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2012 Research Retreat

The Yale Epilepsy Research Retreat is a two day educational meeting in which clinical and basic science researchers from Yale and collaborators from other institutions will discuss the latest advances in cutting-edge epilepsy research. In addition, we are inviting an outstanding leader in epilepsy research, well versed in both human and basic epilepsy research, to speak at the Retreat, provide feedback and guidance, and serve as an external moderator and reviewer for the research program. The Retreat will consist of investigator slide presentations, poster sessions, and break-out discussions on new research approaches and collaborations.

The Retreat took place from Thursday, October 25th – Friday, October 26th.

2012 Research Retreat Content

Guest Speaker

Gregory L. Holmes, MD

Chief of Neurology
Professor of Medicine (Neurology) and Pediatrics
Dartmouth Medical School
Neuroscience Center at Dartmouth
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire

Gregory L. Holmes, MD, studied medicine at the University of Virginia and did his pediatric training at Yale-New Haven Hospital. He then returned to Virginia to train in neurology. Prior to becoming Chair at Dartmouth, he was Professor of Neurology at Harvard Medical School and Director, Center for Research in Pediatric Epilepsy, at Children’s Hospital Boston.

Dr. Holmes has focused his basic research on the short- and long-term effect of seizures on the developing brain, and has had continuous funding from NIH for over two decades. He has a clinical interest in the treatment of pharmacoresistant epilepsy in children, and has been on the editorial boards of the Annals of Neurology, Epilepsy & Behavior, Brain and Development, Journal of Child Neurology, Pediatric Neurology, and Epilepsy Research.

Dr. Holmes has received a number of awards for his research, including the Michael Prize for outstanding work in the field of epilepsy research in 1989, the Milken Family Medical Foundation-American Epilepsy Society Research Award in basic neuroscience in 1989, the Pierre Gloor Award for outstanding achievement in research by the American Clinical Neurophysiology Society in 2000, and the Western Massachusetts Epilepsy Awareness Committee Inspiration for a Cure Award in 2002.

In addition to his committee work for the American Epilepsy Society and Epilepsy Foundation of America, Dr. Holmes has served on the executive boards of the American Clinical Neurophysiology Society and the Child Neurology Society. He was president of the Eastern Association of Electroencephalographers, and is President-Elect of the American Epilepsy Society.

Slide Session I: Neuroimaging

PET Imaging of mGluR5 with [18F]FPEB in Epilepsy

Presenting Author: Mehdi Djekidel

Collaborating Authors: Beata Planeta Wilson, Jenna Sullivan, Evans Morris, Tore Eid, Hitten Zaveri, Colleen Malone, Nihal Chandra deLanerolle, Goncharova Irina, Jullie Pan, Richard Bronen, Pue Farooque, Richard Mattson, Kamil Detynieki, Robert Duckrow, Kenneth Vives, Lawrence Hirsch, Hal Blumenfeld, Dennis Spencer, Richard Carson

Electrochemical imbalances occurring in epilepsy are not well understood. The glutamate system including metabotropic glutamate 5-receptors (mGluR-5) has been implicated in animal and human models of epilepsy. Imaging plays a cornerstone role in epilepsy evaluation. Positron emission tomography (PET) is an optimal modality to noninvasively explore these processes. PET evaluation of glucose metabolism, benzodiazepine and serotonin receptors has been successfully performed in humans and has shown decreases in the seizure onset zone (SOZ) interictally. We seek to gain a new perspective on the role glutamate receptors play in epilepsy, through PET imaging of mGluR-5 changes using [18F]FPEB. Our study includes patients with severe medically refractory epilepsy whom are being evaluated for surgical resection of the SOZ. We identify the SOZ based on a gold standard of intracranial electrico-corticography teager energy measurements, which we then correlate with FPEB imaging results. Our preliminary data includes imaging of 5 subjects with medically refractory epilepsy with an age ranging from 22-53 yo (average age 33.6) and a 4/1 female to male ratio. We found interictally decreased mGluR5 distribution in the SOZ when compared to a normal healthy control reference -constructed from eight healthy control subjects-. Additionally a correlation with glutamate microdialysis data obtained during IEC showed no direct correlation between mGluR5 volume of distribution obtained from [18F]FPEB scans and glutamate levels in three subjects. Further exploration in a larger cohort –which is the goal of our ongoing project- is needed to further validate these results and potentially explore their value in daily clinical practice.

Functional Connectivity of Cognition in Temporal Lobe Epilepsy

Presenting Author: F. Scott Winstanley

Collaborating Authors: Hyang Woon Lee, Jagriti Arora, Dennis D. Spencer, R. Todd Constable

Rationale: Medically refractory mesial temporal lobe epilepsy (MTLE) is associated with cognitive impairment, reduced daily functioning, and overall decreased quality of life. Anterior temporal lobectomy (ATL) is an effective treatment for medically refractory temporal lobe epilepsy; however, this procedure carries the risk of additional postoperative cognitive morbidity. Identifying preoperative neural functioning as well as identifying risk factors for postoperative cognitive morbidity is an essential part of the evaluation for epilepsy surgery. Recent advances in fMRI have demonstrated that resting state intrinsic connectivity contrast (rs-ICC) analysis of fMRI BOLD signal fluctuations has also shown to be a powerful tool in identifying neural underpinnings for various cognitive functions in normal subjects. Analysis of ICC data can identify the tissue elements most affected in TLE, potentially assisting in the management of these patients. This study aims to 1) elucidate neural correlates of cognitive impairment by analyzing the fMRI intrinsic connectivity contrast (ICC) in medically refractory TLE patients; and 2) determine if these ICC correlations can predict postoperative cognitive morbidity in ATL patients.

Methods: We recruited 25 TLE patients who performed resting state fMRI, underwent neuropsychological tests as part of presurgical evaluation, and underwent standard temporal lobectomy with at least one year of post operative follow-up. There were 12 left and 13 right TLE patients, 9 males and 16 females with mean age at surgery of 39.1 ± 11.1 years old. A gradient-echo fMRI sequence was obtained from each patient, and the ICC was measured by a voxel based calculation of the degree of correlation coefficient for each voxel within the brain hemisphere and within medial or medial/lateral temporal lobes to ipsilateral (ipsi-ICC) and contralateral (contra-ICC) to the seizure focus. Analysis of rs-ICC was correlated with preoperative and postoperative scores obtained on a battery of neuropsychological tests including the verbal and non-verbal Selective Reminding Tests (SRT), the California Verbal Learning Test (CVLT), and the Boston Naming test (BNT).

Results: Verbal SRT scores were positively correlated with ipsi-ICC in left hippocampus and contra-ICC in both hippocampi using medial temporal mask. Verbal SRT showed similar positive correlation with ipsi- and contra-ICC values with whole brain mask in left middle and part of inferior temporal gyri. Impaired non-verbal SRT was correlated with decreased ipsi- and contra-ICC in right hippocampus, right superior temporal gyrus with medial/lateral temporal mask. Decreased CVLT scores were correlated with decreased ipsi- and contra-ICC in left middle temporal gyrus, and BNT showed similar positive correlation with left hippocampus, left superior/middle temporal and parahippocampal gyri, using whole brain mask.

Conclusion: These findings suggest that impairments in cognitive function in TLE patients are reflected in the intrinsic functional organization of the brain as measured by ICC. Impairments of verbal learning and naming in TLE patients showed alterations in dominant temporal lobe structures while non-verbal learning abnormalities were closely related to ICC changes in non-dominant temporal structures, in good agreement with the previous knowledge of memory and language networks. This study also demonstrated a relationship between pre and postoperative test scores and rs-ICC, indicating rs-ICC may be a useful predictor of cognitive outcome in patients undergoing ATL.

