The SANTÉ study at 10 years of follow-up: Effectiveness, safety, and sudden unexpected death in epilepsy.

OBJECTIVE: We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10 years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTÉ) study. METHODS: After the 3-month blinded and 9-month unblinded phases, subjects continued to be assessed during long-term follow-up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed. RESULTS: One hundred ten implanted subjects accumulated a total of 938 device-years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase). Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow-up of at least 10 (maximum 14) years. At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite-plus-probable SUDEP rate, based on SANTÉ study experience (two deaths in 938 years) and previous pilot studies (0 deaths in 76 years), indicated a rate of 2.0 deaths for 1000 person-years. Overall mortality was 6.9 deaths per 1000 person-years. SIGNIFICANCE: The long-term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes. Improvement in frequency of the most severe seizure type may reduce SUDEP risk. The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug-resistant focal epilepsy.

Magnetic resonance-guided laser interstitial thermal therapy: Correlations with seizure outcome.

OBJECTIVE: This study was undertaken to identify clinical factors associated with seizure freedom after magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) in temporal lobe epilepsy patients with unilateral mesial temporal sclerosis (MTS). METHODS: We identified 56 patients with magnetic resonance imaging-defined MTS who underwent MRgLiTT with at least 1 year of follow-up. Primary outcome was seizure freedom at 1 year. We examined the association of seizure freedom and the following clinical factors: age at surgery, gender, history of febrile seizures, history of focal to bilateral tonic-clonic seizures, duration of epilepsy at the time of surgery, frequency of interictal epileptiform discharges (IEDs), seizure frequency, and presence of bilateral IEDs. RESULTS: Thirty-five (62.5%) patients were seizure-free at 1 year. The presence of bilateral IEDs and age at surgery were associated with 1-year seizure freedom after MRgLiTT. The presence of bilateral IEDS was associated with lower odds of seizure freedom (odds ratio [OR] = .05, 95% confidence interval [CI] = .01-.46, p = .008), whereas increasing age at surgery was associated with increased odds of seizure freedom (OR = 1.10, 95% CI = 1.03-1.19, p = .009). SIGNIFICANCE: This study demonstrates associations between presence of bilateral IEDs and age at surgery and seizure freedom at 1 year after MRgLiTT.

Thalamus and focal to bilateral seizures: A multiscale cognitive imaging study.

OBJECTIVE: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality. METHODS: FBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality. RESULTS: Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS. CONCLUSIONS: In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Disrupted basal ganglia-thalamocortical loops in focal to bilateral tonic-clonic seizures.

Focal to bilateral tonic-clonic seizures are associated with lower quality of life, higher risk of seizure-related injuries, increased chance of sudden unexpected death, and unfavourable treatment outcomes. Achieving greater understanding of their underlying circuitry offers better opportunity to control these seizures. Towards this goal, we provide a network science perspective of the interactive pathways among basal ganglia, thalamus and cortex, to explore the imprinting of secondary seizure generalization on the mesoscale brain network in temporal lobe epilepsy. Specifically, we parameterized the functional organization of both the thalamocortical network and the basal ganglia-thalamus network with resting state functional MRI in three groups of patients with different focal to bilateral tonic-clonic seizure histories. Using the participation coefficient to describe the pattern of thalamocortical connections among different cortical networks, we showed that, compared to patients with no previous history, those with positive histories of focal to bilateral tonic-clonic seizures, including both remote (none for >1 year) and current (within the past year) histories, presented more uniform distribution patterns of thalamocortical connections in the ipsilateral medial-dorsal thalamic nuclei. As a sign of greater thalamus-mediated cortico-cortical communication, this result comports with greater susceptibility to secondary seizure generalization from the epileptogenic temporal lobe to broader brain networks in these patients. Using interregional integration to characterize the functional interaction between basal ganglia and thalamus, we demonstrated that patients with current history presented increased interaction between putamen and globus pallidus internus, and decreased interaction between the latter and the thalamus, compared to the other two patient groups. Importantly, through a series of 'disconnection' simulations, we showed that these changes in interactive profiles of the basal ganglia-thalamus network in the current history group mainly depended upon the direct but not the indirect basal ganglia pathway. It is intuitively plausible that such disruption in the striatum-modulated tonic inhibition of the thalamus from the globus pallidus internus could lead to an under-suppressed thalamus, which in turn may account for their greater vulnerability to secondary seizure generalization. Collectively, these findings suggest that the broken balance between basal ganglia inhibition and thalamus synchronization can inform the presence and effective control of focal to bilateral tonic-clonic seizures. The mechanistic underpinnings we uncover may shed light on the development of new treatment strategies for patients with temporal lobe epilepsy.

