Low glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy

doi:10.1016/j.eplepsyres.2013.10.014

Epilepsy Research

Volume 108, Issue 1, January 2014, Pages 139-143

https://doi.org/10.1016/j.eplepsyres.2013.10.014 Get rights and content

Highlights

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The low GI diet reduce the expression of generalized seizures by ∼30% in a mouse model.
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Under hypoglycaemic conditions the low GI diet was no longer effective.
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Fluctuating blood glucose levels may act as a seizure precipitant.
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A low GI diet may be an effective alternative dietary manipulation when more conventional diet options have failed.

Summary

Purpose

Clinical evidence suggests that low glycaemic index diets are effective at reducing seizure frequency potentially through the stabilization of blood glucose levels. Here we investigate if diets containing carbohydrates with varying glycaemic index (GI) can modulate seizure susceptibility in a mouse model of generalized epilepsy.

Methods

Electrocortical recordings were made from mice harboring the GABA_Aγ2 (R43Q) epilepsy mutation after three weeks on a low-or high-GI diet. Standard rodent diet was used as a control. Occurrence and durations of spike-wave-discharges (SWDs) were measured. An insulin injection was used to reduce blood glucose to levels known to precipitate SWDs in the GABA_Aγ2 (R43Q) mouse on the low and high-GI diets.

Key findings

SWD occurrence was reduced by approximately 35% in mice on the low-GI compared to high-GI diet. SWD occurrence was not different between high-GI diet and a standard diet suggesting that low-GI diet is protective. Weight gain of mice for all diet groups was identical suggesting that they were equally well tolerated. Under low blood glucose conditions SWD occurrence increased in the low and high-GI diets. Importantly, under low glucose conditions the low-GI diet no longer conferred protection against SWDs.

Significance

SWDs were reduced in mice on a low GI-diet suggesting it may be an effective and well tolerated therapy for generalized epilepsy. The lack of effect of low-GI diet when glucose levels are reduced suggests that seizure protection in the GABA_Aγ2 (R43Q) mouse model may be due to the diets ability to stabilize blood glucose levels.

Introduction

Dietary therapy is now commonly considered a useful treatment option in refractory epilepsy (Levy et al., 2012). Most studies have investigated the high-fat and low-carbohydrate ketogenic diet with varying reports of success (Bailey et al., 2005). Tolerability remains a significant issue, with patients often unable to adhere to the strict dietary regime. The precise mechanism of action of the ketogenic diet is not fully understood, but most likely multi-factorial (Bough and Rho, 2007) potentially including the stabilization of brain glucose levels. Consistent with this, recent evidence indicates efficacy of a low glycaemic index (GI) diet in patients with refractory epilepsy (Pfeifer and Thiele, 2005, Pfeifer et al., 2008, Muzykewicz et al., 2009, Coppola et al., 2011), epilepsy in tuberous sclerosis complex (Larson et al., 2012) and Angelman syndrome-related seizures (Thibert et al., 2012). Small clinical trials in patient populations with severe epilepsy syndromes are feasible because of the large number of seizure events in these patients. These trials become difficult when more heterogeneous epilepsy populations are investigated. Mouse models provide a mechanism for testing varying therapeutic manipulations under conditions in which environmental and genetic factors can be more tightly controlled. Recent genetic discoveries have isolated a number of epilepsy causing genes enabling the engineering of ‘syndrome-specific’ mouse models based on human mutations. The GABA_A γ2 (R43Q) mouse model of generalized epilepsy is remarkable in that it recapitulates the two primary seizure phenotypes seen in humans with the disease, including absence epilepsy and febrile seizures (Reid et al., 2013). Further, the GABA_A γ2 (R43Q) mouse is sensitive to the first-line anti-absence drug, ethosuximide (Tan et al., 2007). We have also recently shown that reducing blood glucose levels, either by overnight fasting or injecting insulin, results in a doubling of spike-and-wave discharge (SWD) events in the GABA_A γ2 (R43Q) mouse (Reid et al., 2011). This is consistent with the idea that fluctuating glucose levels may also be an important determinant of seizure susceptibility in generalized epilepsy. Here we test the impact of low- and high-GI diets on SWD expression in the GABA_A γ2 (R43Q) mouse model.

