Deep Brain Stimulation of the Anterior Nucleus of the Thalamus in Drug-Resistant Epilepsy in the MORE Multicenter Patient Registry.

BACKGROUND AND OBJECTIVES: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. METHODS: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. RESULTS: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. DISCUSSION: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy. TRIAL REGISTRATION INFORMATION: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012.

Long-term seizure outcomes in patients with drug resistant epilepsy.

PURPOSE: Despite the availability of a broad range of treatments for epilepsy, a significant proportion of patients have ongoing seizures. This study aims to characterize the drug resistant population and to report long-term outcomes of patients undergoing different types of pharmacological and surgical treatment. METHODS: Adult patients with drug resistant epilepsy (DRE) were identified from a largely retrospective database of 900 consecutive patients with epilepsy, recruited from two reference centers for DRE in Belgium. We report treatment trajectories and long-term seizure outcomes in the different treatment groups. RESULTS: 640 patients had DRE. 249 (38.9%) underwent presurgical assessment, followed by surgical treatment in 197 (30.8%), resulting in seizure freedom in 86 (13.4%). 443 patients (69.2%) were treated only with further AED trials, of which 163 (25.5%) became seizure free. In the 391 patients with ongoing seizures (61.1%), mean age was 43.2 years, mean disease duration 23 years and mean number of AED trials 6.9. 291 (74.4%) had tonic-clonic seizures, and 43 (11.0%) had one or more episodes of status epilepticus. Patients with hippocampal sclerosis were significantly more likely to be seizure free, while patients with malformation of cortical development and those with temporal lobe epilepsy of unknown etiology were more likely to have ongoing seizures. CONCLUSION: Our findings demonstrate that - even with adequate access to surgical treatment and further AED trials - 61.1% of patients with DRE had ongoing seizures. This illustrates that there is a scope for ongoing development of novel treatments for DRE.

An in vivo [18F]MK-9470 microPET study of type 1 cannabinoid receptor binding in Wistar rats after chronic administration of valproate and levetiracetam.

There is substantial evidence that the endocannabinoid system and in particular the type 1 cannabinoid receptor (CB1R) is involved in epilepsy. We evaluated the in vivo effect of chronic administration of the anti-epileptic drugs valproate (VPA) and levetiracetam (LEV) on rat brain CB1 receptors using the positron emission tomography (PET) tracer [(18)F]MK-9470. Six Wistar rats were treated with VPA (200mg/kg) or LEV (50mg/kg) IP daily for 2 weeks. Dynamic imaging after intravenous injection of 18 MBq [(18)F]MK-9470 was performed on a FOCUS 220 microPET at baseline and after chronic treatment. Six animals were used as controls and were injected with saline, using the same protocol. Parametric images based on standardized uptake values (SUV) were generated and were spatially normalized to Paxinos space. These CB1R images were analyzed using a predefined volume of interest (VOI)-based analysis. Differences in SUV values between chronic and baseline scans in each condition (saline, VPA and LEV treatment) were calculated in each VOI. Direct binding affinity of the drugs at CB1R was assessed by competitive binding assay in Chinese hamster ovarian cells expressing human CB1R. Chronic injections of saline did not produce significant changes in global [(18)F]MK-9470 binding (p=0.43), nor in tracer binding in individual VOIs. We found a significant increase in global cerebral [(18)F]MK-9470 binding after chronic VPA administration compared to sham treated animals (+32.5%, p<0.001), as well as in tracer binding in all individual VOIs. After chronic administration of LEV, there was no significant change in global cerebral CB1R binding (+6.9%, p=0.81), nor in tracer binding in individual VOIs. As VPA does not exhibit high affinity for CB1R (displacement of [(3)H]-SR141716A 1.3+/-14.0%), such upregulation is most likely caused by an indirect effect on the endocannabinoid system. This increase in CB1R tracer binding and possibly signaling may represent a supplementary and new mechanism of VPA, but not LEV, since activation of CB1Rs has been shown to decrease excitability and excitotoxicity on-demand.