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Interest in neurostimulation to treat epilepsy has rekindled over the past decade, with vagus nerve stimulation (VNS) now an accepted part of the algorithm for care of patients with medically refractory epilepsy.1 More than 15 000 VNS devices have been surgically implanted in patients around the world. The reported improvements in seizure control are modest and the mechanism by which VNS may exert its effects is unclear, however, the benefits are presumed to be directly related somehow to the electrical stimulation applied to the nerve. A small number of relevant experimental studies have shown antiepileptic effects related to VNS, although the effects may be non-specific, for example, in rats heating of the tail is equally effective as stimulation of the vagus nerve in stopping seizures and decreasing interictal spikes.2 In our own work with thalamic deep brain stimulation for epilepsy we found that the observed benefits in patients’ seizure control bore no relation to whether the stimulators were actually turned on or not.3 Because patients can sense active VNS in the form of laryngeal side effects, no similar sham stimulation placebo has been possible with VNS.
If stimulation of the vagus nerve is actually a necessary part of VNS for epilepsy, depletion of the stimulator battery would be expected to result in an increase in seizures. Indeed, status epilepticus was recently reported to have occurred in one patient after stopping VNS for an elective brain MRI scan.4
No study has been formally published describing the effects of battery depletion in a large group of patients treated with VNS for epilepsy, however, the data from just such a study have been published informally—in the Cyberonics VNS Physician’s Manual.5 It is of interest to examine these data. Over the course of follow up of patients in the E03 VNS trial,6 a total of 72 battery depletions in 68 patients occurred. Seizure frequency after battery depletion was monitored for one to four weeks after stimulation was stopped, with the outcome results divided into three groups: patients having a greater than 25% increase in seizures, patients unchanged with a less than 25% increase or decrease in seizures, and patients with a greater than 25% decrease in seizures. Forty two of 72 cases (58%) were in the last group—that is, the large majority of patients improved after battery depletion. Nineteen of 72 cases (26%) were unchanged and 11 of 72 (15%) worsened.
A χ2 analysis of the results comparing patients with a greater than 25% seizure reduction with patients with a greater than 25% increase in seizures after battery depletion shows a highly significant benefit to battery failure (p<0.0001; χ2 = 18.14, two tailed test). This is the most significant finding of any statistical analysis performed in all of the VNS studies used to support licensing of the device as a treatment for epilepsy.5–7 As the research hypothesis here specifies the direction in which a change will occur—that is, “there will be an increase in seizures when VNS stops,” the alternative hypothesis is actually one tailed, which makes the significance of the findings even greater (p<0.00005). This means that the probability that the observed findings of improvement with battery depletion in most patients could have occurred by chance is less than 1 in 20 000. It is possible that the findings do represent such a chance occurrence. It is equally possible, or perhaps more probable, that any sort of non-specific change in patients with epilepsy might provide a perturbation sufficient to effect improvements in seizure control, at least in the short term. Either way, benefits in seizure control with VNS in humans seem to have little specific to do with active stimulation of the vagus nerve.