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  • Review Article
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The metabolic basis of epilepsy

Nature Reviews Neurology volume 18, pages 333–347 (2022)Cite this article

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Abstract

The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures have long been known to permanently alter neuronal circuitry and to cause excitotoxic injury and aberrant inflammation. Furthermore, pathological changes in bioenergetics and metabolism are considered downstream consequences of epileptic seizures that begin at the synaptic level. However, as we highlight in this Review, evidence is also emerging that primary derangements in cellular or mitochondrial metabolism can result in seizure genesis and lead to spontaneous recurrent seizures. Basic and translational research indicates that the relationships between brain metabolism and epileptic seizures are complex and bidirectional, producing a vicious cycle that compounds the deleterious consequences of seizures. Metabolism-based treatments such as the high-fat, antiseizure ketogenic diet have become mainstream, and metabolic substrates and enzymes have become attractive molecular targets for seizure prevention and recovery. Moreover, given that metabolism is crucial for epigenetic as well as inflammatory changes, the idea that epileptogenesis can be both negatively and positively influenced by metabolic changes is rapidly gaining ground. Here, we review evidence that supports both pathophysiological and therapeutic roles for brain metabolism in epilepsy.

Key points

  • Epileptic seizures induce widespread derangements in cellular and mitochondrial metabolism, as well as cerebral flood flow.

  • Primary defects in genes that encode mitochondrial proteins and/or metabolic substrates and enzymes can increase neuronal and glial network excitability.

  • Brain metabolic homeostasis and function can be viewed as an interplay among the cerebral circulation, glia and neurons, also known as the neurovascular unit.

  • Epilepsy can be viewed as a metabolic disease, and primordial mechanisms evoked by compounds such as adenosine could be highly relevant to seizures and epileptogenesis.

  • Metabolism-based treatments such as the high-fat ketogenic diet and its variants can help to restore metabolic homeostasis and enable seizure control.

  • As dietary therapies can often control seizures in individuals with medically intractable epilepsy, experimental therapeutics based on metabolic targets should be explored.

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Fig. 1: The astrocyte–neuron lactate shuttle.
Fig. 2: Epilepsy treatment targets in the pyramid of life.
Fig. 3: Adenosine metabolism and epileptogenesis.
Fig. 4: Principal mechanisms involved in the pathogenesis of metabolic epilepsies.
Fig. 5: Metabolic substrates and enzymes that regulate synaptic neurotransmission and neuronal excitability.
Fig. 6: Biochemical pathways and mitochondria.
Fig. 7: Mechanisms underlying the neuroprotective effects of ketogenic and related diets.

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Acknowledgements

J.M.R. has received funding from the Canadian Institutes of Health Research and the NIH (R21 NS104513), and D.B. has received funding from the NIH (R01NS103740, R01NS065957) and a CURE Epilepsy Catalyst Award. The authors thank R. Tobias for editorial assistance.

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Authors and Affiliations

  1. Department of Neuroscience, University of California San Diego, San Diego, CA, USA

    Jong M. Rho

  2. Department of Pediatrics, University of California San Diego, San Diego, CA, USA

    Jong M. Rho

  3. Department of Pharmacology, University of California San Diego, San Diego, CA, USA

    Jong M. Rho

  4. Rady Children’s Hospital, San Diego, CA, USA

    Jong M. Rho

  5. Department of Neurosurgery, Robert Wood Johnson Medical School and New Jersey Medical School, Rutgers University, Piscataway, NJ, USA

    Detlev Boison

  6. Brain Health Institute, Rutgers University, Piscataway, NJ, USA

    Detlev Boison

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The authors contributed equally to all aspects of the article.

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Correspondence to Jong M. Rho.

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J.M.R has been a paid consultant to Aquestive Pharmaceuticals, Danone Nutricia, Mallinckrodt, Eisai Pharma and Zogenix, and has served on the Scientific Advisory Board of The Charlie Foundation for Ketogenic Therapies (Santa Monica, CA, USA). D.B. is a co-founder of PrevEp and J.M.R. is the Chief Medical Officer for Path Therapeutics.

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Rho, J.M., Boison, D. The metabolic basis of epilepsy. Nat Rev Neurol 18, 333–347 (2022). https://doi.org/10.1038/s41582-022-00651-8

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