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  • Review Article
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Autonomic manifestations of epilepsy: emerging pathways to sudden death?

Nature Reviews Neurology volume 17, pages 774–788 (2021)Cite this article

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Abstract

Epileptic networks are intimately connected with the autonomic nervous system, as exemplified by a plethora of ictal (during a seizure) autonomic manifestations, including epigastric sensations, palpitations, goosebumps and syncope (fainting). Ictal autonomic changes might serve as diagnostic clues, provide targets for seizure detection and help us to understand the mechanisms that underlie sudden unexpected death in epilepsy (SUDEP). Autonomic alterations are generally more prominent in focal seizures originating from the temporal lobe, demonstrating the importance of limbic structures to the autonomic nervous system, and are particularly pronounced in focal-to-bilateral and generalized tonic–clonic seizures. The presence, type and severity of autonomic features are determined by the seizure onset zone, propagation pathways, lateralization and timing of the seizures, and the presence of interictal autonomic dysfunction. Evidence is mounting that not all autonomic manifestations are linked to SUDEP. In addition, experimental and clinical data emphasize the heterogeneity of SUDEP and its infrequent overlap with sudden cardiac death. Here, we review the spectrum and diagnostic value of the mostly benign and self-limiting autonomic manifestations of epilepsy. In particular, we focus on presentations that are likely to contribute to SUDEP and discuss how wearable devices might help to prevent SUDEP.

Key points

  • Autonomic manifestations of seizures are frequent; they are generally more prominent in focal seizures that originate from the temporal lobe and are particularly pronounced in focal-to-bilateral and generalized tonic–clonic seizures (TCSs).

  • Ictal autonomic changes might serve as diagnostic clues, provide targets for seizure detection and help us to understand the mechanisms that underlie sudden unexpected death in epilepsy (SUDEP).

  • Ictal asystole is the most frequent clinically relevant seizure-related arrhythmia. The key clinical expressions include flaccid falls with injuries and other signs of syncope (for example, intense pallor, jerks, stiffening and gasping) during the course of a temporal lobe seizure.

  • SUDEP contrasts with self-limiting autonomic features because it typically occurs in the aftermath of a TCS, whereas ictal apnoea and ictal asystole are associated with focal — mostly temporal lobe — seizures.

  • SUDEP has a spectrum of heterogeneous causes but is predominantly attributable to TCS-triggered postictal apnoea–asystole.

  • SUDEP and sudden cardiac death are partially overlapping entities, and the presence of pre-existing or acute cardiac comorbidities might help to differentiate between these two events.

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Fig. 1: Key semiological elements of ictal asystole.
Fig. 2: Key autonomic networks involved in cardiovascular and respiratory homeostasis.
Fig. 3: Modulation of the ictal autonomic response.
Fig. 4: Key pathophysiological events in the SUDEP cascade.

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Acknowledgements

We thank J. Gert van Dijk for drawing the key semiological features of ictal syncope (Fig. 1) and R. Trompert for providing the neuroanatomical illustrations (Fig. 2). P.R. has received research funding from the EU Horizon 2020 Research and Innovation Programme under grant agreements 785907 (HBP SGA2) and 945539 (HBP SGA3). R.D.T. has received research funding from the Human Measurement Models Programme co-funded by Health~Holland, Top Sector Life Sciences & Health and ZonMw under grant agreement 114025101 (Brain@Home).

Review criteria

We searched PubMed and SCOPUS for articles published in English from 1 September 2010 to 1 December 2020, with the keywords ‘epilep*’, ‘autonomic’, ‘seizure detection’ and ‘SUDEP’. We selected seminal work, clinical studies with the highest level of evidence or the most recent meta-analysis. We have also included earlier articles and reviews if they were particularly pertinent to the discussion.

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Authors and Affiliations

  1. Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands

    Roland D. Thijs

  2. Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands

    Roland D. Thijs

  3. NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK

    Roland D. Thijs

  4. Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Philippe Ryvlin

  5. Department of Epileptology, University Hospital Bonn, Bonn, Germany

    Rainer Surges

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R.D.T. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Roland D. Thijs.

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Competing interests

R.D.T. reports lecture and consultancy fees from Medtronic, Union Chimique Belge (UCB), Theravarance, Novartis, Zogenix and Arvelle and grants from the Dutch National Epilepsy Fund, Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie, the AC Thomson Foundation, Medtronic, NewLife Wearables and The Netherlands Organisation for Health Research and Development (grant no. 843002707). P.R. reports lecture and consultancy fees from Arvelle, Eisai, LivaNova, Medtronic, Novartis and UCB Pharma and research grants from the Hassler Foundation (Switzerland), the Swiss National Science Foundation and the European Commission. R.S. reports lecture and consultancy fees from Arvelle, Bial, Angelini, Desitin, Eisai, LivaNova, Novartis, UCB Pharma and UnEEG and research grants from the Boll foundation (Kerpen, Germany), BONFOR research funding (Medical Faculty, University of Bonn, Germany), the Federal Ministry of Education and Research (Germany), the Federal Ministry of Health (Germany), and the Verein zur Förderung der Epilepsieforschung e.V. (Bonn, Germany).

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Glossary

Tonic–clonic seizures (TCSs)

Focal or generalized-onset seizures consisting of a tonic followed by a clonic phase.

Central apnoea

Cessation of airflow for at least 10 s with no respiratory effort.

Asystole

Cardiac standstill with no cardiac output and no ventricular depolarization lasting for at least 3 s.

Focal-to-bilateral TCSs

A seizure type with focal onset, with awareness or impaired awareness, either motor or non-motor, progressing to bilateral tonic–clonic activity.

Baroreflex

Reflex mechanism through which baroreceptors maintain blood pressure homeostasis.

QRS complexes

Combination of three marked graphical deflections seen on a typical ECG, corresponding to the contraction of the large ventricular muscles.

T-wave alternans

Beat-to-beat fluctuations in the morphology and/or amplitude of the ST segments and/or T waves on the surface ECG.

Vasovagal syncope

Transient loss of consciousness due to global cerebral hypoperfusion evoked by a vasovagal reflex.

QT intervals

The time from the beginning of the QRS complex to the end of the T wave.

QT dispersion

The difference between the longest and the shortest QT intervals on a 12-lead ECG recording.

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Thijs, R.D., Ryvlin, P. & Surges, R. Autonomic manifestations of epilepsy: emerging pathways to sudden death?. Nat Rev Neurol 17, 774–788 (2021). https://doi.org/10.1038/s41582-021-00574-w

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