The Face of Category-Selectivity in Human Visual Cortex

Presenting Author: Andrew Engell

Collaborating Authors: Gregory McCarthy

The ultimate goal of cortical resection is to disrupt pathological processes while preserving normal function. Stimulation mapping or fMRI are thus used identify those regions that are critical to typical cognitive, perceptual, or sensorimotor behavior. Importantly, this approach is predicated on understanding the extent of localized function in a given region, and what role the region might play in a broader brain network. Here we investigate the properties of a core set of brain regions that area activated by face perception. Although the role of these regions as 'face-selective' patches of cortex has been reinforced by twenty years of fMRI research, we argue that they play a broader role in the perception of animate agents. For instance, it has been shown that viewing biological motion evokes a greater response in these areas than does non-biological motion. The current study uses a large sample of fMRI data (N > 100) to pursue three aims: 1) investigate the nature of the overlap between face and biological motion activation maps, 2) define and contrast the spatial reliability of activation across key nodes (lateral temporal, ventral temporal, and occipitotemporal cortices) of the face and biological motion networks, and 3) create probabilistic atlases of visual-category perception. We find that face and biological motion activations substantially overlap, but nonetheless have spatially separable peaks. However, in the ventral temporal and inferior occipitotemporal cortices these peaks do not maintain a consistent spatial relationship. We also characterize the spatial reliability of the response to each task and find that the Euclidean distance of the category peaks measured at different times (within-category variance) is not substantially different from the difference between face and biological motion peaks (between-category variance). Finally, we make freely available probabilistic atlases of face-, biological motion-, scene-, and house-selective BOLD activations.

3D Color Brain Movies to Improve Seizure Localization with >200 Channel Intracranial EEG

Presenting Author: Pue Farooque

Collaborating Authors: William Chen, Hyang Woon Lee, Mark W. Youngblood, Xiao Han, Stephen Jhun, Irina Goncharova, Kenneth Vives, Dennis D. Spencer, Hitten Zaveri, Lawrence J. Hirsch, Hal Blumenfeld

In cases of medically intractable epilepsy, intracranial EEG (icEEG) is the gold standard for identifying the seizure generating region. As rapid advancements in acquisition technology have led to improvements in the spatial resolution of icEEG data, the complexity of analyzing a large number of 2D, un-contextualized data channels has become a major impediment to understanding icEEG information. In an attempt to simplify data analysis and increase reviewer consistency, this study aimed to develop a new technique for clinical seizure localization using 3D color movies. The clinical usefulness of this technique was tested through a patient-by-patient comparison with a traditional icEEG analysis and again with surgical resection area. We analyzed 140 seizures from 48 intractable epilepsy patients (28 temporal and 20 extratemporal) with icEEG recordings, epilepsy surgery, and at least one year of postsurgical follow-up. The icEEG data was processed by performing a fast-fourier transform on the calculated signal power and the Beta frequency band was plotted over time onto a MRI-based surface rendering of each patient's cortex. Two independent blinded reviewers interpreted the icEEG data using a conventional visual analysis followed by 3D movies. Agreement between two reviewers was good, especially for 3D movies. Overall agreement rates between 3D movies and icEEG visual analysis or surgery were around 90% for side, 80% for lobe, and slightly lower than 80% for sublobar using a fixed Maximum Power Coloration Value (MPCV) and the Beta frequency range. These agreement rates were improved when variable MPCV and frequency range was allowed during review, especially for sublobar. In general seizure localization using 3D movies was comparable with the traditional icEEG visual analysis, but was measurably faster and considered qualitatively easier by both reviewers. These findings suggest that 3D movies could be a useful diagnostic method for presurgical seizure localization in patients with intractable epilepsy.

EEG and fMRI Correlates of Behavior during Childhood Absence Seizures

Presenting Author: Jennifer Guo

Collaborating Authors: Stephen Jhun, Robert Kim, Jorge Rodriquez-Fernandez, Adam Kundishora, Wendy Xiao, Xiaoiao Bai, Michiro Negishi, Hetal Mistry, Christopher Bailey, Michael Crowley, R. Todd Constable, Linda Mayes, Hal Blumenfeld

Seizures in childhood absence epilepsy (CAE) are characterized by 3-4 Hz spike-and-wave discharges on electroencephalography (EEG) and temporary loss of consciousness. While CAE is considered a generalized type of epilepsy, prior studies using functional magnetic resonance imaging (fMRI) show involvement of focal attentional and default mode networks, including the orbital/medial frontal cortex, medial/lateral parietal cortex, and thalamus. We recorded 256-lead high density EEG in 20 pediatric patients as well as simultaneous 32-lead EEG and fMRI in 34 patients as they performed behavioral tasks requiring attentional vigilance.

Overall, seizures caused greater impaired performance during the more difficult continuous performance task (CPT) compared to the less attentionally demanding repetitive tapping task (RTT). However, performance on both tasks varied from patient to patient and seizure to seizure. Behavioral performance was then related to EEG measures. Time-frequency analysis of ictal data on EEG show greater power changes in the 3-4Hz range for seizures associated with poor behavioral performance (>75% omissions) compared to seizures with good behavioral performance (<25% omissions). Source localization for seizure activity using both distributed and single dipole models localize spikes to medial frontal cortex. Timecourse of fMRI signal changes of seizure activity showed early increases in medial frontal cortex, bilateral insula, thalamus, then occipital cortex followed by decreases in a widespread frontal-parietal network. Finally, concordance between sources on high-density EEG and fMRI regions during seizures was determined. Characterizing electrophysiology and functional imaging signals during absence seizures may shed light on mechanisms of loss of consciousness during absence seizures.

Contribution of 7T MR Spectroscopic Imaging to Seizure Localization in Surgically Resected Epilepsy

Presenting Author: Jullie Pan

Collaborating Authors: RB Duckrow, J Gerrard, C Ong, L Hirsch, SR Resor Jr, Y Zhange, HP Hetherington, DD Spencer

Outcome studies in epilepsy surgery show it to be an excellent option for medically intractable epilepsy. However the challenge in these cases commonly depends on seizure localization with sufficient accuracy for surgery. In this initial report we evaluate the contribution of ultra-high field (7T) MR metabolic imaging in the process of localization for surgical epilepsy. Patient data are included in this analysis if their region of resective surgery overlapped with available MRSI data, resulting in a group of n=24 patients (a mix of medial temporal lobe MTL and neocortical epilepsy patients). The classification of interest was whether MRSI abnormalities completely agree with surgical resection (class 1), partially agreed (class 2), or did not agree (class 3). Two major outcome groups of ILAE I-III and IV-VI are used. With three classes and two outcomes, a 3x2 contingency table is devised. Of the n=24 patients, 16 underwent intracranial EEG monitoring for seizure localization. All MTL patients with MRI=defined asymmetric hippocampal atrophy (n=8) demonstrated concordance between surgery and MRSI (class 1) and excellent outcome (I-III). Out of the n=16 remainder, n=5 good outcome (I-III) was found with class 1 concordance; 10 poor outcomes (IV-VI) were found if there was either partial concordance or discordance (class 2 or class 3). n=1 patient was inaccurately classified, with good outcome and class 3 discordance. We discuss the results of this initial analysis.




1 Concordant: region of surgical resection agrees with MRSI (NA/Cr) abnormality 13 0
2 Partial Concordance: region of surgical resection displays MRSI abnormality but there are other regions of abnormality at least or worse 0 6
3 Discordance: region of surgical resection does not display MRSI abnormality 1 4
Slide Session II: Animal Models

Optogenetic Stimulation of Cholinergic Brain Networks for Preventing Cortical Dysfunction during Seizures

Presenting Author: Moran Furman

Collaborating Authors: Joshua Motelow, Benjamin Lerner, Ilana Witten, Karl Deisseroth, Fahmeed Hyder, Jessica Cardin, Hal Blumenfeld

Ictal and post-ictal loss of consciousness is a major cause of disability, and currently there are no effective treatments for this debilitating side effect of epilepsy. Studies in humans and animal models have shown that during complex partial seizures, the cortex transitions into slow-wave oscillations (1-2Hz), resembling neocortical activity during deep sleep, anesthesia, and coma. Furthermore, this transition is mediated by suppression of subcortical arousal structures, including the brainstem pedunculopontine tegmental nucleus (PPT) and thalamic centro-lateral nucleus (CL), structures that are essential for maintaining the cortex in an alert and awake state. Thus, stimulating these subcortical arousal regions is a promising avenue for improving the level of consciousness during seizures.

We aim to prevent neocortical slow-wave activity in a rat model of complex partial seizures using optogenetic stimulation of subcortical arousal structures. Recent evidence from our lab shows that cholinergic PPT neurons, but not other cell types, are inhibited during limbic seizures. To selectively stimulate cholinergic neurons in the PPT, we performed stereotaxic viral injections into the PPT and confirmed expression of the light sensitive protein channelrhodopsin-2 (ChR2) specifically in PPT cholinergic neurons. Using acute electrophysiological recordings with optogenetic stimulation and in the future also fMRI imaging and behavioral testing, we will examine the effect of stimulating and inhibiting cholinergic subcortical pathways on neocortical function during limbic seizures. These experiments will advance our mechanistic understanding of impaired consciousness in epilepsy and hopefully lead to novel treatments for preventing ictal unconsciousness, particularly in cases when medications or surgical therapies are ineffective or unfavorable.

Optical Approaches to Unraveling the Function of Dendrite-Targeting GABAergic Interneurons

Presenting Author: Michael Higley

Collaborating Authors: Chiayu Chiu, Gyorgy Lur

GABAergic synaptic inhibition plays a critical but poorly understood role in shaping neuronal activity in the neocortex. The disruption of GABAergic signaling is implicated in several neuropsychiatric disorders, including schizophrenia and autism. Hypotheses of inhibitory function have largely focused on perisomatic synapses, which control the magnitude and timing of action potential output from excitatory pyramidal neurons. However, the majority of GABAergic synapses in the neocortex are formed onto pyramidal cell dendrites, where their actions are less clear. Here, using cell type-specific optical stimulation in combination with 2-photon Ca(2+) imaging, we show that dendritic inhibition mediated by somatostatin-expressing interneurons exerts highly compartmentalized control over postsynaptic calcium (Ca(2+)) signals within individual dendritic spines. Anatomical and computational analyses indicate that this highly focal inhibitory action is mediated by a subset of GABAergic synapses that directly target spine heads. Our results demonstrate that GABAergic inhibition participates in localized control of dendritic biochemical signaling.

Neural Hyperactivity Disrupts Cerebral Microvascular Formation during a Postnatal Critical Period

Presenting Author: Christina Whiteus

Collaborating Authors: Catarina Freitas, Jaime Grutzendler

During the first postnatal month extensive synaptic and vascular remodeling occur in the mouse brain, however it is not known how these processes are coordinated. We investigated whether neural activity in the cortex influences the patterning of the vascular bed during this period. We found that increases in neuronal activity through audio and motor stimulation lead to reduced vascular branching in audio and motor cortices respectively, but had no effect in control areas. Pathological high neuronal activity induced by pilocarpine- and tetanus seizures caused an even more dramatic reduction in blood vessel branching. These branching deficits corresponded with a drop endothelial proliferation, though non-endothelial proliferation was unaffected. In vivo two-photon imaging revealed fewer vessel formations in animals experiencing seizures, however, we observed no increased elimination of either vessels or growing sprouts. The observed vascular deficits appear to be long-lasting as mice exposed to a 15 day auditory stimulation exhibit reduced vessel density up to three months later. Our results suggest the existence of a postnatal critical period during which inhibition of vascular growth in the brain might be detrimental later in life. Exposure of stimulated mice to low atmospheric oxygen reveals an increased sensitivity to hypoxia in brains with fewer vessels. This may have important clinical implications, especially during aging when vascular compensatory mechanisms are compromised by arteriosclerosis and stroke.

State-Dependent Inhibitory Control of Local Networks

Presenting Author: Jess Cardin

Collaborating Authors: Ulf Knoblich, Renata Batista-Brito, Mitra Miri

Brain activity is regulated by the interplay between two major types of neural cells: excitatory neurons that use the neurotransmitter glutamate and inhibitory interneurons that use the neurotransmitter GABA. Acute disruption of GABAergic inhibition profoundly alters brain activity patterns and leads to seizure, while constitutive changes in interneuron number and function are strongly linked to psychiatric disorders, such as schizophrenia and autism. In the cerebral cortex, which controls perception, cognition, and action, excitatory neurons receive a continuous barrage of synaptic inputs that must be integrated to produce output to target cells. Synaptic inhibition is thought to shape this integration and to provide a 'brake' on excitatory activity. Inhibition is thus hypothesized to be a critical regulator of healthy brain function and a key mediator of dysfunction in disease. However, little is known about the activity of inhibitory interneurons in the intact brain. Recent work has highlighted two major classes of hippocampal interneurons whose dysfunction is associated with seizure: 1) parvalbumin-expressing, fast-spiking interneurons that target the soma of excitatory neurons (PV) and 2) somatostatin-expressing interneurons that target the dendrites (SOM). These two populations are hypothesized to function differently in maintaining neural network stability. Until recently, it was not possible to target specific interneuron populations for either electrophysiological recording or perturbation of their activity in vivo. However, the recent development of transgenic optical tools for neural stimulation and suppression provides a novel approach for identification and direct manipulation of specific neural classes in vivo. In our current work, we are using a combined electrophysiological and optogenetic approach to record and manipulate the activity of genetically targeted PV and SOM interneurons under healthy conditions and in mouse models of disease.

Glutamine Synthetase and Astrocytes in the Pathophysiology of Localization-Related Epilepsy

Presenting Author: Tore Eid

Collaborating Authors: Ronnie Dhaher, Helen Wang, Nathan Tu, Hitten Zaveri, Benjamin Albright, Caroline Ong, Argyle Bumanglag, Eyiyemisi Damisah

Epilepsy is a common neurological disorder with a prevalence of approximately 1% in the general population. Up to one-third of individuals with epilepsy cannot control their seizures with current antiepileptic drugs, and the available drugs have side effects that limit their use. Uncontrolled seizures are often very disabling due to their unpredictable appearance and frequently associated features such as loss of consciousness, physical injury, and social stigmatization. Epilepsy is also associated with significant comorbidities including depression/suicide, cognitive impairment, and sudden unexpected death. Thus, our long-term goal is to facilitate the development of more efficacious and better tolerated treatments for epilepsy and its comorbidities. To attain this goal, the main scientific objective of the laboratory is to understand the cellular, molecular and metabolic mechanisms of temporal lobe epilepsy (TLE), which is one of the most common forms of medication refractory, localization related epilepsies. Our central hypothesis is that an initial brain insult (seizures, head trauma, intracranial infection) leads to proliferation of phenotypically abnormal ("reactive") astrocytes in the medial temporal lobe. The reactive astrocytes facilitate the development of recurrent seizures by perturbing the brain glutamine-glutamate-GABA homeostasis. We postulate that loss of glutamine synthetase in reactive astrocytes is a critical event in the pathophysiological process that leads to TLE.

