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Objective: Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO 2 drive, measured by the hypercapnic ventilatory response (HCVR)., Methods: We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO 2 ) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created., Results: Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO 2 nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability., Significance: These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Central CO 2 chemoreception (CCR), a major chemical drive for breathing, can be quantified with a CO 2 re-breathing test to measure the hypercapnic ventilatory response (HCVR). An attenuated HCVR correlates with the severity of respiratory dysfunction after generalized convulsive seizures and is a potential biomarker for sudden unexpected death in epilepsy (SUDEP) risk. Vagus nerve stimulation (VNS) may reduce SUDEP risk, but for unclear reasons the risk remains higher during the first 2 years after implantation. The vagus nerve has widespread connections in the brainstem, including key areas related to CCR. Here we examined whether chronic electrical stimulation of the vagus nerve induces changes in CCR., Methods: We compared the HCVR in epilepsy patients with or without an active VNS in a sex- and age-matched case-control study. Eligible subjects were selected from a cohort of patients who previously underwent HCVR testing. The HCVR slope, change in minute ventilation (VE) with respect to change in end tidal (ET) CO2 (∆ VE/ ∆ ETCO2) during the test was calculated for each subject. Key variables were compared between the two groups. Univariate and multivariate analyses were carried out for HCVR slope as dependent variable., Results: A total of 86 subjects were in the study. HCVR slope was significantly lower in the cases compared to the controls. Cases had longer duration of epilepsy and higher number of anti-epileptic drugs (AEDs) tried during lifetime. Having active VNS and ETCO2 were associated with a low HCVR slope while high BMI was associated with high HCVR slope in both univariate and multivariate analyses., Discussion: We found having an active VNS was associated with relatively attenuated HCVR slope. Although duration of epilepsy and number of AEDs tried during lifetime was significantly different between the groups, they were not predictors of HCVR slope in subsequent analysis., Conclusion: Chronic electrical stimulation of the vagus nerve by VNS may be associated with an attenuated CCR [Correction added on 24 November 2021, after first online publication: The preceding sentence has been revised from “Chronic electrical stimulation of VNS nerve by VNS…”]. A larger prospective study may help to establish the time course of this effect in relation to the time of VNS implantation, whether there is a causal relationship, and determine how it affects SUDEP risk., (© 2021 International League Against Epilepsy.)

Objective: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO 2 (hypercapnic ventilatory response [HCVR] or central respiratory CO 2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs)., Methods: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (V E ), tidal volume, respiratory rate, end tidal (ET) CO 2 and O 2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔV E /ΔETCO 2 ) for each subject was determined by linear regression. During the video-electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO 2 , and capillary oxygen saturation (SPO 2 )., Results: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from -0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO 2 . Both the duration and magnitude of postictal tcCO 2 rise following GCSs were inversely correlated with HCVR slope., Significance: Measurement of the HCVR is well tolerated and can be performed rapidly and safely at the bedside in the EMU. A subset of individuals has a very low sensitivity to CO 2 , and this group is more likely to have a prolonged increase in postictal CO 2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms., Methods: We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral capillary oxygen saturation (SpO 2 ), electrocardiography, and video electroencephalography (VEEG) in 473 patients in a multicenter study of SUDEP. Seizures were classified according to the International League Against Epilepsy (ILAE) 2017 seizure classification based on the most prominent clinical signs during VEEG. The putative epileptogenic zone was defined based on clinical history, seizure semiology, neuroimaging, and EEG., Results: Complete datasets were available in 126 patients in 312 seizures. Ictal central apnea (ICA) occurred exclusively in focal epilepsy (51/109 patients [47%] and 103/312 seizures [36.5%]) (P < .001). ICA was the only clinical manifestation in 16/103 (16.5%) seizures, and preceded EEG seizure onset by 8 ± 4.9 s, in 56/103 (54.3%) seizures. ICA ≥60 s was associated with severe hypoxemia (SpO 2 <75%). Focal onset impaired awareness (FOIA) motor onset with automatisms and FOA nonmotor onset semiologies were associated with ICA presence (P < .001), ICA duration (P = .002), and moderate/severe hypoxemia (P = .04). Temporal lobe epilepsy was highly associated with ICA in comparison to extratemporal epilepsy (P = .001) and frontal lobe epilepsy (P = .001). Isolated postictal central apnea was not seen; in 3/103 seizures (3%), ICA persisted into the postictal period., Significance: ICA is a frequent, self-limiting semiological feature of focal epilepsy, often starting before surface EEG onset, and may be the only clinical manifestation of focal seizures. However, prolonged ICA (≥60 s) is associated with severe hypoxemia and may be a potential SUDEP biomarker. ICA is more frequently seen in temporal than extratemporal seizures, and in typical temporal seizure semiologies. ICA rarely persists after seizure end. ICA agnosia is typical, and thus it may remain unrecognized without polygraphic measurements that include breathing parameters., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)