Abstract
Recent studies suggest that epilepsy that is unresponsive to medical therapy is likely to be refractory from the onset. Identifying such patients early and treating them with nonpharmacologic therapies may improve their outcome. We hypothesized that patients who had adjunctive therapy with vagus nerve stimulation (VNS) earlier in the course of their epilepsy would have a better response compared with patients who had VNS therapy instituted later in the course. Patients in the VNS patient outcome registry who were more than 5 years post onset of their seizure disorder at implantation and had seizure frequency data available at both baseline and 3 months comprised the control group (n = 2785). These data were obtained retrospectively. Patients who were implanted between August 15, 2000 and July 31, 2001 who had epilepsy for 5 years or less at implantation or who had tried four or fewer standard antiepileptic drugs (AEDs) before implantation, and who were evaluated at baseline and at 3-month intervals for seizure frequency and quality of life, comprised the early adjunctive registry (EAR group; n = 120). This group was identified prospectively by participating physicians at multiple centers. The data describe patient demographics, medical history, seizure frequency, and physician-graded quality of life measures. The two populations were demographically similar except for statistically significant differences in age, duration of epilepsy, institutionalized patients, and seizure type (partial and generalized). Although the median reduction in seizure frequency for all patients at 3 months was similar between groups (48.2% control versus 50.0% EAR), 15.0% of the patients in the EAR group reported no seizures at 3 months compared with 4.4% of those in the control group (p < 0.001). In addition, significantly more patients in the EAR group (20% versus 8%; p < 0.001) reported no seizures with alteration or loss of consciousness, and 32% of EAR patients reported no complex partial seizures compared with 17% in the control group (p = 0.002). Improvements in all areas of quality of life were reported by both populations, but more patients in the EAR group were reported as “much better/better” for postictal state (p = 0.030) and seizure clustering (p = 0.002). Typically, 5% of patients report having no seizures after 3 months of VNS therapy. The proportion increased threefold, from 5% to 15%, for patients who received VNS therapy earlier in the treatment process. Patients reported even higher rates of no seizures when simple partial seizures were excluded from the analysis or when only complex partial seizures were considered. Although these results are preliminary, they offer promise of success in achieving seizure control among patients with refractory seizures who have been diagnosed with epilepsy for less than 5 years or who have tried four or fewer AEDs. We suggest future prospective studies evaluating VNS therapy versus best medical therapy after the first two to three AEDs have failed, which typically occurs within 2 years of seizure onset.
Although most patients with epilepsy achieve seizure control with minimal side effects with one antiepileptic drug (AED), more than 30% of patients do not receive adequate control with drug therapy, including treatment regimens with combinations of two or more AEDs. A recent study showed that, of 525 adult epilepsy patients, only 14% of patients who did not respond to treatment with the first AED became seizure-free with monotherapy using a second or third drug, and only 3% became seizure-free while receiving a combination of two drugs.1 Results such as these suggest that a lack of response to initial AED therapy may be an indication of refractory epilepsy.
Other recent studies indicate that a second possible predictive factor for refractory epilepsy is the number of pretreatment seizures patients experience. A strong correlation exists between the number of seizures before AED therapy and their eventual remission on treatment, suggesting that AED-resistant epilepsy may be refractory from the onset.1,2⇓ On the basis of this hypothesis, many specialists are recommending evaluation of patients for nonpharmacologic treatment options earlier in their treatment course, i.e., after two first-line AEDs fail to control seizures.1,3-5⇓⇓⇓ Such options include resective surgery, the ketogenic diet, and vagus nerve stimulation (VNS) therapy. Identifying patients with refractory epilepsy early during treatment and offering them potentially effective nonpharmacologic treatments may greatly benefit them by improving outcome and curtailing the potentially irreversible psychosocial consequences of continuing seizures.1,3⇓
Patients treated with VNS therapy in a multicenter, double-blind, randomized study had an average duration of epilepsy of 23 years, high seizure frequencies, and failed treatment with approximately seven AEDs.6 Those patients randomized to receive high stimulation (n = 103) experienced a mean seizure frequency reduction of 27.9% compared with baseline. Patients who received low stimulation (n = 95) experienced a mean reduction of 15.2%. This prospective analysis focuses on earlier treatment with VNS than has typically been the case, to determine whether earlier VNS treatment further improves efficacy, i.e., patients within 5 years after epilepsy onset or who have tried four or fewer AEDs.
