The goal of antiepileptic treatment is long-term complete seizure control without adverse effects (Duncan et al., 2006). Long-term observational studies including newly diagnosed patients at the point of treatment initiation represent valuable sources of evidence to gauge the chance of seizure control with successive AED therapy, but few have specifically addressed the relationship between outcome and course of AED treatment. In one such study, among 470 patients who were previously never treated, 47% became seizure-free on their first drug, 13% on the second drug, but only 4% on the third drug or a combination of two drugs (Kwan & Brodie, 2000). Therefore, the probability of seizure freedom diminished progressively with successive AED regimens, whether substitution or add-on therapy, particularly after failure of two regimens (Fig. 1). Similar results were obtained in the analysis of the expanded cohort of 780 newly diagnosed patients from the same center: 50% became seizure-free with the first monotherapy, another 7% responded to the second monotherapy, and only 7% became seizure-free with the subsequent monotherapies or with polytherapy (Mohanraj & Brodie, 2005, 2006). In both analyses, patients who failed to respond to treatment due to lack of efficacy had worse outcome compared with those whose treatment failed for reasons such as adverse effects. These observations in mainly adult patients suggest that few become seizure-free after failure of two AEDs, particularly due to lack of efficacy.
Figure 1. Probability of seizure freedom in patients with newly diagnosed epilepsy, according to the number of antiepileptic drug (AED) regimens. Dotted lines represent 95% confidence intervals (CIs) (From Brodie & Kwan, 2002).
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Instead of following patients at diagnosis/treatment initiation, several recent studies recruited patients with chronic epilepsy who have already failed one or two AEDs. In an observational study of 155 adults who had previously failed one or more AEDs, 23% became seizure-free for 12 months or more after further drug trials, although it took up to six trials for some (Luciano & Shorvon, 2007). Observations from other adult cohorts who had failed at least two AEDs previously showed that subsequent seizure freedom (for at least 12 months) occurred upon further drug manipulation in approximately 4–5% of patients per year (Callaghan et al., 2007; Choi et al., 2008a), but with a probability of seizure relapse of 44% within 3 years (Choi et al., 2008a). These data suggest that in patients who have failed two or more AEDs, seizure freedom may still be attained in a small proportion, but it may involve repeated drug manipulations over considerable time, and may be temporary in nearly half of those who enter remission. Certain clinical features may help determine prognosis for remission with further medical treatment (Callaghan et al., 2007). Patients with an idiopathic etiology and epilepsy duration of less than 10 years had a greater chance of attaining remission. In contrast, patients with cryptogenic or symptomatic epilepsy and a longer duration of disease were more prone to experience continued seizures.
A fluctuating or remitting-relapsing course might be particularly common in childhood-onset epilepsy. In a prospective cohort of 140 children who had failed to respond to trials of at least two different AEDs considered appropriate for their seizures and type of epilepsy, some subsequently experienced repeated remissions and relapses, and only a small proportion became seizure-free for each of the additional drugs tried (Berg et al., 2009).
It is remarkable that within the cohort of 246 patients observed by Callaghan et al. (2007), 21 received surgery and 11 (52%) became seizure-free, compared with a seizure-free rate of only 11% in the rest of the cohort who were treated medically. The superiority of surgery over continued medication in terms of seizure control at short term was demonstrated conclusively by Wiebe et al. (2001). In this landmark study, 80 patients with temporal lobe epilepsy who failed treatment with two or more AEDs were randomized to surgical (in the form of anterior temporal lobectomy) or medical treatment. At one year, 58% of patients in the surgical group were free of complex partial or secondarily generalized seizures compared with only 8% in the medical group.
Because of ethical reasons, it would be difficult to conduct such randomized trials with prolonged follow-up; however, long-term data are available from observational, albeit mostly uncontrolled, studies. In the prospective Multicenter Study of Epilepsy Surgery, of 339 patients followed for 2–7.3 years after resective surgery (mainly temporal lobectomy), 66% were seizure-free for at least 2 years (Spencer et al., 2005). Outcome showed a trend to be better in patients who had mesial temporal lobe resection (68% seizure-free) than those who had extratemporal neocortical resections (50% seizure-free). A nonrandomized, controlled study analyzed outcomes of 242 patients with temporal lobe epilepsy who had failed at least two AEDs seen at a single epilepsy center (Bien et al., 2001). After a mean follow-up of approximately 5 years, 44.6% of those who eventually underwent surgery (n = 148) were seizure-free during the 12 months before follow-up compared with only 4.3% of those treated by AEDs alone (n = 94).
