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

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Sudden 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.


The 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.


The 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).


The 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.

ABBREVIATIONS EEG = electroencephalography; EMU = epilepsy monitoring unit; FSL = FMRIB Software Library; MNI = Montreal Neurological Institute; NMH = Northwestern Memorial Hospital; SUDEP = sudden unexpected death in epilepsy; TLE = temporal lobe epilepsy.

Downloadable materials

  • Supplementary Figs 1 and 2 (PDF 1.47 MB)

Article Information

Correspondence William P. Nobis: Vanderbilt University Medical Center, Nashville, TN.

INCLUDE WHEN CITING Published online April 5, 2019; DOI: 10.3171/2019.1.JNS183157.

C.Z. and S.S. share senior authorship of this work.

Disclosures Dr. Gerard reports being a speaker for UCB-China and receiving study-related clinical or research support from SAGE and Sunovion.

© AANS, except where prohibited by US copyright law.



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    Flowchart of study design and patient selection.

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    Electrode placement. Electrode coordinates for each patient were converted into MNI space. The 3D brain surface plot (left) shows the position of the amygdala depth wire in each patient (P1, P2, etc.). The light blue areas indicate the amygdala mask from the Harvard-Oxford atlas (HarvardOxford-submaxprob-thr0–1 mm) implemented in FSL. The coronal brain slices from T1-weighted MR images (right) show the location of amygdala contacts (blue circles) in each patient in native anatomical space.

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    A: Scatterplot of delay in apnea onset for each seizure. Delay in onset from the amygdala is not included for the seizures from patient 2 because the apnea preceded the spread to the amygdala, as noted in Table 2. B: Box plot of delay in apnea onset after spread to either the amygdala or hippocampus (squares indicate mean values, X’s signify extremes, boxes indicate the interquartile range [25%–75%], and whiskers indicate 5%–95%).

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    Apnea onset and seizure spread: example of invasive EEG of a left temporal seizure with an apnea event (patient 8, seizure 1) shown in 3 consecutive 30-second pages. A bipolar montage is shown, with all electrodes visible. In panel A, prior to the onset of the seizure the patient is sleeping with normal respirations as noted by the chest (green) and abdomen (teal) respiratory belts. The onset of the seizure is noted by the red arrow. Focal onset can be seen, with building rhythmic low-voltage fast activity in the basal temporal grid. Panel B shows the seizure spread and the onset of the apnea—visible in traces from the respiratory leads—about 39 seconds after seizure onset. Panel C shows the diffuse seizure spread to the other electrodes and the apnea ending 16 seconds after it started. The inset for panel B shows a detailed look at traces from the hippocampal and amygdala depth electrodes. The presence of rhythmic activity emerging from the background is seen first in the posterior hippocampus, as noted by the blue arrow. Similar activity is seen emerging in the amygdala, as noted by the green arrow. This precedes the apnea onset, as noted by the respiratory traces. Electrode locations: lateral temporal grid, middle basal temporal grid, anterior basal temporal strip, posterior basal temporal strip, amygdala depth, anterior hippocampus depth, and posterior hippocampus depth. All channels are shown. Ant = anterior; EKG = electrocardiogram; post = posterior; s = seconds.

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    Example of invasive EEG of a left mesial temporal seizure without an apnea event (patient 7, seizure 1) shown in 3 consecutive 30-second pages. A bipolar montage is shown, with all electrodes visible. In panel A, prior to the onset of the seizure the patient is awake and interacting with family in the room, with some irregular respirations as noted by the chest (green) and abdomen (teal) respiratory belts. The onset of the seizure is noted by the red arrow. Focal onset can be seen with building spikes in the left anterior hippocampus. Panel B shows the seizure continuing in the left hippocampal electrodes and normal respirations, which are visible in the respiratory leads. Panel C shows the seizure continuing and then some degradation in the signal as the patient is being interviewed and moves, prior to again returning to normal respirations. Electrode locations: left amygdala depth, left anterior hippocampus depth, left middle hippocampus depth, left posterior hippocampus depth, right amygdala depth, right anterior hippocampus depth, right middle hippocampus depth, and right posterior hippocampus depth. All channels are shown.




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