Methods.
Data used for the control group in this analysis were taken retrospectively from the Cyberonics, Inc. (Houston, TX) VNS patient outcome registry. The registry was established in 1998 to monitor several aspects of VNS therapy patient outcomes since the treatment device received approval by the FDA. A detailed description of the registry is provided in another article in this supplement.7
The constant cohort used for the control group consisted of those VNS registry patients who were more than 5 years postonset of their epilepsy diagnosis at implantation and had seizure frequency and quality-of-life data available at both baseline and 3 months (n = 2785). Data for the early adjunctive registry (EAR) group were collected prospectively from multiple centers by participating physicians who treated patients implanted with the pulse generator between August 15, 2000 and July 31, 2001. Patients had been diagnosed with epilepsy for 5 years or less or had tried four or fewer AEDs before implantation (n = 120). This analysis includes only those patients with seizure frequency and quality-of-life data collected at baseline and 3 months. Patient demographics, medical history, seizure frequency, and physician-graded quality of life were considered in the analysis of the two groups.
In line with the standard medical practice for treating patients with VNS therapy, investigators adjusted the stimulation parameters for each patient according to the clinical response. AEDs were not changed, if possible, for the first 3 months of VNS treatment.
Results.
Medical history and demographics.
Based on the Fisher’s exact test, patients in the control group compared with patients in the EAR group were similar in terms of medical history except for a significantly higher percentage of those in the control group being evaluated for epilepsy surgery (p < 0.001), receiving a previous callosotomy for epilepsy (p < 0.006), receiving a previous lobectomy for epilepsy (p < 0.011), experiencing behavioral problems (p < 0.015), and who were mentally retarded (p = 0.003) compared with those patients in the EAR group (table 1). The demographic characteristics of the two groups are shown in table 2. Patients in the control group were older in terms of mean age (p < 0.001) and median age (p < 0.001), and had a significantly longer mean duration of epilepsy (p < 0.001) compared with the EAR group. The control group also was composed of more institutionalized patients (p = 0.002) and more patients experiencing partial seizures (p = 0.006). Significantly more patients in the EAR group experienced generalized seizures (p = 0.008).
Table 1 Medical history*
Table 2 Patient demographics
Seizure frequency.
Before implantation, the median number of seizures per day was 0.9 (range 0–1071.3) for the control group and 1.1 (range 0–108.2) for the EAR group (NS). The median reduction in seizure frequency for all patients at 3 months was similar between groups, with 48.2% in the control versus 50.0% in the EAR group. No significant differences were found in the median percent change in seizure frequency for all seizures combined or for any grouping of seizure type analyzed (table 3). However, 15% of the patients in the EAR group reported no seizures at 3 months compared with 4.4% of those in the control group (p < 0.001) (figure 1). In addition, 20% of patients in the EAR group reported experiencing no seizures with alteration or loss of consciousness (seizures other than simple partial) at 3 months compared with 8% in the control group (p < 0.001) (figure 2A). The percentage of patients experiencing any increase in seizure frequency for seizures excluding simple partial were similar (14.7% in the control versus 20.0% in the EAR group), as was the percentage of patients experiencing a greater than 25% increase in seizure frequency (10.5% in the control versus 13.3% in the EAR group). Moreover, of EAR patients reporting complex partial seizures at baseline (n = 71), 32% reported having no complex partial seizures at 3 months compared with 17% in the control group (p = 0.002) (figure 2B). The percentage of patients experiencing complex partial seizures who showed any increase in seizure frequency was similar, with 15.0% in the control versus 16.9% in the EAR group. The percentage of patients experiencing more than a 25% increase in seizure frequency for complex partial seizures also was similar (11.1% in the control versus 11.3% in the EAR group).
Table 3 Median percent change in seizure frequency:*†‡
Figure 1. Reduction in seizure frequency at 3 months, all seizures.
Figure 2 (A). Percent change in seizure frequency at 3 months. Seizures with alteration or loss of consciousness (seizures excluding simple partial). (B) Percent change in seizure frequency at 3 months (complex partial seizures only).
Quality of life.
