Investigators from five university medical centers in France performed an observational case-control study evaluating cardiac autonomic responses to sympathetic stimulation in patients who subsequently died of sudden unexplained death in epilepsy (SUDEP). They retrospectively analyzed ECG tracings from ante mortem EEGs for heart rate (HR) and HR variability (HRV) before, during and after hyperventilation (HV). All cases of definite or probable SUDEP registered between January 2010, and March 2019 with available EEG data were compared to controls matched for type of epilepsy, drug resistance, sex, age at epilepsy onset, age at EEG recording, duration of epilepsy and survival time after EEG. Patients with vagus nerve stimulators, without a sinus rhythm and/or with a poor-quality ECG were excluded. EEGs recording seizure(s), performed during treatment withdrawal or in an intensive care unit were also excluded.
Of the 35 identified SUDEP cases, 20 met inclusion and exclusion criteria (3 definite SUDEP, 17 probable SUDEP). The main finding of the study was the absence of physiologic changes in HR during and after HV in patients who subsequently experienced SUDEP as compared to controls. Moreover, the change in HR between the end of hyperventilation and 4 minutes after hyperventilation discriminated between patients with SUDEP and control patients with a sensitivity of 85% and a specificity of 75%. These findings suggest that SUDEP patients show impaired cardiac autonomic response to sympathetic stimulation, and that HR variation indices during HV may be predictive of SUDEP risk.
COMMENTARY. The exact pathophysiology of SUDEP remains unknown, however, animal models and patients with epilepsy show disturbed baroreflex sensitivity, changes in sympathetic nervous system activity and blood pressure, as well as impaired heart rate variability and cerebrovascular autoregulation, suggesting that autonomic dysregulation might play a role in SUDEP .
Heart rate (HR) and heart rate variability (HRV) provide an easy, non-invasive way to study cardiacautonomic function. The quantification of HRV is defined by changes in the time between beats and several parameters can be analyzed to assess vagal and sympathetic activity. A 2012 systematic review and meta-analysis of 39 studies investigating HRV in epilepsy found diminished HRV and decreased vagal activity in patients with epilepsy compared to controls.  A more recent study retrospectively evaluated baseline HRV in patients with drug-resistant epilepsy with or without sodium channel mutations, including 10 who died from SUDEP, to assess the potential contribution of autonomic dysregulation to SUDEP risk. The SUDEP patients displayed severe autonomic dysregulation, with lower awake HRV and extremely high or low ratios of sleep-to-awake HRV. 
The current study demonstrates impaired autonomic response to sympathetic activation in epilepsy patients with SUDEP, suggesting that variations in HR during hyperventilation might predict SUDEP risk. Further studies in both adult and pediatric populations are needed to validate HRV as a biomarker of SUDEP
The author has declared that no competing interests exist.