Medically refractory epilepsy is a morbid condition, and many patients are poor candidates for surgical resection because of multifocal seizure origin or eloquence near epileptic foci. Vagus nerve stimulation (VNS) was approved in 1997 by the US Food and Drug Administration as an adjunctive treatment of intractable epilepsy for individuals aged 12 years and more with partial epilepsy. Controversy persists regarding the efficacy of VNS for epilepsy and about which patient populations respond best to therapy. In this article, the authors retrospectively studied a patient outcome registry and report the largest, to their knowledge, analysis of VNS outcomes in epilepsy.
Nearly 1% of the population has epilepsy, and approximately 30% of these patients are refractory to medical therapy, resulting in significant morbidity. Although resection of an epileptic focus can be curative in selected patients with intractable epilepsy, others are poor surgical candidates because of multifocal seizure origin or eloquence near epileptic foci. In 1997, the US Food and Drug Administration (FDA) approved left-sided vagus nerve stimulation (VNS) as an adjunctive treatment of medically refractory partial epilepsy, and stimulators have now been implanted in more than 60,000 patients. The neurobiological mechanisms of VNS in epilepsy remain poorly understood, although data from humans and animals have suggested that vagal stimulation may desynchronize activity and decrease abnormal spiking patterns on electroencephalography. Two randomized controlled trials have evaluated the efficacy of VNS in epilepsy, finding a reduction in seizure frequency of between 23% and 57% after 3 months of therapy. However, controversy regarding the utility of VNS in epilepsy persists because of inconsistent results, small sample sizes, and short duration of follow-up in many clinical studies. In particular, although VNS was approved in the United States only for patients aged 12 years and more with partial seizures, its benefit in children and patients with generalized epilepsy syndromes remains unclear. Furthermore, it is not known whether preoperative duration of epilepsy or seizure semiology predicts varied clinical response to VNS therapy.
In this article, we provide a retrospective analysis of seizure outcomes after VNS for pharmacologically resistant epilepsy from a large patient registry. Clinical response to VNS was evaluated at various time points after device implantation, and patient age, duration of epilepsy, predominant seizure type, and the presence of epileptic encephalopathy were investigated as potential prognostic indicators of a favorable outcome.
Materials and methods
Patient Outcome Registry Data Collection
All data were obtained from the VNS therapy patient outcome registry maintained by the manufacturer of the device, Cyberonics, Inc (Houston, TX, USA). This database was established in 1999, after FDA approval of VNS for epilepsy in 1997, to systematically monitor patient outcomes. Data were voluntarily provided by 1285 prescribing physicians from 978 centers (911 in the United States and Canada and 67 international) at patients’ preoperative baseline and at various intervals during therapy. Previous investigators have authenticated the integrity of the systems for collecting and processing registry data using an independent auditing agency. The database was queried in March 2011 for all seizure outcomes reported at 3, 6, 12, and 24 months after VNS device implantation compared with preoperative baseline. Overall decrease in seizure frequency and response rates to VNS therapy were measured at each follow-up, with favorable clinical response defined as a decrease in seizure frequency of 50% or more versus baseline. Outcomes were stratified by (1) age (<6, 6–18, or >18 years), (2) preoperative duration of epilepsy (<5, 5–10, or >10 years), (3) predominant preoperative seizure type (aura-only, simple-partial, complex-partial, primary generalized tonic-clonic, secondarily generalized tonic-clonic, atonic, absence, other, or multiple predominant seizure types), and (4) the presence or absence of Lennox-Gastaut syndrome or other epileptic encephalopathy.
Statistical Analysis
Between-group comparisons for seizure outcomes after 1 year of VNS therapy were performed across subgroups of patients using Pearson chi-square test. Variables found to be significant on chi-square test were then further interrogated using binary logistic regression to elucidate possible predictors of seizure outcome. Odds ratios (ORs) were calculated with a 95% confidence interval (CI). The level of significance was set at 0.05 for all analyses. Statistical analysis was performed using SPSS version 17 (IBM Corp, Armonk, NY, USA).
