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1.  What is the importance of abnormal “background” activity in seizure generation? 
Investigations of interictal epileptiform spikes and seizures have played a central role in the study of epilepsy. The background EEG activity, however, has received less attention. In this chapter we discuss the characteristic features of the background activity of the brain when individuals are at rest and awake (resting wake) and during sleep. The characteristic rhythms of the background EEG are presented, and the presence of 1/f β behavior of the EEG power spectral density is discussed and its possible origin and functional significance. The interictal EEG findings of focal epilepsy and the impact of interictal epileptiform spikes on cognition are also discussed.
doi:10.1007/978-94-017-8914-1_3
PMCID: PMC4276130  PMID: 25012365
Electroencephalogram; Epilepsy; Local Field Potential Oscillations; High Frequency Oscillations; Sleep
2.  Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial 
Epilepsia  2014;55(3):432-441.
Objective
To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.
Methods
Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up.
Results
All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood.
Significance
Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.
doi:10.1111/epi.12534
PMCID: PMC4233950  PMID: 24621228
Cortical stimulation; Partial seizures; Focal seizures; Responsive stimulation; Neurostimulator
3.  Interictal Scalp Electroencephalography and Intraoperative Electrocorticography in Magnetic Resonance Imaging–Negative Temporal Lobe Epilepsy Surgery 
JAMA neurology  2014;71(6):702-709.
IMPORTANCE
Scalp electroencephalography (EEG) and intraoperative electrocorticography (ECoG) are routinely used in the evaluation of magnetic resonance imaging–negative temporal lobe epilepsy (TLE) undergoing standard anterior temporal lobectomy with amygdalohippocampectomy (ATL), but the utility of interictal epileptiform discharge (IED) identification and its role in outcome are poorly defined.
OBJECTIVES
To determine whether the following are associated with surgical outcomes in patients with magnetic resonance imaging–negative TLE who underwent standard ATL: (1) unilateral-only IEDs on preoperative scalp EEG; (2) complete resection of tissue generating IEDs on ECoG; (3) complete resection of opioid-induced IEDs recorded on ECoG; and (4) location of IEDs recorded on ECoG.
DESIGN, SETTING, AND PARTICIPANTS
Data were gathered through retrospective medical record review at a tertiary referral center. Adult and pediatric patients with TLE who underwent standard ATL between January 1, 1990, and October 15, 2010, were considered for inclusion. Inclusion criteria were magnetic resonance imaging–negative TLE, standard ECoG performed at the time of surgery, and a minimum follow-up of 12 months. Univariate analysis was performed using log-rank time-to-event analysis. Variables reaching significance with log-rank testing were further analyzed using Cox proportional hazards.
MAIN OUTCOMES AND MEASURES
Excellent or nonexcellent outcome at time of last follow-up. An excellent outcome was defined as Engel class I and a nonexcellent outcome as Engel classes II through IV.
RESULTS
Eighty-seven patients met inclusion criteria, with 48 (55%) achieving an excellent outcome following ATL. Unilateral IEDs on scalp EEG (P = .001) and complete resection of brain regions generating IEDs on baseline intraoperative ECoG (P = .02) were associated with excellent outcomes in univariate analysis. Both were associated with excellent outcomes when analyzed with Cox proportional hazards (unilateral-only IEDs, relative risk = 0.31 [95% CI, 0.16-0.64]; complete resection of IEDs on baseline ECoG, relative risk = 0.39 [95% CI, 0.20-0.76]). Overall, 25 of 35 patients (71%) with both unilateral-only IEDs and complete resection of baseline ECoG IEDs had an excellent outcome.
CONCLUSIONS AND RELEVANCE
Unilateral-only IEDs on preoperative scalp EEG and complete resection of IEDs on baseline ECoG are associated with better outcomes following standard ATL in magnetic resonance imaging–negative TLE. Prospective evaluation is needed to clarify the use of ECoG in tailoring temporal lobectomy.
doi:10.1001/jamaneurol.2014.585
PMCID: PMC4183227  PMID: 24781216
4.  Feasibility Study of a Caregiver Seizure Alert System in Canine Epilepsy 
Epilepsy research  2013;106(3):456-460.
Summary
A device capable of detecting seizures and alerting caregivers would be a major advance for epilepsy management, and could be used to guide early intervention and prevent seizure-related injuries. The objective of this work was to evaluate a seizure advisory system (SAS) that alerts caregivers of seizures in canines with naturally occurring epilepsy. Four dogs with epilepsy were implanted with a SAS that wirelessly transmits continuous intracranial EEG (iEEG) to an external device embedded with a seizure detection algorithm and the capability to alert caregivers. In this study a veterinarian was alerted by automated text message if prolonged or repetitive seizures occurred, and a rescue therapy protocol was implemented. The performance of the SAS caregiver alert was evaluated over the course of 8 weeks. Following discontinuation of antiepileptic drugs, the dogs experienced spontaneous unprovoked partial seizures that secondarily generalized. Three prolonged or repetitive seizure episodes occurred in 2 of the dogs. On each occasion, the SAS caregiver alert successfully alerted an on call veterinarian who confirmed the seizure activity via remote video-monitoring. A rescue medication was then administered and the seizures were aborted. This study demonstrates the feasibility of a SAS caregiver alert for prolonged or repetitive seizures, and enabling rescue medications to be delivered in a timely manner. The SAS may improve the management of human epilepsy by alerting caregivers of seizures, enabling early interventions, and potentially improving outcomes and quality of life of patients and caregivers.
doi:10.1016/j.eplepsyres.2013.06.007
PMCID: PMC3903427  PMID: 23962794
epilepsy; seizure management; seizure advisory; caregiver alert; EEG; device
5.  Electrocortical source imaging of intracranial EEG data in epilepsy 
Here we report first results of numerical methods for modeling the dynamic structure and evolution of epileptic seizure activity in an intracranial subdural electrode (iEEG, ECoG) recording from a patient with partial refractory epilepsy. A 15-min dataset containing two seizures was decomposed using up to five competing adaptive mixture ICA (AMICA) models. Multiple models modeled early or late ictal, or pre-or post-ictal periods in the data, respectively. To localize sources, a realistic Boundary Element Method (BEM) head model was constructed for the patient with custom open skull and plastic (non-conductive) electrode holder features. Source localization was performed using Sparse Bayesian Learning (SBL) on a dictionary of overlapping multi-scale cortical patches constructed from 80,130 dipoles in gray matter perpendicular to the cortical surface. Remaining mutual information among seizure-model AMICA components was dominated by two dependent component subspaces with largely contiguous source domains localized to superior frontal gyrus and precentral gyrus; these accounted for most of the ictal activity. Similar though much weaker dependent subspaces were also revealed in pre-ictal data by the associated AMICA model. Electrocortical source imaging appears promising both for clinical epilepsy research and for basic cognitive neuroscience research using volunteer patients who must undergo invasive monitoring for medical purposes.
doi:10.1109/IEMBS.2011.6090971
PMCID: PMC4135517  PMID: 22255194
6.  Modeling Cortical Source Dynamics and Interactions During Seizure 
Mapping the dynamics and spatial topography of brain source processes critically involved in initiating and propagating seizure activity is critical for effective epilepsy diagnosis, intervention, and treatment. In this report we analyze neuronal dynamics before and during epileptic seizures using adaptive multivariate autoregressive (VAR) models applied to maximally-independent (ICA) sources of intracranial EEG (iEEG, ECoG) data recorded from subdural electrodes implanted in a human patient for evaluation of surgery for epilepsy. We visualize the spatial distribution of causal sources and sinks of ictal activity on the cortical surface (gyral and sulcal) using a novel combination of multivariate Granger-causal and graph-theoretic metrics combined with distributed source localization by Sparse Bayesian Learning applied to a multi-scale patch basis. This analysis reveals and visualizes distinct, seizure stage-dependent shifts in inter-component spatiotemporal dynamics and connectivity including the clinically-identified epileptic foci.
doi:10.1109/IEMBS.2011.6090332
PMCID: PMC4136461  PMID: 22254582
7.  Network oscillations modulate interictal epileptiform spike rate during human memory 
Brain  2013;136(8):2444-2456.
Eleven patients being evaluated with intracranial electroencephalography for medically resistant temporal lobe epilepsy participated in a visual recognition memory task. Interictal epileptiform spikes were manually marked and their rate of occurrence compared between baseline and three 2 s periods spanning a 6 s viewing period. During successful, but not unsuccessful, encoding of the images there was a significant reduction in interictal epileptiform spike rate in the amygdala, hippocampus, and temporal cortex. During the earliest encoding period (0–2000 ms after image presentation) in these trials there was a widespread decrease in the power of theta, alpha and beta band local field potential oscillations that coincided with emergent focal gamma frequency activity. Interictal epileptiform spike rate correlated with spectral band power changes and broadband (4–150 Hz) desynchronization, which predicted significant reduction in interictal epileptiform spike rate. Spike-triggered averaging of the field potential power spectrum detected a burst of low frequency synchronization 200 ms before the interictal epileptiform spikes that arose during this period of encoding. We conclude that interictal epileptiform spikes are modulated by the patterns of network oscillatory activity that accompany human memory offering a new mechanistic insight into the interplay of cognitive processing, local field potential dynamics and interictal epileptiform spike generation.
doi:10.1093/brain/awt159
PMCID: PMC3722348  PMID: 23803305
interictal epileptiform spikes; epilepsy; memory
8.  Intravenous Recording of Intracranial, Broadband EEG 
Journal of neuroscience methods  2013;214(1):21-26.
The most direct evaluation of human brain activity has been obtained from intracranial electrodes placed either on the surface of the brain or inserted into the brain to record from deep brain structures. Currently, the placement of intracranial electrodes implies transcranial surgery, either through a burr hole or a craniotomy, but the high degree of invasiveness and potential for morbidity of such major surgical procedures limits the applicability of intracranial recording. The vascular system provides a natural avenue to reach many brain regions that currently are reached by transcranial approaches, along with deep brain structures that cannot be reached via a transcranial approach without significant risk. To determine the applicability of intravascular approaches to high-frequency intracranial monitoring, a catheter containing multiple macro- and micro-electrodes was placed into the superior sagittal sinus of anesthetized pigs in parallel with clinical, subdural electrode grids to record epileptiform activity induced by direct, cortical injection of penicillin and to record responses to electrical stimulation. Intravascular electrodes recorded epileptiform spikes with similar magnitudes and waveshapes to those obtained by surface electrodes, both for macroelectrodes and microelectrodes, including the spatiotemporal evolution of epileptiform activity, suggesting that intravascular electrodes might provide localizing information regarding seizure foci. Sinusoidal electrical stimulation showed that intravascular electrodes provide sufficient broadband fidelity to record high-frequency, physiological events that may also prove useful in localizing seizure onset zones. As intravascular techniques have transformed cardiology, so intravascular neurophysiology may transform intracranial monitoring, in general, and the treatment of epilepsy, in particular.
doi:10.1016/j.jneumeth.2012.12.027
PMCID: PMC3593671  PMID: 23313850
9.  Multivariate Principal Oscillation Pattern Analysis of ICA Sources During Seizure 
Mapping the dynamics of neural source processes critically involved in initiating and propagating seizure activity is important for effective epilepsy diagnosis, intervention, and treatment. Tracking time-varying shifts in the oscillation modes of an evolving seizure may be useful for both seizure onset detection as well as for improved non-surgical interventions such as microstimulation. In this report we apply a multivariate eigendecomposition method to analyze the time-varying principal oscillation patterns (POPs, or eigenmodes) of maximally-independent (ICA) sources of intracranial EEG data recorded from subdural electrodes implanted in a human patient for evaluation of surgery for epilepsy. Our analysis of a subset of the most dynamically important eigenmodes reveals distinct shifts in characteristic frequency and damping time before, throughout, and following seizures providing insight into the dynamical structure of the system throughout seizure evolution.
doi:10.1109/EMBC.2012.6346575
PMCID: PMC3920590  PMID: 23366536
10.  Long-term Outcomes After Nonlesional Extratemporal Lobe Epilepsy Surgery 
JAMA neurology  2013;70(8):1003-1008.
Importance
A focal lesion detected by use of magnetic resonance imaging (MRI) is a favorable prognostic finding for epilepsy surgery. Patients with normal MRI findings and extratemporal lobe epilepsy have less favorable outcomes. Most studies investigating the outcomes of patients with normal MRI findings who underwent (nonlesional) extratemporal epilepsy surgery are confined to a highly select group of patients with limited follow-up.
Objective
To evaluate noninvasive diagnostic test results and their association with excellent surgical outcomes (defined using Engel classes I–IIA of surgical outcomes) in a group of patients with medically resistant nonlesional extratemporal epilepsy.
Design
A retrospective study.
Setting
Mayo Clinic, Rochester, Minnesota.
Participants
From 1997 through 2002, we identified 85 patients with medically resistant extratemporal lobe epilepsy who had normal MRI findings. Based on a standardized presurgical evaluation and review at a multi-disciplinary epilepsy surgery conference, some of these patients were selected for intracranial electroencephalographic (EEG) monitoring and epilepsy surgery.
Exposure
Nonlesional extratemporal lobe epilepsy surgery.
Main Outcomes and Measures
The results of non-invasive diagnostic tests and the clinical variables potentially associated with excellent surgical outcome were examined in patients with a minimum follow-up of 1 year (mean follow-up, 9 years).
Results
Based on the noninvasive diagnostic test results, a clear hypothesis for seizure origin was possible for 47 of the 85 patients (55%), and 31 of these 47 patients (66%) proceeded to intracranial EEG monitoring. For 24 of these 31 patients undergoing long-term intracranial EEG (77%), a seizure focus was identified and surgically resected. Of these 24 patients, 9 (38%) had an excellent outcome after resective epilepsy surgery. All patients with an excellent surgical outcome had at least 10 years of follow-up. Univariate analysis showed that localized interictal epileptiform discharges on scalp EEGs were associated with an excellent surgical outcome.
Conclusions and Relevance
Scalp EEG was the most useful test for identifying patients with normal MRI findings and extratemporal lobe epilepsy who were likely to have excellent outcomes after epilepsy surgery. Extending outcome analysis beyond the resective surgery group to the entire group of patients who were evaluated further highlights the challenge that these patients pose. Although 9 of 24 patients undergoing resective surgery (38%) had excellent outcomes, only 9 of 31 patients undergoing intracranial EEG (29%) and only 9 of 85 patient with nonlesional extratemporal lobe epilepsy (11%) had long-term excellent outcomes.
doi:10.1001/jamaneurol.2013.209
PMCID: PMC3920594  PMID: 23732844
11.  Patient-assessed satisfaction and outcome after microsurgical resection of cavernomas causing epilepsy 
Neurosurgical focus  2010;29(3):E16.
Object
Microsurgical resection of supratentorial cavernomas associated with intractable epilepsy is performed frequently. Despite its common occurrence, little is known about patient perceptions of microsurgical resection for cavernomas. This survey study was performed to investigate patient perceived outcome after surgery for cavernomas associated with intractable epilepsy.
Methods
The authors’ surgical database was searched for cavernoma resection performed between 1971 and July of 2006. Of the initial 173 patients identified, 102 met criteria for medically intractable seizures. These 102 patients were then mailed a survey to determine follow-up and patient satisfaction. Thirty-nine surveys were returned as undeliverable, and 30 (48%) of the remaining 63 patients responded.
Results
The average age at surgery for patients responding to this survey was 40 ± 16 years compared with 35 ± 15 years for all 102 patients. At prolonged follow-up, 87% of patients reported being seizure-free. Of those with seizures, 2 (7%) reported being nearly seizure-free (rare disabling seizures), 2 (7%) believed they had a worthwhile improvement in seizure frequency, and no patient (0%) in this series believed they did not have a worthwhile improvement in seizure frequency. Ninety percent of responders stated they definitely, and 10% probably, would have surgery again. No patient responded that they probably or definitely would not have epilepsy surgery. Mean clinical follow-up was 36 ± 8 months and survey follow-up was 97 ± 13 months for these 30 patients. Use of the mail-in survey increased follow-up length 2.7 times longer compared with clinical follow-up.
Conclusions
It is clear from this select group of survey responders that patients undergoing surgery for cavernomas associated with medically intractable epilepsy are happy they underwent surgery (100%) and had excellent surgical outcomes (87% seizure-free) at prolonged follow-up of 97 ± 13 months. These survey results support that microsurgical resection for cavernomas is highly effective and significantly improves these patients’ quality of life.
doi:10.3171/2010.6.FOCUS10127
PMCID: PMC3920597  PMID: 20809757
cavernoma; epilepsy; survey; patient outcome; postal questionnaire
12.  Forecasting Seizures in Dogs with Naturally Occurring Epilepsy 
PLoS ONE  2014;9(1):e81920.
Seizure forecasting has the potential to create new therapeutic strategies for epilepsy, such as providing patient warnings and delivering preemptive therapy. Progress on seizure forecasting, however, has been hindered by lack of sufficient data to rigorously evaluate the hypothesis that seizures are preceded by physiological changes, and are not simply random events. We investigated seizure forecasting in three dogs with naturally occurring focal epilepsy implanted with a device recording continuous intracranial EEG (iEEG). The iEEG spectral power in six frequency bands: delta (0.1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), low-gamma (30–70 Hz), and high-gamma (70–180 Hz), were used as features. Logistic regression classifiers were trained to discriminate labeled pre-ictal and inter-ictal data segments using combinations of the band spectral power features. Performance was assessed on separate test data sets via 10-fold cross-validation. A total of 125 spontaneous seizures were detected in continuous iEEG recordings spanning 6.5 to 15 months from 3 dogs. When considering all seizures, the seizure forecasting algorithm performed significantly better than a Poisson-model chance predictor constrained to have the same time in warning for all 3 dogs over a range of total warning times. Seizure clusters were observed in all 3 dogs, and when the effect of seizure clusters was decreased by considering the subset of seizures separated by at least 4 hours, the forecasting performance remained better than chance for a subset of algorithm parameters. These results demonstrate that seizures in canine epilepsy are not randomly occurring events, and highlight the feasibility of long-term seizure forecasting using iEEG monitoring.
doi:10.1371/journal.pone.0081920
PMCID: PMC3885383  PMID: 24416133
13.  Efficacy of a Reduced Electroencephalography Electrode Array for Detection of Seizures 
The Neurohospitalist  2014;4(1):6-8.
Background:
The expertise required for proper electroencephalography (EEG) setup can make the 10-20 array unwieldy in the hospital setting. There may be a role for an EEG array with reduced leads to improve the efficiency of inpatient practice.
Methods:
Clips from 100 EEG records, 50 ictal and 50 non-ictal, in adult inpatients from January 1, 2007, to January 1, 2012, were retrospectively reviewed and selected for digital lead reduction and blind review. Two epileptologists reviewed these tracings and documented the presence of seizures and severe disturbance of background. The reduced array included 7 leads spanning the scalp. Three different montages were available. Sensitivity and specificity of the reduced array were calculated using the formal EEG report as the comparison standard.
Results:
For the detection of any seizure, the reduced array EEG had a sensitivity of 70% and specificity of 96%. Sensitivity for identifying encephalopathic patterns was 62% and specificity was 86%. Focal seizures were more readily identified by the reduced array (20 of 25) than were generalized ictal patterns (13 of 25).
Conclusion:
The reduced electrode array was insufficiently sensitive to seizure detection. Reducing EEG leads might not be a preferred means of optimizing hospital EEG efficiency.
doi:10.1177/1941874413507930
PMCID: PMC3869310  PMID: 24381704
EEG; montage; seizure; hospital; reduced; array
14.  Dynamic imaging of seizure activity in pediatric epilepsy patients 
Objective
To investigate the feasibility of using noninvasive EEG source imaging approach to image continuous seizure activity in pediatric epilepsy patients.
Methods
Nine pediatric patients with medically intractable epilepsy were included in this study. Eight of the patients had extratemporal lobe epilepsy and one had temporal lobe epilepsy. All of the patients underwent resective surgery and seven of them underwent intracranial EEG (iEEG) monitoring. The ictal EEG was analyzed using a noninvasive dynamic seizure imaging (DSI) approach. The DSI approach separates scalp EEGs into independent components and extracts the spatio-temporal ictal features to achieve dynamic imaging of seizure sources. Surgical resection and intracranial recordings were used to validate the noninvasive imaging results.
Results
The DSI determined seizure onset zones (SOZs) in these patients were localized within or in close vicinity to the surgically resected region. In the seven patients with intracranial monitoring, the estimated seizure onset sources were concordant with the seizure onset zones of iEEG. The DSI also localized the multiple foci involved in the later seizure propagation, which were confirmed by the iEEG recordings.
Conclusions
Dynamic seizure imaging can noninvasively image the seizure activations in pediatric patients with both temporal and extratemporal lobe epilepsy.
Significance
EEG seizure imaging can potentially be used to noninvasively image the SOZs and aid the pre-surgical planning in pediatric epilepsy patients.
doi:10.1016/j.clinph.2012.04.021
PMCID: PMC3438337  PMID: 22608485
Pediatric patients; Epilepsy; EEG; Dynamic seizure imaging; Intracranial recording; Surgical resection
15.  Use of Anterior Temporal Lobectomy for Epilepsy in a Community-Based Population 
Archives of neurology  2012;69(11):1476-1481.
Objective
To assess the hypothesis that use of anterior temporal lobectomy (ATL) for temporal epilepsy has diminished over time.
Design
Population-based cohort study.
Setting
The Rochester Epidemiology Project based in Olmsted County, Minnesota.
Participants
Residents of Olmsted County.
Main Outcome Measures
Poisson regression was used to evaluate changes in ATL use over time by sex.
Results
Over a 17-year period, from 1993 to 2009, 847 ATLs were performed with the primary indication of epilepsy (average, 50 procedures/y). Of these, 26 occurred among Olmsted County residents. The use rates de clined significantly between 1993 and 2000 (8 years) and 2001 and 2009 (9 years) according to Poisson regression analysis, from 1.9 to 0.7 per 100 000 person-years (P=.01). The rate of ATL use among Olmsted County residents was 1.2 (95% CI, 0.9 to 2.4) per 100 000 person-years of follow-up over this 17-year period. The sex-specific rates were 1.6 (95% CI, 0.9 to 2.4) and 0.7 (95% CI, 0.2 to 1.3) per 100 000 person-years for females and males, respectively.
Conclusions
In this community-based cohort, the rate of ATL use was 1.2 per 100 000 person-years of follow-up. Use of this procedure has declined over time; the reasons for this are unknown but do not include referral pattern changes.
doi:10.1001/archneurol.2012.1200
PMCID: PMC3526693  PMID: 22911042
16.  Spectral and spatial shifts of post-ictal slow waves in temporal lobe seizures 
Brain  2012;135(10):3134-3143.
Temporal lobe seizures have a significant chance to induce impairment of normal brain functions. Even after the termination of ictal discharges, during the post-ictal period, loss of consciousness, decreased responsiveness or other cognitive dysfunctions can persist. Previous studies have found various anatomical and functional abnormalities accompanying temporal lobe seizures, including an abnormal elevation of cortical slow waves. Intracranial electroencephalography studies have shown a prominent increase of lower frequency components during and following seizures that impair (complex partial seizures) but not those that preserve (simple partial seizures) normal consciousness and responsiveness. However, due to the limited spatial coverage of intracranial electroencephalography, the investigation of cortical slow waves cannot be easily extended to the whole brain. In this study, we used scalp electroencephalography to study the spectral features and spatial distribution of post-ictal slow waves with comprehensive spatial coverage. We studied simple partial, complex partial and secondarily generalized seizures in 28 patients with temporal lobe seizures. We used dense-array electroencephalography and source imaging to reconstruct the post-ictal slow-wave distribution. In the studied cohort, we found that a ‘global’ spectral power shift to lower frequencies accompanied the increased severity of seizures. The delta spectral power relative to higher frequency bands was highest for secondarily generalized seizures, followed by complex partial seizures and lastly simple partial seizures. In addition to this ‘global’ spectral shift, we found a ‘regional’ spatial shift in slow-wave activity. Secondarily generalized seizures and complex partial seizures exhibited increased slow waves distributed to frontal areas with spread to contralateral temporal and parietal regions than in simple partial seizures. These results revealed that a widespread cortical network including temporal and fronto-parietal cortex is involved in abnormal slow-wave activity following temporal lobe seizures. The differential spectral and spatial shifts of post-ictal electroencephalography activity in simple partial, complex partial and secondarily generalized seizures suggest a possible connection between cortical slow waves and behavioural and cognitive changes in a human epilepsy model.
doi:10.1093/brain/aws221
PMCID: PMC3470709  PMID: 22923634
cortical slowing; temporal lobe seizure; post-ictal state; consciousness; responsiveness
17.  Seizure source imaging by means of FINE spatio-temporal dipole localization and directed transfer function in partial epilepsy patients 
Clinical Neurophysiology  2011;123(7):1275-1283.
Objective
To investigate the usage of a high-density EEG recording system and source imaging technique for localizing seizure activity in patients with medically intractable partial epilepsy.
Methods
High-density, 76-channel scalp EEG signals were recorded in ten patients with partial epilepsy. The patients underwent routine clinical pre-surgical evaluation and all had resective surgery with seizure free outcome. After applying a FINE (first principle vectors) spatial-temporal source localization and DTF (directed transfer function) connectivity analysis approach, ictal sources were imaged. Effects of number of scalp EEG electrodes on the seizure localization were also assessed using 76, 64, 48, 32, and 21 electrodes, respectively.
Results
Surgical resections were used to assess the source imaging results. Results from the 76-channel EEG in the ten patients showed high correlation with the surgically resected brain regions. The localization of seizure onset zone from 76-channel EEG showed improved source detection accuracy compared to other EEG configurations with fewer electrodes.
Conclusions
FINE together with DTF was able to localize seizure onset zones of partial epilepsy patients. High-density EEG recording can help achieve improved seizure source imaging.
Significance
The present results suggest the promise of high-density EEG and electrical source imaging for noninvasively localizing seizure onset zones.
doi:10.1016/j.clinph.2011.11.007
PMCID: PMC3327757  PMID: 22172768
High-density EEG; Ictal activities; EEG source imaging; FINE; Epilepsy; directed transfer function
18.  Spatiotemporal Neuronal Correlates of Seizure Generation in Focal Epilepsy 
Epilepsia  2012;53(5):807-816.
