Mapping Lesion-Related Epilepsy to a Human Brain Network.

Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P < .001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P < .001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P < .001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies.

Initial case series of a novel sensing deep brain stimulation device in drug-resistant epilepsy and consistent identification of alpha/beta oscillatory activity: A feasibility study.

OBJECTIVE: Here, we report a retrospective, single-center experience with a novel deep brain stimulation (DBS) device capable of chronic local field potential (LFP) recording in drug-resistant epilepsy (DRE) and explore potential electrophysiological biomarkers that may aid DBS programming and outcome tracking. METHODS: Five patients with DRE underwent thalamic DBS, targeting either the bilateral anterior (n = 3) or centromedian (n = 2) nuclei. Postoperative electrode lead localizations were visualized in Lead-DBS software. Local field potentials recorded over 12-18 months were tracked, and changes in power were associated with patient events, medication changes, and stimulation. We utilized a combination of lead localization, in-clinic broadband LFP recordings, real-time LFP response to stimulation, and chronic recordings to guide DBS programming. RESULTS: Four patients (80%) experienced a >50% reduction in seizure frequency, whereas one patient had no significant reduction. Peaks in the alpha and/or beta frequency range were observed in the thalamic LFPs of each patient. Stimulation suppressed these LFP peaks in a dose-dependent manner. Chronic timeline data identified changes in LFP amplitude associated with stimulation, seizure occurrences, and medication changes. We also noticed a circadian pattern of LFP amplitudes in all patients. Button-presses during seizure events via a mobile application served as a digital seizure diary and were associated with elevations in LFP power. SIGNIFICANCE: We describe an initial cohort of patients with DRE utilizing a novel sensing DBS device to characterize potential LFP biomarkers of epilepsy that may be associated with seizure control after DBS in DRE. We also present a new workflow utilizing the Percept device that may optimize DBS programming using real-time and chronic LFP recording.

Three-layer model with absorption for conservative estimation of the maximum acoustic transmission coefficient through the human skull for transcranial ultrasound stimulation.

Transcranial ultrasound stimulation (TUS) has been shown to be a safe and effective technique for non-invasive superficial and deep brain stimulation. Safe and efficient translation to humans requires estimating the acoustic attenuation of the human skull. Nevertheless, there are no international guidelines for estimating the impact of the skull bone. A tissue independent, arbitrary derating was developed by the U.S. Food and Drug Administration to take into account tissue absorption (0.3 dB/cm-MHz) for diagnostic ultrasound. However, for the case of transcranial ultrasound imaging, the FDA model does not take into account the insertion loss induced by the skull bone, nor the absorption by brain tissue. Therefore, the estimated absorption is overly conservative which could potentially limit TUS applications if the same guidelines were to be adopted. Here we propose a three-layer model including bone absorption to calculate the maximum pressure transmission through the human skull for frequencies ranging between 100 kHz and 1.5 MHz. The calculated pressure transmission decreases with the frequency and the thickness of the bone, with peaks for each thickness corresponding to a multiple of half the wavelength. The 95th percentile maximum transmission was calculated over the accessible surface of 20 human skulls for 12 typical diameters of the ultrasound beam on the skull surface, and varies between 40% and 78%. To facilitate the safe adjustment of the acoustic pressure for short ultrasound pulses, such as transcranial imaging or transcranial ultrasound stimulation, a table summarizes the maximum pressure transmission for each ultrasound beam diameter and each frequency.

Low Intensity Focused Ultrasound for Epilepsy- A New Approach to Neuromodulation.

Patients with drug-resistant epilepsy (DRE) who are not surgical candidates have unacceptably few treatment options. Benefits of implanted electrostimulatory devices are still largely palliative, and many patients are not eligible to receive them. A new form of neuromodulation, low intensity focused ultrasound (LIFUS), is rapidly emerging, and has many potential intracranial applications. LIFUS can noninvasively target tissue with a spatial distribution of highly focused acoustic energy that ensures a therapeutic effect only at the geometric focus of the transducer. A growing literature over the past several decades supports the safety of LIFUS and its ability to noninvasively modulate neural tissue in animals and humans by positioning the beam over various brain regions to target motor, sensory, and visual cortices as well as frontal eye fields and even hippocampus. Several preclinical studies have demonstrated the ability of LIFUS to suppress seizures in epilepsy animal models without damaging tissue. Resection after sonication to the antero-mesial lobe showed no pathologic changes in epilepsy patients, and this is currently being trialed in serial treatments to the hippocampus in DRE. Low intensity focused ultrasound is a promising, novel, incisionless, and radiation-free alternative form of neuromodulation being investigated for epilepsy. If proven safe and effective, it could be used to target lateral cortex as well as deep structures without causing damage, and is being studied extensively to treat a wide variety of neurologic and psychiatric disorders including epilepsy.

