Electrical and autonomic cardiac function in patients with Dravet syndrome

Abstract

Summary Dravet syndrome (DS) is an epileptic encephalopathy related mainly to mutations in the SCN1A gene, encoding for neuronal sodium channels. Patients with DS have a high risk of sudden unexpected death in epilepsy (SUDEP). In this study we investigated whether patients with DS present abnormalities in electrical and autonomic cardiac function. To this aim we assessed ventricular repolarization and heart rate variability (HRV) on standard electrocardiography (ECG) and on 24‐h ECG Holter monitoring, respectively, in 20 patients affected by DS (6.8 ± 4 years, 11 female). As age‐ and sex‐matched control groups, we also studied 20 patients with other epileptic syndromes receiving antiepileptic drugs (ES/AED, 6.0 ± 5 years, 12 female), 20 patients with other epileptic syndromes without treatment (ES/no‐AED, 6.7 ± 4 years, 10 female), and 20 healthy children (HC, 7.2 ± 5 years, 11 females). Data analysis showed that patients with DS had depressed HRV variables compared to both ES patients (ES/AED and ES/no‐AED) and HC control group, whereas no significant differences in HRV variables were found between ES patients (with and without treatment) and HC. There was no significant difference between patients with DS and all the other control groups in RR intervals, QT, and QTc interval analysis. In conclusion, DS patients display an imbalance of cardiac autonomic function toward a relative predominance of adrenergic tone compared to both healthy children and patients with other forms of epilepsy, independent of antiepileptic therapy. Follow‐up studies should clarify the clinical significance of this autonomic impairment and whether HRV analysis can be helpful in predicting the risk of sudden death in patients with DS.

Sudden Unexpected Death in Dravet Syndrome

“…In addition, they observed an increased number of atrioventricular blocks and decreased interictal heart rate variability in mice with global or brain-specific Na v 1.1 deletion. Consistent with this, children with Dravet syndrome exhibit decreased heart rate variability compared to age-and sex-matched children with other epilepsy syndromes or with healthy controls (10). This suggests that there may be abnormal regulation of sinoatrial node activity by the autonomic nervous system.…”

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…For example, mutations of SCN1A in patients with DS cause increased QT and P wave dispersion and a decrease in heart rate variability (HRV) (12,37). However, there are no published reports of ECG changes after fatal or nonfatal generalized seizures in patients with DS, other than a single case report after status epilepticus (38).…”

“…A variety of mechanisms have been proposed for SUDEP (1,2,(4)(5)(6), including cardiac arrhythmias (7)(8)(9)(10), dysfunction of autonomic control (11)(12)(13)(14)(15), apnea/hypoventilation (3,(16)(17)(18)(19)(20)(21), airway obstruction (22), pulmonary edema (23), brain stem spreading depolarization (BSD) (24), and postictal generalized EEG suppression (PGES) (25). Many investigators have focused on cardiac tachyarrhythmias as the cause of death, in part because of an association between SUDEP and mutations of genes expressed in the heart, such as those that underlie long QT syndrome (10,(26)(27)(28).…”

Sudden unexpected death in a mouse model of Dravet syndrome

“…Several other aspects of our studies of DS mice also correlate with observations of DS patients. Notably, as in DS mice, Delogu and colleagues (47) found that DS patients have suppressed resting heart-rate variability compared with other epileptic patients or nonepileptic individuals. Similarly, as in DS mice, most SUDEP cases in patients with DS and other types of epilepsy occur in sleep (9,12,47,48).…”