Summary
Purpose
Focal seizures are thought to reflect simultaneous activation of a large population of neurons within a discrete region of pathological brain. Resective surgery targeting this focus is an effective treatment in carefully selected patients, but not all. While in vivo recordings of single-neuron (i.e., “unit”) activity in patients with epilepsy have a long history, no studies have examined long–term firing rates leading into seizures and the spatial relationship of unit activity with respect to the seizure onset zone.
Methods
Microelectrode arrays recorded action potentials from neurons in mesial temporal structures (often including contralateral mesial temporal structures) in seven patients with mesial temporal lobe epilepsy.
Key Findings
Only 7.6% of microelectrode recordings showed increased firing rates prior to seizure onset and only 32.4% of microelectrodes showed any seizure-related activity changes. Surprisingly, firing rates on the majority of microelectrodes (67.6%) did not change throughout the seizure, including some microelectrodes located within the seizure onset zone. Furthermore, changes in firing rate prior to and at seizure onset were observed on microelectrodes located outside the seizure onset zone and even in contralateral mesial temporal lobe. These early changes varied from seizure to seizure, demonstrating the heterogeneity of ensemble activity underlying the generation of focal seizures. Increased neuronal synchrony was primarily observed only following seizure onset.
Significance
These results suggest that cellular correlates of seizure initiation and sustained ictal discharge in mesial temporal lobe epilepsy involve a small subset of the neurons within and outside the seizure onset zone. These results further suggest that the “epileptic ensemble or network” responsible for seizure generation are more complex and heterogeneous than previously thought and that future studies may find mechanistic insights and therapeutic treatments outside the clinical seizure onset zone.
doi:10.1111/j.1528-1167.2012.03417.x
PMCID: PMC3339564  PMID: 22352423
multi-unit; ictogenesis; ensemble; microelectrode; electrophysiology; mesial temporal lobe
19.  Autoimmune Epilepsy 
Archives of neurology  2012;69(5):582-593.
Objective
To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy.
Design
Observational, retrospective case series.
Setting
Mayo Clinic Health System.
Patients
Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each.
Intervention
Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide.
Main Outcome Measure
Seizure frequency.
Results
After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone.
Conclusion
When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.
doi:10.1001/archneurol.2011.2985
PMCID: PMC3601373  PMID: 22451162
20.  Effect of General Anesthesia in Patients With Cerebral Palsy at the Turn of the New Millennium: A Population-Based Study Evaluating Perioperative Outcome and Brief Overview of Anesthetic Implications of This Coexisting Disease 
Journal of child neurology  2011;27(7):859-866.
The severity of preoperative cerebral palsy appears to correlate directly with postoperative complications. The primary aim of this study was to characterize the frequency of perioperative morbidity and mortality in cerebral palsy patients undergoing anesthesia. This was accomplished by undertaking a systematic review of the Mayo Database. The risk for perioperative adverse events was 63.1% (95% confidence interval 59.8%–66.5%). However, it deserves clarification that hypothermia and clinically significant yet non–life-threatening hypotension represented the majority (80%) of these complications. When these 2 events are excluded, the rate of adverse perioperative events was 13.1% (95% confidence interval 10.8%–15.5%). Risk factors associated with increased risk included American Society of Anesthesiologists physical status score exceeding 2, history of seizures, upper airway hypotonia, general surgery procedures, and adults. Our findings are useful to counsel patients with cerebral palsy, their caregivers, and their guardians regarding the risk of general anesthesia.
doi:10.1177/0883073811428378
PMCID: PMC3561730  PMID: 22190505
cerebral palsy; general anesthesia; morbidity; outcome; perioperative
21.  Statistical parametric mapping demonstrates asymmetric uptake with Tc-99m ECD and Tc-99m HMPAO SPECT in normal brain 
Tc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety of neurologic disorders. Although these tracers have been very helpful in diagnosing and guiding treatment of neurologic disease, data describing the distribution and laterality of these tracers in normal resting brain are limited. Advances in quantitative functional imaging have demonstrated the value of using resting studies from control populations as a baseline to account for physiologic fluctuations in cerebral perfusion. Here, we report results from 30 resting Tc-99m ECD SPECT scans and 14 resting Tc-99m HMPAO scans of normal volunteers with no history of neurologic disease. Scans were analyzed with regions of interest and with statistical parametric mapping, with comparisons performed laterally (left vs. right), as well as for age, gender, and handedness. The results show regions of significant asymmetry in the normal controls affecting widespread areas in the cerebral hemispheres, but most marked in superior parietotemporal region and frontal lobes. The results have important implications for the use of normal control SPECT images in the evaluation of patients with neurologic disease.
doi:10.1038/jcbfm.2011.123
PMCID: PMC3323300  PMID: 21934696
brain asymmetry; brain imaging; SPECT
22.  Data mining neocortical high-frequency oscillations in epilepsy and controls 
Brain  2011;134(10):2948-2959.
