Responsive neurostimulation in epilepsy

Abstract

Various neurostimulation modalities have emerged in the field of epilepsy. Despite the fact that delivery of an electrical current to the hyperexcitable epileptic brain might, at first, seem contradictory, neurostimulation has become an established therapeutic option with a promising efficacy and adverse effects profile. In “responsive” neurostimulation the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or even prevent an upcoming seizure. The design of technology required for responsive stimulation is more challenging compared with devices for open-loop neurostimulation. The achievement of therapeutic success is dependent on adequate sensing and stimulation algorithms and a fast coupling between both. The benefits of delivering current only at the time of an approaching seizure merit further investigation. Current experience with responsive neurostimulation in epilepsy is still limited, but seems promising.

KEYWORDS:

• epilepsy
• neurostimulation
• closed-loop
• responsive
• deep brain stimulation (DBS)
• vagus nerve stimulation (VNS)
• responsive neurostimulation system (RNS)
• optogenetics
• drug delivery system

Key issues

• Various forms of neurostimulation are becoming available for the treatment of refractory epilepsy.

• Closed-loop or responsive neurostimulation is a novel approach in the treatment of epilepsy, delivering current upon detection of seizure activity in an attempt to abort or prevent seizure activity.

• Two devices for responsive neurostimulation are currently commercially available and FDA approved for the treatment of refractory epilepsy: the responsive neurostimulation (RNS) System and vagus nerve stimulation with automated cardiac-based seizure detection (AspireSR).

• The responsive neurostimulation (RNS) system was cleared by the FDA in 2013 for add-on treatment of partial onset seizures in adults with medically refractory epilepsy. This is a cranially implantable neurostimulator connected to one or two depth or cortical strip electrodes implanted at the ictal onset zone.

• Vagus nerve stimulation has been used widely since its FDA clearance in 1997.

  • Manual activation of the pulse generator with a handheld magnet allows on-demand stimulation when an aura or seizure occurs, but due to reasons such as cognitive impairment, sleep, lack of an aura or the disabling effects of the seizure itself, this may be hard to achieve in practice.

  • A novel type of VNS device, the AspireSR, provides closed-loop VNS stimulation based on typical cardiac changes that often occur as a result of ictal activity, on top of the conventional open-loop settings. This device was FDA cleared in May 2015 and is currently under investigation for its add-on benefit in adult refractory epilepsy patients.

• Optogenetics is a novel highly-advanced technique that allows super selective activation or inhibition of neuronal subsets. Investigators are currently exploring this technique for the treatment of refractory epilepsy and preclinical results demonstrate the feasibility of in vivo closed-loop interruption of seizures.

• A rational approach for seizure control in epilepsy may be to combine neurostimulation and pharmacological intervention to achieve superior efficacy. This can also be developed in a closed-loop set-up.

• The available technology is rapidly evolving and drives the development of novel neurostimulation techniques. However a number of challenges, such as the optimal stimulation parameters and targets remain unsolved. Further fundamental research into the mechanism of action of the different neurostimulation treatments is encouraged, taking into account the dynamics and kinetics of electrical fields applied to the brain and how they affect physiological and pathological network activity, as well as various states of cortical excitability.

• Guidelines for the identification of optimal patient candidates for a particular type of neurostimulation treatment will become indispensable in daily practice.

Acknowledgements

S Carrette is supported by an aspirant grant from “Fonds voor Wetenschappelijk Onderzoek” (FWO) Flanders. She has received a travel grant from Magventure to participate in a TMS course. P Boon is supported by grants from FWO, grants from the “Bijzonder Onderzoeksfonds (BOF)” and by the Clinical Epilepsy Grant from Ghent University Hospital. He has received personal compensation for consulting from LivaNova, Medtronic and UCB. He also received research support (including for clinical trials) through his institution from Cerbomed, LivaNova, Medtronic, Neurosigma and UCB. M Sprengers is supported by an aspirant grant from FWO Flanders. R Raedt is supported by a grant from the BOF from Ghent University. He has received research support (including for clinical trials) through his institution from Cerbomed, LivaNova and UCB. K Vonck is supported by a grant from the BOF from Ghent University. She has received personal compensation for consulting from LivaNova, Medtronic, Neurosigma and UCB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Financial & competing interests disclosure

S.C. and M.S. are both supported by an aspirant grant from “Fonds voor Wetenschappelijk Onderzoek” (FWO) Flanders. R.R. ;and K.V. are supported by a grant from the “Bijzonder Onderzoeksfonds (BOF)” from Ghent University. P.B. is supported by grants from FWO, grants from BOF and by the Clinical Epilepsy Grant from Ghent University Hospital. S.C. has received a travel grant from Magventure to participate in a TMS course. K.V. has received personal compensation for consulting for LivaNova. P.B. has received personal compensation for consulting from LivaNova, Medtronic and UCB. K.V. and P.B. have received research support (including for clinical trials) through their institution from Cerbomed, LivaNova, Medtronic, Neurosigma and UCB. R.R. has received research support (including for clinical trials) through his institution from Cerbomed, LivaNova and UCB.

ORCID

Sofie Carrette http://orcid.org/0000-0002-6570-3124