Clinical 7T MRI for epilepsy care: Value, patient selection, technical issues, and outlook.

Ultra-high-field 7.0 Tesla (T) MRI offers substantial gains in signal-to-noise ratio (SNR) over 3T and 1.5T, but for over two decades has remained a research tool, while 3T scanners have achieved widespread clinical use. This much slower translation of 7T relates to daunting technical challenges encountered in ultra-high-field human MR imaging. The recent introduction of United States Food and Drug Administration (FDA)-approved clinical 7T scanners promises to be a watershed for many 7T neuroimaging applications, including epilepsy imaging. The high SNR of 7T allows clinical imaging of fine neuroanatomic detail at unprecedented spatial resolution, helping with detection and differentiation of subtle, potentially treatable lesions undetectable or suboptimally assessed at 3T. The accompanying research paper reports our group's analysis of 7T MRI efficacy in epilepsy treatment planning. Here, we introduce the technical background and clinical approach we currently use, in order to assist clinical epileptologists and neuroimagers contemplating, creating, or referring patients to a clinical 7T epilepsy imaging service. We describe a tiered epilepsy imaging strategy and protocols designed to optimize 7T value and work around signal intensity variation and signal loss artifacts, which remain significant challenges to full exploitation of 7T clinical value. We describe FDA-approved techniques for mitigating these artifacts and briefly outline techniques currently under development, but not yet FDA approved. Finally, we discuss the major issues in 7T patient safety and toleration, outlining their physical causes and effects on workflow, and provide references to more comprehensive technical reviews for readers seeking greater technical detail.

7T versus 3T MRI in the presurgical evaluation of patients with drug-resistant epilepsy.

BACKGROUND AND PURPOSE: MRI has a crucial role in presurgical evaluation of drug-resistant focal epilepsy patients. Whether and how much 7T MRI further improves presurgical diagnosis compared to standard of care 3T MRI remains to be established. We investigate the added value 7T MRI offers in surgical candidates with remaining clinical uncertainty after 3T MRI. METHODS: 7T brain MRI was obtained on sequential patients with drug-resistant focal epilepsy undergoing presurgical evaluation at a comprehensive epilepsy center, including patients with and without suspected lesions on standard 3T MRI. Clinical information and 3T images informed the interpretation of 7T images. Detection of a new lesion on 7T or better characterization of a suspected lesion was considered to add value to the presurgical workup. RESULTS: Interpretable 7T MRI was acquired in 19 patients. 7T MRI identified a lesion relevant to the seizures in three of eight patients (38%) without a lesion on 3T MRI; no lesion in 7/11 patients (64%) with at least one suspected lesion on 3T MRI, contributing to the final classification of all seven as nonlesional; and confirmed and better characterized the lesion suspected at 3T MR in the remaining 4/11 patients. CONCLUSIONS: 7T MRI detected new lesions in over a third of 3T MRI nonlesional patients, confirmed and better characterized a 3T suspected lesion in one third of patients, and helped exclude a 3T suspected lesion in the remainder. Our initial experience suggests that 7T MRI adds value to surgical planning by improving detection and characterization of suspected brain lesions in drug-resistant focal epilepsy patients.

Seizures Among Patients with Brain Metastases: A Population- and Institutional-level Analysis.