Results
Seizure outcomes were identified and analyzed across 4483, 3040, 2698, and 1104 patients at 3, 6, 12, and 24 months after VNS therapy, respectively. Outcomes for all patients are summarized in Table 1 . Three months after initiation of VNS therapy, patients experienced a median decrease of 46% in seizure frequency compared with baseline, and 1990 of 4483 patients (44%) responded favorably to therapy by achieving a decrease of 50% or more in seizures (see Table 1 ). At 1- and 2-year follow-up, individuals experienced 56% and 62% fewer seizures (median), respectively, with 53% and 56% of patients achieving notable benefit from therapy, respectively (see Table 1 ). These results suggest that the clinical benefit of VNS for epilepsy progressively increases with treatment duration, with slightly greater than half of all patients responding to VNS after 1 year of therapy.
| Duration of Implant (mo) | N | Median % Decrease in Seizure Frequency (Interquartile Range) | Number of Responders (%) a |
|---|---|---|---|
| 3 | 4483 | 46 (77) | 1990 (44) |
| 6 | 3040 | 50 (82) | 1498 (49) |
| 12 | 2698 | 56 (76) | 1432 (53) |
| 24 | 1104 | 62 (72) | 619 (56) |
a Defined by a decrease of 50% or more in seizure frequency versus baseline.
We next analyzed whether or not age predicted response to VNS, as summarized in Fig. 1 . After 1 year of therapy, children younger than 6 years and of 6 to 18 years experienced 60% fewer seizures (median) compared with baseline, whereas adults (>18 years old) achieved a decrease of 53% in seizure frequency (see Fig. 1 A). Rates of clinical response (≥seizure reduction) differed significantly across the 3 age groups (χ 2 = 8.1, P = .018, 1-year follow-up). Specifically, 56% to 57% of children but only 51% of adults responded favorably to VNS at 1 year of treatment (see Fig. 1 B). Overall, age of 18 years or less significantly predicted a higher likelihood of favorable response with an OR of 1.27 (95% CI, 1.07–1.50; P = .006). These findings suggest that despite the initial FDA approval of VNS for adults and adolescents, children may receive the greatest clinical benefit from therapy.
We next investigated the duration of epilepsy before VNS device implantation as a potential predictor of clinical response to VNS. Outcomes were stratified across individuals with less than 5, 5 to 10, and more than 10 years of preoperative seizures ( Fig. 2 ). We noted that individuals with a shorter duration of epilepsy tended to respond more favorably to VNS, experiencing a larger decrease in seizures after 1 to 2 years of therapy compared with those with longer seizure histories (see Fig. 2 A). Also, responder rates at 1 year (see Fig. 2 B) differed significantly by epilepsy duration (χ 2 = 6.7, P = .035). Overall, a seizure history of 10 years or less predicted a somewhat higher likelihood of favorable clinical response (56%) than a history of more than 10 years of epilepsy (52%) (OR, 1.19; 95% CI, 1.00–1.41). This difference approached, but did not reach, statistical significance ( P = .053). Thus, although clinical effects of VNS are relatively similar between individuals with a shorter or longer epilepsy history, additional benefit may be gained from early intervention.
Next, given the initial FDA approval of VNS for patients with partial epilepsy only, we examined seizure outcomes after therapy stratified by predominant preoperative seizure type. As shown in Fig. 3 , rates of clinical response differed significantly across various seizure types (χ 2 = 40.0, P <.001, 1-year follow-up). Individuals with predominantly simple-partial seizures, including those with mostly auras, achieved the greatest clinical benefit (see Fig. 3 ). Overall, these patients were significantly more likely to become responders by 1 year than those with other seizure types (OR, 1.37; 95% CI, 1.04–1.81, P = .025). In contrast, the lowest rates of clinical response were seen among patients with either primary generalized or secondarily generalized tonic-clonic seizures (see Fig. 3 ). Together, generalized tonic-clonic seizures were negatively predictive of clinical response to VNS at 1 year with an OR of 0.77 (95% CI, 0.63–0.93; P = .008). Patients with other generalized seizure types, including atonic drop attacks, responded to therapy in more than 57% of cases by 1 year (see Fig. 3 ). These results suggest that patients with predominantly partial seizures, particularly simple-partial seizures and auras, respond most favorably to VNS, whereas those with generalized tonic-clonic seizures respond least favorably. Nevertheless, 46% to 49% of patients with predominantly generalized tonic-clonic seizures still achieve a decrease of 50% or more in seizures after 1 year of VNS.
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