Epileptiform Discharges in Transgenic Alzheimer's Mice Correlate with Impairments in Spatial Memory and are Reduced by Ethosuximide

Presenting Author: Haakon B. Nygaard

Collaborating Authors: Adam Kaufman, Linda L. Huh, Stephen M. Strittmatter

Background: Hyperexcitability and seizures have emerged as possible mechanisms underlying the neuronal dysfunction in Alzheimer's Disease (AD). Despite recent advances, it is not known to what extent seizures affect memory function or disease progression in AD, or whether reducing seizures could be an effective therapy in this disease.Here, we address these questions in detail utilizing rodent models of Alzheimer's disease.

Methods: APP-PSEN and 3xTg-AD mice were used, both of which harbor APPswe and PSEN1 transgenes, with the latter model also harboring the P301L tau mutation. All underwent continuous EEG monitoring for 72 hours. The APP-PSEN mice were tested in the Morris Water Maze, and their memory function correlated to the presence and severity of seizures. Subgroups with frequentseizures then underwent anticonvulsant therapy with Phenytoin, Ethosuximide, and Levetiracetam to assess effectiveseizure reduction. In addition, APP-PSEN mice lacking expression of cellular prion protein (PrPC) were also assessed for seizure reduction. The therapeutic effect of anticonvulsant therapy on the memory impairments in AD mice is now being tested.

Results: 40% ofaged APP-PSEN mice had at least 1 convulsive seizure over a 72 hour recording period, and approximately half had frequent non-convulsive spike-wave discharges (SWDs), lasting 1-2 seconds. Many SWDs were accompanied by a 1-3 second behavioral arrest.The presence of SWDs correlated with both learning and memory, with SWD-positive mice performing significantly worse in both the acquisition phase and the subsequent probe trial of the Morris Water Maze.Ethosuximide was most effective in reducing SWD frequency, with a complete resolution lasting 4 hours after dosing, with returnto baseline over 12 hours. Levetiracetam produced more than 50% reduction of SWD frequency, while phenytoin caused a slight increase in SWDs. The lack of PrPC expression completely reversed the SWD phenotype in APP-PSEN mice.

Conclusions: Our study is the firstto detail the correlation betweennon-convulsive SWDs and the behavioral impairments of AD mice. Our data suggest that the use ofanticonvulsants in the treatment of AD has therapeutic potential, either as an alternative or complimentary to current anti-amyloid interventions.

Slide Session III: Clinical / Electrophysiology

Psychiatric and Behavioral Side Effects of Anti-epileptic Drugs in Adults with Epilepsy

Presenting Author: Cel Ezeani

Collaborating Authors: Baibing Chen, Asif Javed, Kamil Detyniecki, Richard Buchsbaum, Hyunmi Choi, Stanley R. Resor, Lawrence J. Hirsch

Objective: Psychiatric/behavioral side effects (PSE) are commonly associated with the use of antiepileptic drugs (AED). An earlier study looked at PSEs of the newer AEDs alone. The purpose of this study was to examine the PSE profiles of a broad list of AEDs in addition to using a larger cohort of adult patients. PSE profiles were also compared to that of lamotrigine.

Methods: We reviewed the charts of 2246 adult patients (age ≥ 16) seen at both Columbia and Yale Comprehensive Epilepsy Centers and who were newly started on one of the AEDs between January 1 2000 and October 1 2012. PSE attributed to each AED was compared to PSE rates of the other AEDs using a logistic regression model. AEDs were also compared to lamotrigine because of its relatively safe PSE profile and wide therapeutic use in epilepsy therapy. Rates of toxicity - defined as PSE causing a change in drug dose or discontinuation - were also compared between AEDs.

Results: Overall, 178 of 2246 (8%) patients newly started on one of these AEDs experienced PSEs. The average rate of AED-related PSEs for a single AED was 3.8%. We found that levetiracetam (OR 4.91, p<0.0001) and tiagabine (OR 3.87, p=0.005) had significantly greater rates of PSE compared to other AEDs. PSEs attributed to either of these two AEDs were also more likely to be toxic (levetiracetam: OR 3.95, p<0.0001; tiagabine: OR 5.97, p=<0.0001). On the other hand, lamotrigine, (OR 0.33, p<0.0001), gabapentin (OR 0.33, p=0.016), carbamazepine (OR 0.38, p=0.020), pregabalin (OR 0.39, p=0.039), and valproate (OR 0.26, p=0.008) had significantly lower PSE rates. However, only lamotrigine (OR 0.27, p<0.0001) and valproate (OR 0.30, p=0.037) were significantly less likely than other AEDs to be toxic (See table). Levetiracetam and tiagabine were eight and ten times respectively more likely to cause PSEs (p<0.001) when compared to lamotrigine. They were also significantly more likely to cause discontinuation (<0.001). A history of any psychiatric condition was found to significantly influence AED-related PSEs (OR 1.79, p<0.001). When we controlled for psychiatric history levetiracetam (OR 6.44, p<0.0001) and tiagabine (OR 6.68, p=0.002) had a seemingly stronger influence on causing PSEs. Both also had a greater likelihood of causing toxicity than other AEDs (p<0.0001).

Conclusions: Significant differences exist amongst several AEDs with regard to their PSE profiles. Patients taking levetiracetam and tiagabine experienced significantly more PSEs than other AEDs and were more likely to be toxic. A history of a psychiatric condition significantly predicts PSEs in adult patients with epilepsy. Knowledge of the PSE profile of AEDs will aid clinicians in providing more effective treatment and possibly improve patient compliance.



PSE attributed (%)

OR (95% CI)


PSE causing toxicity (%)

OR (95% CI)





0.38 (0.17, 0.86)



0.38 (0.14, 1.04)





0.28 (0.04, 2.04)



0.43 (0.06, 3.13)





0.33 (0.14, 0.81)



0.41 (0.15, 1.11)





1.15 (0.53, 2.48)



1.24 (0.50, 3.06)





4.91 (3.72, 6.48)



3.95 (2.81, 5.54)





0.33 (0.21, 0.53)



0.27 (0.15, 0.51)





0.64 (0.31, 1.31)



0.48 (0.18, 1.30)





0.33 (0.05, 2.42)



0.51 (0.07, 3.71)





0.39 (0.16, 0.95)



0.48 (0.18, 1.30)





1.11(0.61, 2.01)



1.74 (0.95, 3.19)





3.87 (1.49, 10.03)



5.97 (2.29, 15.57)





0.70 (0.37, 1.34)



0.98 (0.49, 1.94)





1.08 (0.26, 4.49)








0.26 (0.10, 0.70)



0.30 (0.09, 0.93)





1.20(0.75, 1.90)



1.21 (0.69, 2.11)


Recording Gamma Frequencies Using Scalp Electrodes: Comparison of Simultaneous Scalp and Subdural EEG

Presenting Author: Ognen Petroff

Collaborating Authors: Irina Goncharova, Hitten Zaveri

The first studies recording both scalp and cortical EEG noted a significant loss of EEG power and loss of fidelity in the scalp recordings. Most of the subsequent work focused on the loss of fidelity of epileptiform activity and evoked potentials (30-200 ms transients). A special interest for gamma frequency range events emerged as they correlated with cognitive functions. Intracranial EEG reliably records gamma (20-80 Hz) and omega (60-120 Hz) frequencies and, with specialized amplifiers and electrodes, ripples, fast ripples and 600 Hz bursts.

Twenty patients (age 18–55) from the Yale University Epilepsy Surgery Program undergoing intracranial EEG monitoring for surgical evaluation were recruited. Scalp EEG recordings were made using Grass platinum needle electrodes located over the C3, C4, O1, and O2 sites. Simultaneous recordings were obtained from subjacent subdural strip electrodes (4mm diameter platinum disks with 2.3mm exposed surface diameter) as previously reported (Zaveri et al Clin Neurophysiol 2010;121:311–317). Offline analysis was performed with custom software written in a mixture of high level languages and MATLAB. Scalp and intracranial EEG epochs, 1 hour in duration, at least 6 hours removed from a seizure, 3 or 4 days after electrode implantation surgery, during wakefulness between 9–10 AM were selected for analysis. Scalp and subdural recordings were examined for artifacts (EMG, movements, ECG, 60 Hz interference, etc) and segmented with 1-second resolution. EEG power of artifact-free EEG segments was obtained for each electrode contact studied and averaged over the epoch. Average power (millivolts2) was calculated as the signal power between 0.5 and 128 Hz in 0.5 Hz increments. The ratio of scalp EEG electrode to subjacent subdural EEG electrode signal power was calculated between 0.5 and 128 Hz in 0.5 Hz increments.

Overall intracranial and scalp EEG power decreased from 1 to 60 Hz by three orders of magnitude. The ratio of scalp to intracranial power in the beta (13-25 Hz) frequencies ranged from 0.05 to 0.06, whereas the gamma (35-55 Hz) from 0.06 to 0.10. The scalp to intracranial EEG power ratio increased linearly with frequency from 40 to 60 Hz, which suggests a linear increase in scalp power at higher frequencies. Extracranial signals likely account for this significant increase in scalp EEG power and would confound measurement of the gamma frequencies using scalp EEG.

Lateralized Rhythmic Delta Activity in Critically Ill Patients

Presenting Author: Nicolas Gaspard

Rationale: To describe a new variant of rhythmic delta activity encountered in the critically ill, its clinical correlates and compare it with focal polymorphic slowing and lateralized periodic discharges (LPDs or PLEDs).

Methods: Retrospective review of urgent EEG and continuous EEG reports 05/01/2011 and 04/30/2012 to identify patients with lateralized rhythmic delta activity (LRDA). Recordings, medical reports and imaging studies were reviewed. Statistical comparisons were performed with the Chi2-test or the Fisher Exact t-test.

Results: We identified 27 patients (4.7% of all the) with lateralized rhythmic delta activity (LRDA). Mean age was 52+/-3.5years (4mo-87years) and 11 were female. Twenty patients were admitted to an ICU and 17 were stuporous or comatose. Nineteen had a lateralizing neurological examination and the side of LRDA always agreed with the examination.

Twenty-four had a single unilateral focus, 2 had bilateral independent RDA (BIRDA) and 1 had two ipsilateral independent foci; 30 different patterns were identified. Eighteen were located in the frontal region, eight in the temporal region and four in the posterior region; this distribution was similar for LPDs. Most commonly, runs of LRDA consisted in 1-2c/s, 50-200µV, sinusoidal or saw-tooth monomorphic non-evolving waves and lasted less than 10s, although faster frequencies (2-3/s) and longer duration (up to 1 min) were encountered.

All patients except one had an acute or remote focal brain lesion. The most common etiologies were intracranial hemorrhage, ischemic stroke, subarachnoid hemorrhage, subdural hematoma, traumatic brain injury and CNS inflammatory/infectious disorder. This was overall similar to LPDs and focal polymorphic slow activity (PSA) except that acute intracranial hemorrhage was more frequent in the LRDA group than in the PSA group (p < 0.01). Systemic factors (infection, metabolic imbalance) were present in half of the cases.

Twenty-six patients had brain imaging and it was found to be abnormal in 24. Lesions involved the cortex or subcortical white matter, the deep white matter or deep grey structures in 18, 9 and 5 cases respectively. In case of a single focal lesion, it co-localized in the same region as LRDA in all but two cases (17/19) who had a thalamic (same side) and an extensive brainstem hemorrhage (including the upper midbrain and thalamus).

Focal periodic (LPDs or BIPDs/BIPLEDs) and sporadic epileptiform discharges were found in 12/27 and 7/27 patients respectively and always co-localized with LRDA. Seventeen patients (63%) had acute clinical and/or electrographic seizures during their stay; this proportion was similar to the one observed with LPDs/BIPDs (28/49 or 57%) but significantly higher than the one observed with PSA (14/105 or 13%; p=0.001). All were focal seizures and co-localized with LRDA.

Conclusions: We describe a new focal variant of RDA encountered in critically ill patients with an acute or remote brain lesion that bears the same clinical significance as LPDs/PLEDs, as more than half of the patients had acute seizures.

Consciousness during Seizures Determines the Accuracy of Patient Seizure Descriptions

Presenting Author: Kamil Detyniecki

Collaborating Authors: Cel Ezeani, Andrew Bauerschmidt, Robert B. Duckrow, F. Scott Winstanley, Lawrence J. Hirsch, Hal Blumenfeld

The goal of this study was to assess patients' reporting of their seizures. We also looked at predictors that could influence the accuracy of their report. Further, we examined the impact that deficits in memory and consciousness could have on patients' seizure descriptions.

We recruited patients undergoing VEEG evaluation in our institution. Daily, a member of the research team asked them if they had any seizure in the previous 24 hours. We compared their subjective response with a more objective measure by analyzing the video recordings of their seizures. Seizure type, localization, and presence of impaired consciousness were among the characteristics documented. We determined statistical significance using Chi-square or Fisher's exact tests where appropriate to evaluate relationships between patients' characteristics and seizure reporting. To determine which factors impacted seizure reporting, a multivariate binary logistic regression was performed.

115 patients were recruited, of which 65 met all criteria for analysis (confirmed epilepsy, completed questionnaires, seizures captured during VEEG monitoring).

Overall, we captured a total of 295 partial and 42 sGTC seizures. 30% of all seizures were not reported while 70% were reported. We found that SPS were more often reported than both CPS and sGTC in pair-wise comparisons (p=0.008 and <0.001 respectively). This was consistent with our finding on patient level, where patients with only SPS more often reported their seizures. We also found that loss of consciousness (OR 0.25; 95% CI 0.07 – 0.92; p=0.037) and temporal lobe onset (OR 0.17; 95% CI 0.08 – 0.37; p<0.001) had a negative influence on seizure reporting. Although patients who were awake at seizure onset reported more of their seizures (Chi-square 17.34; p<0.0001), sleep state was not a significant independent predictor of seizure reporting. We didn't observe an effect of seizure lateralization on seizure reporting.

This study demonstrates that seizures with impaired consciousness were more likely to go unreported suggesting that consciousness may be a factor influencing the ability of patients to recognize and accurately report their seizures. In addition, temporal lobe onset but not lateralization significantly influenced if seizures were reported. Further study is needed to investigate the impact of altered memory function and language impairment on seizure reporting.

Data Contradicting the New ILAE Classification of "Focal" Seizures

Presenting Author: Courtney Cunningham

Collaborating Authors: Andrew Shorten, Bridget Kiely, Michael McClurkin, Tenzin Choezom, Andrew Bauerschmidt, Hal Blumenfeld

Impaired consciousness in epilepsy has a major negative impact on patient quality of life. Our lab recently developed a standardized testing battery, the Responsiveness in Epilepsy Scale (RES), designed to assess altered behavior during seizures in an objective, prospective fashion. 92 patients undergoing continuous video/EEG monitoring (VEEG) for seizure evaluation at Yale New Haven Hospital were recruited for this study. Patients were tested with RES or RES-II during the ictal and immediate postictal periods. Ictal testing was performed for a total of 80 seizures (31 patients). Scores from RES-I testing were later converted from a 5-point to a 4-point scale, corresponding with RES-II, in order to simplify analysis.