Neuronal phase consistency tracks dynamic changes in acoustic spectral regularity.

The brain parses the auditory environment into distinct sounds by identifying those acoustic features in the environment that have common relationships (e.g., spectral regularities) with one another and then grouping together the neuronal representations of these features. Although there is a large literature that tests how the brain tracks spectral regularities that are predictable, it is not known how the auditory system tracks spectral regularities that are not predictable and that change dynamically over time. Furthermore, the contribution of brain regions downstream of the auditory cortex to the coding of spectral regularity is unknown. Here, we addressed these two issues by recording electrocorticographic activity, while human patients listened to tone-burst sequences with dynamically varying spectral regularities, and identified potential neuronal mechanisms of the analysis of spectral regularities throughout the brain. We found that the degree of oscillatory stimulus phase consistency (PC) in multiple neuronal-frequency bands tracked spectral regularity. In particular, PC in the delta-frequency band seemed to be the best indicator of spectral regularity. We also found that these regularity representations existed in multiple regions throughout cortex. This widespread reliable modulation in PC - both in neuronal-frequency space and in cortical space - suggests that phase-based modulations may be a general mechanism for tracking regularity in the auditory system specifically and other sensory systems more generally. Our findings also support a general role for the delta-frequency band in processing the regularity of auditory stimuli.

Automated trajectory planning for laser interstitial thermal therapy in mesial temporal lobe epilepsy.

OBJECTIVE: Surgical resection of the mesial temporal structures brings seizure remission in 65% of individuals with drug-resistant mesial temporal lobe epilepsy (MTLE). Laser interstitial thermal therapy (LiTT) is a novel therapy that may provide a minimally invasive means of ablating the mesial temporal structures with similar outcomes, while minimizing damage to the neocortex. Systematic trajectory planning helps ensure safety and optimal seizure freedom through adequate ablation of the amygdalohippocampal complex (AHC). Previous studies have highlighted the relationship between the residual unablated mesial hippocampal head and failure to achieve seizure freedom. We aim to implement computer-assisted planning (CAP) to improve the ablation volume and safety of LiTT trajectories. METHODS: Twenty-five patients who had previously undergone LiTT for MTLE were studied retrospectively. The EpiNav platform was used to automatically generate an optimal ablation trajectory, which was compared with the previous manually planned and implemented trajectory. Expected ablation volumes and safety profiles of each trajectory were modeled. The implemented laser trajectory and achieved ablation of mesial temporal lobe structures were quantified and correlated with seizure outcome. RESULTS: CAP automatically generated feasible trajectories with reduced overall risk metrics (P < .001) and intracerebral length (P = .007). There was a significant correlation between the actual and retrospective CAP-anticipated ablation volumes, supporting a 15 mm diameter ablation zone model (P < .001). CAP trajectories would have provided significantly greater ablation of the amygdala (P = .0004) and AHC (P = .008), resulting in less residual unablated mesial hippocampal head (P = .001), and reduced ablation of the parahippocampal gyrus (P = .02). SIGNIFICANCE: Compared to manually planned trajectories CAP provides a better safety profile, with potentially improved seizure-free outcome and reduced neuropsychological deficits, following LiTT for MTLE.

Presurgical thalamic "hubness" predicts surgical outcome in temporal lobe epilepsy.