OBJECTIVE: To test the hypothesis that subets of patients with brain metastases (BrM) without seizures at intracranial presentation are at increased risk for developing seizures, we characterized the incidence and risk factors for seizure development among seizure-naïve patients with brain metastases (BrM). METHODS: We identified 15,863 and 1,453 patients with BrM utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2016) and Brigham and Women's Hospital/Dana Farber Cancer Institute (2000-2015) institutional data, respectively. Cumulative incidence curves and Fine/Gray's competing risks regression were used to characterize seizure incidence and risk factors, respectively. RESULTS: Among SEER-Medicare and institutional patients, 1,588 (10.0%) and 169 (11.6%) developed seizures, respectively. On multivariable regression of the SEER-Medicare cohort, African American vs. White race (hazard ratio [HR]=1.45 [95% CI, 1.22-1.73], p<0.001), urban vs. non-urban residence (HR=1.41 [95% CI, 1.17-1.70], p<0.001), melanoma vs. NSCLC as primary tumor type (HR=1.44 [95% CI, 1.20-1.73], p<0.001), and receipt of brain-directed stereotactic radiation (HR=1.67 [95% CI, 1.44-1.94], p<0.001) were associated with greater seizure risk. On multivariable regression of the institutional cohort, melanoma vs. NSCLC (HR=1.70 [95% CI, 1.09-2.64], p=0.02), >4 BrM at diagnosis (HR=1.60 [95% CI, 1.12-2.29], p=0.01), presence of BrM in a high-risk location (HR=3.62 [95% CI, 1.60-8.18], p=0.002), and lack of local brain-directed therapy (HR=3.08 [95% CI, 1.45-6.52], p=0.003) were associated with greater risk of seizure development. CONCLUSIONS: The role of antiseizure medications among select patients with BrM should be re-explored, particularly for those with melanoma, a greater intracranial disease burden, and/or BrM in high-risk locations.

Focused Ultrasound Platform for Investigating Therapeutic Neuromodulation Across the Human Hippocampus.

Pulsed low-intensity focused ultrasound (PLIFUS) has shown promise in inducing neuromodulation in several animal and human studies. Therefore, it is of clinical interest to develop experimental platforms to test repetitive PLIFUS as a therapeutic modality in humans with neurologic disorders. In the study described here, our aim was to develop a laboratory-built experimental device platform intended to deliver repetitive PLIFUS across the hippocampus in seizure onset zones of patients with drug-resistant temporal lobe epilepsy. The system uses neuronavigation targeting over multiple therapeutic sessions. PLIFUS (548 kHz) was emitted across multiple hippocampal targets in a human subject with temporal lobe epilepsy using a mechanically steered piezoelectric transducer. Stimulation was delivered up to 2.25 W/cm2 spatial peak temporal average intensity (free-field equivalent), with 36%-50% duty cycle, 500-ms sonications and 7-s inter-stimulation intervals lasting 140 s per target and repeated for multiple sessions. A first-in-human PLIFUS course of treatment was successfully delivered using the device platform with no adverse events.

Positive Airway Pressure Therapy Is Challenging for Patients With Epilepsy.

STUDY OBJECTIVES: To investigate whether patients with epilepsy and comorbid obstructive sleep apnea (OSA) are more likely to be nonadherent to positive airway pressure (PAP) therapy than adults with OSA but without epilepsy. METHODS: This retrospective study included patients with epilepsy diagnosed with OSA and age-, sex-, and apnea-hypopnea index (AHI)-matched controls with OSA but without epilepsy who started PAP treatment between February 2014 and August 2017. Subjects' adherence to PAP therapy was continuously recorded electronically, and comparisons were made at 1 month, 3 months, and 1 year following PAP initiation. Predictors to poor adherence were also evaluated. RESULTS: Patients with epilepsy (n = 23) were less adherent to PAP than controls (n = 23) during the first month of treatment (13% versus 78%, P = .03). During this first month, average PAP use was lower in patients with epilepsy (4.7 ± 2.1 hours) relative to controls (6.1 ± 1.2 hours, P = .03). Despite sustained PAP treatment, patients with epilepsy had a greater residual AHI and were five times more likely than controls to have residual apnea events above normal range at 3-month and 1-year follow-up. However, no clinical characteristics could significantly predict poor adherence in patients. CONCLUSIONS: Patients with epilepsy are less likely to be adherent to PAP therapy during the first month of treatment, as compared to adults with OSA but no epilepsy. Moreover, PAP therapy could not sufficiently reduce AHI in up to 72% of patients. These findings highlight the need for careful monitoring of PAP treatment in patients with epilepsy, as untreated OSA may worsen seizure burden.

