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  • Review Article
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Identification of clinically relevant biomarkers of epileptogenesis — a strategic roadmap

Nature Reviews Neurology volume 17, pages 231–242 (2021)Cite this article

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Abstract

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

Key points

  • Many forms of epilepsy manifest and/or are diagnosed months or even years after an epileptogenic insult or identification of a genetic defect.

  • Epilepsies that result from an insult or genetic defect could be amenable to secondary prevention but preventive treatments are not available.

  • Development of preventive therapies is complicated by the fact that only a subset of at-risk individuals develop clinical epilepsy.

  • Biomarkers are needed to clearly identify individuals who have the highest risk of developing epilepsy after an epileptogenic insult.

  • We propose a strategic roadmap designed to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis.

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Fig. 1: SWOT analysis for the biomarker development roadmap.

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Acknowledgements

The contents of this article are based on proposals made at a workshop organized by the National Institute of Neurological Disease and Stroke (NINDS) to accelerate therapies for anti-epileptogenesis and disease modification (Bethesda, MD, USA, 6th–8th August 2018). M.S. is supported in part by the European Community (FP7-HEALTH project 602102 [EPITARGET]). D.C.H. is supported by the Science Foundation Ireland (SFI) grant number 13/IA/1891 and 16/RC/3948 and co-funded under the European Regional Development Fund and by FutureNeuro industry partners. Other support to D.C.H. was from the European Union’s ‘Seventh Framework’ Programme (FP7) under Grant Agreement no. 602130 (EpimiRNA) and Medical Research Charities Group (2016-9). A.P. is supported by the Academy of Finland, European Community (FP7-HEALTH project 602102 [EPITARGET]), the National Institute of Neurological Disorders and Stroke (NINDS) Centers without Walls [grant number U54 NS100064]. W.H.T. is supported by the Division of Intramural Research, NINDS NIH. F.H.K. and K.K.W. are supported in part by a CURE grant received from the United States Army Medical Research and Materiel Command, Department of Defense (DoD), through the Psychological Health and Traumatic Brain Injury Research Program under award no. W81XWH-15-2-0069. K.S.W. is in part supported with Federal funds from the NINDS, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN271201600048C.

Review criteria

We searched PubMed for articles published up to August 2020, including experimental and clinical studies published in English. Generic searches using free terms (such as “epilepsy” AND “biomarker”) had low specificity and retrieved a large number of articles (2,812 articles), the majority of which provided no clear evidence to support the notion that a particular molecular, imaging, electroencephalography (EEG) or behavioural alteration could be considered a biomarker of epilepsy or epileptogenesis. Use of medical subject heading (MeSH) terms (such as “Epilepsy”[Majr] AND “Biomarkers”[Majr]) had low sensitivity and retrieved few articles (149 articles). Similarly, unsatisfactory results were obtained when using the generic search “epileptogenesis” AND “biomarker” or “Biomarkers”[Majr] (339 and 45 articles, respectively). Therefore, we refined the generic search with specific biomarker types (molecular, imaging, EEG, behavioural) by adding one or more subtopic-specific additional query term. Eligible papers were then read and filtered on the basis of experimental methodology — studies that included a receiver operating characteristic (ROC) analysis or an equivalent methodology for ascertaining discriminative value were prioritized. In addition, articles from leaders in the field of epilepsy and epileptogenesis were included on the basis of the investigators’ expertise. Consequently, the final selection of biomarkers discussed in this Review comes from a narrative rather than a systematic search. For Table 1, rates and other information were compiled from reviews or, in some cases, original references identified by use of tailored search terms for each risk factor.

Author information

Authors and Affiliations

  1. Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy

    Michele Simonato

  2. Division of Neuroscience, IRCCS San Raffaele Hospital, Milan, Italy

    Michele Simonato

  3. Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD, USA

    Denes V. Agoston

  4. Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA

    Amy Brooks-Kayal

  5. Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA

    Chris Dulla

  6. Research and New Therapies, Epilepsy Foundation, Landover, MD, USA

    Brandy Fureman

  7. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland

    David C. Henshall

  8. FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland

    David C. Henshall

  9. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    Asla Pitkänen

  10. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    William H. Theodore & Vicky Whittemore

  11. Amron Neuroscience, LLC, Darby, MT, USA

    Roy E. Twyman

  12. Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Department of Emergency Medicine, University of Florida, Gainesville, FL, USA

    Firas H. Kobeissy & Kevin K. Wang

  13. Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon

    Firas H. Kobeissy

  14. Brain Rehabilitation Research Center, Malcom Randall Veterans Affairs Medical Center (VAMC), Gainesville, FL, USA

    Kevin K. Wang

  15. Department of Pharmacology & Toxicology and Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, USA

    Karen S. Wilcox

Authors
  1. Michele Simonato
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  2. Denes V. Agoston
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  3. Amy Brooks-Kayal
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  4. Chris Dulla
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  5. Brandy Fureman
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  6. David C. Henshall
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  7. Asla Pitkänen
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  8. William H. Theodore
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  9. Roy E. Twyman
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  10. Firas H. Kobeissy
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  11. Kevin K. Wang
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  12. Vicky Whittemore
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  13. Karen S. Wilcox
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Contributions

The Review was envisioned and planned as a collaborative activity within the Biomarkers and Translational Science Working Group organized by the National Institute of Neurological Disease and Stroke within the initiative “Accelerating Therapies for Antiepileptogenesis and Disease Modification”. All authors contributed to the conception, design, literature search and writing for this Review.

Corresponding author

Correspondence to Michele Simonato.

Ethics declarations

Competing interest

K.S.W. is on the scientific advisory board for and is shareholder of Blackfynn, and is a consultant for Xenon Pharmaceuticals. All other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks I. Ali, R. Surges and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

EpiBioS4Rx: https://epibios.loni.usc.edu

EpimiRNA: https://www.epimirna.eu

EPISTOP: http://epistop.eu

EPITARGET: https://www.epitarget.eu

Supplementary Information

Glossary

Receiver operating characteristic (ROC) analysis

A standard method to determine the sensitivity and specificity of a proposed biomarker.

Autoradiography

A technique in which an image is produced on an X-ray film or nuclear emulsion by the pattern of decay emissions from the distribution of a radioactive substance in a cellular or histological preparation.

Sleep spindles

Trains of distinct waves with frequency at 11–16 Hz detectable on the EEG during sleep.

Negative predictive value

The probability that a patient does not have the disease when the biomarker is negative.

Positive predictive value

The probability that a patient has the disease when the biomarker is positive.

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Simonato, M., Agoston, D.V., Brooks-Kayal, A. et al. Identification of clinically relevant biomarkers of epileptogenesis — a strategic roadmap. Nat Rev Neurol 17, 231–242 (2021). https://doi.org/10.1038/s41582-021-00461-4

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