Long-term studies also suggest that temporal lobe resections were often associated with a good outcome. Téllez-Zenteno et al. (2005) performed a meta-analysis of 83 published studies including 7,343 patients undergoing resective or nonresective epilepsy surgery and followed for a mean/median of at least 5 years (Table 1). The median proportion of seizure freedom at the last reported follow-up was higher (66%) with temporal lobe resections. In contrast, although many patients benefit, results were less impressive after occipital or parietal (both 46% seizure-free) or frontal (27% seizure-free) lobe resections, as well as nonresective operations (16% seizure-free after multiple subpial transections and 35% free of most disabling seizures after callosotomy). Among patients undergoing temporal lobe resections, those with discrete abnormalities identified preoperatively, such as hippocampal sclerosis and other foreign tissue lesions, had a higher probability of seizure freedom than those without obvious abnormality (Mcintosh et al., 2004). Indeed it has been consistently shown that patients with hippocampal sclerosis as the pathologic substrate have the best prognosis after temporal lobe resections (Radhakrishnan et al., 1998; Mcintosh et al., 2004; Tonini et al., 2004; Spencer et al., 2005), but within this group, no reliable predictive clinical factor (Kilpatrick et al., 1999; Hennessy et al., 2001; Hardy et al., 2003; Janszky et al., 2005; Aull-Watschinger et al., 2008) or biologic marker for long-term outcome has been identified. The preceding data indicate that temporal lobe surgery has a reasonably high probability of providing seizure relief, particularly when the preoperative magnetic resonance imaging (MRI) discloses a lesion. Extratemporal surgery, however, results in remission less often. Frontal lobe surgery, in particular, produces an excellent outcome far less often than desired. Hence, it would appear that temporal lobe surgery is superior to continued medical therapy after failure of two drugs. However, the case for superiority of frontal lobe surgery to continued drug therapy after failure of only two medications is not overwhelming. In this case, the relative risks of each course of treatment might serve as a guide for the most appropriate choice. This topic is addressed later in this review.
Table 1. Meta-analysis of long-term seizure freedom after different types of epilepsy surgery
|Type of surgery||No. of patients (studies)||% seizure-free at 5 years (95% CI)|
|Temporal||3895 (40)||66 (62–71)|
|“Extratemporal”||169 (2)||34 (28–40)|
|Frontal||486 (7)||27 (23–30)|
|Parietal||82 (1)||46 (56–62)|
|Occipital||35 (1)||46 (29–63)|
Similar as in medical therapy, relapse may occur in patients who had surgery after a considerable period of seizure freedom that may not be temporally related to AED withdrawal (Spencer et al., 2005). Sperling et al. (2008) reported that in a cohort of 159 patients who had been seizure free for at least 5 years postsurgery (88% had anterior temporal lobectomy), there was still a probability of seizure relapse of 4% per year (Fig. 2). However, at the last follow-up of the study (mean follow-up duration 12.2 years), 89.9% of patients had been seizure free for at least the previous year, suggesting that seizure relapses in these patients are often isolated events and that seizure control can be regained in the majority. Nonetheless, the notion that surgery produces a “cure” in a majority of patients is not substantiated by the data. Although surgery leads to prolonged periods of remission, most patients experience relapses after surgery.
Finally, one other advantage might be offered by surgery. It offers the possibility for some patients to reduce or stop AED therapy, which may be associated with a sense of “cure” by the patients. However, only a minority of seizure-free patients stop or reduce their medication successfully (Berg et al., 2006). Moreover, the regular occurrence of postoperative relapses might lead many physicians to err on the side of caution and advise continuation of therapy.
Mortality and quality of life
The pursuit of ineffective therapy is encumbered not only by the risks of that therapy, but also by the risk of continued seizures. Significantly, seizure freedom after surgery is associated with decreased mortality and improved quality of life. In a cohort of 583 patients undergoing epilepsy surgery, those with recurrent seizures after surgery (n = 325) had a higher standardized mortality ratio [SMR = 5.75, 95% confidence interval (CI) 3.51–9.27] compared to those who were seizure-free (n = 258, SMR = 0.45, 95% CI 0.02–2.94), implying that the excess mortality associated with refractory epilepsy is eliminated after epilepsy surgery when seizures are abolished (Sperling et al., 2005). A clinical trial to establish the putative positive effect of surgery on mortality rate would require long-term follow-up of a large number of patients and likely be prohibitively costly. Choi et al. (2008b) recently used a decision analytic model and predicted that for a 35-year-old patient with temporal lobe epilepsy inadequately controlled by at least two AEDs, surgical therapy would be associated with an increase in life expectancy of 5.0 years and 7.5 in quality-adjusted life-years. In addition, prospective studies have shown that absolute seizure freedom postsurgery is associated with a durable improvement in quality of life measures (Markand et al., 2000; Spencer et al., 2007).