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.

Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

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

Experiments in acute and chronic animal models of epilepsy provide mechanistic insight into the acute abortive, acute prophylactic, and chronic progressive prophylactic, anti-seizure effects of vagus nerve stimulation (VNS) observed in human epilepsies, and demonstrate antiepileptogenic effects of VNS in the kindling model. Anatomic-physiologic studies, experimental epilepsy studies, and human imaging, EEG, and CSF studies suggest that multiple mechanisms underlie the antiseizure effects of VNS and that alterations of vagal parasympathetic efferent activities do not underlie these antiseizure effects. Putative antiseizure mechanisms are mediated by altered vagal afferent activities, and probably include altered activities in the reticular activating system, the central autonomic network, the limbic system, and the diffuse noradrenergic projection system. Anatomic-physiologic studies fully account for the common and rare adverse effects of VNS. Current understandings of antiepileptic drug (AED) and VNS therapeutic mechanisms strongly support the "common sense" interpretation of the clinical studies: i.e., adjunctive VNS can add antiseizure effect to any AED regimen, with no interactive toxicity and no effect on drug distribution and elimination.

Summary:Purpose: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date.Methods: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal E05 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute E05 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study.Results: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures.Conclusions: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures. Key Words: Vagus nerve stimulation-Intractable epilepsy.Vagus nerve stimulation (VNS) has emerged as an effective treatment for medically intractable epilepsy ( 1-3). VNS uses an implantable, programmable pulse generator powered by a lithium battery, which is connected to a helical bipolar lead. The lead is attached to the midcervical portion of the left vagus nerve and delivers

Currently available therapeutic interventions for treatment-resistant depression, including switch, combination, and augmentation strategies, are less than ideal. Observations of mood elevation during vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy suggested a role for VNS therapy in refractory major depression and prompted clinical investigation of this neurostimulation modality. The VNS Therapy System has been available for treatment of pharmacoresistant epilepsy since 1997 and was approved by the US Food and Drug Administration for treatment-resistant depression in July, 2005. The physiology of the vagus nerve, mechanics of the VNS Therapy System, and efficacy and safety in pharmacoresistant epilepsy are reviewed. Promising results of VNS therapy for treatment-resistant depression have been forthcoming from both acute and long-term studies, evidenced in part by progressive improvements in depression rating scale scores during the 1st year of treatment with maintenance of response thereafter. VNS therapy is well tolerated in patients with either pharmacoresistant epilepsy or treatment-resistant depression. As in epilepsy, the mechanisms of VNS therapy of treatment-resistant depression are incompletely understood. However, evidence from neuroimaging and other studies suggests that VNS therapy acts via innervation of the nucleus tractus solitarius, with secondary projections to limbic and cortical structures that are involved in mood regulation, including brainstem regions that contain serotonergic (raphe nucleus) and noradrenergic (locus ceruleus) perikarya that project to the forebrain. Mechanisms that mediate the beneficial effects of VNS therapy for treatment-resistant depression remain obscure. Suggestions for future research directions are described.

Summary:Purpose: To describe the electrographic and clinical features of nonconvulsive status epilepticus (NCSE) in the critically ill elderly and to identify potential predictors of outcome.Methods: We prospectively identified 25 episodes of altered mentation and NCSE in 24 critically ill elderly patients associated with generalized, focal, or bihemispheric epileptiform EEG patterns. Patients with anoxic encephalopathy were excluded.Results: Of 25 hospitalizations, 13 (52%) resulted in death, and 12 (48%) patients survived to discharge. Death was associated with the number of acute, life-threatening medical problems on presentation (survivors, 1.8; fatalities, 2.8; p = 0.013) and with generalized EEG pattern (p = 0.017).

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