Long-term Seizure Freedom Research Articles

Delayed time to first remission identifies poor long-term drug response of childhood-onset epilepsy: A prospective population-based study

We determined if time to first remission predicts long-term antiepileptic drug response. We assessed time to first 1-year remission (1YR) as a determinant of entering future terminal 5-year remission (5YTR) in a population-based cohort of 144 children prospectively followed-up since their first unprovoked seizure before the age of 16 years up to the mean age of 48 years. The proportion of patients entering 5YTR was highly dependent on the length of time to first 1YR after starting adequate treatment. For 144 patients, the overall 5YTR rate decreased from 32% for those in remission at year 1 to 24% at year 2, to 5% after 3 and 4 years, to 2% after 5 years or longer. Patients who entered 1YR within the first 5 years of treatment had an 11-fold better chance to enter 5YTR (odds ratio = 11.4, 95% CI = 2.9–45.3, P = 0.0005) and a 9-fold chance for uninterrupted 5YTR off medications (OR = 9.0, 95% CI = 1.171.9, P = 0.0383) compared with those who did not enter 1YR within the first 5 years of treatment. Three additional independent prognostic factors for predicting terminal 5YTR were confirmed: etiology, seizure frequency prior to treatment, and seizure frequency during treatment. We conclude that delayed efficacy after starting drug treatment gradually diminishes chances for long-term seizure remission, whether on medication or not. Not entering remission within 5 years of starting treatment predicts failure to achieve long-term seizure freedom in the future for the vast majority of patients.

Refractory seizures: Try additional antiepileptic drugs (after two have failed) or go directly to early surgery evaluation?

The goal of antiepileptic therapy is to achieve long-term seizure freedom with minimal or no adverse effects. Current evidence suggests that in many patients who have failed two appropriate antiepileptic drugs (AEDs) because of lack of efficacy, the chance of subsequent seizure freedom with further drug manipulation is low (reports ranging from as little as a few percent to nearly one-fourth of patients). Achieving this may require repeated drug manipulations. Surgery, in appropriately selected candidates, may render up to 70% of patients seizure-free when temporal resection is done, although frontal resection may have only a 25% yield. Both courses of actions (further drug trials and surgery) are associated with a plethora of potential adverse outcomes. Therefore, it is recommended that such patients be promptly referred to an epilepsy center for a comprehensive review of the diagnosis and management, which may include initial evaluation for surgery. Because presurgical evaluation and surgery itself may entail discomfort and risk, the decision to offer surgical treatment requires individual risk-benefit analysis that includes an assessment of possible success with additional trials of medication.

Electrical Stimulation for the Treatment of Epilepsy

Despite the advent of new pharmacological treatments and the high success rate of many surgical treatments for epilepsy, a substantial number of patients either do not become seizure-free or they experience major adverse events (or both). Neurostimulation-based treatments have gained considerable interest in the last decade. Vagus nerve stimulation (VNS) is an alternative treatment for patients with medically refractory epilepsy, who are unsuitable candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. Although responder identification studies are lacking, long-term VNS studies show response rates between 40% and 50% and long-term seizure freedom in 5% to 10% of patients. Surgical complications and perioperative morbidity are low. Research into the mechanism of action of VNS has revealed a crucial role for the thalamus and cortical areas that are important in the epileptogenic process. Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies. There is little evidence-based information on rational targets and stimulation parameters. Amygdalohippocampal DBS has yielded a significant decrease of seizure counts and interictal EEG abnormalities during long-term follow-up. Data from pilot studies suggest that chronic DBS for epilepsy may be a feasible, effective, and safe procedure. Further trials with larger patient populations and with controlled, randomized, and closed-loop designs should now be initiated. Further progress in understanding the mechanism of action of DBS for epilepsy is a necessary step to making this therapy more efficacious and established.

Long-term seizure and psychosocial outcomes of epilepsy surgery

Most results reported in studies focusing on long-term outcomes of epilepsy surgery resemble those reported in studies with shorter follow-up, indicating that many of the surgical results are enduring. In general, about 60% of patients with temporal epilepsy and 25% to 40% of those with extratemporal epilepsy achieve long-term seizure freedom after epilepsy surgery. Over a long term, about 20% of patients discontinue antiepileptic drugs, whereas 41% continue monotherapy and 31% use polytherapy. Evidence concerning the impact of epilepsy surgery on mortality is inconclusive, but some data support a reduction in the risk of death if patients become seizure-free. The information regarding long-term cognitive outcomes is limited but is similar to that derived from short-term studies. Decline in verbal memory occurs frequently after resections of the left temporal lobe; better memory outcomes are reported in seizure-free patients, and memory decline has been documented in patients with intractable epilepsy who do not undergo surgery. However, important confounders such as the effects of antiepileptic drugs, practice effects, and regression to the mean have not been adequately accounted for in these studies. All uncontrolled long-term studies report improved psychosocial outcomes with epilepsy surgery, including employment, education, driving status, satisfaction, and quality of life, but the results of the few existing controlled studies are less persuasive.

