Abstracts

Rationale: Peri-ictal respiratory depression has been proposed to be a biomarker for risk of sudden unexpected death in epilepsy patients (SUDEP). Under normal conditions, ventilation is determined primarily by central CO2 chemoreceptors in the brainstem, which include serotonergic neurons in the raphe nuclei, and non chemoreflex drives including cortical drive. We hypothesize that in the post-ictal state CO2 chemoreception is blunted, contributing to impai`red arousal and ventilation in response to hypercapnia. In patients with low baseline CO2 chemosensitivity, post-ictal hypoventilation may be more severe, and this could predispose these patients to SUDEP. Baseline CO2 chemosensitivity has not previously been studied in patients with epilepsy. Here we studied the ventilatory response to hypercapnia of patients with epilepsy compared to that of patients without epilepsy. Methods: Adult (>18 years) subjects without cardio-pulmonary disease admitted to an epilepsy monitoring unit (EMU) for seizure localization or spell characterization were enrolled. The hypercapnic ventilatory response (HCVR) during wakefulness was measured during an inter-ictal period using a hyperoxic modified rebreathing technique. The intensity and unpleasantness of CO2 inhalation was assessed using the Multidimensional Dyspnea Profile. Overall respiratory drive was evaluated prior to CO2 inhalation by measuring the inspiratory occlusion pressure (P0.1).Least squares regression lines were fitted to minute ventilation (VE), respiratory rate (RR) and tidal volume (VT) (y axis) vs end tidal CO2 (ETCO2, x axis). Slopes of the lines were called HCVR VE, RR & VT respectively. Student’s t test and Mann Whitney test were used to test for differences in parameter slopes and in P0.1 between groups. Univariate analyses were performed using Spearman’s correlation test with HCVR VE slope as the dependent variable.  Results: Of 66 subjects enrolled, 65 (48 with epilepsy) completed the study. The test was safe and well tolerated with no serious adverse events. The HCVR VE slope ranged from -1.36 to 6.24 L/min/mm Hg. Median HCVR VE slope was not different between the two groups (1.67 epilepsy vs 1.56 without epilepsy, p=0.45). HCVR VE slope was positively correlated with the unpleasantness and intensity of dyspnea (rho= 0.36 & 0.43, p= 0.016 & 0.003), HCVR RR slope (rho= 0.66, p= 2 (rho= -0.42, p=0.003). Correlations with other clinical variables were not significant (table 1).One subject with drug-resistant temporal lobe epilepsy and a markedly blunted (0.19 L/min/mm Hg) HCVR VE slope was unexpectedly found dead in the prone position in his bed, nearly a year after being studied (fig 1). Conclusions: Individuals with epilepsy exhibit considerable variation in CO2 responsiveness that does not differ from that of those without epilepsy. A subset of individuals is highly insensitive to CO2.  This low CO2 chemosensitivity may be a genetically determined risk factor for SUDEP and warrants further study. Funding: U01 NS090414 Richerson, G (Project PI) Lhatoo, S and Noebels, J (Co-Directors) Center for SUDEP Research: Respiratory and Arousal Mechanisms