OBJECTIVE: To characterize the presurgical brain functional architecture presented in patients with temporal lobe epilepsy (TLE) using graph theoretical measures of resting-state fMRI data and to test its association with surgical outcome. METHODS: Fifty-six unilateral patients with TLE, who subsequently underwent anterior temporal lobectomy and were classified as obtaining a seizure-free (Engel class I, n = 35) vs not seizure-free (Engel classes II-IV, n = 21) outcome at 1 year after surgery, and 28 matched healthy controls were enrolled. On the basis of their presurgical resting-state functional connectivity, network properties, including nodal hubness (importance of a node to the network; degree, betweenness, and eigenvector centralities) and integration (global efficiency), were estimated and compared across our experimental groups. Cross-validations with support vector machine (SVM) were used to examine whether selective nodal hubness exceeded standard clinical characteristics in outcome prediction. RESULTS: Compared to the seizure-free patients and healthy controls, the not seizure-free patients displayed a specific increase in nodal hubness (degree and eigenvector centralities) involving both the ipsilateral and contralateral thalami, contributed by an increase in the number of connections to regions distributed mostly in the contralateral hemisphere. Simulating removal of thalamus reduced network integration more dramatically in not seizure-free patients. Lastly, SVM models built on these thalamic hubness measures produced 76% prediction accuracy, while models built with standard clinical variables yielded only 58% accuracy (both were cross-validated). CONCLUSIONS: A thalamic network associated with seizure recurrence may already be established presurgically. Thalamic hubness can serve as a potential biomarker of surgical outcome, outperforming the clinical characteristics commonly used in epilepsy surgery centers.

JOURNAL CLUB: Longitudinal Qualitative Characterization of MRI Features After Laser Interstitial Thermal Therapy in Drug-Resistant Epilepsy.

OBJECTIVE: Laser interstitial thermal therapy (LITT), a method for ablating brain tissue under real-time MR thermometry, has been used more frequently in recent years to treat nonmalignant lesions. The purpose of this study is to longitudinally characterize MRI features after LITT in patients with drug-resistant epilepsy, primarily in the setting of mesial temporal sclerosis. MATERIALS AND METHODS: MR images from 23 consecutive patients who underwent LITT were retrospectively reviewed. All patients had images obtained immediately after the ablation. Multiple patients had follow-up imaging at various time points after treatment, from postoperative days 7 through 1539. A total of 54 MRI studies were reviewed. RESULTS: Immediately after LITT, MR images showed a ring-enhancing lesion at the ablation site with minimal surrounding edema. Seven images showed increased enhancement of the ipsilateral choroid plexus. Images in the subacute phase showed a mild increase in edema with similar enhancement. Images in the transitional phase showed a decrease in edema with variable enhancement. Images in the chronic phase showed minimal gliosis with or without cavity formation or cavity formation alone, with either decreased or no enhancement. CONCLUSION: This report describes the time course of the imaging findings after LITT for drug-resistant epilepsy. The typical stages include rim-enhancing lesion with minimal edema, followed by an increase in edema, to eventual gliosis and nonenhancing cavity formation. Radiologists need to be familiar with the postablation findings to minimize misdiagnosis and prevent unnecessary workup.

Clinical features and postoperative seizure outcome in patients with drug-resistant gelastic seizures without hypothalamic hamartoma.

OBJECTIVES: The objective of this study was to describe the clinical characteristics and surgical outcome in patients with gelastic seizures without hypothalamic hamartoma. METHODS: We retrospectively reviewed all the video-EEG reports over a 5-year period (2007-2011) for the occurrence of the terms "laugh" or "giggle" in the text body. All the patients with at least one documented gelastic seizure at the epilepsy monitoring unit were studied. In patients who underwent epilepsy surgery, seizure outcomes were analyzed. RESULTS: Sixteen patients (10 females and 6 males) with a mean age of 46.3years were studied. Seven patients had invasive intracranial EEG recordings. Seizure onset zone was in a temporal lobe in four patients and the frontal lobe in one patient. Two patients did not have gelastic seizures during their intracranial EEG monitoring. Nine patients underwent resective epilepsy surgery for their seizures. Six patients (67%) were seizure-free after surgery. CONCLUSION: In adult patients, gelastic seizures can be seen in patients with focal epilepsy without hypothalamic hamartoma. Nonhypothalamic hamartoma gelastic seizures originating from the temporal lobe can be amenable to surgery.

The functional anatomy of non-verbal (pitch memory) function in left and right anterior temporal lobectomy patients.

