Rationale:
An attenuated interictal ventilatory response to CO2 a.k.a. hypercapnic ventilatory response (HCVR), a measure of central CO2 chemoreceptor (CCR) function, correlates with the severity of respiratory dysfunction after generalized convulsive seizures, therefore it may be a surrogate for SUDEP risk. Serotonergic and noradrenergic neurons in the brainstem may both contribute to the HCVR. VNS is frequently used to treat drug resistant epilepsy. Given widespread connections of the vagus nerve in the brainstem, including key areas related to CCRs and respiratory control e.g. nucleus tractus solitarius, nucleus ambiguus, locus coeruleus, parabrachial nuclei, etc, we hypothesize that chronic electrical stimulation would induce changes in CCRs. Therefore, using a case-control design we studied the effect of VNS on the HCVR.
Method:
This is a retrospective case control study matched (1:1) for age (+/- 5 years) and gender. Eligible subjects were selected from a cohort of epilepsy patients aged > 18 years who underwent HCVR testing using a modified hyperoxic CO2 rebreathing technique at the University of Iowa Hospitals and Clinics from June 2015 to April 2019. The HCVR slope (i.e. change in minute ventilation (VE) with respect to change in end tidal (ET) CO2 [∆ VE/ ∆ ETCO2]) during the test was calculated for each subject.
Cases had a functional VNS device for > 6 months, while controls did not have a VNS. Variables analyzed included age, gender, presence of VNS, VNS stimulation parameters, duration of epilepsy and VNS implant, BMI, active SSRI/SNRI use, number of AEDs at the time of HCVR testing, number of lifetime AEDs, history of OSA, and history of depression.
Spearman’s correlation was calculated to determine if there was any relationship between HCVR slope and duration of VNS. Univariate and multivariate linear models were fit to assess the unadjusted and adjusted differences in HCVR slope between cases and controls with alpha set at 0.05. Comparisons between different predictor sets were made using the Akaike information criterion (AIC), where a smaller value indicates a more appropriate model fit. Estimates and confidence intervals of the mean differences in HCVR slope are provided for each predictor.
Results:
Of a total of 86 subjects, 26 (30.23%) were women. The HCVR slope was significantly lower (mean estimate of -0.5147 [95% CI of -1.0086 to -0.0208] L/min/mm Hg, p = 0.0411) in the cases compared to the controls; cases had longer duration of epilepsy (mean 25.31 vs 13.9 yrs) and higher number of lifetime AEDs (mean 7.7 vs 3.3) compared to controls. In the multivariate analysis, the model with the smallest AIC (261.1) indicated that having a VNS and lower BMI were the best predictors of a smaller HCVR slope.
Conclusion:
These results suggest that chronic electrical stimulation of the vagus nerve by VNS may be associated with relatively attenuated CCRs, although we cannot determine a causal relationship, or if there is an association with some other variable such as severity of epilepsy. A larger prospective study may help to confirm our findings and to establish a causal relationship.
Funding:
:NIH, NINDS: Center for SUDEP Research: Respiratory and Arousal Mechanisms- U01 NS090414
The University of Iowa Clinical and Translational Science Award - NIH-UL1TR002537
FIGURES
Figure 1