Associate editor: G. Dusting
Epilepsy, energy deficiency and new therapeutic approaches including diet

https://doi.org/10.1016/j.pharmthera.2014.06.001Get rights and content

Abstract

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.

Introduction

Metabolic dysfunction occurs in approximately 1 in 3000 live births (Dhamija, Patterson, & Wirrell, 2012). While seizures are a symptom of severe and rare metabolic failure in many inborn cases it is becoming increasingly clear that metabolic dysfunction can also cause common epilepsy syndromes (Arsov, Mullen, Damiano, et al., 2012, Arsov, Mullen, Rogers, et al., 2012, Mullen et al., 2010, Mullen et al., 2011, Suls et al., 2009). Further, the effectiveness of dietary therapy highlights how epilepsy can be treated through modulating metabolism (Freeman et al., 2009, Neal et al., 2008). In this review we will discuss the metabolic basis and modulation of seizures in epilepsy.

Section snippets

What is epilepsy?

Seizures are episodes of excessive or abnormally synchronised neuronal activity leading to transient clinical symptoms or signs (Berg et al., 2010). Epilepsy is the tendency to have repeated seizures without provocation. Epilepsy is a broad group comprising over 50 syndromes encompassing illnesses with multiple aetiologies and widely varied clinical manifestations and are an important health problem. The lifetime incidence of all seizures is estimated to be as high as 10% (Hauser, Annegers, &

Metabolic causes of epilepsy

Metabolic causes of epilepsy can trigger seizures due to effects on neurotransmission, neuronal structural changes or through metabolic dysfunction impacting energy production. Several reviews cover the various syndromes and mechanisms underlying metabolic disorders associated with neurotoxicity and structural dysfunction and these will not be covered here (eg. Rahman, Footitt, Varadkar, & Clayton, 2013). Instead this review will focus on epilepsy caused by energy disruption.

Energy deficiency and epilepsy

Epilepsies caused by the disruption of energy supply can be classified into three broad classes; mitochondrial disorders, creatine deficits and glucose transport deficiency.

Molecular and cellular mechanisms underlying epilepsy due to energy deficiency

The next section of this review focuses on the potential molecular and cellular mechanisms that may underlie an increase in seizure susceptibility during energy deficiency. We explore a few candidates integrating genetic information and experimental work to support our conclusions. All three groups of genetic diseases described above implicate a loss of energy as the likely cause of epilepsy. Our over-riding hypothesis is that a reduction in adenosine-5′-triphosphate (ATP) availability to

Astrocytes, energy deficiency and epilepsy

To date this review has largely taken a neuron centric view of excitability. Obviously, energy deficiency can equally interrupt astrocytic function within the central nervous system. In fact, glucose is transported and metabolized to a high extent in astrocytes (Jakoby et al., 2014). An improved understanding of the role of astrocytes in modulating the acute function of neurons has rekindled interest in their role in seizure genesis. These cells are well positioned to influence many aspects of

Diet therapy in epilepsy

The KD represents the gold-standard by which all dietary therapy is compared. The diet is a high-fat, low-carbohydrate diet that results in the inhibition of glucose metabolism and the overproduction of ketone bodies. Its efficacy in reducing seizures is well documented (Freeman et al., 2009, Neal et al., 2008). One of the major clinical difficulties with the KD is its poor tolerability and compliance. Variants of the KD have been developed in order to improve palatability including

Conclusion

There is now strong genetic, therapeutic and animal experimental evidence of the integral role that metabolism plays in setting seizure susceptibility. A primary point of this review is to highlight that low uncompensated brain glucose levels, through genetic or environmental causes, act as a seizure precipitant most likely as a consequence of reduced ATP. Greater than 90% of a neuron's energy demands are used maintaining the ionic gradient across their membranes with most ATP used to drive

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgments

CAR was supported by an Australian Future Fellowship, Australian Research Council (#FT0990628) and the Dowd Fellowship. SP was supported by a NHMRC fellowship. The Florey Institute of Neuroscience and Mental Health is supported by the Department of Health, Victorian State Government infrastructure funds. SAM was supported by a Viertel Clinical Investigatorship.

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