Introduction: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Case studies suggest that the cause of SUDEP may be respiratory depression induced by seizures. Consistent with this possibility, non-fatal seizures, both focal and generalized, are often associated with apnea and oxygen desaturation. However, the mechanisms for the respiratory effects in both fatal and non-fatal seizures remain unclear.

Methods: Because impaired breathing is thought to play a critical role in SUDEP, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We monitored breathing in a medically refractory epilepsy patient (JK) during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We used intracranial electrical stimulation to examine the function of candidate forebrain sites in three subjects.

Results: We found that central apnea and oxygen (O2) desaturation occurred when seizures spread to the left amygdala. Localized electrical stimulation of the left amygdala reproduced the apnea and O2 desaturation. Localized electrical stimulation of the right amygdala also produced apnea and O2 desaturation. These effects of amygdala stimulation were also observed in two additional subjects (KD and SP). Surprisingly, even when patients were awake and vigilant, they were completely unaware of the apnea evoked by stimulation and expressed no dyspnea. In contrast, voluntary breath holding of similar duration caused severe dyspnea. Using an intermittent stimulation paradigm, amygdala stimulation-evoked apnea and respiratory agnosia persisted over several minutes, as would likely be the case in a seizure that could lead to SUDEP.

Conclusions: These findings indicate a functional connection between the amygdala and medullary respiratory network in humans. Due to inhibition of breathing, respiratory agnosia and loss of dyspnea, our data suggest that seizure activity within the amygdala may lead to SUDEP. Identifying strategies to target this process might prevent SUDEP.

Patient Care: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in chronic refractory epilepsy patients. However, the pathophysiological mechanisms underlying SUDEP are unclear. Determining the mechanisms that leads to death will allow identification of proper preventative strategies to prevent SUDEP.

Learning Objectives: By the conclusion of this session, participants should be able to 1) Describe the importance of sudden unexpected death in epilepsy (SUDEP), 2) Discuss, in small groups, the amygdala's role in breathing, and 3) Identify an effective treatment for SUDEP.

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