Neuromodulation for Drug-Refractory Epilepsy and Chronic Heart Failure: Targets, Delivery, Composition and Titration

Abstract

Background: Vagus nerve stimulation (VNS) is used currently in the management of drug-refractory epilepsy (DRE), and is in development for treating chronic heart failure (HF). HF is accompanied by autonomic nervous system (ANS) dysfunction, consisting of sustained sympathetic hyper-activation and withdrawal of parasympathetic tone, and associated with progressive worsening of cardiovascular (CV) function and increased morbidity and mortality. We sought to compare how VNS is utilized for DRE and may potentially be employed for HF. Methods: A search was conducted in PubMed for all published articles using the search terms “vagus” OR “vagal” OR “VNS” AND “epilepsy”, and a separate search used similar search terms AND “heart failure”. Further filtering yielded the articles available as free full text, and clinical trial, prospective study, and retrospective study publications. The final selection of clinical trial/study publications in epilepsy or HF was based upon at least 3 months of follow-up and exclusion of pediatric studies. Additional information was obtained subsequently from references within these publications, and technical manuals available in the public domain. Results: For DRE, VNS is administered via the left cervical vagus nerve (CVN), and directed toward the central nervous system (CNS). No known biomarkers exist currently for real-time VNS adjustment. VNS is titrated empirically, using large and infrequent adjustments of VNS intensity and based upon achieving long term reduction in seizure frequency (RSF) and/or reaching the maximum tolerated VNS intensity. A significantly greater mean RSF has been observed after 3 months of VNS delivery using pulse frequency 30 Hz and duty cycle 9% (30 seconds on, 5 minutes off) when compared to using 1 Hz and duty cycle 14% (30 seconds on, 3 minutes off). A further reduction of mean RSF has been observed after 12 months by increasing the pulse frequency at 3 months from 1 to 30 Hz. For HF, VNS has been administered via the left or right CVN, targeting both the CNS and/or peripheral hierarchical autonomic reflex arcs that control cardiovascular function. Real-time changes in heart rate dynamics (HR and HR variability) have served as a biomarker of ANS engagement (ANSE) for titration. Titration to ANSE has been completed in 2.5 (median; range 1.6-3.6) months using 10 Hz and duty cycle 23% (18 seconds on, 1 minute off), using smaller and more frequent adjustments of VNS intensity, and has been associated with significant improvements after 6 months in HR, HR variability, CV function, and HF symptoms. Use of 1 Hz may have less clinical efficacy than occurs with a higher pulse frequency, however, intolerable side effects have occurred before ANSE using 20 Hz. Conclusions: Neuromodulation for the treatment of epilepsy and HF is not a one-size-fits-all therapy. The magnitude of long term reduction of seizure frequency in DRE, and improvements in function and symptoms in HF, may have a potential dose-dependent relationship to the intensity of VNS delivery. However, VNS for these disorders differs in neurologic targets, the technology platforms and paradigms used for titration, and the time and the frequency needed for up-titrating VNS. *Corresponding author: Inder S Anand, MD, FRCP, DPhil (Oxon), Division of Cardiology, VA Medical Center, University of Minnesota, Cardiology 111-C, One Veterans Drive, Minneapolis, MN 55417, USA, Tel: +1-(612)-467-3663, Fax: +1-(612)970-5899 OrIgInAL ArtICLe