Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Long-Term Distributed Repetitive Transcranial Magnetic Stimulation for Tinnitus: A Feasibility Study.

OBJECTIVES: To assess feasibility and tolerability of long-term distributed therapeutic rTMS for refractory tinnitus, distributed over seven months. MATERIALS AND METHODS: Eight subjects with refractory tinnitus underwent five weekly sessions of 1800 pulses of 1 Hz rTMS targeted toward the temporoparietal junction. Five weeks later (study week 10), subjects meeting predefined responder criteria entered a monthly rTMS treatment phase, for the next five months. Outcome measures were subject satisfaction and compliance, tinnitus severity daily diaries, standardized tinnitus self-rating scales, and adverse events. RESULTS: Subject satisfaction was high, and compliance was virtually 100%. The tinnitus handicap inventory and mini-tinnitus questionnaire scores improved significantly at study week 5 compared with baseline. There were four responders at study week 5; three responders at study week 10; and one responder at study week 30. There were no serious adverse events. CONCLUSIONS: Our study demonstrated that rTMS can be delivered in a distributed schedule that is well-tolerated, feasible and may prove to be clinically beneficial. A long-term distributed rTMS schedule for tinnitus may warrant investigation as an alternative to the short-term aggregated treatment schedules more frequently used previously. For the many varied therapeutic uses of rTMS (established and investigational), treatment schedules are relatively unexplored, and deserve further attention.

Intensity dependent effects of transcranial direct current stimulation on corticospinal excitability in chronic spinal cord injury.

OBJECTIVE: To investigate the effects of anodal transcranial direct current stimulation (a-tDCS) intensity on corticospinal excitability and affected muscle activation in individuals with chronic spinal cord injury (SCI). DESIGN: Single-blind, randomized, sham-controlled, crossover study. SETTING: Medical research institute and rehabilitation hospital. PARTICIPANTS: Volunteers (N = 9) with chronic SCI and motor dysfunction in wrist extensor muscles. INTERVENTIONS: Three single session exposures to 20 minutes of a-tDCS (anode over the extensor carpi radialis [ECR] muscle representation on the left primary motor cortex, cathode over the right supraorbital area) using 1 mA, 2 mA, or sham stimulation, delivered at rest, with at least 1 week between sessions. MAIN OUTCOME MEASURES: Corticospinal excitability was assessed with motor-evoked potentials (MEPs) from the ECR muscle using surface electromyography after transcranial magnetic stimulation. Changes in spinal excitability, sensory threshold, and muscle strength were also investigated. RESULTS: Mean MEP amplitude significantly increased by approximately 40% immediately after 2mA a-tDCS (pre: 0.36 ± 0.1 mV; post: 0.47 ± 0.11 mV; P = .001), but not with 1 mA or sham. Maximal voluntary contraction measures remained unaltered across all conditions. Sensory threshold significantly decreased over time after 1mA (P = .002) and 2mA (P = .039) a-tDCS and did not change with sham. F-wave persistence showed a nonsignificant trend for increase (pre: 32% ± 12%; post: 41% ± 10%; follow-up: 46% ± 12%) after 2 mA stimulation. No adverse effects were reported with any of the experimental conditions. CONCLUSIONS: The a-tDCS can transiently raise corticospinal excitability to affected muscles in patients with chronic SCI after 2 mA stimulation. Sensory perception can improve with both 1 and 2 mA stimulation. This study gives support to the safe and effective use of a-tDCS using small electrodes in patients with SCI and highlights the importance of stimulation intensity.

Effects of responsive electrical brain stimulation on intracranial electroencephalogram spikes.

OBJECTIVES: Responsive cortical electrical stimulation with implanted devices is under investigation for seizures. While designed to terminate seizures, might this stimulation also affect the underlying epileptic process of seizure generation? MATERIALS AND METHODS: Four patients undergoing intracranial electroencephalogram (EEG) for seizure localization had an external responsive neurostimulator (eRNS) connected to their seizure-onset zones. The eRNS detected interictal EEG spikes and stimulated at the focus. We quantified spikes at three locations: (1) near stimulation, (2) remote but in the same lobe as stimulation, and (3) in different lobe from stimulation. Ten-minute windows were analyzed at three times: (1) baseline, (2) after the first four hours of stimulation, and (3) poststimulation. One blinded investigator performed manual spike counts. Quantitative measures were total spikes, spike-free intervals (continuous ten-sec segments with no spikes), and spike clusters (one-sec intervals with three or more spikes). RESULTS: Some changes in spikes occurred in each patient, but no uniform pattern emerged. Two general observations were made: (1) spike counts within a given patient exhibited internally consistent changes with stimulation; (2) across patients, the nature of spike count changes varied, indicating patient-to-patient variability. For example, poststimulation, two patients had more and two patients had fewer total spikes. However, when spikes decreased near stimulation, they decreased at other sites, and when spikes increased near stimulation, they increased at other sites. CONCLUSIONS: Changes in spike occurrence, organization, and topography with stimulation suggest the eRNS affected spike generation and may affect the underlying interictal epileptic process. Case-to-case variability may be due to individual patient factors, and its significance is yet to be determined.

