Seizure‐related apneas have an inconsistent linkage to amygdala seizure spread

Abstract

Objective: Sudden unexpected death in epilepsy (SUDEP) is a frequent cause of death in epilepsy. Respiratory dysfunction is implicated as a critical factor in SUDEP pathophysiology. Human studies have shown that electrical stimulation of the amygdala resulted in apnea, indicating that the amygdala has a role in respiration control.Unilateral amygdala stimulation resulted in immediate onset of respiratory dysfunction occurring only during nose breathing. In small numbers of patients, some but not all spontaneous seizures resulted in apnea occurring shortly after seizure spread to the amygdala. With this study we aimed to determine whether seizure onset or spread to the amygdala was necessary and sufficient to cause apnea. Methods: We investigated the temporal relationship between apnea/hypopnea (AH) onset and initial seizure involvement within the amygdala in patients with implanted depth electrodes. Results: Data from 17 patients (11 female) with 47 seizures were analyzed. With seven seizures (three patients), AH preceded amygdala seizure involvement by 2 to 55 seconds. There was no AH with four seizures (three patients) that involved the amygdala. With eight seizures (four patients) AH occurred within 2 seconds following amygdala seizure onset. With 28 seizures, AH started >2 seconds after amygdala seizure onset (range 3-158 seconds). Following seizure onset, there was a significant difference between AH onset time and amygdala seizure onset (P < .001). The mean ± standard deviation (SD) AH onset was 27.8 ± 41.06 seconds, and the mean time to amygdala involvement was 8.83 ± 20.19 seconds. Significance: There is a wide range of AH onset times relative to amygdala seizure involvement. With some seizures, amygdala seizure involvement occurs without AH. With other seizures, AH precedes amygdala seizures, suggesting that, with spontaneous seizures, involvement of the amygdala may not be crucial to induction of AH with all seizures. Other pathophysiology impacting brainstem respiratory networks may be of greater relevance to seizure-triggered apneas.

Enhanced Synaptic Transmission in the Extended Amygdala and Altered Excitability in an Extended Amygdala to Brainstem Circuit in a Dravet Syndrome Mouse Model

“…Similarly, seizure spread to these regions may be driving ictal apneas ( Dlouhy et al, 2015 ; Nobis et al, 2019 ). The involvement of the extended amygdalar regions (CeA and BNST) in ictal apneas may explain why the amygdala at large does not always produce apneas when activated by seizures ( Park et al, 2020 ). The PBN has a known role in the modulation of breathing ( Dutschmann and Herbert, 2006 ; Navarrete-Opazo et al, 2020 ) and has been targeted to rescue respiratory dysfunction in developmental disorders ( Abdala et al, 2016 ).…”

Autonomic dysfunction in epilepsy mouse models with implications for SUDEP research

“…These brain areas include the amygdala (32, 36, 64), the hippocampus head and body, anterior parahippocampal gyrus, and antero-mesial fusiform gyrus (65, 66). A pediatric study found apneas and seizure spread to the amygdala were strongly correlated (67), an adult study failed to replicate this (64). Electrical stimulation to the insula and left cingulate gyrus decreased cardiac output and induced cardiac asystole in epilepsy patients without effects on breathing (68,69).…”

Perspectives on the basis of seizure-induced respiratory dysfunction

“…For example, stimulation of the basolateral, basomedial, and central regions consistently resulted in apnea, whereas stimulation of the more lateral amygdala failed to affect breathing (Rhone et al, 2020 ). Therefore, not all amygdala seizures result in apnea (Park et al, 2020 ). It is also worth mentioning that amygdala stimulation elicited apnea even during sleep (Nobis et al, 2018 ) when SUDEP occurs most frequently (Nobili et al, 2011 ).…”