Section snippets

Materials and methods

All experiments were approved by the Animal Ethics Committee at the Florey Institute for Neuroscience and Mental Health in accordance with The Code of Ethics of the World Medical Association for experiments involving animals. The GABA_Aγ2 (R43Q) mutation bred into the DBA/2J background strain mice (>N20 generations) was used between the ages of P42-45. Genotyping was done at P12 using a PCR-based method (Tan et al., 2007). All mice were housed under a 12 h light dark cycle with free access to

Low-GI diet reduces SWD occurrence

ECoGs recorded from GABA_Aγ2 (R43Q) mice on all diets display clear SWD events arising from a quiet background (Fig. 1A). Mice fed a high-GI diet for three weeks showed almost identical SWD occurrence when compared to those fed a standard mouse diet (34.6 ± 3.1 vs. 36.2 ± 4.4 SWD/h, n = 8 and 8, P = 0.76) suggesting that high-GI diets were not exacerbating seizures. Next we more specifically address the issue of the role of GI index in modulating SWD susceptibility by comparing diets that only differ in

Discussion

Dietary treatments that modulate energy substrates, such as the ketogenic diet, are now an important therapeutic option in epilepsy. Three broad mechanisms have been proposed for the ketogenic diet; stabilization of blood (and hence brain) glucose levels, the provision of alternative energy substrates and/or the antiepileptic action of metabolic products (Bough and Rho, 2007). Triheptanoin is a triglyceride containing heptanoate that is metabolized to produce intermediates of the citric acid

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgments

This study was supported by the National Health and Medical Research Council of Australia (grant numbers 400121, 628520 and 631541). CAR was also supported by an Australian Future Fellowship, Australian Research Council (#FT0990628). SP was supported by a NHMRC fellowship. Florey Institute of Neuroscience and Mental Health is supported by Victorian State government infrastructure funds.

