Faculty Bibliography

Pro AED: The central issue in medical decision-making is risk-benefit assessment. Surgery of any type is still considered to be a major undertaking. To warrant these risks, the patient has a right to expect that they have a greater chance of a good outcome with an invasive therapy than with a non-invasive one. The main question is when, if ever, this becomes the case when comparing implantation of a VNS Therapy System versus adding an antiepileptic drug (AED)? After the first drug? The second? After all AEDs have failed? To date, no randomized trial comparing the addition of an AED against vagus nerve stimulation (VNS Therapy) has been undertaken, although several are currently being contemplated. Without this information, it is more difficult to make a case for early implementation of VNS Therapy. Unfortunately, few data are available regarding the potential for patients to become seizure-free after implantation of a VNS Therapy System. Another issue is side effects. It is important to remember that VNS Therapy also produces adverse events, albeit very different in character than those associated with AEDs, to which physicians have become accustomed. These include cough, dyspnea, pharyngitis, voice alteration and sleep apnea. A less frequently discussed, potentially negative consequence of VNS Therapy relates to the ability to obtain imaging of the patient. Patients who have undergone VNS Therapy System implantation are not candidates for imaging of the chest, breast, or abdomen. A second issue is that imaging of the brain can only be performed with MRI scanners that meet certain requirements, and as MRI technology develops, scanners meeting these requirements may become harder to find. However, to summarize, VNS Therapy is an excellent and useful treatment choice. Fortunately, the choice between AEDs and VNS Therapy is not an 'either/or' decision. Each has a role in the treatment of patients with epilepsy, and the advantages and disadvantages of each should be kept in perspective. Pro VNS Therapy: VNS Therapy is no longer a new treatment for patients with refractory epilepsy. The first implant was performed in l988, and since then more than 30,000 patients have received this therapy. It is no longer considered an unusual or dangerous procedure, but it is still used almost exclusively for refractory epilepsy patients and it has not been generally accepted for use as a first line or even second line therapy. However, compared to the new AEDs, VNS Therapy has similar efficacy results in clinical trials and in many epilepsy syndromes and the long-term efficacy results are even more positive, with continued improvement in seizure reduction for up to two years. Two of the major reasons for not using VNS Therapy early are that it is a surgical procedure, and its safety during MRI procedures, especially with 3 Tesla, has not yet been elucidated. The safety profile of VNS Therapy is very favorable; the side effects being totally different from those seen with AEDs. The most important aspects are that there have been no pharmacological interactions, cognitive or sedative side effects reported, and it is safe for use in all age groups. Side effects are restricted to local irritation, hoarseness, coughing and, in a few cases, swallowing difficulties when the stimulator is on, but these tend to disappear with time. No idiosyncratic side effect has emerged during the 16 years of use. Compliance is guaranteed. The cost of the implantation of the VNS Therapy System, when spread out over 8 years (battery life), is actually less than the cost of using a new AED over an eight-year period, and real savings as regards hospital costs due to seizures can be expected

PURPOSE: To investigate whether the efficacy of levetiracetam (LEV) is sustained in adult patients with refractory partial seizures over a 3-month period. METHODS: Treatment effect was assessed in a post hoc analysis by determining the proportion of seizure-free days during each week of a 3-month period after the initiation of treatment. Pooled data from three randomized, double-blind, placebo-controlled trials (n = 883) were analyzed. RESULTS: The mean proportion of seizure-free days was greater in the LEV group than in the placebo group. The difference, which was statistically significant, was observed as early as the first week after the initiation of treatment. It was higher in the first week of treatment and subsequently was maintained for each week over the 3-month period (p < 0.001 or p = 0.002 at each time point). Patients in the LEV group had on average 74% to 81% days each week without any seizure, compared with 69% to 72% in the placebo group. CONCLUSIONS: LEV is efficient in controlling seizures from the first week of drug initiation, during uptitration, and throughout the first 3 months of treatment. An interesting amplification of efficacy occurs in the first week of therapy, which is intriguing and warrants further investigation

Few comparative clinical trials of newer antiepileptic drugs (AEDs) in patients with refractory partial epilepsy are available. Therefore, meta-analysis is a widely used and useful method for comparing them. Despite the limitations of indirect comparisons, and recognizing that these drugs were tested at different doses, such comparisons can be helpful to physicians making practical treatment decisions. The purposes of this study were to present newer meta-analysis results for add-on levetiracetam compared with placebo and to estimate its efficacy and tolerability compared with other new AEDs (gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide) in a meta-analysis using methods for making indirect comparisons. Randomized placebo-controlled clinical trials of add-on therapy with levetiracetam, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide in patients with refractory partial epilepsy were identified in the Cochrane Library 2002. A fixed-effects model was used to estimate Mantel-Haenszel odds ratios for the responder rate (efficacy measure) and withdrawal rate (mainly tolerability measure) of levetiracetam and other new AEDs versus placebo. Because no head-to-head clinical trials comparing these new AEDs exist, adjusted indirect comparisons were then made between levetiracetam and each other AED using the meta-analysis results. At the doses tested, levetiracetam was more effective in terms of responder rate than gabapentin (odds ratio 2.64 with 95% CI 1.51-4.63) and lamotrigine (odds ratio 1.86 with 95% CI 1.04-3.34) and equally well tolerated. Levetiracetam had a significantly lower withdrawal rate than topiramate (odds ratio 0.52 with 95% CI 0.29-0.93) and oxcarbazepine (odds ratio 0.55 with 95% CI 0.33-0.92), with comparable efficacy. Although levetiracetam did not differ significantly from the other AEDs, numerical trends favoring levetiracetam were obtained in response rate and in withdrawal rate (tiagabine, zonisamide). Indirect comparisons based on meta-analysis suggest that add-on therapy with levetiracetam has a favorable responder and/or withdrawal rate relative to several AEDs in patients with partial epilepsy with doses used in clinical trials. These meta-analyses give only short-term efficacy and safety data. Comparative clinical trials and long-term studies of these agents are needed to confirm these findings

PURPOSE: To investigate whether rapid achievement of levetiracetam (LEV) steady state is translated into an immediate measurable efficacy. The time to onset of action of LEV immediately after its initiation in adult patients with refractory partial seizures was analyzed. METHODS: Treatment effect was assessed in a pooled analysis (n=883) from three randomized, double-blind, placebo-controlled add-on trials. RESULTS: The increase in the proportion of seizure-free patients over baseline was 15, 17, and 17% for the first, second, and third day, respectively, for the LEV 1,000-mg group (all differences statistically significant; McNemar p value<0.001), whereas the increase was 7, 9, and 9% for the 333-mg LEV group (differences not significant). No major changes were observed for the placebo group. For differences in proportion of seizure-free patients between groups, the probability of being seizure free in the LEV groups was twofold higher than in the placebo group. For the 1,000-mg LEV group, odds ratios were 2.3, 2.5, and 2.7 for the first, second, and third day of therapy, respectively; all differences versus placebo were statistically significant (logistic regression p values, all <0.001). The addition of LEV significantly increased the proportion of patients without a seizure as of the first day of therapy. Each of the first 3 days, seizure freedom was twice as likely to occur with LEV 1,000 mg than with placebo. CONCLUSIONS: Evidence of a rapid onset of action of LEV 1,000 mg was demonstrated through a significant increase in the proportion of seizure-free patients as of the first day of therapy