Heart Rate Variability in Patients with SCN Mutations and SUDEP Ken Myers MD PhD FRCPC (Paeds Neuro) Epilepsy Fellow – Austin Health, University of Melbourne

Faculty/Presenter Disclosure Faculty: Ken Myers Relationships with commercial interests: None.

Disclosure of Commercial Support This program has not received financial or in-kind support from any commercial entities. Potential for conflict of interest: None.

Mitigating Potential Bias N/A

Heart Rate Variability Various measures, including standard deviation over time or beat-to-beat variability Common measure of beat-to-beat variability is root mean square of successive differences (rMSSD) Typically, calculated automatically from Holter monitor or other cardiac monitoring device

Physiologic Significance Parasympathetic Sympathetic HRV

Clinical Utility of HRV Lower HRV values predictive of mortality in post-MI, CHF, and elderly (1-3) HRV is lower in people with epilepsy, independent of medications HRV even lower in Dravet syndrome (4) HRV is disproportionately increased in sleep (5) Kleiger et al 1987; (2) Nolan et al 1998; (3) Tsuji et al 1994; (4) Delogu et al 2011; (5) Sivakumar et al 2016

HRV and SUDEP HRV abnormalities hypothesized to explain SUDEP as partly due to autonomic dysregulation 2 cases demonstrated altered HRV prior to sudden death during VEM HRV as a risk factor for SUDEP unclear

Hypothesis Baseline HRV is lower in people with SCN-related epilepsy who die of SUDEP

How?

Methods Reviewed EEGs of patients with SCN gene mutations and age-matched controls with refractory epilepsy Manually extracted interbeat intervals from ECG derivation for 5 minute periods awake and in light sleep (if available) Calculated rMSSD (primary outcome variable) and ratio of awake to sleep rMSSD

Results 31 patients with SCN mutations (30 SCN1A, 1 SCN2A), 20 of whom had sleep on EEG Median age 7 years (range 6 months to 44 years) 2 definite SUDEP, 1 possible SUDEP* * Nashef et al 2012

Results rMSSD Wilcoxon Rank Sum test Awake Sleep * p < 0.02 SCN Mutation Control Wilcoxon Rank Sum test

Results * rMSSD Wilcoxon Rank Sum test * p < 0.02 Non-SUDEP SUDEP SCN Mutation Wilcoxon Rank Sum test

Results * rMSSD Sleep:Waking Ratio Wilcoxon Rank Sum test * p = 0.05 Non-SUDEP SUDEP SCN Mutation Wilcoxon Rank Sum test

Conclusions No statistically significant difference in HRV between patients with SCN-related epilepsy when compared to other refractory epilepsy patients HRV may have clinical utility as a biomarker of SUDEP risk

Acknowledgements Patients and families Alberta Children’s Hospital/ University of Calgary Luis Bello-Espinosa Robin Clegg Jeffrey Buchhalter Austin Health/ University of Melbourne Ingrid Scheffer Royal Hospital for Sick Children/ University of Glasgow Joe Symonds Sameer Zuberi

Interval between EEG and SUDEP EEG at 14 years, died at 16 years EEG at 20 months, died at 22 months EEG at 17 months, died at 7.5 years

Age-HRV Relationship

SUDC during VEM