The value of intraoperative electrocorticography in surgical decision making for temporal lobe epilepsy with normal MRI.

PURPOSE: We hypothesized that acute intraoperative electrocorticography (ECoG) might identify a subset of patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) who could proceed directly to standard anteromesial resection (SAMR), obviating the need for chronic electrode implantation to guide resection. METHODS: Patients with TLE and a normal MRI who underwent acute ECoG prior to chronic electrode recording of ictal onsets were evaluated. Intraoperative interictal spikes were classified as mesial (M), lateral (L), or mesial/lateral (ML). Results of the acute ECoG were correlated with the ictal-onset zone following chronic ECoG. Onsets were also classified as "M,""L," or "ML." Positron emission tomography (PET), scalp-EEG (electroencephalography), and Wada were evaluated as adjuncts. KEY FINDINGS: Sixteen patients fit criteria for inclusion. Outcomes were Engel class I in nine patients, Engel II in two, Engel III in four, and Engel IV in one. Mean postoperative follow-up was 45.2 months. Scalp EEG and PET correlated with ictal onsets in 69% and 64% of patients, respectively. Wada correlated with onsets in 47% of patients. Acute intraoperative ECoG correlated with seizure onsets on chronic ECoG in all 16 patients. All eight patients with "M" pattern ECoG underwent SAMR, and six (75%) experienced Engel class I outcomes. Three of eight patients with "L" or "ML" onsets (38%) had Engel class I outcomes. SIGNIFICANCE: Intraoperative ECoG may be useful in identifying a subset of patients with MRI-negative TLE who will benefit from SAMR without chronic implantation of electrodes. These patients have uniquely mesial interictal spikes and can go on to have improved postoperative seizure-free outcomes.

Effect of levetiracetam on testosterone levels in male patients.

We sought to determine whether the testosterone increase found with levetiracetam exposure in animal studies also occurs in patients. Adult male patients were evaluated for reproductive hormone levels before and 1 month after levetiracetam therapy. Eight subjects met inclusion/exclusion criteria (mean age 46 years, range 29-75 years). Total testosterone prior to starting levetiracetam ranged from 206-787 ng/dl [mean 445, standard deviation (SD) 227]. The mean total testosterone after levetiracetam therapy increased to 592 ng/dl (range 216-981, SD 297), an increase of 16% (p = 0.036). The free testosterone increased from a mean of 64 pg/ml (range 36-115, SD 30) to a mean of 76 pg/ml (range 35-155, SD 44), an increase of 19% (p = 0.080). The magnitude of change in testosterone levels correlated with the initial testosterone level (p = 0.038, r = 0.734). These results suggest that levetiracetam increases testosterone levels and that an initial testosterone level may predict the magnitude of increase.

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.

PURPOSE: 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.

Machine Learning Methods Predict Individual Upper-Limb Motor Impairment Following Therapy in Chronic Stroke.