Long-term follow-up outcome after surgical treatment for lesional temporal lobe epilepsy

Objectives: Lateral or neocortical temporal lobe epilepsy (TLE) is regarded as a distinct clinical entity from medial TLE. Surgery for neocortical TLE can be considered as a viable treatment option; however, there is very limited information available on aspects such as long-term seizure outcome. Thus, we retrospectively reviewed our ten surgical cases of lateral TLE with a minimum 2 year follow-up outcome.Methods: The series comprised four male and six female patients, ranging in age from 3 to 46 years (mean: 28.8 years). Seven cases were found to be drug-resistant. Invasive pre-surgical evaluation for intractable epilepsy was performed in six patients.Results: The pathologic lesions were removed completely in nine cases. Lesionectomy alone was performed in four cases and total epileptogenic focus resection was confirmed in four cases. The epileptogenic regions within eloquent areas were preserved in two cases. The medial temporal structure was intact and preserved in all cases. Neuropathologic diagnoses were cavernoma in three cases, astrocytoma (grade 2) in two cases, arteriovenous malformation in two cases, gliosis in two cases and ganglioglioma in one case. The mean duration of follow-up was 6.5 years (range: 2.2–9.3 years). Outcomes categorized according to Engel classes were class I (E1) in six cases and class II (E2) in four cases. Patients who had post-operative seizures may also achieve long-term seizure decrease or freedom in three cases: case 5 (E4–E2), case 6 (E4–E2) and case 7 (E3–E1). Thus, worthwhile improvement was achieved in 100% of the cases in this series, with 60% of patients being seizure-free during the followed-up period.Conclusions: The controlled long-term follow-up results suggested that surgery for lesional TLE can be considered as a viable treatment option to control seizure with a low morbidity rate and good outcomes.

Optimizing therapy of seizures in stroke patients

Stroke is the leading cause of symptomatic epilepsy in adults, accounting for up to one-third of newly diagnosed seizures among the elderly. About 3% to 5% of stroke patients will suffer a remote seizure, 54% to 66% of whom will develop epilepsy. Thus far, the optimal timing and type of antiepileptic treatment for patients with post-stroke seizure and epilepsy have not been specifically assessed. Although several studies suggest that seizures alter the functional recovery after a stroke, it remains difficult to determine whether or not the occurrence of a second seizure in an untreated stroke patient might hamper the overall outcome. The decision to initiate antiepileptic drug (AED) treatment after a first or a second post-stroke seizure should therefore be individualized, primarily based on the functional impact of the first seizure episode and the patient's preference. Several converging findings suggest that the majority of first-generation AEDs, particularly phenytoin, are not the most appropriate choice in stroke patients because of their potential harmful impact on functional recovery and bone health, their suboptimal pharmacokinetic profile and interaction with anticoagulants or salicylates, their greater likelihood to be poorly tolerated, and the lack of level A evidence regarding their specific use in elderly patients. Among the new-generation AEDs that do not interact with anticoagulants, antiplatelet agents, or bone health, lamotrigine and gabapentine are the only two drugs that proved to be more effective than immediate-release carbamazepine in elderly patients, providing level A evidence for their use in this indication. In addition, gabapentin remains the only drug that has been specifically evaluated in stroke patients, demonstrating a high rate of long-term seizure freedom. At present, low-dose lamotrigine or gabapentin appears to represent the optimal first-line therapy for post-stroke seizure and epilepsy in elderly patients or in younger patients requiring anticoagulants. However, low-dose extended-release carbamazepine might be a reasonable and less expensive option in patients with appropriate bone health who do not requiring anticoagulation.

Predictors of outcome after temporal lobectomy for the treatment of intractable epilepsy

To assess short- and long-term seizure freedom, the authors reviewed 371 patients who underwent anterior temporal lobectomy to treat pharmacoresistant epilepsy. The mean follow-up duration was 5.5 years (range 1 to 14.1 years). Fifty-three percent of patients were seizure free at 10 years. The authors identified multiple predictors of recurrence. Results of EEG performed 6 months postoperatively correlated with occurrence and severity of seizure recurrence, in addition to breakthrough seizures with discontinuation of antiepileptic drugs.