Performance on the initial cycle of questions asked upon onset of partial seizures showed a bimodal distribution. On these initial questions, patients tended to be either entirely unimpaired or completely unresponsive in most seizures. For instance, 28 of 80 seizures scored the maximal score of "4" on the first question asked, while 44 of 80 seizures received the minimal score of "0". Only 8 seizures received intermediate scores on this initial question. This distribution of impairment was typically sustained until seizure termination.

These distinct patterns of impairment correlate with those seen in the traditional categories of "simple partial" and "complex partial" seizures. Our results demonstrate that focal seizures can often be cleanly separated into those with or without impaired responsiveness. This distinction is of critical importance in clinical decision making regarding a patient's ability to work, drive a car, or participate in other daily activities. The latest revision of the ILAE classification guidelines eliminates the distinction of simple partial vs. complex partial seizures; however our findings support the validity of this traditional classification.

Functional Connectivity in the Seizure Onset and Peri-Seizure Onset Area

Presenting Author: Hitten P. Zaveri

Collaborating Authors: Steven M. Pincus, Irina I. Goncharova, Robert B. Duckrow, Lawrence J. Hirsch, Dennis D. Spencer

Rationale: To test if functional connectivity measured from the background intracranial EEG (icEEG) varies with distance to the seizure onset area and with frequency of icEEG activity.

Methods: This study was conducted on 12 unselected adult patients with localization related epilepsy undergoing icEEG monitoring for possible surgery. Intracranial EEG electrode contacts were located from post-implantation CT and MR images and registered to the MRI of a standard brain to allow interpretation of results in the same space. A 1 hr icEEG epoch, recorded during wake and removed from seizures, was studied.

Coherence was estimated for all pairs of electrode contacts ipsilateral to the seizure onset area in 6 frequency bands: delta, theta, alpha, beta, gamma and a high-frequency band. The connectivity of each electrode contact was estimated as the average coherence between it and all electrode contacts within a specified distance.

Results: A graded relationship was observed between connectivity and distance to the seizure onset area such that electrodes with the greatest connectivity were closest to the seizure onset area and electrodes with the lowest connectivity were at a distance of several cm from the seizure onset area. The relationship between distance and connectivity was present primarily in the theta, alpha, beta and gamma frequency bands. Similar relationships were not observed for spike counts or spectral power in different frequency bands.

Conclusions: Patients who suffer from localization-related epilepsy have altered functional connectivity in the seizure onset and peri-seizure onset areas.

Poster Session

Predicting Seizures in Intracranial EEG Data Using Diffusion Maps

Presenting Author: Dominique Duncan

Collaborating Authors: Ronen Talmon, Ronald R. Coifman, Hitten P. Zaveri

Often medication or surgery are not viable options for patients with epilepsy, thus it is important to find a reliable tool to predict seizures. This way the patient may be warned at least a few minutes prior to the seizure and take the necessary precautions. Finding an accurate predictor of seizures has become a major focus of research during the last few decades.

The goal of this study is to predict a seizure from intracranial EEG (icEEG) data. A novel approach is proposed that capitalizes on the diffusion map framework, which was recently presented and is considered to be one of the current leading manifold learning methods. Diffusion mapping provides dimensionality reduction of the data as well as pattern recognition that may be used to distinguish different states of the patient, for example, resting and preseizure. Based on diffusion maps, a new nonlinear independent component analysis (ICA) algorithm is developed to construct coordinates that generate efficient geometric representations of the complex underlying data structures.

The algorithm is tested on icEEG data recorded from several electrodes from patients being evaluated for possible epilepsy surgery at the Yale-New Haven Hospital. Artifacts are removed from the data prior to the analysis. Preliminary results show that the proposed approach provides a distinction between resting and preseizure states.

Technology for Sensing the Brain and Controlling Seizures

Presenting Author: Hitten P. Zaveri

Collaborating Authors: Ronnie Dhaher, Tore Eid, Lawrence J. Hirsch, Dennis D. Spencer

This presentation describes innovative technologies which are being brought to bear on the direct sensing of the brain in epilepsy and intervention to control seizures. This research is being conducted through two related projects being pursued in collaboration with ITN Energy Systems (Littleton, CO) and the Department of Electrical and Computer Engineering at the University of North Carolina at Charlotte. These projects address the battery free wireless transmission of intracranial EEGs (icEEGs), and the fault-tolerant monitoring of brain activity. In the first project we have designed, fabricated and tested a prototype 64 channel brain implantable device for the wireless transmission of icEEGs. The device allows digital icEEG acquisition and transmission through a standard infra-red (IR) data link and has the potential to perform electrical stimulation. The device can be powered by an embedded battery, wired external power or battery free power through a radio frequency (RF) power link. Bench-top, ex-vivo and in-vivo rat evaluations of the 64-channel wireless icEEG device demonstrate proof-of-principle for an implantable solution to sense, condition, amplify, digitize and wirelessly transmit multi-channel icEEGs. The second project stems from an argument for the inclusion of fault-tolerance in brain implantable devices to extend their dependability. We focus on multielectrode arrays (MEAs) and propose two redundancy based solutions. The first solution uses rows or columns of spare modules to replace faulty modules within a MEA. The second solution uses space redundancy with local reconfiguration. Different fault-tolerant solutions with varying degrees of redundancy and the equivalent graph models for these solutions are described. A maximum matching algorithm is described to match faulty primary to functioning spare modules for MEA reconfiguration. The results of our analysis demonstrate that a considerable improvement in MEA dependability can be achieved with a well-designed increase in redundancy.

Testing Multi-Modal Attention and Awareness with Intracranial EEG

Presenting Author: Paul Guillod

Collaborating Authors: Nicole Tsai, William Chen, Leisel Martin, Mark Youngblood, Ryan Aronberg, William Walker, Andrew Engell, Jason Gerrard, Dennis D. Spencer, Gregory McCarthy, Hal Blumenfeld

Modern neuroimaging allows researchers to probe the mechanisms that give rise to consciousness. This has yielded great insight into how the brain manages and attends to incoming sensory data. Studies have already shown signatures of conscious perception through synchronized, long-range, high frequency oscillations; however, the precise timing and neural correlates behind perception remain elusive.

Our study investigates mechanisms of conscious perception by presenting faint, simultaneous auditory (beeps) and visual (circular gratings) stimuli and measuring the neural response. Stimuli intensities are first calibrated such that subjects report perceiving stimuli half the time. They then run through ~1200 trials that ask them to focus on one of the stimuli (circle or beep) each trial. The stimuli are briefly shown simultaneously and subjects subsequently report which side and whether they perceived one of the two stimuli. They are most often asked about the cued stimulus.

By presenting stimuli at the threshold of perception, we can group events by subjective awareness during analysis. Directing subject's focus on visual or auditory stimuli allows us to dissociate attention from awareness related effects. Furthermore, the incorporation of two sensory modalities can demonstrate how localized and generalized neural correlates of perception are by sense.

So far we have run the task on over 30 subjects and 1 intracranial EEG patient with plans to add scalp EEG combined with fMRI. Recent task performance results can be seen in figure 1 below.

Many patients with epilepsy are unable to perceive and respond to sensory input during seizures. A greater knowledge of the neural circuitry involved in perception will allow us to eventually diagnose and gear therapies in such a way to avoid disruption of those vital circuits.

