Assessment of Effect of Vagal Nerve Stimulator (VNS) on Electrocorticograms Recorded by Responsive Neurostimulator (RNS) in Patients With Drug Resistant Epilepsy

Drug resistant epilepsy, is defined by the International League Against Epilepsy (ILAE) as "the failure of adequate trials of two tolerated and appropriately chosen and used AED (Antiepileptic drug) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom." About a third of epilepsy cases are drug resistant and are considered for non-pharmacologic treatment. Surgical removal (resection) of the seizure focus is the treatment of choice in drug resistant epilepsy with focal onset. However, curative surgery is not always feasible, e.g. if it would lead to unacceptable deficits, or if there are seizure onset areas in both sides of the brain. In addition, depending on the circumstances, patients treated with surgery do not become seizure free in about 10-80% of cases, depending on presence or absence of a lesion and location of the seizure focus. Other surgical options include implantation of neuromodulatory devices, such as Vagus Nerve Stimulator (VNS) and Responsive Neurostimulator (RNS).

IIa. Vagus Nerve Stimulator (VNS) Brain surgery was the only surgical option for some patients in this drug-resistant patient population until 1997 when the VNS was approved by the FDA. VNS is approved for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over age 12 diagnosed with medically refractory partial onset seizures (FDA 1997). The vagus nerve and its centers (nuclei) in the brainstem have, in general, an inhibitory effect on organs. VNS therapy can suppress seizures by sending mild pulses of electrical energy to the vagus nerve in regular intervals. The default setting of stimulation are cycles of 30-seconds "on" and 5-minutes "off". These stimulation pulses are supplied by a thin, round battery-containing device which is placed under the skin on the left side of the chest, like a pacemaker, with wires connecting the generator to the vagus nerve on the left side of the neck. VNS is not likely to stop seizures (seizure freedom rate with VNS added range from 2-9%), but it provides a ~50% chance of cutting the seizure frequency in half (Ben-Menachem 1999, Scherrmann 2001,Morris 1999, Kuba 2009).

IIb. Responsive Neurostimulator (RNS) The RNS was FDA approved in 2013. The RNS System provides responsive cortical stimulation through an implanted programmable neurostimulator connected to depth and/or subdural cortical strip leads targeted to the seizure focus. The RNS device continually monitors brain activity (electrocorticography [ECoG]). It is programmed by the physician to detect seizure patterns and provide appropriate electrical stimulation within a few seconds of the seizure onset. RNS was approved by the FDA for use as an adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial (focal) onset seizures who have undergone diagnostic testing that localized to no more than two epileptogenic foci, are refractory to two or more antiepileptic medications, and currently have frequent and disabling seizures (FDA 2013). The generator of the device is implanted in the patient's skull and wires connect to the leads in or on the brain (see Figure 2). Depending on where in the brain it is implanted, RNS is associated with seizure free intervals of 6 months in 26-29% of patients and of 12 months in 14-15% of cases. The rate of seizure freedom is relatively low, compared to resections, but the chance of a marked (~70%) seizure reduction is high (Geller 2017, Jobst 2017).

IIc. No studies to date have investigated the effect of VNS stimulation on the more recently FDA approved RNS. The initial RNS feasibility study listed VNS as an exclusion criteria as it was not clear how the two devices would interact. However, before RNS was available, patients with a seizure focus or several foci that could not be surgically removed, were implanted with VNS. Therefore, in the current post-approval phase of RNS treatment, many patients already have a VNS which has not brought the hoped for seizure relief. Across centers it has been standard practice to implant RNS in patients who have a VNS, and to keep the VNS turned on, if the patient reported clinical benefit. Even though there are no guidelines, the rationale for not removing a VNS before RNS implantation appears to be as follows:

1. The devices are not linked or physically close together and are not enabled to communicate with each other.
2. Current delivered by either device penetrates only targeted tissue in the immediate vicinity of the electrodes and is not able to reach the other device.
3. Each device provides a different mechanism of action and is a separate, independent modality to influence seizures, similar to medications and VNS being different therapy modalities that act in a complementary fashion.
4. To date, no case of a concerning interaction has been described.