De novo ADGRV1 variant in a patient with ictal asystole provides novel clues for increased risk of SUDEP

Abstract

Background: Various cardiac and autonomic manifestations are frequently reported during seizures. Among the seizure-related arrhythmia, ictal tachycardia is the most common, followed by ictal bradycardia, with ictal asystole being the rarest. The occurrence of ictal asystole may obscure the clinical presentation and delay the diagnosis, representing a life-threatening presentation of epilepsy, with an elevated risk of sudden unexpected death in epilepsy patients (SUDEP). These cardiac abnormalities are being increasingly recognized as the key to elucidating the mechanisms of SUDEP.

Case presentation: We present a 35-year-old man with a history of focal-onset seizures with impaired consciousness since his mid-20 s. He developed different types of seizures for 2 years, described as tonic seizure and atonic seizure (drop attack). During such clinical events, he suffered from falls and cardiac arrest. However, thorough cardiac electrophysiology and imaging workup failed to reveal a cardiac etiology. Subsequent video electroencephalograph (EEG) monitoring was performed, and ictal bradycardia and ictal asystole were discovered. A cardiac pacemaker was implanted, and at 3-year follow-up, the patient did not suffer more atonic seizures, or falls. Genetic tests discovered a de novo variant of Adhesion G Protein-Coupled Receptor V1 (ADGRV1), which may provide a clue for the patient's ictal asystole and the increased risk of SUDEP.

Conclusions: Considering the important impact of ictal bradycardia and asystole on the morbidity and potential mortality of epileptic patients, it is important to simultaneously utilize EEG and electrocardiogram to confirm the diagnosis. This case report highlights the link between the de novo variant of ADGRV1 and the ictal bradycardia/asystole phenotype and implicates the importance of genetic testing in adult epilepsy patients.

Keywords: ADGRV1; Drug resistant epilepsy; Ictal asystole; SUDEP.

Fig. 1

a Atonic seizure recorded during video EEG (vEEG) monitoring. vEEG showed ictal generalized delta slowing, followed by tonic (stiffening) and clonic (jerking) phases; and subsequent diffuse voltage attenuation and diffuse distribution of delta slowing (purple arrows). The one lead ECG recording (red lines in the figure) showed HR change (red arrows) when bradycardia and asystole; b Ictal asystole was further confirmed by the ECG traces recorded during cardiac telemetry monitoring

Fig. 2

a A focal-onset seizure arising from the left temporal region. Purple arrow shows EEG focal slowing in the left temporal region at ictal onset and when ictal phase evolution. b A focal-onset seizure arising from the right temporal region. Purple arrow shows EEG focal slowing in the right temporal region at ictal onset and when ictal phase evolution, and red arrow indicates onset of clinical symptoms. c Ictal prolongation of RR interval during the focal-onset seizures, as recorded by the concurrent ECG monitoring. Blue arrow indicates the cardiac pacemaker pacing artifacts

Fig. 3

a Brain MRI showed left temporal and hippocampal sclerosis in the last follow up. Yellow arrow shows the increased T2/FLAIR signal and volume loss in the left hippocampus. b Brain PET showed no lateralized hypometabolism

Fig. 4

ADGRV1 variants associated with epilepsy and SUDEP. Red,gene variants associated with genetic generalized epilepsy (GGE); black, variants associated with other type of epilepsy; blue, reported variants associated with SUDEP; purple, the de novo variant reported in our case. LGS: Lennox-Gastaut Syndrome; EOAE: early-onset absence epilepsy; ID: intellectual disability; EAR: epilepsy-associated repeat; GPS: G-protein-coupled receptors (GPCR) proteolytic site