Ventilatory response to CO₂ in patients with epilepsy

Abstract

Summary 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 CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 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 (VE), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔVE/ΔETCO2) 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) CO2, and capillary oxygen saturation (SPO2). 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 ETCO2. Both the duration and magnitude of postictal tcCO2 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 CO2, and this group is more likely to have a prolonged increase in postictal CO2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study.

Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy

“…It is not unexpected that mechanisms of seizure‐induced death and SUDEP will be multifactorial, and different SUDEP mechanisms may exist for different epilepsy etiologies. Other mechanisms that may inhibit recovery from tonic phase apnea include spreading depolarization to the brain stem, impaired homeostatic breathing (ie, central apnea), and cardiovascular dysfunction 2,46–48 . Cardiac dysfunction appears to vary considerably in different mouse SUDEP models.…”

Disordered breathing in a mouse model of Dravet syndrome

“…For example, recent work in humans showed that apnea and arterial oxygen desaturation occurred when cortical seizure activity spread to the amygdala (Dlouhy et al, 2015) and presumably activated descending inhibitory projections to brainstem respiratory centers. However, SUDEP can also occur in epilepsy patients in the absence of an overt seizure or outside the peri-ictal period (Lhatoo and Shorvon, 1998) and some epilepsy patients exhibit breathing problems including a suppressed ventilatory response to CO 2 (Sainju et al, 2019), thus suggesting factors other than acute seizures disrupt respiratory control and predispose individuals to SUDEP. For example, it is possible that repeated bombardment of brainstem respiratory centers by frequent cortical seizure events alters cellular or neural network function, leading to progressive respiratory disruption and increased SUDEP propensity.…”

“…This possibility is supported by evidence that pharmacological augmentation of serotonergic signaling can prevent seizure-induced respiratory arrest in a mouse model of epilepsy and may improve seizure control in DS patients (Tupal and Faingold, 2019). However, some epilepsy patients show breathing abnormalities under baseline inter-ictal conditions including a reduced ventilatory response to CO 2 (i.e., chemoreflex) (Sainju et al, 2019), suggesting factors other than seizure activity compromise respiratory control. Based on this, we consider a yet unexplored possibility that epilepsy-associated mutations may directly affect brainstem respiratory centers to compromise breathing under inter-ictal conditions, and thus serve as a common substrate for both seizures and respiratory dysfunction.…”

Role of Adenosine in Epilepsy and Seizures

“…27,204 Indeed, epileptic seizures can induce significant hypoventilation. 205,206 However, apnea and O 2 desaturation are more common than previously realized after generalized partial or convulsant seizures, 26 and recent evidence supports a significant role of apnea and hypoventilation in SUDEP. 207 Respiration is controlled mainly by two neuronal groups located at the brainstem: (1) the parafacial respiratory group (pFRG) and (2) the pre-Bötzinger complex (inspiratory pacemaker population).…”