Limbic Seizures Decrease Subcortical Arousal in Brainstem Cholinergic and Thalamic Neurons

Presenting Author: Joshua E. Motelow

Collaborating Authors: Geoffrey Liu, Hyun Seung Lee, Victoria Chu, Abhijeet Gummadavelli, Asht M. Mishra, Robert N. Sachdev, Basavaraju Sanganahalli, Moran Furman, Dario Englot, Fahmeed Hyder, Hal Blumenfeld

The mechanism of impaired consciousness during partial limbic seizures is not understood. Cortical intracranial EEG recordings in epilepsy patients demonstrate high-frequency, poly-spike seizure activity in the temporal lobe but simultaneous low frequency oscillations across the neocortex. These low-frequency ictal neocortical oscillations are similar to those seen in sleep or deep anesthesia, which provides a clue to the mechanism underlying loss of consciousness. We have developed a rodent model of complex partial limbic seizures in which an electrically induced hippocampal seizure causes the frontal cortex to convert from high-frequency to low-frequency slow oscillations. Blood oxygen level dependent (BOLD) fMRI data during these seizures show increased signal in hippocampus, septal nuclei and hypothalamus associated with widespread BOLD signal decreases in cortex, thalamus, and brainstem. During seizures, multiunit electrophysiology recordings show increased neuronal activity in hypothalamus, decreased activity in brainstem cholinergic nuclei and spindle-like activity in thalamic relay nuclei. Because the brainstem cholinergic nuclei are heterogeneous, juxtacellular recordings were conducted from single labeled cholinergic and non-cholinergic neurons. Cholinergic neurons decrease their firing dramatically during seizures (during which the cortex converts to slow oscillations) while non-cholinergic neurons show mixed behavior. At the same time, we have recorded decreased levels of choline (as a proxy for acetylcholine) in the cortex and thalamus. These data suggest a mechanism for the transition from consciousness to loss of consciousness: (1) hippocampal seizures propagate to limbic structures including the septal nuclei and hypothalamus, (2) descending inhibition from the septal nuclei and hypothalamus depress subcortical arousal systems, and (3) suppression of ascending arousal systems such as the brainstem cholinergic nuclei lead to cortical rhythms normally present during non-REM sleep.

Sudden Unexpected Death in the Multicenter Study of Epilepsy Surgery Outcomes

Presenting Author: Cel Ezeani

Collaborating Authors: Friedman D, Detyniecki K, Hamid H, Spencer DD, Hirsch LJ, Devinsky O

Background: Sudden unexpected death in epilepsy (SUDEP) is death occurring in people with epilepsy in the absence of a known structural cause. Although the frequency of SUDEP varies depending on severity of epilepsy and other factors, the risk is known to be more than 20 times higher than that in the general population. In a seven-center, prospective study of resective epilepsy surgery, we examined the frequency of SUDEP over a five-year follow-up period.

Methods: Patients aged 12 years and above were enrolled at time of referral for epilepsy surgery, and underwent standardized evaluation, treatment, and follow-up procedures. SUDEP cases were classified as definite, probable, or possible. 386 postsurgical and 127 non-surgical patients who had follow-up data were analyzed. In 1648.75 total person-years of follow-up, we examined the effects of seizure freedom, history of generalized convulsions, and resective surgery with respect to predicting an outcome of SUDEP.

Results: Among the 386 post-surgical patients, there were 19 deaths (5%; 12 per 1000 PYs); 5 of these deaths were attributed to definite (1), probable (1) or possible (3) SUDEP (1%; 3 per 1000 PYs). 1 out of the 182 seizure free patients died from SUDEP (0.6%; 1.3 per 1000 PYs), compared to 4 of 204 non-seizure free patients (2%; 4.5 per 1000 PYs). 4 of 97 patients who had persistent generalized tonic-clonic (GTC) seizures after surgery died from SUDEP (4%; 10 per 1000 PYs). On the other hand, only 1 death was due to SUDEP out of 289 patients who did not have persistent GTC seizures (Fisher's Exact Test, p=0.015). We also found that 2 of 6 deaths in the non-surgical group were due to SUDEP (1 probable and 1 possible) although when compared with the post-surgical group, this finding was not significant (See table).

Conclusion: In our cohort of patients, persistent GTCs after epilepsy surgery appear to have an effect on incidence of SUDEP. Although there was a lower rate of SUDEP in the seizure free group compared to the non-seizure free group, this did not reach significance.


Definite SUDEP

Definite or Probable


Definite, Probable or possible SUDEP

Surgery, not seizure free

Surgery, seizure free

P value



1/204 = 0.49%



2/204 = 0.98%



4/204 = 2%

1/182 = 0.6%


Surgery, still has GTCs

Surgery, no GTCs

P value



1/97 = 1%



2/97 = 2%



4/97 = 4%

1/289 = 0.4%



No surgery

P value



1/386 = 0.3%






5/386 = 1%



Pre-op GTCs, then surgery

Pre-op GTCs, no surgery

P value








4/282 = 1.4%

1/92 = 1.1%


Ictal and Interictal Attention Performance in Childhood Absence Epilepsy Patients

Presenting Author: Robert Kim

Collaborating Authors: J. Rodríguez-Fernández, J. Guo, S. Jhun, W. Xiao, H. Mistry, N. Michiro, RT. Constable, H. Blumenfeld

Childhood absence seizures are characterized by brief impaired consciousness and generalized 3-4 Hz spike-wave discharges on the electroencephalogram. Prior studies have shown impaired attention performance during absence seizures.

Here we investigate relationships between variably impaired ictal attention and: (1) task difficulty; (2) seizure duration; (3) behavioral time course during the ictal period; and (4) interictal attention deficits. We tested patients with a diagnosis of childhood absence epilepsy. Each subject underwent either a Repetitive Tapping Task (RTT), or a more difficult Continuous Performance Task (CPT). Out of a total of 90 children, 34 had absence seizures during testing (235 seizures during RTT and 291 during CPT). Mean seizure duration was 5.09±0.17 s (mean±SD). Mean ictal omission rate was 73% for CPT and 51% for RTT, compared to the mean interictal omission rate for CPT 18.66±1.8 and RTT 22.68±0.6. Interestingly, we observed a higher omission rate in seizures longer than 10 seconds (CPT omission rate 89.97±1.9 and RTT omission rate 79.15±2.4) than in less than 5 seconds seizures (CPT omission rate 51.8±4.5 vs RTT omission rate 33.33±3.4). Clear outliers exist in CPT and RTT where short seizures have severely impaired performance and longer seizures have relatively spared performance. For both CPT and RTT, omissions were least severe toward the end of the seizure (last 1s of the seizure): CPT and RTT omission rates were 49.72±5 and 26.4±4.3 respectively. For RTT, performance was also relatively spared on average during the first ~1s of the seizure (performance 55.39±4.9). Also we observed an increased variability in reaction times for both CPT and RTT, and increased duration and variability in inter-response intervals for RTT during the ictal period. These data suggest that task difficulty and task timing have important effects on attention performance during absence seizures. Ictal attention impairment may be related to interictal deficits, suggesting chronic dysfunction in attention networks. This investigation will help us to understand the neural mechanisms of attention deficits observed in CAE patients.

IV Ketamine for the Treatment of Refractory Status Epilepticus: A Retrospective Multicenter Study

Presenting Author: Nicolas Gaspard

Collaborating Authors: B. Foreman, L.M. Judd, J.N. Brenton, B.M. McCoy, A. Al-Otaibi, R. Kilbride, I Sanchez Fernandez, S. Samuel, A. Zakaria, G.P. Kalamangalam, T. Loddenkemper, C.D. Hahn, H.P. Goodkin, J. Claassen, L.J. Hirsch, S.M. LaRoche

Rationale: The treatment of refractory status epilepticus (RSE) is notoriously difficult. Evidence from animal models suggests that inhibition of glutamate antagonists might be more efficient in the late stage of status epilepticus than GABA agonists.

