SUMMARYPurpose: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. Methods: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. Results: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and ''most severe'' seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. Discussion: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Objective: To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localizationrelated epilepsy.Methods: This long-term follow-up is a continuation of a previously reported trial of 5-vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries.Results: The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate ($50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p , 0.001).Conclusion: Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population. Classification of evidence:This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years. Approximately 3 million people in the United States have epilepsy and approximately 30% remain resistant to medical treatment. Some of these patients are candidates for resective surgery.1,2 For those who are not surgical candidates, or who continue to have seizures after surgery, neuromodulation may offer a viable therapeutic option. Several pilot studies, [3][4][5][6] and recent trials including the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial 7 and a trial of responsive cortical stimulation, 8 have demonstrated reduction in seizures. The SANTE trial in 110 subjects with localization-related epilepsy found that seizures were significantly reduced by stimulation. 7 We now report the 5-year efficacy and safety outcomes of this trial.METHODS The SANTE trial 7 utilized a design with a 3-month baseline, 1-month postoperative recovery, followed by 3 months of double-blind treatment randomized to 5 V or 0 V of stimulation, then an open-label conversion of all subjects to 5-V stimulation for 9

Summary:Purpose: Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open-label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data. Methods:We report an open-label pilot study of intermittent electrical stimulation of the anterior nucleus of the thalamus in five patients (three men, two women; age range, 24-47 years), with follow-up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable, programmable devices by using an intermittent, relatively high-frequency protocol. Stimulation parameters were 100 cycles per second with charge-balanced alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline.Results: Four of the five patients showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters.Conclusions: Electrical stimulation of the ANT appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of intractable patients. Further controlled study of deep brain stimulation of the anterior nucleus is warranted. Key Words: Thalamus-Anterior nucleus-Electrical stimulation-Deep brain stimulationIntractable epilepsy.Many patients with epilepsy remain inadequately controlled despite optimal use of antiepileptic medications (AEDs) and also are not candidates for resective brain surgery. The search for alternative therapies for such patients has renewed interest in electrical stimulation of deep brain structures for treating intractable epilepsy.The rationale that electrical stimulation of the nervous system can be effective in treating epileptic seizures is based on both animal data and preliminary human studies. In animal models, electrical stimulation of the thalamus at slow frequencies drives or synchronizes activity in distant brain regions (1,2), whereas stimulation at fast frequencies (>60 cycles/s; cps) can desynchronize intrinsic cortical Accepted January 8, 2004. Address correspondence and reprint requests to Dr. J.F. Kerrigan at Barrow Neurological Institute, 500 West Thomas Road, S-930, Phoenix, AZ 85013, U.S.A. E-mail: jkerrigan@chw.edu activity in distant areas (3). High-f...

SUMMARYThe American Epilepsy Society and the Epilepsy Foundation jointly convened a task force to assess the state of knowledge about sudden unexplained death in epilepsy (SUDEP). The task force had five charges: (1) develop a position statement describing if, when, what, and how SUDEP should be discussed with patients and their families and caregivers; (2) design methods by which the medical and lay communities become aware of the risk of SUDEP; (3) recommend research directions in SUDEP; (4) explore steps that organizations can take to perform large-scale, prospective studies of SUDEP to identify risk factors; and (5) identify possible preventive strategies for SUDEP. Some of the major task force recommendations include convening a multidisciplinary workshop to refine current lines of investigation and to identify additional areas of research for mechanisms underlying SUDEP; performing a survey of patients and their families and caregivers to identify effective means of education that will enhance participation in SUDEP research; conducting a campaign aimed at patients, families, caregivers, coroners, and medical examiners that emphasizes the need for complete autopsy examinations for patients with suspected SUDEP; and securing infrastructure grants to fund a consortium of centers that will conduct prospective clinical and basic research studies to identify preventable risk factors and mechanisms underlying SUDEP. For now, the principal effort in preventing SUDEP should be prompt and optimal control of seizures, especially generalized convulsive seizures.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.