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Low glycemic index therapy: What it is and how it compares to other epilepsy diets
2023, Diet and Nutrition in Neurological Disorders
The dietary interventions initially limited to nutritional recommendations for obesity or cardiovascular disorders are now used as a therapeutic modality for various neurological conditions. The ketogenic diet (KD), which has been around for more than a century, is limited by its restrictive nature, issues with palatability, and adverse events. The classic KD has undergone modifications over time to make it more acceptable to the patient without compromising its efficacy. The low glycemic index therapy (LGIT) diet is one of its derivatives that restrict carbohydrates to those with a glycemic index of less than 50. This LGIT diet is safer, palatable, and acceptable to the patient and is highly efficacious in reducing the seizure burden among children with drug-resistant epilepsy. Beyond epilepsy, KD (and to some extent its derivatives, including LGIT) is also being considered for neurodegenerative, neurodevelopmental, neuropsychiatric, and neoplastic disorders. This chapter summarizes the main evidence on LGIT application in epilepsy and other neurological disorders.
The ‘epileptic diet’- ketogenic and/or slow release of glucose intervention: A review
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Citation Excerpt :
The author suggested further that deficiencies in insulin signalling may represent a critical factor in the susceptibility to seizure-induced cell death - with important consequences for epilepsy, hypoxia, stroke and related pathologies. From epilepsy induced mice studies, it has been reported that a low glycaemic index diet may be an effective and well tolerated therapy for generalised epilepsy [69]. For the low glycaemic index diet, patients may consume 40–60 g carbohydrate per day and is thus more liberal than the low calorie (classical) ketogenic diet regime [70].
The ketogenic diet is high in fat content, adequate with respect to protein but low in carbohydrate and designed to provide brain energy as ketone bodies rather than glucose. The consequence is that epilepsy can be managed and endurance (sport) related energy be derived from fat rather than ingested or stored (glycogen) carbohydrate. This review aims to set the diet in context for seizure related intervention, sport and potential modern variants with respect to glucose management – which have many medical (including epilepsy potentially) and activity related applications.
The literature was reviewed using relevant data bases (e.g. Pubmed, Science Direct, Web of Science, Wiley on Line Library) and relevant articles were selected to provide historic and contemporary data for the text and associated Tables.
It is clear great health related benefits have been achieved by feeding the ketogenic to individuals subject to seizures where it helps manage the malaise. Sports applications are evident to. Glucose control diets provide health benefits of the ketogenic diet potentially and there is some evidence they are/can be very effective.
Key to epilepsy and sport performance is the control of blood glucose. The ketogenic diet has proven to be very effective in this regard but now other approaches to control blood glucose ae being evaluated which have advantages over the ketogenic diet. This therapeutic approach of clinical nutrition will undoubtedly move forwards over the next few years in view of the negative aspects of the ketogenic diet.
Low glycemic index treatment in patients with drug-resistant epilepsy
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LGIT particularly focuses on stabilizing blood glucose levels by only allowing the consumption of carbohydrates that increase postprandial blood glucose slowly with small fluctuations [12]. Abrupt changes in blood glucose levels are known to reduce seizure threshold [13]. Our goal in this study was to assess whether LGIT shows tolerability and efficacy against epilepsy.
Low glycemic index treatment (LGIT) is a newly developed dietary therapeutic option for epilepsy that is less restrictive than the ketogenic diet (KD). Our objective was to determine the efficacy and tolerability of LGIT.
From March 2014 to February 2015, 36 patients received LGIT at Severance Children’s Hospital. One-year seizure outcomes and side effects were evaluated.
A total of 36 patients were assessed. Fourteen were female. Common diagnoses were Lennox-Gastaut syndrome (33%, 12/36) and Dravet syndrome (14%, 5/36). The median age at the initiation of the LGIT was 12.6 years (min. = 1.5, max. = 28, interquartile range (IQR) 8–17). After 3 months of therapy, 20 (56%) patients experienced a 50% or greater reduction in seizure frequency, which was maintained in 19 (53%) patients for 1 year. Two (6%) patients became seizure-free after 3 months of LGIT; they remained seizure-free for 1 year. These two had Dravet syndrome and generalized epilepsy. Only three (8%) patients discontinued treatment within 1 year. Adverse events were rare, and two patients (6%) reported transient diarrhea.
LGIT effectively reduced seizure frequency in the present study, although seizure freedom was infrequently achieved. LGIT may be considered as a therapeutic option for patients with drug-resistant epilepsy, particularly those who find KD effective but intolerable.
Dravet and GEFS+ Syndromes
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Genetic Generalized Epilepsy (GGE) encompasses two well-studied syndrome specific epilepsies. Here we discuss recent advances in our understanding of mouse models of Generalized Epilepsy with Febrile Seizures plus (GEFS+) and Dravet syndrome. This disease spectrum includes individuals with a broad range of clinical features, from mildly to severely affected, and often associated with the same genetic mutation. Insight gained through the analyses of genetic mouse models have advanced our understanding of the mechanisms that transform monogenic lesions to cell-type specific, network, and whole brain dysfunction. Growing evidence suggests that while ion channel gene mutations are primarily linked to seizure genesis, structural changes are also evident and may contribute to epileptogenesis, including increased seizure susceptibility and disease severity.
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Consistent with this, recent evidence indicates efficacy of a low glycemic index (GI) diet in patients with refractory epilepsy (Muzykewicz et al., 2009; Pfeifer, Lyczkowski, & Thiele, 2008; Pfeifer & Thiele, 2005), epilepsy in tuberous sclerosis complex (Larson, Pfeifer, & Thiele, 2012) and Angelman syndrome-related seizures (Thibert et al., 2012). Our animal data supports the idea that the stabilisation of glucose reduces seizure susceptibility (Kim, Petrou, & Reid, 2014; Reid et al., 2011). Another mechanism via which the KD may be acting to reduce seizure susceptibility is through the inhibition of glycolysis (Hartman, Gasior, Vining, & Rogawski, 2007).
Metabolic dysfunction leading to epilepsy is well recognised. Dietary therapy, in particular the ketogenic diet, is now considered an effective option. Recent genetic studies have highlighted the central role that metabolism can play in setting seizure susceptibility. Here we discuss various metabolic disorders implicated in epilepsy focusing on energy deficiency due to genetic and environmental causes. We argue that low, uncompensated brain glucose levels can precipitate seizures. We will also explore mechanisms of disease and therapy in an attempt to identify common metabolic pathways involved in modulating seizure susceptibility. Finally, newer therapeutic approaches based on diet manipulation in the context of energy deficiency are discussed.

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Short communicationLow glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy

Highlights

Summary

Purpose

Methods

Key findings

Significance

Introduction

Section snippets

Materials and methods

Low-GI diet reduces SWD occurrence

Discussion

Conflict of interest

Acknowledgments

Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency

Epilepsia

Cortical excitability changes correlate with fluctuations in glucose levels in patients with epilepsy

Epilepsy Behav.

The use of diet in the treatment of epilepsy

Epilepsy Behav.

Astrocyte-neuron interactions: implications for epilepsy

Neurology

Anticonvulsant mechanisms of the ketogenic diet

Epilepsia

Low glycemic index diet in children and young adults with refractory epilepsy: first Italian experience

Seizure

Childhood absence epilepsy: genes, channels, neurons and networks

Nat. Rev. Neurosci.

Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy

Epilepsy Res.

Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet

Epilepsia

Low glycemic index treatment for epilepsy in tuberous sclerosis complex

Epilepsy Res.

Short communication
Low glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy