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.

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.

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

A comparison of personality disorder characteristics of patients with nonepileptic psychogenic pseudoseizures with those of patients with epilepsy.

We sought to determine the type of personality disorder cluster associated with patients with nonepileptic psychogenic seizures (NES) compared with that of patients with epileptic seizures (ES). Consecutive adult patients admitted for video/EEG monitoring found to have NES were compared with a simultaneously admitted patient with confirmed epilepsy. Personality was assessed using the Structured Clinical Interview for DSM-IV-TR Axis II Personality Disorders. Personality disorders were then divided into personality clusters described in the DSM-IV-TR: A = paranoid, schizotypal, schizoid; B = borderline, histrionic, antisocial, narcissistic; or C = avoidant, dependent, obsessive-compulsive. Thirteen of 16 patients with NES and 12 of 16 patients with ES met criteria for personality disorders. Patients with NES were more likely to meet criteria for a personality disorder in Cluster A or B, compared with patients with ES, who were more likely to have Cluster C personality disorders (chi(2) test, P=0.007). We propose that the personality traits of patients with NES contribute to the development of nonepileptic psychogenic seizures. However, the large proportion of patients with ES with Cluster C personality disorders was unexpected, and further, for the patients with epilepsy, the direction of the association of their personality traits with the development of epilepsy is unknown.

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.

Stimulation parameters after vagus nerve stimulator replacement.

Objectives. This study aims to assess tolerability and efficacy of stimulation parameters after vagus nerve stimulator (VNS) pulse generator replacement. Materials and Methods. We carried out an observational, retrospective study, reviewing our experience with VNS generator replacements in 28 epilepsy patients. Results. Seven patients had actual end of battery life (EOBL) (with symptoms), and 21 patients had asymptomatic projected EOBL. When we reprogrammed stimulation parameters postoperatively, 17 of the 28 patients could not tolerate the preoperative baseline current settings, even one year later. There were no differences in pre- vs. postoperative seizure rates between patients who did or did not return to baseline settings. Failure to return to baseline current was not related to previous VNS duration, same- vs. different-battery generator replacements, or antiepileptic medication changes. Conclusions. After VNS generator replacement, patients' common inability to tolerate preoperative current settings does not lead to more seizures. A chronic modification of the vagus nerve system's sensitivity to stimulation changes may be hypothesized.

The effect of seizure severity on quality of life in epilepsy.

Seizure severity is an important aspect of epilepsy. The relationship between seizure severity and quality of life in epilepsy, however, has been incompletely explored. With a data set of 118 women from the baseline phase of a clinical treatment trial, the relationship between seizure severity and aspects of quality of life was evaluated. Two domains of the Quality of Life in Epilepsy-31 (QOLIE-31) correlated highly significantly with seizure severity: Seizure Worry (r=-0.265, P=.004) and Social Functioning (r=-0.280, P=0.002). Two additional domains were significantly correlated: Overall Quality of Life (r=-0.210, P=0.023) and Cognitive (r=-0.209, P=0.024). When the potentially confounding effect of depression, measured by the Beck Depression Inventory, was controlled for, the regression of seizure severity with QOLIE-31 Seizure Worry remained significant (P=0.006, R(2)=0.153), as did the regression with QOLIE-31 Social Functioning (P=0.002, R(2)=0.184) and the regression with QOLIE-31 Cognitive (P=0.037, R(2)=0.30). These findings indicate that severe and potentially injurious seizure behaviors contribute to anxiety and socially avoidant behavior for persons with intractable epilepsy.

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.

Reaction to epilepsy in the workplace.

PURPOSE: The purpose of this study was to determine the characteristics of epilepsy that produce avoidant behavior in the workplace and therefore contribute to the actual stigma that persons with epilepsy are subjected to on the job. METHODS: We developed a survey consisting three vignettes briefly describing a coworker with either depression, multiple sclerosis, or epilepsy. Each vignette was followed by eight identical questions addressing the level of comfort during interactions with the vignette subject. The epilepsy vignette did not describe a seizure. The surveys were hand-distributed in two companies in New York City and returned anonymously by mail. The results of the responses to each illness were compared by chi2, and the responses were correlated with demographic information by using Pearson's correlation. RESULTS: Seventy-four of 200 distributed questionnaires were returned. Respondents reported more anxiety at the thought of interacting with a coworker with epilepsy than with depression or multiple sclerosis, but this difference did not reach significance. Worry about sudden, unpredictable behavior for the coworker with epilepsy was significantly greater than that with multiple sclerosis (p = 0.014). The level of comfort regarding providing first aid for the coworker with epilepsy was significantly less (p = 0.018) than that for depression and multiple sclerosis. Lower job level and lower income level correlated with more social discomfort for all three illnesses. CONCLUSIONS: The idea of a having a coworker with epilepsy may produce some social avoidance. However, the worry about a sudden, unpredictable event and the discomfort regarding providing first aid for a coworker with epilepsy is significant when compared with that with depression or multiple sclerosis. These findings suggest that education about first aid for epilepsy will reduce the worry and discomfort surrounding persons with epilepsy in the workplace.