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.

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.

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.

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.

Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study.

PURPOSE: Previous reports have suggested that hormone replacement therapy (HRT) could increase seizure activity in women with epilepsy. We sought to determine whether adding HRT to the medication regimen of postmenopausal women with epilepsy was associated with an increase in seizure frequency. METHODS: This was a randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy, taking stable doses of antiepileptic drugs (AEDs), and within 10 years of their last menses. After a 3-month prospective baseline, subjects were randomized to placebo, Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period. RESULTS: Twenty-one subjects were randomized after completing baseline. The subjects' ages ranged from 45 to 62 years (mean, 53 years; SD, +/-5), and the number of AEDs used ranged from none to three (median, one). Five (71%) of seven subjects taking double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared with four (50%) of eight taking single-dose CEE/MPA and one (17%) of six taking placebo (p = 0.05). An increase in seizure frequency of the subject's most severe seizure type was associated with increasing CEE/MPA dose (p = 0.008). An increase in complex partial seizure frequency also was associated with increasing CEE/MPA dose (p = 0.05). Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25-30% while taking CEE/MPA. CONCLUSIONS: CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels.

Cerebral activation during vagus nerve stimulation: a functional MR study.

PURPOSE: To study the short-term effects of vagus nerve stimulation (VNS) on brain activation and cerebral blood flow by using functional magnetic resonance imaging (fMRI). METHODS: Five patients (three women, two men; mean age, 35.4 years) who were treated for medically refractory epilepsy with VNS, underwent fMRI. All patients had a nonfocal brain MRI. The VNS was set at 30 Hz, 0.5-2.0 mA for intervals of activation of 30 s on and 30 s off, during which the fMRI was performed. Statistical parametric mapping (SPM) was used to determine significant areas of activation or inhibition during vagal nerve stimulation (p < 0.05). RESULTS: VNS-induced activation was detected in the thalami bilaterally (left more than right), insular cortices bilaterally, ipsilateral basal ganglia and postcentral gyri, right posterior superior temporal gyrus, and inferomedial occipital gyri (left more than right). The most robust activation was seen in the thalami (left more than right) and insular cortices. CONCLUSIONS: VNS-induced thalamic and insular cortical activation during fMRI suggests that these areas may play a role in modulating cerebral cortical activity, and the observed decrease in seizure frequency in patients who are given VNS may be a consequence of this increased activation.

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.

A Pilot Study of Mood in Epilepsy Patients Treated with Vagus Nerve Stimulation.

Context. Antiepileptic drugs (AEDs) are frequently used for their beneficial mood effects.Objective. We sought to determine if there was a quantifiable effect on mood of the vagus nerve stimulator (VNS) when used as an antiseizure treatment.Design. Mood was assessed before and 3 months after VNS implantation in adult epilepsy patients. A group of adult epilepsy patients on stable AED regimens were used as a comparison group. AED regimens were unchanged during the study. The change in mood scale scores across time was assessed by t test (intragroup) and two-factor repeated-measures ANOVA (intergroup).Setting. An epilepsy center in a university hospital was the setting.Subjects. Twenty consecutive adult epilepsy patients undergoing VNS implantation to improve seizure control and twenty adult seizure patients with no intervention were enrolled.Main outcome measures. The mood scales used were the Cornell Dysthymia Rating Scale (CDRS) and the Hamilton Depression (Ham-D), Hamilton Rating Scale for Anxiety (Ham-A), and Beck Depression Inventory (BDI) scales.Results. The VNS group showed a significant decrease in mood scale scores across time (t test CDRS P = 0.001, Ham-D P = 0.017, BDI P = 0.045), indicating a decrease in depressive symptoms. The Ham-A scores in the VNS group and the comparison group scores did not significantly change across time. There were no significant differences between groups across time, although the BDI approached significance at P = 0.07. The VNS group had a significant decrease in seizure frequency compared with the comparison group (P = 0.01). There was no difference in mood scales over time between the VNS treatment responders (defined by >50% decrease in seizure frequency) and nonresponders, suggesting dissociation between seizure frequency reduction and mood change.Conclusion. VNS treatment is associated with mood improvement as measured by multiple scales, but differences in mood scale scores over time between the VNS and a comparison group were not found.