Diagnosing refractory epilepsy: response to sequential treatment schedules

Diagnosing refractory epilepsy would facilitate referral for specialist pharmacological review and early consideration of epilepsy surgery. An outcomes study was undertaken in an unselected cohort of newly diagnosed patients to determine the number of antiepileptic drug (AED) regimens needed to be failed before the epilepsy could be designated as pharmacoresistant. Between July 1982 and May 2001, 780 adolescents and adults prescribed their first AED at the Western Infirmary in Glasgow, Scotland provided longitudinal data suitable for analysis. Overall, 504 (64.6%) patients became seizure free for at least 12 months. Of these, 462 (59.2%) remained in remission, while 42 (5.4%) relapsed and subsequently developed refractory epilepsy. The relapse rate peaked at 10.4% after 8 years of follow-up. The other 276 (35.4%) patients were uncontrolled from the outset. Prognosis appeared better in seniors (85% remission, P < 0.001) and adolescents (65% remission, P < 0.01) than in the remainder of the population (55% remission). Overall response rates with the first, second and third treatment schedules were 50.4, 10.7 and 2.7%, respectively, with only 0.8% patients responding optimally to further drug trials. Patients not tolerating at least one AED schedule did better than those failing because of lack of efficacy. These data suggest that suitable patients failing two AED regimens should be referred for epilepsy surgery. Those who do not attain long-term seizure freedom with the first three treatment schedules are likely to have refractory epilepsy.

Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis

Assessment of long-term outcomes is essential in brain surgery for epilepsy, which is an irreversible intervention for a chronic condition. Excellent short-term results of resective epilepsy surgery have been established, but less is known about long-term outcomes. We performed a systematic review and meta-analysis of the evidence on this topic. To provide evidence-based estimates of long-term results of various types of epilepsy surgery and to identify sources of variation in results of published studies, we searched Medline, Index Medicus, the Cochrane database, bibliographies of reviews, original articles and book chapters to identify articles published since 1991 that contained > or =20 patients of any age, undergoing resective or non-resective epilepsy surgery, and followed for a mean/median of > or =5 years. Two reviewers independently assessed study eligibility and extracted data, resolving disagreements through discussion. Seventy-six articles fulfilled our eligibility criteria, of which 71 reported on resective surgery (93%) and five (7%) on non-resective surgery. There were no randomized trials and only six studies had a control group. Some articles contributed more than one study, yielding 83 studies of which 78 dealt with resective surgery and five with non-resective surgery. Forty studies (51%) of resective surgery referred to temporal lobe surgery, 25 (32%) to grouped temporal and extratemporal surgery, seven (9%) to frontal surgery, two (3%) to grouped extratemporal surgery, two (3%) to hemispherectomy, and one (1%) each to parietal and occipital surgery. In the non-resective category, three studies reported outcomes after callosotomy and two after multiple subpial transections. The median proportion of long-term seizure-free patients was 66% with temporal lobe resections, 46% with occipital and parietal resections, and 27% with frontal lobe resections. In the long term, only 35% of patients with callosotomy were free of most disabling seizures, and 16% with multiple subpial transections remained free of all seizures. The year of operation, duration of follow-up and outcome classification system were most strongly associated with outcomes. Almost all long-term outcome studies describe patient cohorts without controls. Although there is substantial variation in outcome definition and methodology among the studies, consistent patterns of results emerge for various surgical interventions after adjusting for sources of heterogeneity. The long-term (> or =5 years) seizure free rate following temporal lobe resective surgery was similar to that reported in short-term controlled studies. On the other hand, long-term seizure freedom was consistently lower after extratemporal surgery and palliative procedures.

Failed surgery for temporal lobe epilepsy: Predictors of long-term seizure-free course

Objectives: To identify prognostic factors which predict the outcome 2 years after TLE surgery in those patients who were not seizure-free at the 6-month postoperative examination. Methods: We included 86 postoperative TLE patients who had undergone presurgical evaluation, including video-EEG and high-resolution MRI, and who had seizures between the second and sixth postoperative months. Results: 32% of patients were seizure-free in the second postoperative year. We found that normal MRI findings and secondarily generalized seizures (SGTCS) preoperatively were associated with a non-seizure-free outcome, while rare postoperative seizures and ipsilateral temporal IED with seizure-free outcome. Newly administered levetiracetam showed a significant positive effect on the postoperative outcome independent of other prognostic factors. Five of seven patients who received levetiracetam became seizure-free ( p = 0.006). Conclusion: One-third of patients who did not become seizure-free immediately after surgery, eventually achieved long-term seizure freedom. We suggest watching for long-term seizure freedom after failed epilepsy surgery especially in patients who had rare postoperative seizures, focal MRI abnormality, ipsilateral temporal spikes, or no SGTCS preoperatively. Levetiracetam may have a positive effect on postsurgical seizures.