Scalp sensor for simultaneous acoustic emission detection and electroencephalography during transcranial ultrasound.

Focused ultrasound is now capable of noninvasively penetrating the intact human skull and delivering energy to specific areas of the brain with millimeter accuracy. The ultrasound energy is supplied in high-intensities to create brain lesions or at low-intensities to produce reversible physiological interventions. Conducting acoustic emission detection (AED) and electroencephalography (EEG) during transcranial focused ultrasound may lead to several new brain treatment and research applications. This study investigates the feasibility of using a novel scalp senor for acquiring concurrent AED and EEG during clinical transcranial ultrasound. A piezoelectric disk is embedded in a plastic cup EEG electrode to form the sensor. The sensor is coupled to the head via an adhesive/conductive gel-dot. Components of the sensor prototype are tested for AED and EEG signal quality in a bench top investigation with a functional ex vivo skull phantom.

Sleep-dependent memory consolidation in the epilepsy monitoring unit: A pilot study.

OBJECTIVE: We sought to examine whether patients with focal epilepsy exhibit sleep dependent memory consolidation, whether memory retention rates correlated with particular aspects of sleep physiology, and how the process was affected by seizures. METHODS: We prospectively recruited patients with focal epilepsy and assessed declarative memory using a task consisting of 15 pairs of colored pictures on a 5×6 grid. Patients were tested 12h after training, once after 12h of wakefulness and once after 12h that included sleep. EMG chin electrodes were placed to enable sleep scoring. The number and density of sleep spindles were assessed using a wavelet-based algorithm. RESULTS: Eleven patients were analyzed age 21-56years. The percentage memory retention over 12h of wakefulness was 62.7% and over 12h which included sleep 83.6% (p=0.04). Performance on overnight testing correlated with the duration of slow wave sleep (SWS) (r=+0.63, p<0.05). Three patients had seizures during the day, and 3 had nocturnal seizures. Day-time seizures did not affect retention rates, while those patients who had night time seizures had a drop in retention from an average of 92% to 60.5%. CONCLUSIONS: There is evidence of sleep dependent memory consolidation in patients with epilepsy which mostly correlates with the amount of SWS. Our preliminary findings suggest that nocturnal seizures likely disrupt sleep dependent memory consolidation. SIGNIFICANCE: Findings highlight the importance of SWS in sleep dependent memory consolidation and the adverse impact of nocturnal seizures on this process.

Interprofessional simulation to improve safety in the epilepsy monitoring unit.

OBJECTIVE: Patient safety is critical for epilepsy monitoring units (EMUs). Effective training is important for educating all personnel, including residents and nurses who frequently cover these units. We performed a needs assessment and developed a simulation-based team training curriculum employing actual EMU sentinel events to train neurology resident-nurse interprofessional teams to maximize effective responses to high-acuity events. METHODS: A mixed-methods design was used. This included the development of a safe-practice checklist to assess team response to acute events in the EMU using expert review with consensus (a modified Delphi process). All nineteen incoming first-year neurology residents and 2 nurses completed a questionnaire assessing baseline knowledge and attitudes regarding seizure management prior to and following a team training program employing simulation and postscenario debriefing. Four resident-nurse teams were recorded while participating in two simulated scenarios. Employing retrospective video review, four trained raters used the newly developed safe-practice checklist to assess team performance. We calculated the interobserver reliability of the checklist for consistency among the raters. We attempted to ascertain whether the training led to improvement in performance in the actual EMU by comparing 10 videos of resident-nurse team responses to seizures 4-8months into the academic year preceding the curricular training to 10 that included those who received the training within 4-8months of the captured video. RESULTS: Knowledge in seizure management was significantly improved following the program, but confidence in seizure management was not. Interrater agreement was moderate to high for consistency of raters for the majority of individual checklist items. We were unable to demonstrate that the training led to sustainable improvement in performance in the actual EMU by the method we used. CONCLUSIONS: A simulated team training curriculum using a safe-practice checklist to improve the management of acute events in an EMU may be an effective method of training neurology residents. However, translating the results into sustainable benefits and confidence in management in the EMU requires further study.

Beyond standard polysomnography: advantages and indications for use of extended 10-20 EEG montage during laboratory sleep study evaluations.

