The effect of seizure spread to the amygdala on respiration and onset of ictal central apnea

Abstract

OBJECTIVESudden unexpected death in epilepsy (SUDEP) is the leading cause of death for patients with refractory epilepsy, and there is increasing evidence for a centrally mediated respiratory depression as a pathophysiological mechanism. The brain regions responsible for a seizure’s inducing respiratory depression are unclear—the respiratory nuclei in the brainstem are thought to be involved, but involvement of forebrain structures is not yet understood. The aim of this study was to analyze intracranial EEGs in combination with the results of respiratory monitoring to investigate the relationship between seizure spread to specific mesial temporal brain regions and the onset of respiratory dysfunction and apnea.METHODSThe authors reviewed all invasive electroencephalographic studies performed at Northwestern Memorial Hospital (Chicago) since 2010 to identify those cases in which 1) multiple mesial temporal electrodes (amygdala and hippocampal) were placed, 2) seizures were captured, and 3) patients’ respiration was monitored. They identified 8 investigations meeting these criteria in patients with temporal lobe epilepsy, and these investigations yielded data on a total of 22 seizures for analysis.RESULTSThe onset of ictal apnea associated with each seizure was highly correlated with seizure spread to the amygdala. Onset of apnea occurred 2.7 ± 0.4 (mean ± SEM) seconds after the spread of the seizure to the amygdala, which was significantly earlier than after spread to the hippocampus (10.2 ± 0.7 seconds; p < 0.01).CONCLUSIONSThe findings suggest that activation of amygdalar networks is correlated with central apnea during seizures. This study builds on the authors’ prior work that demonstrates a role for the amygdala in voluntary respiratory control and suggests a further role in dysfunctional breathing states seen during seizures, with implications for SUDEP pathophysiology.

A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy

“…Forebrain sites likely influence brainstem respiratory networks through neural projections, which might provide pathways for seizure-induced apnea. Consistent with these possibilities, recent studies indicate that loss of breathing in adult patients with epilepsy coincides with seizure spread to the amygdala (16,23). In adults, electrical stimulation of the amygdala reproduced this apnea (16,17).…”

Neuropeptide depletion in the amygdala in sudden unexpected death in epilepsy: A postmortem study

“…Functional connectivity maps of the human amygdala confirm regional amygdala differences that correlate with histologically defined subnuclei; the lateral‐basal nuclear groups show widespread cortical connections and the centromedial groups project to regions with putative roles in arousal and autonomic regulation, including brainstem reciprocal connections . The lateral nucleus can generate spontaneous interictal activity, and ictal central apnea has been reported with seizure spread to the amygdala . In a recent study of the amygdala kindling model of epilepsy, amygdala stimulation was associated with reduced ictal ventilation and c‐fos expression in neurons in brainstem respiratory nuclei .…”

“…10 The lateral nucleus can generate spontaneous interictal activity, 38 and ictal central apnea has been reported with seizure spread to the amygdala. 5 In a recent study of the amygdala kindling model of epilepsy, amygdala stimulation was associated with reduced ictal ventilation and c-fos expression in neurons in brainstem respiratory nuclei. 39 Clinical studies have demonstrated apnea following electrode stimulation of the amygdala in people with epilepsy under investigation [6][7][8] ; apnea occurred following stimulation of the medial amygdala in one study 6 but following stimulation of lateral and basolateral nuclei in an earlier study but without lateralization.…”

“…3 Volumetric studies show increased right-sided amygdala gray matter volumes. 4 Ictal central apnea can arise with seizure spread to the amygdala, 5 and several studies have demonstrated apnea following electrode stimulation of the amygdala in people with epilepsy undergoing investigations. [6][7][8] One interpretation of these findings is that amygdala networks influence breathing through downstream activation of cortical or extended amygdala regions connected to respiratory regulatory centers, including the brainstem, which can be affected by seizures.…”

“…[6][7][8] One interpretation of these findings is that amygdala networks influence breathing through downstream activation of cortical or extended amygdala regions connected to respiratory regulatory centers, including the brainstem, which can be affected by seizures. 5,8 The amygdala is formed of six subnuclei with extensive interconnections. 9,10 It is enriched in inhibitory, neuropeptidergic neurons and axonal networks [11][12][13] that modulate neuronal function [14][15][16][17] and are themselves modulated or augmented by chronic seizures.…”