Patients in both groups were reported as showing improvements in each quality-of-life measure. More patients in the EAR group than the control group were reported as improved for postictal state (p = 0.030) and seizure clustering (p < 0.002) (figure 3). The number of patients reported worse for both quality-of-life measures was similar between the two groups.
Figure 3. Quality of life at 3 months: percent of patients “better” or “much better.”
Discussion.
Patients with epilepsy characterized by uncontrolled seizures face a variety of risks, including higher mortality rates, higher rates of accidents and injuries, a higher incidence of cognitive and psychiatric impairments, poor self-esteem, higher levels of anxiety and depression, and social stigmatization or isolation.8 Therefore, effective treatment to control seizures is fundamental to improving overall outcome. The ability to diagnose and treat medically refractory epilepsy early and with more aggressive therapies is hampered not only by the lack of predictive factors but also by the imprecise definition of refractory. Two factors that help to identify patients with refractory seizures earlier in the course of the disease include a high number of seizures and the fact that such patients are less likely to be helped by pharmacotherapy. Nonpharmacologic options such as surgery should not be considered a last resort in this population.3
Current guidelines published by the National Association of Epilepsy Centers suggest that, when a neurologist cannot control seizures within the first 12 months, other options should be considered.9 We hypothesized that earlier nonpharmacologic treatment using VNS therapy in patients with medically refractory seizures would be more efficacious than later adjunctive use of VNS therapy. The results obtained by the analysis of early adjunctive treatment, considered to be VNS therapy system implantation within 5 years of onset or treatment with four or fewer AEDs before implantation, show promise in controlling refractory seizures among patients with epilepsy of a shorter duration.
The statistically significant differences between the groups in the medical histories and demographics were to be expected, given the larger population used for the control group. Even though the EAR group had a shorter duration of epilepsy (mean 6 years versus 22 years for the control group), it is important to note that these patients still represent a challenging treatment group, as reflected by the fact that the MRIs were abnormal in almost half of the patients (42.4%), seizure frequency averaged one per day, and 40% had a known etiology. Despite these treatment challenges, 15% of all EAR patients reported no seizures of any type at 3 months, and 20% reported no seizures with alteration or loss of consciousness (seizures excluding simple partial). In addition, analysis of only complex partial seizures showed that 32% of EAR patients were free of such seizures after 3 months of VNS therapy. These reductions were all statistically significant compared with those of the control group. Moreover, although differences in the reductions in frequencies for other seizure types were not found to be statistically significant between the two groups, those differences may be clinically relevant.
Consistent with this improvement in seizure control were quality-of-life measures showing significant improvements in postictal state and seizure clustering. In addition, all other quality-of-life areas showed higher percentages of “much better/better” scores in the EAR group. These findings documenting improved seizure control and quality of life support the use of VNS therapy much earlier in the treatment of patients with pharmacoresistant epilepsy.
This study had several limitations. First, prospectively collected data were compared with data from an existing outcome registry. Data from a double-blind, randomized controlled trial would be considered much stronger. In addition, differences between the groups other than seizure duration might have influenced the results of this study. Efficacy was assessed only at 3 months. Patients should be followed for a longer period to determine whether the group differences persist.
Conclusions.
We believe that pharmacoresistant epilepsies can be identified early in the disease course and that such patients should be evaluated for nonopharmacologic treatment options. These findings support this approach, offering promise of success in achieving seizure control and improving quality of life among patients with refractory seizures who have shorter durations of epilepsy than are now typically being treated with VNS therapy. A threefold improvement in 100% seizure frequency reduction was achieved among patients treated within 5 years after onset or after having tried four or fewer AEDs. At 3 months, one patient in five reported no seizures with a loss of consciousness, and one in three with complex partial seizures reported complete control of the complex partial seizures. The data indicate that earlier identification of appropriate candidates for VNS therapy (i.e., after two or three AED failures and duration of epilepsy less than 2 years) would enhance seizure control and subsequent quality of life. Future prospective studies using adjunctive VNS therapy versus medical therapy after failure of two or three AEDs are recommended and should be performed.
Footnotes
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Publication of this supplement was supported by an unrestricted educational grant from Cyberonics, Inc. The sponsor has provided J.B.R. and J.W.W. with grant support and other honoraria during their professional careers.
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