Temporal lobe epilepsy with hippocampal sclerosis: predictors for long-term surgical outcome

Temporal lobe epilepsy (TLE) accompanied by hippocampal sclerosis (HS) is the type of epilepsy most frequently operated on. The predictors for long-term seizure freedom after surgery of TLE-HS are unknown. In this study, we aimed to identify prognostic factors which predict the outcome 6 months and 2, 3 and 5 years after epilepsy surgery of TLE-HS. Our working hypothesis was that the prognostic value of potential predictors depended on the post-operative time interval for which the assessment was made. We included 171 patients (100 females and 71 males, aged 16-59 years) who had undergone presurgical evaluation, including video-EEG, who had had MRI-defined HS, and who had undergone temporal lobectomy. We found that secondarily generalized seizures (SGTCS) and ictal dystonia were associated with a worse 2-year outcome. Both these variables together with older age and longer epilepsy duration were also related to a worse 3-year outcome. Ictal limb dystonia, older age and longer epilepsy duration were associated with long-term surgical failure evaluated 5 years post-operatively. In order to determine the independent predictors of outcomes, we calculated multivariate analyses. The presence of SGTCS and ictal dystonia independently predicted the 2-year outcome. Longer epilepsy duration and ictal dystonia predicted the 3-year outcome. Longer epilepsy duration (P = 0.003) predicted a poor 5-year outcome. Conclusively, predictors for the long-term surgical results of TLE with HS are different from those variables that predict the short-term outcome. Epilepsy duration is the most important predictor for long-term surgical outcome. Our results strongly suggest that surgery for TLE-HS should be performed as early as possible.

Levetiracetam: review clinica ed economica di un nuovo antiepilettico

Uncontrolled epilepsy has a significant negative impact on patient’s quality of life, on his emotional well-being and his social functioning. Seizure places an undue economic burden on the patient and community. The increased costs are direct and indirect (e.g.,inpatient care and loss of earnings associated with time lost from work). Levetiracetam is a new antiepileptic drug used as adjuntive therapy in the treatment of refractory epilepsy. Its nonconventional mechanism of action is not completely understood, but preclinical studies suggest that its antiepileptic action.may depend on a reversible, saturable and stereoselective binding site in CNS membranes. In this paper, we review the main clinical and economic data available in the scientific literature. Levetiracetam has a favourable pharmacokinetic profile characterised by rapid and nearly complete absorption, very low potential for drug interactions and a prolonged pharmacodynamic effect that permits twice-daily dosing. Several placebo-controlled clinical trials have demonstrated that its efficacy has enabled many patients who were refractory to treatment with other antiepileptic drugs to achieve long-term seizure freedom; furthermore in levetiracetam trials the frequency of adverse events is low and withdrawal rates are comparable with those of placebo. A cost/effectiveness analysis compared direct medical costs of levetiracetam add-on therapy with maintenance of standard therapy alone within the UK National Health Service. A 1-year dose escalation decision model was set up in refractory patients who failed to respond to two or more other currently available therapies, with seizure freedom selected as the measure of effectiveness. Available pharmacoeconomic data show that the incremental cost of treating patients with levetiracetam is low when compared with the benefits of seizure freedom, at least in the UK. Furthermore, current studies suggest that this antiepileptic drug has a potential as first-line treatment for many types of epilepsy and in many different patient populations.

Surgical Treatment of Pediatric Epilepsy

Children with medically refractory epilepsy may benefit from neurosurgical interventions. As in adults, temporal lobectomy in patients with temporal lobe seizure focus gives good rates of long-term seizure freedom. Neocortical foci are more common in children and often require invasive monitoring with different resective surgeries to treat. Hemispherectomy in patients with unilateral epilepsy and hemispheric deficits has a good outcome as well. Corpus callosotomy and vagus nerve stimulation are effective tools to reduce seizure severity and frequency in children who are not candidates for resective surgery.