BACKGROUND: Neuromodulation-based treatments have become increasingly important in epilepsy treatment. Most patients with epilepsy treated with neuromodulation do not achieve complete seizure freedom, and, therefore, previous studies of vagus nerve stimulation (VNS) therapy have focused instead on reduction of seizure frequency as a measure of treatment response.
OBJECTIVE: To elucidate rates and predictors of seizure freedom with VNS.
METHODS: We examined 5554 patients from the VNS therapy Patient Outcome Registry, and also performed a systematic review of the literature including 2869 patients across 78 studies.
RESULTS: Registry data revealed a progressive increase over time in seizure freedom after VNS therapy. Overall, 49% of patients responded to VNS therapy 0 to 4 months after implantation (≥50% reduction seizure frequency), with 5.1% of patients becoming seizure-free, while 63% of patients were responders at 24 to 48 months, with 8.2% achieving seizure freedom. On multivariate analysis, seizure freedom was predicted by age of epilepsy onset >12 years (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.38-2.58), and predominantly generalized seizure type (OR, 1.36; 95% CI, 1.01-1.82), while overall response to VNS was predicted by nonlesional epilepsy (OR, 1.38; 95% CI, 1.06-1.81). Systematic literature review results were consistent with the registry analysis: At 0 to 4 months, 40.0% of patients had responded to VNS, with 2.6% becoming seizure-free, while at last follow-up, 60.1% of individuals were responders, with 8.0% achieving seizure freedom.
CONCLUSION: Response and seizure freedom rates increase over time with VNS therapy, although complete seizure freedom is achieved in a small percentage of patients.
Approximately 1% of the population has epilepsy, and seizures are refractory to antiepileptic drugs (AEDs) in approximately 30% of these individuals.1 Many patients with drug-resistant temporal or extratemporal lobe epilepsy can become seizure-free with surgical resection or ablation, but other patients with epilepsy are not candidates for resection given the presence of primary generalized seizures, nonlocalizable or multifocal seizure onset, or seizure onset from an eloquent brain region.2-5 Treatments based on neuromodulation, such as vagus nerve stimulation (VNS), have, therefore, become an increasingly important part of multimodal epilepsy treatment. VNS therapy was approved by the US Food and Drug Administration in 1997 as an adjunctive therapy for reducing seizures in patients with medically refractory epilepsy, and more than 80 000 patients have received treatment with VNS.6-8 The efficacy of VNS therapy has been evaluated by randomized controlled trials,9,10 retrospective case series,11,12 meta-analysis,13 and registry-based studies.14 These studies show that about 50% to 60% of patients achieve ≥50% reduction in seizure frequency after 2 years of treatment, and response rates increase over time, likely related to neuromodulatory effects with ongoing stimulation.13 Complete seizure freedom, however, is less common with VNS therapy and other neuromodulation treatment modalities.
Given that a minority of patients achieve seizure freedom with VNS, rates and predictors of seizure freedom have not been well studied and remain poorly understood. The vast majority of studies that evaluate VNS therapy focus on rate of response over time (defined as ≥50% reduction in seizures) and predictors of response; there has never been a large-scale evaluation of seizure freedom as a primary end point in patients treated with VNS. However, seizure freedom is the single best predictor of quality of life in patients with epilepsy,15,16 and therefore a better understanding of seizure freedom rates and predictors in patients treated with VNS therapy is critically needed. Importantly, this information may lead to improved patient selection and counseling in the treatment of drug-resistant epilepsy.
Here, we provide the first large-scale study of VNS therapy with a primary goal of defining seizure freedom rates and predictors, and comparing predictors of seizure freedom with those of overall response to treatment. Our study includes univariate and multivariate analyses of registry data including 5554 patients treated with VNS, and also includes a systematic review of the literature including 2869 patients across 78 studies, to help confirm registry-based results.