PURPOSE: Standard polysomnography (PSG) typically utilizes 4-6 channels of electroencephalography (EEG), which is inadequate to evaluate focal epileptiform activity. Though technical capability has long existed for more extensive EEG recording, few sleep laboratories have utilized this technique. The objective of this study was to determine the utility of combining PSG with 18-channel EEG in select patients with paroxysmal nocturnal events or other symptoms concerning for sleep disorders, nocturnal seizures or both. METHODS: Consecutive combined PSG-EEG studies (n=237) were performed between 10/1/2005 and 8/1/2009. Demographics, referral source, indications, and results were reviewed and analyzed. RESULTS: Of the 237 consecutive combined PSG-EEG studies performed, 93% revealed the presence of a primary sleep disorder, 38% were shown to have abnormal EEGs, and 37% had both. Among the 221 subjects (93%) shown to have sleep disorders, the majority of these cases were obstructive sleep apnea (OSA) 89%, followed by periodic limp movements of sleep (PLMS) 22% and rapid eye movement behavior disorder (RBD) 6%. Significantly more patients with known epilepsy were diagnosed with OSA then were patients without a seizure history. CONCLUSIONS: Combined PSG-EEG, utilizing 18-channel EEG, is an under-utilized technique which can assist in diagnosing paroxysmal nocturnal events, and differentiate between the presence of a primary sleep disorder, seizure activity, or both. Our study further illustrates the importance of considering sleep disorders in epilepsy patients.

The role of sleep in forgetting in temporal lobe epilepsy: a pilot study.

The purpose of this study was to examine how sleep impacts memory function in temporal lobe epilepsy (TLE). Patients with TLE (n=7) and control subjects (n=9) underwent training and overnight testing on (1) a motor sequence task known to undergo sleep-dependent enhancement in healthy subjects, and (2) the selective reminding test, a verbal memory task on which patients with TLE have shown impaired performance 24 hours after training. Sleep data were collected by polysomnography. Results indicate that patients with TLE display greater forgetting on the selective reminding test compared with controls over 12 hours of daytime wakefulness, but not over a similar period including a night of sleep. Slow wave sleep is correlated with overnight performance change on the selective reminding test. Patients with TLE show no deficit in sleep-dependent motor sequence task improvement. The findings provide potential insight into the pattern and pathophysiology of forgetting in TLE.

An empirical investigation of motion effects in eMRI of interictal epileptiform spikes.

We recently developed a functional neuroimaging technique called encephalographic magnetic resonance imaging (eMRI). Our method acquires rapid single-shot gradient-echo echo-planar MRI (repetition time=47 ms); it attempts to measure an MR signal more directly linked to neuronal electromagnetic activity than existing methods. To increase the likelihood of detecting such an MR signal, we recorded concurrent MRI and scalp electroencephalography (EEG) during fast (20-200 ms), localized, high-amplitude (>50 µV on EEG) cortical discharges in a cohort of focal epilepsy patients. Seen on EEG as interictal spikes, these discharges occur in between seizures and induced easily detectable MR magnitude and phase changes concurrent with the spikes with a lag of milliseconds to tens of milliseconds. Due to the time scale of the responses, localized changes in blood flow or hemoglobin oxygenation are unlikely to cause the MR signal changes that we observed. While the precise underlying mechanisms are unclear, in this study, we empirically investigate one potentially important confounding variable - motion. Head motion in the scanner affects both EEG and MR recording. It can produce brief "spike-like" artifacts on EEG and induce large MR signal changes similar to our interictal spike-related signal changes. In order to explore the possibility that interictal spikes were associated with head motions (although such an association had never been reported), we had previously tracked head position in epilepsy patients during interictal spikes and explicitly demonstrated a lack of associated head motion. However, that study was performed outside the MR scanner, and the root-mean-square error in the head position measurement was 0.7 mm. The large inaccuracy in this measurement therefore did not definitively rule out motion as a possible signal generator. In this study, we instructed healthy subjects to make deliberate brief (<500 ms) head motions inside the MR scanner and imaged these head motions with concurrent EEG and MRI. We compared these artifactual MR and EEG data to genuine interictal spikes. While per-voxel MR and per-electrode EEG time courses for the motion case can mimic the corresponding time courses associated with a genuine interictal spike, head motion can be unambiguously differentiated from interictal spikes via scalp EEG potential maps. Motion induces widespread changes in scalp potential, whereas interictal spikes are localized and have a regional fall-off in amplitude. These findings make bulk head motion an unlikely generator of the large spike-related MR signal changes that we had observed. Further work is required to precisely identify the underlying mechanisms.