An fMRI pitch memory task was administered to left and right anterior temporal lobectomy (ATL) patients. The goal was to verify the neuroanatomical correlates of non-verbal memory, and to determine if pitch memory tasks can identify cognitive risk prior to ATL. The data showed that the bilateral posterior superior temporal lobes implement pitch memory in both ATL patients and NCs (normal controls), indicating that the task can be accomplished with either anterior temporal lobe resected. NCs activate the posterior temporal lobes more strongly than ATL patients during highly accurate performance. In contrast, both ATL groups activate the anterior cingulate in association with accuracy. While our data clarifies the functional neuroanatomy of pitch memory, it also indicates that such tasks do not serve well to lateralize and functionally map potentially "at risk" non-verbal memory skills prior to ATL.

Impedance variations over time for a closed-loop neurostimulation device: early experience with chronically implanted electrodes.

OBJECTIVE: Responsive neurostimulation (RNS®) is an investigational treatment modality for intractable focal epilepsy. We analyzed impedance values over time to gain a better understanding of RNS device stability, potential differences between depth and strip electrodes, and general implications of long-term electrode implantation. MATERIALS AND METHODS: Impedance measurements were retrospectively reviewed from seven patients over a 3-year period. Statistical analysis was performed to investigate trends in impedance values over time and to determine if any differences existed between the means and variances of impedance values for the two different electrodes. RESULTS: Intraparenchymal depth electrodes demonstrated lower mean impedances and had less variation over time when compared to subdural strip electrodes. There was no significant change in mean impedance over time for depth electrodes, while that of subdural electrodes increased over time to peak at 16-20 months and returned to baseline by 2 years. CONCLUSION: The RNS device provides unique long-term data for both depth and subdural electrodes in human subjects. Although changes in impedance were observed with respect to time after implantation and electrode type, these variations were of a clinically insignificant magnitude. As a constant-current system, the device is ultimately able to administer stable therapeutic doses in the setting such minor variability. While further animal research and post mortem investigations in human subjects are necessary to broaden our understanding of the mechanisms occurring at the electrode-neural interface and the biocompatibility of chronically implanted electrodes, the relative stability of impedances seen in this cohort of chronic implants brings promise to future implementations of chronic intracranial neural implants.

Nutritional supplements, foods, and epilepsy: is there a relationship?

Anecdotal reports suggest that certain foods and dietary contents might influence the occurrence of seizures. However, the existing data are scanty and sometimes controversial. Some studies have found that the supplementation with individual nutrients reduced seizure frequency or improved other aspects of health in patients with epilepsy, while other studies have failed to confirm those findings. Nutrient supplementation may be necessary to prevent or reverse the effects of certain deficiencies that frequently result from the use of antiepileptic drugs (AEDs). However, the potential benefits of nutrient supplementation in patients with epilepsy must be weighed against reports that large doses of certain nutrients can interfere with the action of some AEDs. This paper reviews dietary and nutritional considerations in patients with epilepsy and also the relationship between foods, dietary elements, and seizures.

Refractory generalized seizures: response to corpus callosotomy and vagal nerve stimulation.

PURPOSE: The vagal nerve stimulator (VNS) and corpus callosotomy can reduce seizure frequency when seizures are refractory to medications. However, the efficacy and safety of these two procedures have not been compared. This study evaluates the two procedures for generalized seizures. METHODS: All patients with refractory generalized seizures (generalized tonic-clonic, tonic, or atonic) who underwent a corpus callosotomy (anterior or complete) (n = 53) without other forms of epilepsy surgery and those who underwent VNS placement (n = 25) were evaluated for this study. Seizure response and procedure complications were evaluated. RESULTS: For those with a corpus callosotomy and generalized tonic-clonic seizures (n = 50), 79.5% had >or=50% decrease in the frequency of generalized tonic-clonic seizures, and 60% had >or=80% seizure reduction. For those with a VNS and generalized tonic-clonic seizures (n = 21), 50% had >or=50% seizure reduction, and 33% had >or=80% seizure reduction. Tonic and atonic seizures decreased after either VNS or a corpus callosotomy. The complication rate for corpus callosotomy was higher (21% all complications, 3.8% permanent) than that for VNS (8%; none permanent), but complications for both corpus callosotomy and VNS were rarely permanent. CONCLUSIONS: Both corpus callosotomy and VNS are effective in reducing generalized seizures. Corpus callosotomy is associated with greater efficacy but higher risk for complications, although these were generally transient.