Incidence, Recurrence, and Risk Factors for Peri-ictal Central Apnea and Sudden Unexpected Death in Epilepsy

Abstract

Introduction: Peri-ictal breathing dysfunction was proposed as a potential mechanism for SUDEP. We examined the incidence and risk factors for both ictal (ICA) and post-convulsive central apnea (PCCA) and their relationship with potential seizure severity biomarkers (i. e., post-ictal generalized EEG suppression (PGES) and recurrence. Methods: Prospective, multi-center seizure monitoring study of autonomic, and breathing biomarkers of SUDEP in adults with intractable epilepsy and monitored seizures. Video EEG, thoraco-abdominal excursions, capillary oxygen saturation, and electrocardiography were analyzed. A subgroup analysis determined the incidences of recurrent ICA and PCCA in patients with ≥2 recorded seizures. We excluded status epilepticus and obscured/unavailable video. Central apnea (absence of thoracic-abdominal breathing movements) was defined as ≥1 missed breath, and ≥5 s. ICA referred to apnea preceding or occurring along with non-convulsive seizures (NCS) or apnea before generalized convulsive seizures (GCS). Results: We analyzed 558 seizures in 218 patients (130 female); 321 seizures were NCS and 237 were GCS. ICA occurred in 180/487 (36.9%) seizures in 83/192 (43.2%) patients, all with focal epilepsy. Sleep state was related to presence of ICA [RR 1.33, CI 95% (1.08-1.64), p = 0.008] whereas extratemporal epilepsy was related to lower incidence of ICA [RR 0.58, CI 95% (0.37-0.90), p = 0.015]. ICA recurred in 45/60 (75%) patients. PCCA occurred in 41/228 (18%) of GCS in 30/134 (22.4%) patients, regardless of epilepsy type. Female sex [RR 11.30, CI 95% (4.50-28.34), p < 0.001] and ICA duration [RR 1.14 CI 95% (1.05-1.25), p = 0.001] were related to PCCA presence, whereas absence of PGES was related to absence of PCCA [0.27, CI 95% (0.16-0.47), p < 0.001]. PCCA duration was longer in males [HR 1.84, CI 95% (1.06-3.19), p = 0.003]. In 9/17 (52.9%) patients, PCCA was recurrent. Conclusion: ICA incidence is almost twice the incidence of PCCA and is only seen in focal epilepsies, as opposed to PCCA, suggesting different pathophysiologies. ICA is likely to be a recurrent semiological phenomenon of cortical seizure discharge, whereas PCCA may be a reflection of brainstem dysfunction after GCS. Prolonged ICA or PCCA may, respectively, contribute to SUDEP, as evidenced by two cases we report. Further prospective cohort studies are needed to validate these hypotheses.

Keywords: apnea; breathing; epilepsy; ictal central apnea (ICA); post-convulsive central apnea (PCCA); seizures; sudden unexpected death in epilepsy (SUDEP).

Figure 1

Ictal central apnea (ICA) timing with respect to EEG onset (A) and clinical onset (B).

Figure 2

Example of ictal central apnea (ICA). Sensitivity 7 μV, High Frequency Filter: 70 Hz, Time constant: 0.1 s. (A) Twelve seconds after the electrographic onset, ICA is noted without any other clinical signs. (B) Continuation of ICA, with a total duration of 14 s, followed by breathing resumption. ABD, abdominal; EEG sz onset, electrographic seizure onset; EKG, electrocardiogram; ICA, Ictal central apnea; s, seconds; THOR, thoracic.

Figure 3

Example of post-convulsive central apnea (PCCA). Sensitivity 20 μV, High Frequency Filter: 70 Hz, Time constant: 0.1 s. (A). After the end of convulsive phase, the patient is apneic for 7 s. After the electrographic end, there are 2 noticeable breaths which are followed by another brief apnea. Lastly, regular breathing resumes. (B) Continuation from (A), regular breathing continues. ABD, abdominal; Clinical sz end, end of clinical seizure. EEG sz end, electrographic seizure end; EKG, electrocardiogram; PCCA, post-convulsive central apnea; s, seconds; THOR, thoracic.