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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Long-term repetitive transcranial magnetic stimulation therapy: new research questions arising from one tinnitus case?

Tinnitus may become refractory to treatment and disabling. Brain transcranial magnetic stimulation (TMS) has shown promise as a therapy, but has been employed primarily short-term. We treated a patient with 5 weeks of weekly repetitive TMS (rTMS), followed by 6 months of monthly rTMS. He was a 75-year-old dentist with chronic tinnitus from occupational noise exposure. Physical examination and MRIs of the auditory canals and brain had revealed no lesions. The patient showed a general gradual, progressive improvement on per cent of severe tinnitus diary days (from baseline 100% to 33%), tinnitus handicap inventory (from baseline score 70 to 18), and mini-tinnitus questionnaire (from baseline score 17 to 6). No changes occurred in serial audiograms. Transient adverse events were a headache during stimulation, and dizziness 30 min after treatment. Implications and questions for future non-invasive neuromodulation clinical research raised by our case are discussed.

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.

Efficacy of vagus nerve stimulation as a treatment for medically intractable epilepsy in brain tumor patients. A case-controlled study using the VNS therapy Patient Outcome Registry.

PURPOSE: Vagus nerve stimulation (VNS) therapy is a procedure to control seizure frequency in patients with medically intractable epilepsy. However, there is no data on efficacy in the subset of these patients with brain tumors. The purpose of this study is to evaluate the efficacy of VNS therapy in patients with brain tumor-associated medically intractable epilepsy. METHODS: Data from the VNS therapy Patient Outcome Registry, maintained by the manufacturer of the device, Cyberonics Inc. (Houston, TX, USA), was queried to characterize the response of patients in whom a brain tumor was listed as the etiology of epilepsy. A case-control analysis was implemented and patient outcome was measured by Engel classification, median seizure response and responder rate (≥50% seizure reduction) using t-tests and chi-squared tests. RESULTS: In 107 patients with an epilepsy etiology related to a brain tumor, seizure reduction was 45% at 3 months and 79% at 24 months with a responder rate of 48% at 3 months and 79% at 24 months. There was no statistical difference in seizure reduction compared with 326 case-control patients from the registry without brain tumors. There was no significant difference in anti-epileptic drug (AED) usage from baseline to 24 months post implant in either group. CONCLUSIONS: VNS therapy is equally effective in patients who suffer seizures secondary to brain tumors as in patients without history of a brain tumor. VNS therapy is a viable treatment option for patients with brain tumor associated medically intractable epilepsy, assuming cytoreductive and other adjuvant therapies have been fully explored.

Efficacy of vagus nerve stimulation in brain tumor-associated intractable epilepsy and the importance of tumor stability.

OBJECT: Vagus nerve stimulation (VNS) is a viable option for patients with medically intractable epilepsy. However, there are no studies examining its effect on individuals with brain tumor-associated intractable epilepsy. This study aims to evaluate the efficacy of VNS in patients with brain tumor-associated medically intractable epilepsy. METHODS: Epilepsy surgery databases at 2 separate epilepsy centers were reviewed to identify patients in whom a VNS device was placed for tumor-related intractable epilepsy between January 1999 and December 2011. Preoperative and postoperative seizure frequency and type as well as antiepileptic drug (AED) regimens and degree of tumor progression were evaluated. Statistical analysis was performed using odds ratios and t-tests to examine efficacy. RESULTS: Sixteen patients were included in the study. Eight patients (50%) had an improved outcome (Engel Class I, II, or III) with an average follow-up of 39.6 months. The mean reduction in seizure frequency was 41.7% (p = 0.002). There was no significant change in AED regimens. Seizure frequency decreased by 10.9% in patients with progressing tumors and by 65.6% in patients with stable tumors (p = 0.008). CONCLUSIONS: Vagus nerve stimulation therapy in individuals with brain tumor-associated medically intractable epilepsy was shown to be comparably effective in regard to seizure reduction and response rates to the general population of VNS therapy patients. Outcomes were better in patients with stable as opposed to progressing tumors. The authors' findings support the recommendation of VNS therapy in patients with brain tumor-associated intractable epilepsy, especially in cases in which imminent tumor progression is not expected. Vagus nerve stimulation may not be indicated in more malignant tumors.

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.

Bilateral intracranial electrodes for lateralizing intractable epilepsy: efficacy, risk, and outcome.

OBJECTIVE: Medically refractory epilepsy is amenable to neurosurgical intervention if the epileptogenic focus is accurately localized. If the scalp video-electroencephalography (EEG) and magnetic resonance imaging are nonlateralizing, yet a single focus is suspected, video-EEG monitoring with bilateral intracranial electrode placement is helpful to lateralize the ictal onset zone. We describe the indications, risks, and utility of such bilateral surveys at our institution. METHODS: We retrospectively reviewed 26 patients with medically refractory seizures who were treated over a 5-year period and underwent bilateral placement of intracranial electrodes. Subdural strips were used in all cases, and additional stereotactic implantation of depth electrodes into mesial temporal lobes occurred in 50%. The mean patient age was 37.7 years, and 65.4% of patients were male. RESULTS: The most common indication for bilateral invasive monitoring was bilateral ictal onsets on surface video-EEG (76.9%), followed by frequent interictal spikes contralateral to a single ictal focus (7.7%). Intracranial monitoring lasted an average of 8.2 days, with ictal events recorded in all cases. Ten patients (38.5%) subsequently underwent more extensive unilateral monitoring via implantation of subdural and depth electrodes through a craniotomy. A therapeutic procedure was performed in 17 patients (65.4%), whereas 1 patient underwent a palliative corpus callosotomy (3.8%). Nine patients underwent a resection without unilateral invasive mapping. Reasons for no therapeutic surgery (n = 8) included multifocal onsets, failing the Wada test, refusal of further treatment, and negative intraoperative electrocorticogram. There was 1 surgical complication, involving a retained electrode fragment that was removed in a separate minor procedure. Of the 26 patients, 15 (57.7%) are now seizure-free or have seizure disorders that have substantially improved (modified Engel classes I and II). Of the 17 patients who underwent a potentially curative surgery, 13 (76.5%) were Engel classes I and II. CONCLUSION: Bilateral placement of subdural strip and depth electrodes for epilepsy monitoring in patients with nonlateralizing scalp EEG and/or discordant imaging studies but clinical suspicion for focal seizure origin is both safe and effective. Given the safety and efficacy of this procedure, epileptologists should have a low threshold to consider bilateral implants for suitable patients.