Background. Accurate prediction of clinical impairment in upper-extremity motor function following therapy in chronic stroke patients is a difficult task for clinicians but is key in prescribing appropriate therapeutic strategies. Machine learning is a highly promising avenue with which to improve prediction accuracy in clinical practice. Objectives. The objective was to evaluate the performance of 5 machine learning methods in predicting postintervention upper-extremity motor impairment in chronic stroke patients using demographic, clinical, neurophysiological, and imaging input variables. Methods. A total of 102 patients (female: 31%, age 61 ± 11 years) were included. The upper-extremity Fugl-Meyer Assessment (UE-FMA) was used to assess motor impairment of the upper limb before and after intervention. Elastic net (EN), support vector machines, artificial neural networks, classification and regression trees, and random forest were used to predict postintervention UE-FMA. The performances of methods were compared using cross-validated R2. Results. EN performed significantly better than other methods in predicting postintervention UE-FMA using demographic and baseline clinical data (median REN2=0.91,RRF2=0.88,RANN2=0.83,RSVM2=0.79,RCART2=0.70;P < .05). Preintervention UE-FMA and the difference in motor threshold (MT) between the affected and unaffected hemispheres were the strongest predictors. The difference in MT had greater importance than the absence or presence of a motor-evoked potential (MEP) in the affected hemisphere. Conclusion. Machine learning methods may enable clinicians to accurately predict a chronic stroke patient's postintervention UE-FMA. Interhemispheric difference in the MT is an important predictor of chronic stroke patients' response to therapy and, therefore, could be included in prospective studies.

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.

Spectral Content of Electroencephalographic Burst-Suppression Patterns May Reflect Neuronal Recovery in Comatose Post-Cardiac Arrest Patients.

PURPOSE: To assess the potential biologic significance of variations in burst-suppression patterns (BSPs) after cardiac arrest in relation to recovery of consciousness. In the context of recent theoretical models of BSP, bursting frequency may be representative of underlying network dynamics; discontinuous activation of membrane potential during impaired cellular energetics may promote neuronal rescue. METHODS: We reviewed a database of 73 comatose post-cardiac arrest patients who underwent therapeutic hypothermia to assess for the presence of BSP and clinical outcomes. In a subsample of patients with BSP (n = 14), spectral content of burst and suppression periods were quantified using multitaper method. RESULTS: Burst-suppression pattern was seen in 45/73 (61%) patients. Comparable numbers of patients with (31.1%) and without (35.7%) BSP regained consciousness by the time of hospital discharge. In addition, in two unique cases, BSP initially resolved and then spontaneously reemerged after completion of therapeutic hypothermia and cessation of sedative medications. Both patients recovered consciousness. Spectral analysis of bursts in all patients regaining consciousness (n = 6) showed a prominent theta frequency (5-7 Hz) feature, but not in age-matched patients with induced BSP who did not recover consciousness (n = 8). CONCLUSIONS: The prognostic implications of BSP after hypoxic brain injury may vary based on the intrinsic properties of the underlying brain state itself. The presence of theta activity within bursts may index potential viability of neuronal networks underlying recovery of consciousness; emergence of spontaneous BSP in some cases may indicate an innate neuroprotective mechanism. This study highlights the need for better characterization of various BSP patterns after cardiac arrest.

Implicit and explicit memory for affective passages in temporal lobectomy patients.

Eighteen temporal lobectomy patients (9 left, LTL; 9 right, RTL) were administered four verbal tasks, an Affective Implicit Task, a Neutral Implicit Task, an Affective Explicit Task, and a Neutral Explicit Task. For the Affective and Neutral Implicit Tasks, participants were timed while reading aloud passages with affective or neutral content, respectively, as quickly as possible, but not so quickly that they did not understand. A target verbal passage was repeated three times; this target passage was alternated with other previously unread passages, and all passages had the same number of words. The Explicit Affective and Neutral Tasks were administered at the end of testing, and consisted of multiple choice questions regarding passage content. Verbal priming effects in terms of improved reading speed with repetition for the target but not non-target passages were found for patients with both left and right temporal lobectomies. As in the Burton, Rabin et al. [Burton, L., Rabin, L., Vardy, S.B., Frohlich, J., Wyatt, G., Dimitri, D., Constante, S., Guterman, E. (2004). Gender differences in implicit and explicit memory for affective passages. Brain and Cognition, 54(3), 218-224] normative study, there were no interactions between this priming effect and affective/neutral content. For the explicit tasks, items from the repeated passages were remembered better than the unrepeated passages, and there was a trend for information from the affective passages to be remembered better than the neutral passages, similar to the normative pattern. The RTL group did not show the normative pattern of slower reading speed for affective compared to neutral passages that the LTL group showed. Thus, the present findings support the idea that intact right medial temporal structures are important for affective content to influence some aspects of verbal processing.

Latency to first spike in the EEG of epilepsy patients.

BACKGROUND: Routine EEGs in individuals with epilepsy have interictal spikes in 56% of cases. The availability of prolonged EEG has changed the use of EEG in the assessment of epilepsy. OBJECTIVE: To determine the time to first epileptiform activity on EEG in patients with epilepsy. This data will help optimize the duration of electrographic assessment for interictal activity in epileptic individuals. METHODS: 46 consecutive patients aged 10 years or older with epilepsy were evaluated. Individuals with seizures in the prior 24h or with acute symptomatic seizures were excluded. Continuous EEG (for 1-7 days) was analyzed to find the first definite epileptiform activity and the latency assessed. RESULTS: 37% of the patients had epileptiform activity in the first 20min of the continuous recording (duration of a routine EEG). 89% had epileptiform activity within 24h. The yield drops beyond 24h. 8% of the individuals had no epileptiform activity even after 72h. CONCLUSIONS: The study suggests the need to consider a change in EEG strategy to assess interictal epileptiform activity. The greatest probability of capturing an interictal abnormality within 20min was in individuals with generalized epilepsy. In individuals with suspected epilepsy in whom electrographic interictal spike confirmation is deemed necessary, after a first nonspecific or normal routine EEG, a 24h EEG should be the next step in the electrographic assessment. This study suggests that there may not be much benefit in monitoring for durations longer than 24h, unless capturing a seizure is the intent.

EEG Characteristics in Cooled and Rewarmed Periods in Post-cardiac Arrest Therapeutic Hypothermia Patients.

PURPOSE: Continuous video EEG is a tool to assess brain function in injuries, including cardiac arrest (CA). In post-CA therapeutic hypothermia (TH) studies, some EEG features are linked to poor prognosis, but the evolvement of EEG characteristics during two temperature phases and its significance is unclear. We systematically analyzed EEG characteristics in cooled and rewarmed phases of post-CA therapeutic hypothermia patients and investigated their correlation to patient outcome. METHODS: This is a retrospective study of EEG analyses, from a single academic center, of 20 patients who underwent CA and therapeutic hypothermia. For each patient, three 30-minute EEG segments in cooled and rewarmed phases were analyzed for continuity, frequency, interictal epileptiform discharges, and seizures. Mortality at the time of discharge was used as outcome. RESULTS: Rewarming was associated with the emergence of interictal epileptiform discharges, 2.6 times as likely compared with the cooled period (P = 0.03), and was not affected by systemic factors. Continuity, frequency, and discrete seizures were unaffected by temperature and did not show variance within each temperature phase. There was a trend toward the emergence of interictal epileptiform discharges upon rewarming and mortality, but it was not statistically significant. CONCLUSIONS: Increased interictal epileptiform discharges with rewarming in post-CA therapeutic hypothermia patients may suggest poor prognosis, but a larger scale prospective study is needed.

SSEP in Therapeutic Hypothermia Era.

PURPOSE: The reliability of somatosensory evoked potentials (SSEPs) in predicting outcome in comatose survivors of cardiac arrest treated with therapeutic hypothermia (TH) has been questioned. We investigated whether the absence of cortical (N20) responses was a reliable predictor of a nonawakening in the setting of TH. METHODS: A retrospective review was conducted in cardiac arrest survivors treated with TH admitted to a single tertiary care hospital from April, 2010 to March, 2013 who underwent SSEP testing at various time points after cardiac arrest. N20 responses were categorized as normal, present but abnormal, bilaterally absent, or inadequate for interpretation. Neurologic outcome was assessed at discharge by the Cerebral Performance Category Scale (CPC). RESULTS: Ninety-three SSEP studies were performed in 73 patients. Fourteen patients had absent N20 responses; all had poor outcome (CPC 4-5). Eleven patients had absent N20 s during hypothermia, three of whom had follow-up SSEPs after rewarming and cortical responses remained absent. Fifty-seven patients had N20 peaks identified and had variable outcomes. Evaluation of 1 or more N20 peaks was limited or inadequate in 11.4% of SSEPs performed during the cooling because of artifact. CONCLUSIONS: Somatosensory evoked potentials remain a reliable prognostic indicator in patients undergoing TH. The limited sample size of patients who had SSEP performed during TH and repeated after normothermia added to the effect of self-fulfilling prophecy limit the interpretation of the reliability of this testing when performed during cooling. Further prospective, multicenter, large scale studies correlating cortical responses in SSEPs during and after TH are warranted. Technical challenges are commonplace during TH and caution is advised in the interpretation of suboptimal recordings.

A Framework for Combining rTMS with Behavioral Therapy.

Upon its inception, repetitive transcranial magnetic stimulation (rTMS) was delivered at rest, without regard to the potential impact of activity occurring during or around the time of stimulation. rTMS was considered an experimental intervention imposed on the brain; therefore, the myriad features that might suppress or enhance its desired effects had not yet been explored. The field of rTMS has since grown substantially and therapeutic benefits have been reported, albeit with modest and inconsistent improvements. Work in this field accelerated following approval of a psychiatric application (depression), and it is now expanding to other applications and disciplines. In the last decade, experimental enquiry has sought new ways to improve the therapeutic benefits of rTMS, intended to enhance underlying brain reorganization and functional recovery by combining it with behavioral therapy. This concept is appealing, but poorly defined and requires clarity. We provide an overview of how combined rTMS and behavioral therapy has been delineated in the literature, highlighting the diversity of approaches. We outline a framework for study design and reporting such that the effects of this emerging method can be better understood.

Frameless stereotactic placement of depth electrodes in epilepsy surgery.

OBJECT: Depth electrodes are useful in the identification of deep epileptogenic foci. Computerized tomography-magnetic resonance (CT/MR)- and angiography-guided frame-based techniques are safe and accurate but require four-point skull fixation that limits cranial access for the placement of additional grids and strips. The authors investigated the viability and accuracy of placing depth electrodes by using a commercially available frameless system. METHODS: A slotted, custom-designed adapter was built to interface with the StealthStation Guide Frame-DT and 960-525 StealthFighter. The Cranial Navigation software was used to plan the trajectory and entry site based on preoperative spoiled gradient MR imaging studies. Forty-one depth electrodes were placed in 51 targets in 20 patients. Thirty-one of these electrodes were inserted through the temporal neocortex following craniotomy and placement of subdural grids, whereas 10 were placed through burr holes. All electrodes had contact either within (71%) or touching (29%) the target, 50 of which (98%) provided adequate recordings. Although the mean distance of the distal electrode contact from the intended target was 3.1 +/- 0.5 mm, the mean distance to the edge of the anatomical structure was 0.4 +/- 0.9 mm. Placement via the laterotemporal approach was significantly (p < 0.001) more accurate than that via the occipitotemporal approach. No complication occurred. CONCLUSIONS: Depth electrodes can be placed safely and accurately by using a commercially available frameless stereotactic navigation system and a custom-made adapter. Depth electrode placement to record ictal onsets during epilepsy surgery only requires the contacts to touch rather than to reside within the intended structure. The laterotemporal approach is a more accurate method of placing electrodes than is the occipitotemporal one, likely due to the increased distance from the entry point to the target.

Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

OBJECTIVE: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. METHODS: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. RESULTS: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). CONCLUSIONS: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Long-term efficacy and safety of thalamic stimulation for drug-resistant partial 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 localization-related 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.

Antiepileptic drug use during the first 12 months of vagus nerve stimulation therapy: a registry study.

Understanding interrelationships between antiepileptic drugs (AEDs) and vagus nerve stimulation (VNS) therapy can guide research into epilepsy treatment. A constant cohort of patients with data available at baseline and 12 months were drawn from the VNS patient outcome registry and analyzed for changes in AEDs and seizure rates. Of the 1,407 patients, group 1 (n = 896) took fewer (n = 228) or the same (n = 668) AEDs at 12 months compared to baseline. Group 2 (n = 511) took additional (n = 251) or different (n = 260) AEDs. Median seizure rate reductions after 12 months of VNS therapy were 58% in group 1 and 55% in group 2. The number of and specific AEDs remained unchanged for 668 patients and dosages remained the same for 269 (40%) of these patients. The most commonly discontinued drugs were topiramate (n = 115), tiagabine (n = 78), carbamazepine (n = 62), lamotrigine (n = 56), and gabapentin (n = 52). Changes in seizure rates were not significantly different among patients who added levetiracetam (n = 151), zonisamide (n = 71), or oxcarbazepine (n = 46) to VNS. Changes in seizure rates were not significantly different among patients whose baseline AEDs were carbamazepine (n = 273), lamotrigine (n = 238), valproate (n = 201), topiramate (n = 190), or phenytoin (n = 151). Our results suggest the following: (a) patients commonly stay on the same AEDs during 12 months of treatment with VNS; (b) the registry cohort who had reduced AEDs by month 12 did not appear to experience any seizure exacerbation; and (c) no specific AED shows promise of unique additive antiepileptic effects in combination with VNS.