Fast human brain magnetic resonance responses associated with epileptiform spikes.

Neuronal currents produce local electromagnetic fields that can potentially modulate the phase of the magnetic resonance signal and thus provide a contrast mechanism tightly linked to neuronal activity. Previous work has demonstrated the feasibility of direct MRI of neuronal activity in phantoms and cell culture, but in vivo efforts have yielded inconclusive, conflicting results. The likelihood of detecting and validating such signals can be increased with (i) fast gradient-echo echo-planar imaging, with acquisition rates sufficient to resolve neuronal activity, (ii) subjects with epilepsy, who frequently experience stereotypical electromagnetic discharges between seizures, expressed as brief, localized, high-amplitude spikes (interictal discharges), and (iii) concurrent electroencephalography. This work demonstrates that both MR magnitude and phase show large-amplitude changes concurrent with electroencephalography spikes. We found a temporal derivative relationship between MR phase and scalp electroencephalography, suggesting that the MR phase changes may be tightly linked to local cerebral activity. We refer to this manner of MR acquisition, designed explicitly to track the electroencephalography, as encephalographic MRI (eMRI). Potential extension of this technique into a general purpose functional neuroimaging tool requires further study of the MR signal changes accompanying lower amplitude neuronal activity than those discussed here.

Nonepileptic psychogenic status: markedly prolonged psychogenic nonepileptic seizures.

Little is known about markedly prolonged psychogenic nonepileptic seizures (PNES) though they are reported in up to 78% of PNES. Entry to the tertiary referral epilepsy monitoring unit (EMU) is often urgent and the stay usually brief, resulting thus far in almost no data regarding outcomes. The American Epilepsy Society (AES) Nonepileptic Seizure Task Force was asked to gather evidence for consensus of practice and treatment for PNES and its spectrum. As part of the subcommittee focusing on "pseudostatus epilepticus," we sent questionnaires to AES membership inquiring about markedly prolonged events, which we call nonepileptic psychogenic status (NEPS). Ninety U.S. and international neurologists from at least 19 states in the United States responded, with approximately 45% reporting that they do not distinguish NEPS from PNES. Eighty percent of responders considered a period of 20 minutes or longer as "prolonged." Lack of consensus between responders on how to manage these patients was uncovered. The NES Task Force subcommittee on "pseudostatus" recommends that the duration of PNES is tracked and those events lasting 20 minutes or longer, with or without change in level of consciousness, are considered NEPS. Future research needs are discussed.

Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis.

The automatic substitution of bioequivalent generics for brand-name antiepileptic drugs (AEDs) has been linked by anecdotal reports to loss of seizure control. To evaluate studies comparing brand-name and generic AEDs, and determine whether evidence exists of superiority of the brand-name version in maintaining seizure control. English-language human studies identified in searches of MEDLINE, EMBASE and International Pharmaceutical Abstracts (1984 to 2009). Randomized controlled trials (RCTs) and observational studies comparing seizure events or seizure-related outcomes between one brand-name AED and at least one alternative version produced by a distinct manufacturer. We identified 16 articles (9 RCTs, 1 prospective nonrandomized trial, 6 observational studies). We assessed characteristics of the studies and, for RCTs, extracted counts for patients whose seizures were characterized as 'controlled' and 'uncontrolled'. Seven RCTs were included in the meta-analysis. The aggregate odds ratio (n = 204) was 1.1 (95% CI 0.9, 1.2), indicating no difference in the odds of uncontrolled seizure for patients on generic medications compared with patients on brand-name medications. In contrast, the observational studies identified trends in drug or health services utilization that the authors attributed to changes in seizure control. Although most RCTs were short-term evaluations, the available evidence does not suggest an association between loss of seizure control and generic substitution of at least three types of AEDs. The observational study data may be explained by factors such as undue concern from patients or physicians about the effectiveness of generic AEDs after a recent switch. In the absence of better data, physicians may want to consider more intensive monitoring of high-risk patients taking AEDs when any switch occurs.