Transient high-frequency (100–500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100–250 Hz) and fast ripple (250–500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100–500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.
doi:10.1093/brain/awr212
PMCID: PMC3187540  PMID: 21903727
high-frequency oscillations; epilepsy; intracranial EEG
23.  A Novel Implanted Device to Wirelessly Record and Analyze Continuous Intracranial Canine EEG 
Epilepsy research  2011;96(1-2):116-122.
We present results from continuous intracranial electroencephalographic (iEEG) monitoring in 6 dogs with naturally occurring epilepsy, a disorder similar to the human condition in its clinical presentation, epidemiology, electrophysiology and response to therapy. Recordings were obtained using a novel implantable device wirelessly linked to an external, portable real-time processing unit. We demonstrate previously uncharacterized intracranial seizure onset patterns in these animals that are strikingly similar in appearance to human partial onset epilepsy. We propose: (1) canine epilepsy as an appropriate model for testing human antiepileptic devices and new approaches to epilepsy surgery, and (2) this new technology as a versatile platform for evaluating seizures and response to therapy in the natural, ambulatory setting.
doi:10.1016/j.eplepsyres.2011.05.011
PMCID: PMC3175300  PMID: 21676591
24.  Scalp and Intracranial EEG in Medically Intractable Extratemporal Epilepsy with Normal MRI 
ISRN Neurology  2012;2012:942849.
Purpose. To investigate EEG and SPECT in the surgical outcome of patients with normal MRI (nonlesional) and extratemporal lobe epilepsy. Methods. We retrospectively identified 41 consecutive patients with nonlesional extratemporal epilepsy who underwent epilepsy surgery between 1997 and 2007. The history, noninvasive diagnostic studies (scalp EEG, MRI, and SPECT) and intracranial EEG (iEEG) monitoring was reviewed. Scalp and iEEG ictal onset patterns were defined. The association of preoperative studies and postoperative seizure freedom was analyzed using Kaplan-Meier analysis, log-rank test, and Cox proportional hazard. Results. Thirty-six of 41 patients had adequate information with a minimum of 1-year followup. Favorable surgical outcome was identified in 49% of patients at 1 year, and 35% at 4-year. On scalp EEG, an ictal onset pattern consisting of focal beta-frequency discharge (>13–125 Hz) was associated with favorable surgical outcome (P = 0.02). Similarly, a focal fast-frequency oscillation (>13–125 Hz) on iEEG at ictal onset was associated with favorable outcome (P = 0.03). Discussion. A focal fast-frequency discharge at ictal onset identifies nonlesional MRI, extratemporal epilepsy patients likely to have a favorable outcome after resective epilepsy surgery.
doi:10.5402/2012/942849
PMCID: PMC3389725  PMID: 22792484
25.  Dynamic imaging of ictal oscillations using non-invasive high-resolution EEG 
Neuroimage  2011;56(4):1908-1917.
Scalp electroencephalography (EEG) has been established as a major component of the pre-surgical evaluation for epilepsy surgery. However, its ability to localize seizure onset zones (SOZ) has been significantly restricted by its low spatial resolution and indirect correlation with underlying brain activities. Here we report a novel non-invasive dynamic seizure imaging (DSI) approach based upon high-density EEG recordings. This novel approach was particularly designed to image the dynamic changes of ictal rhythmic discharges that evolve through time, space and frequency. This method was evaluated in a group of 8 epilepsy patients and results were rigorously validated using intracranial EEG (iEEG) (n = 3) and surgical outcome (n = 7). The DSI localized the ictal activity in concordance with surgically resected zones and ictal iEEG recordings in the cohort of patients. The present promising results support the ability to precisely and accurately image dynamic seizure activity from non-invasive measurements. The successful establishment of such a non-invasive seizure imaging modality for surgical evaluation will have a significant impact in the management of medically intractable epilepsy.
doi:10.1016/j.neuroimage.2011.03.043
PMCID: PMC3359824  PMID: 21453776
High-resolution EEG; Dynamic seizure imaging; Pre-surgical planning

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