante 6 meses. Se evaluó el tipo de dieta, la adherencia, frecuencia mensual de crisis en el primer, tercer y sexto mes de tratamiento, efectos secundarios, estado nutricional, paraclínicos, uso concomitante de otros fármacos antiepilépticos y calidad de vida.
Se observó beneficios en el 80% (n = 8) del total de pacientes que completaron el seguimiento (10), con reducción de la frecuencia de crisis entre el 50% y el 100% a los 6 meses, siendo la dieta tipo Atkins modificada la más prescrita en combinación con la fórmula cetogénica. El 60% de los pacientes fueron adherentes a la dieta, los efectos secundarios se encontraron en el 20%.
La dieta cetogénica demostró efectividad en la reducción de la frecuencia de crisis epilépticas en el 80% de los pacientes, con efectos secundarios comparables a los reportados por otros autores. Se requiere de un programa institucional de seguimiento para evaluar los efectos a largo plazo.
Ketogenic diet has been described as an effective adjuvant therapeutic option to treat drug resistant epilepsy. Although it is commonly prescribed in children, in recent years more evidence of its benefits in adult population has been obtained.
The aim of this study was to evaluate the effects of the ketogenic diet as an adjuvant treatment for refractory epilepsy in adults. The target group corresponded to patients from Neurology department of 2 institutions in Bogota (Colombia) between 2016 and 2020.
Seventeen adults with drug resistant epilepsy were included, who initiated ketogenic diet under nutritionist supervision for at least 6 months. We evaluated the type of dietary treatment, adherence, seizure frequency at the first, third and sixth months since the beginning of the diet, adverse effects, nutritional state, laboratories, concomitant use of antiepileptic drugs and the quality of life.
This case series study reported benefits in 80% (n = 8) of patients, with a seizure frequency reduction between 50% and 100% after 6 months, being the modified Atkins diet the most prescribed in combination with a ketogenic formula. The frequency of adverse events was 20%, and 60% of patients were adherent to the diet.
The ketogenic diet was effective in the reduction of seizure frequency in 80% of the patients, who exhibited adverse effects comparable to previous reports. The implementation of an institutional program for following and evaluation of its long term outcome effects is recommended.
Host-microbial interactions in the metabolism of different dietary fats
2021, Cell MetabolismAlthough generally presumed to be isocaloric, dietary fats can differ in their energetic contributions and metabolic effects. Here, we show how an explicit consideration of the gut microbiome and its interactions with human physiology can enrich our understanding of dietary fat metabolism. We outline how variable human metabolic responses to different dietary fats, such as altered ileal digestibility or bile acid production, have downstream effects on the gut microbiome that differentially promote energy gain and inflammation. By incorporating host-microbial interactions into energetic models of human nutrition, we can achieve greater insight into the underlying mechanisms of diet-driven metabolic disease.
Blood–Brain Barrier Dynamics to Maintain Brain Homeostasis
2021, Trends in NeurosciencesThe blood–brain barrier (BBB) is a dynamic platform for exchange of substances between the blood and the brain parenchyma, and it is an essential functional gatekeeper for the central nervous system (CNS). While it is widely recognized that BBB disruption is a hallmark of several neurovascular pathologies, an aspect of the BBB that has received somewhat less attention is the dynamic modulation of BBB tightness to maintain brain homeostasis in response to extrinsic environmental factors and physiological changes. In this review, we summarize how BBB integrity adjusts in critical stages along the life span, as well as how BBB permeability can be altered by common stressors derived from nutritional habits, environmental factors and psychological stress.