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  • Review Article
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Neurobehavioural comorbidities of epilepsy: towards a network-based precision taxonomy

Nature Reviews Neurology volume 17, pages 731–746 (2021)Cite this article

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Abstract

Cognitive and behavioural comorbidities are prevalent in childhood and adult epilepsies and impose a substantial human and economic burden. Over the past century, the classic approach to understanding the aetiology and course of these comorbidities has been through the prism of the medical taxonomy of epilepsy, including its causes, course, characteristics and syndromes. Although this ‘lesion model’ has long served as the organizing paradigm for the field, substantial challenges to this model have accumulated from diverse sources, including neuroimaging, neuropathology, neuropsychology and network science. Advances in patient stratification and phenotyping point towards a new taxonomy for the cognitive and behavioural comorbidities of epilepsy, which reflects the heterogeneity of their clinical presentation and raises the possibility of a precision medicine approach. As we discuss in this Review, these advances are informing the development of a revised aetiological paradigm that incorporates sophisticated neurobiological measures, genomics, comorbid disease, diversity and adversity, and resilience factors. We describe modifiable risk factors that could guide early identification, treatment and, ultimately, prevention of cognitive and broader neurobehavioural comorbidities in epilepsy and propose a road map to guide future research.

Key points

  • The cognitive and behavioural complications of the epilepsies have traditionally been examined in relation to the core characteristics of the disorder, such as the epilepsy syndrome, its aetiology, the frequency and severity of seizures, and treatments.

  • This ‘lesion model’ has been the predominant paradigm for more than 100 years; however, substantial evidence of patient heterogeneity from cognitive, behavioural, neuroimaging, neuropathological, network science and clinical studies is inconsistent with this model.

  • A precision approach to epilepsy neurobehavioural comorbidities requires an understanding of this natural heterogeneity, which could be aided by a new taxonomy based on cognitive and behavioural phenotyping.

  • This Review surveys the literature that has identified cognitive and behavioural phenotypes in children and adults with epilepsy and provides a synopsis of the evolving taxonomy.

  • A new and expanded paradigm is proposed, which includes sophisticated neurobiological measures, genomics, comorbid medical disease, diversity and adversity, and resilience factors.

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Fig. 1: Classic paradigm of neurobehavioural comorbidities of epilepsy.
Fig. 2: Subcortical, cortical and diffusion findings in ENIGMA-Epilepsy.
Fig. 3: Cognitive phenotypes and their distribution.
Fig. 4: Diffusion and network findings across discrete cognitive phenotypes of TLE.
Fig. 5: Next-generation paradigm for neurobehavioural phenotypes of epilepsy.

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Acknowledgements

The authors acknowledge funding from National Institutes of Health (NIH) KL2 TR000440 (R.M.B.), NIH R01 NS097719 (R.M.B.), NIH R01 NS065838 (C.R.M.), NIH R21 NS107739 (C.R.M.), NIH T32 MH018399 (E.K.), NIH R01 NS111022 (A.F.S. and B.P.H.) and NIH F31 NS111883-01 (A.R.). The authors thank M. L. Smith for reading of a pre-submission draft.

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Authors and Affiliations

  1. Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Bruce P. Hermann & Aaron F. Struck

  2. Department of Neurology, William S. Middleton Veterans Administration Hospital, Madison, WI, USA

    Aaron F. Struck

  3. Epilepsy Center and Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    Robyn M. Busch

  4. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Robyn M. Busch

  5. Department of Psychiatry and Center for Multimodal Imaging and Genetics, University of California, San Diego, San Diego, CA, USA

    Anny Reyes, Erik Kaestner & Carrie R. McDonald

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  1. Bruce P. Hermann
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Contributions

B.P.H. organized the overall structure and content of the Review and the whole team wrote targeted discipline-specific sections of the paper and all reviewed and edited the ensuing versions of the manuscript and approved the final version. The various authors contributed predominantly to different sections of the manuscript, including neuropsychology (B.P.H., R.M.B., C.R.M. and A.R.), neuroimaging (C.R.M., E.K., A.R. and B.P.H.), genetics (R.M.B.), behaviour (B.P.H., R.M.B., C.R.M. and A.R.), networks (A.F.S. and E.K.) and conceptual models (B.P.H., R.M.B., C.R.M., A.R. and E.K.).

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Correspondence to Bruce P. Hermann.

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Nature Reviews Neurology thanks R. C. Scott, M. Mula and J. Wagner for their contribution to the peer review of this work.

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Hermann, B.P., Struck, A.F., Busch, R.M. et al. Neurobehavioural comorbidities of epilepsy: towards a network-based precision taxonomy. Nat Rev Neurol 17, 731–746 (2021). https://doi.org/10.1038/s41582-021-00555-z

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