Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation

Abstract

Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O 2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O 2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP.

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…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).…”

Multicenter clinical assessment of improved wearable multimodal convulsive seizure detectors

“…SUDEP is more likely to occur in patients who have at least one (primary or secondarily) generalized tonic-clonic (GTC) seizure a year, and when a patient is unattended after a seizure [2][3] . While SUDEP's general cause remains unknown, SUDEP can occur after prolonged post-ictal generalized EEG suppression (PGES), and is associated with autonomic dysfunction such as terminal apnea preceding terminal asystole 4,5,6 .…”

“…It is crucial to develop systems to detect seizures, to measure possible biomarkers of SUDEP, and to alert caregivers for assistance, as an early application of aid can be protective 6,7 .…”

“…focal motor to bilateral tonic-clonic seizures (FTCb), showing that combining EDA with ACM leads to more sensitive and specific detection than ACM alone 22 . The combination takes advantage of the detection, by a comfortably-worn wristband, of a wide range of motor seizures using ACM sensors -tonic-clonic, tonic, clonic, myoclonic, hypermotor 24 -and of the measurement of the sympathetic nervous system activity using EDA 25 , including peri-ictal autonomic dysregulation 6,23,26 . The primary contribution of this work is two improved detection algorithms trained on a significantly larger dataset containing focal motor tonic-clonic (FTC) and FTCb seizures (hereafter referred to as CS, convulsive seizures).…”

Conscious control of breathing: A key to prevention of sudden unexpected death in epilepsy?

“…In a patient with bilateral frontotemporal electrode implantation, central apnea was noted during seizure spread into the amygdala, and localized electrical stimulation reproduced this finding. Patients were not aware of apneas 5. With the re‐emergence of stereo‐electroencephalographic recordings in the presurgical epilepsy workup, anatomically precise stimulation of amygdala and hippocampal regions is now feasible.…”