Ketamine is an NMDA receptor antagonist occasionally used in this indication. The rationale of this study is to review the use of ketamine in RSE, including doses, efficacy and adverse events.

Methods: We conducted a retrospective multicenter study involving 6 academic centers. Medical records and EEG reports were reviewed. We included children and adults. Continuous EEG was used in all but one case.

Results: We identified 22 patients (11 female) and 23 episodes of RSE treated with ketamine. Mean age was 28+/- 4 years (range: 7 months-74 years). The most common etiologies of RSE were CNS infection (5), inflammatory disease (4), malformation of cortical development (4) and genetic disorder (3). Status epilepticus was primary generalized in 6 cases and secondary generalization occurred in 12 cases. Five cases had purely electrographic status epilepticus while the remaining patients had associated clinical manifestations, including generalized (4), partial (3) and subtle (7) motor activity. In most cases, ketamine was introduced at least 1 week after the onset of SE. An initial loading dose was commonly used (usually 1.5-2.5 mg/kg), followed by continuous infusion (usual initial rate of 0 .1-0.5 mg/kg/h). The maximal infusion rate was most frequently 1-2mg/kg/h, although in 4 patients it was superior to 5mg/kg/h. The duration of the treatment with ketamine ranged from 2 to 24 days. Three patients developed cardiorespiratory depression and two required mechanical ventilation. All 3 were concomitantly treated with benzodiazepines and/or barbiturates. Vasopressors were increased in 8 patients but only one developed significant hypotension. No patient demonstrated signs of raised intracranial pressure. Three patients developed severe acidosis that was attributed to shock and acute kidney injury in 2 cases. The third patient developed a syndrome similar to the Propofol Infusion Syndrome (PRIS), while on high dose of ketamine (7.5mg/kg/h) and midazolam. Status epilepticus was permanently controlled in 10 cases. All 10 were alive at discharge from the hospital but significantly impaired. Ketamine was the last drug to be used in 3 of them. The others received at least one other additional drug after ketamine, most commonly benzodiazepine (7), phenytoin/fosphenytoin (6) and topiramate (4). Length of stay in the ICU ranged from 13 to 244 days.

Conclusion: Assessing the efficacy of ketamine in RSE is difficult as it is used in the late stage of refractory SE and with a wide range of doses. This study indicates that it is associated with a low incidence of serious adverse events, although we describe for the first time its association with a syndrome similar to PRIS. Further study is needed before recommendation can be made to extend its usage and this multicenter effort will be pursued.

Relationship between Depression, Anxiety, and Quality of Life Outcomes Post Epilepsy Surgery: A Prospective Multicenter Study

Presenting Author: Hamada Hamid

Rationale: People with seizures have a lower quality of life (QOL) compared to people without. Depression and anxiety scores strongly correlate with QOL scores in cross-sectional studies. However, the role of depression and anxiety symptoms on QOL outcomes after epilepsy surgery has not been explored prospectively.

Methods: The design, measures, and subject recruitment of the Epilepsy Surgery Multicenter Study has been detailed elsewhere. Briefly, 7 tertiary epilepsy centers enrolled 396 patients and completed a comprehensive diagnostic workup that included a comprehensive medical history and physical exam; neuropsychological, neuroimaging and neurophysiology testing; and a psychiatric as well as quality of life evaluation. Subjects were evaluated prior to surgery, then at 3, 6, 12, 48, and 60 months after surgery. Standardized, assessments included The Quality of Life in Epilepsy Inventory-89 (HRQOL) and Beck Depression (BDI) and Anxiety (BAI) Inventories. Seizure outcome was classified into one of four categories: "excellent" for subjects seizure free (and no auras) for all five years, "good" for two consecutive years but not all five, "fair" if subjects were seizure free for one year but never two consecutive years, and "poor" if subjects never had a one year period of seizure freedom.

Statistical Analysis: The mixed-model repeated-measures analysis was used to analyze overall HRQOL score and four dimension subscores (cognitive distress, physical health, mental health, epilepsy-targeted) association with depression, anxiety, seizure outcome, seizure history, with overall HRQOL score and the four dimension subscores, respectively, over time. The model included gender, race, education, duration of seizure history, laterality of seizure focus, resection location, BDI and BAI scores, and time as fixed effect as well as random intercept and slope.

Results: All four subscores of QOL improved over time (p<0.0001). Excellent and good seizure control groups both have significant positive impact on the overall QOL compared to the fair and poor seizure control group; interestingly, there is no difference in change in overall QOL over time between the fair and poor groups. The time and seizure control interaction was marginal significant (p=0.0606). Subjects who had left sided resections shown significant lower rate of improvement in overall QOL score compared to those with right sided resection. The BDI and BAI score are both highly and negatively associated with overall QOL; increases in BDI and BAI score are associated with decreased overall QOL score. This association appeared to be driven by the cognitive subscore and the association was not significant in the other subscores. Duration of seizure history, gender, race, education and temporal versus extratemporal resection did not show significant association with overall QOL.

Conclusion: Depression and anxiety are strongly and independently associated with worse QOL post epilepsy surgery. Management of mood and anxiety is a critical component to post-surgical care.

Distinct Contribution of Different Interneuron Subtypes to Network Stability in Vivo

Presenting Author: Mitra Miri

Collaborating Authors: M. Miri, J.A. Cardin

GABAergic inhibition is critical for regulation of excitation and is thought to maintain neural network stability through a precise balancing process. Loss or dysfunction of inhibitory interneurons is thought to lead to abnormal activity patterns and ultimately to seizure initiation. Two major interneuron classes are the Parvalbumin-expressing (PV), fast-spiking cells and Somatostatin-expressing (SOM), low-threshold spiking cells. Due to differing physiology, biophysical properties, and synaptic targeting, they may contribute differently to ongoing computations in the surrounding local network. Previous studies have examined preferential interneuron vulnerability leading to or resulting from seizures, but there the roles of specific sources of inhibition in seizure generation remain unclear. Using combined optical and electrophysiological tools, we can investigate network dynamics during the development of seizures by monitoring the activity of individual interneurons and synchronization between multiple hippocampal cell types.

Here we used two transgenic mouse lines: PV-Cre and SOM-Cre. Using AAV-DIO ChR2-mCherry, we selectively targeted optogenetic tools to PV or SOM interneurons in CA1. During experiments, we used stereotrode arrays to extracellularly record the activity of many simultaneous cells in hippocampal CA1 in animals lightly anesthetized with ketamine/xylazine. We identified targeted ChR2-expressing PV and SOM interneurons in the recorded population by stimulating with brief pulses of blue light at 473nm. Light pulses were continued throughout the experiment to track identified neurons without altering the pattern of spontaneous activity. Using a pharmacological model of seizure induction (PTZ), we performed measurements of neural activity during three periods: 1) baseline 2) early preictal and 3) late preictal. We first assessed the recruitment of local excitatory neurons by ictal activity. We further assessed the temporal pattern of identified interneuron activity during each period and the relationship between interneuron and excitatory neuron activity.

To examine the relationship between local network activity and interneuron spiking, we calculated the spike-triggered LFP average for each cell during each period. We find that PV+ cells have a lower spike probability in response to blue light pulses that progressively decreases from baseline to late preictal stages. Additionally, we find that average local synaptic activity increases surrounding spike times of identified RS cells during both early and late preictal periods, as compared to baseline. These preliminary results demonstrate that these combined approaches provide a powerful set of tools for dissecting network activity during seizure initiation.