EEG/MEG source imaging of deep brain activity within the maximum entropy on the mean framework: Simulations and validation in epilepsy.

Electro/Magneto-EncephaloGraphy (EEG/MEG) source imaging (EMSI) of epileptic activity from deep generators is often challenging due to the higher sensitivity of EEG/MEG to superficial regions and to the spatial configuration of subcortical structures. We previously demonstrated the ability of the coherent Maximum Entropy on the Mean (cMEM) method to accurately localize the superficial cortical generators and their spatial extent. Here, we propose a depth-weighted adaptation of cMEM to localize deep generators more accurately. These methods were evaluated using realistic MEG/high-density EEG (HD-EEG) simulations of epileptic activity and actual MEG/HD-EEG recordings from patients with focal epilepsy. We incorporated depth-weighting within the MEM framework to compensate for its preference for superficial generators. We also included a mesh of both hippocampi, as an additional deep structure in the source model. We generated 5400 realistic simulations of interictal epileptic discharges for MEG and HD-EEG involving a wide range of spatial extents and signal-to-noise ratio (SNR) levels, before investigating EMSI on clinical HD-EEG in 16 patients and MEG in 14 patients. Clinical interictal epileptic discharges were marked by visual inspection. We applied three EMSI methods: cMEM, depth-weighted cMEM and depth-weighted minimum norm estimate (MNE). The ground truth was defined as the true simulated generator or as a drawn region based on clinical information available for patients. For deep sources, depth-weighted cMEM improved the localization when compared to cMEM and depth-weighted MNE, whereas depth-weighted cMEM did not deteriorate localization accuracy for superficial regions. For patients' data, we observed improvement in localization for deep sources, especially for the patients with mesial temporal epilepsy, for which cMEM failed to reconstruct the initial generator in the hippocampus. Depth weighting was more crucial for MEG (gradiometers) than for HD-EEG. Similar findings were found when considering depth weighting for the wavelet extension of MEM. In conclusion, depth-weighted cMEM improved the localization of deep sources without or with minimal deterioration of the localization of the superficial sources. This was demonstrated using extensive simulations with MEG and HD-EEG and clinical MEG and HD-EEG for epilepsy patients.

Real-world practices in reproductive health and counselling for women with epilepsy: A Canadian perspective.

Canadian women of reproductive potential living with epilepsy present unique care challenges due to the complex interplay of hormones, seizures, and medications. This study explores reproductive health practices and counselling for women with epilepsy. Through a questionnaire developed by the Canadian League Against Epilepsy women with epilepsy (WWE) workgroup, we are the first to report demographic and real-world practice characteristics of Canadian healthcare professionals providing care for WWE with specific focus on family planning, birth plans, and postpartum care counselling. Among respondents, 76.9% routinely reviewed contraception with patients and an intrauterine device (IUD) was the most popular recommended method (85.3%). With regards to preconception planning, 50% of respondents routinely had a preconception drug level prior to pregnancy. A significant proportion, 44.9%, reported not communicating a neurology-informed birth plan to obstetrical health practitioners. The majority recommended breastfeeding for WWE on anti-seizure medications (92.3%) and regularly provided safety counselling for women in the postpartum period (84.6%). Overall, our study demonstrates that Canadian practice patterns conform reasonably well to existing evidence and guidelines, although important gaps in care exist.

Fostering Education in Epilepsy: A Canadian League Against Epilepsy Teaching Initiative.

The Canadian League Against Epilepsy initiated a virtual epilepsy education program, conducting 29 webinars from March 2021 to September 2023. We report our experience, with the goal to inspire other groups to develop inclusive, equitable, and free educational spaces with a worldwide reach. Monthly sessions drew a median attendance of 118 participants, predominantly Canadian but also international, including physicians (58.9%) and trainees (22.8%). Post-webinar surveys (average 40% response rate) noted high satisfaction, a strong inclination to recommend the sessions, and an interest in clinical case-based topics. We plan to consider integrating a self-assessment section evaluating knowledge gained after each seminar.

Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-ß positive individuals.

INTRODUCTION: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aß) positive participants using plasma biomarkers. METHODS: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [18 F]AZD4694 and tau-PET with [18 F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aß+ individuals. RESULTS: Highest associations with tau positivity in Aß+ individuals were found for plasma pTau-217 (AUC [CI95% ] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI95% ] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95%  = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity. DISCUSSION: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice. HIGHLIGHTS: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aß+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification.

14-3-3 [Formula: see text]-reported early synaptic injury in Alzheimer's disease is independently mediated by sTREM2.

INTRODUCTION: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. METHODS: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. RESULTS: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. CONCLUSIONS: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.

Real-world practices for the care of women with epilepsy during pregnancy: A Canadian perspective.

OBJECTIVE: Approximately 150,000 Canadian women live with epilepsy, a population that presents with unique challenges. Our objective was to capture demographic and real-world practice characteristics of Canadian healthcare professionals providing care for women with epilepsy (WWE) with specific focus on reproductive considerations to identify potential gaps in knowledge and care. METHODS: A questionnaire developed by the Canadian League Against Epilepsy WWE workgroup was distributed to Canadian healthcare professionals from February 2021 to October 2022 to capture participant demographic characteristics and practice patterns in key areas of the reproductive cycle in WWE. RESULTS: A total of 156 participants completed the questionnaire, most being physicians (81.4%), epilepsy specialists (69.0%), and those who cared for adult patients (86.5%), with a significant proportion based at an academic center (65.4%). The majority of participants counselled on folic acid supplementation (89.7%). Participants selected lamotrigine and levetiracetam most frequently for either focal or generalized epilepsies during pregnancy. Additionally, 85.9% performed therapeutic drug monitoring during pregnancy. Almost all practitioners always or often counseled WWE on valproic acid on the benefits of switching to a less teratogenic medication (96.2%). Some geographic variability in practice patterns was noted with valproic acid being one of the top three medications selected for patients with generalized epilepsies in Western regions, although participants in Eastern regions had brivaracetam more commonly included as one of their top three agents for this population. SIGNIFICANCE: This is the first report of real-world Canadian practices in epilepsy care for women in pregnancy. Overall, our study reports that Canadian practice patterns conform well to current evidence and best-practice guidelines. Important variations in antiseizure medication selection across different regions were identified.

Resting state network connectivity is attenuated by fMRI acoustic noise.

INTRODUCTION: During the past decades there has been an increasing interest in tracking brain network fluctuations in health and disease by means of resting state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI however does not provide the ideal environmental setting, as participants are continuously exposed to noise generated by MRI coils during acquisition of Echo Planar Imaging (EPI). We investigated the effect of EPI noise on resting state activity and connectivity using magnetoencephalography (MEG), by reproducing the acoustic characteristics of rs-fMRI environment during the recordings. As compared to fMRI, MEG has little sensitivity to brain activity generated in deep brain structures, but has the advantage to capture both the dynamic of cortical magnetic oscillations with high temporal resolution and the slow magnetic fluctuations highly correlated with BOLD signal. METHODS: Thirty healthy subjects were enrolled in a counterbalanced design study including three conditions: a) silent resting state (Silence), b) resting state upon EPI noise (fMRI), and c) resting state upon white noise (White). White noise was employed to test the specificity of fMRI noise effect. The amplitude envelope correlation (AEC) in alpha band measured the connectivity of seven Resting State Networks (RSN) of interest (default mode network, dorsal attention network, language, left and right auditory and left and right sensory-motor). Vigilance dynamic was estimated from power spectral activity. RESULTS: fMRI and White acoustic noise consistently reduced connectivity of cortical networks. The effects were widespread, but noise and network specificities were also present. For fMRI noise, decreased connectivity was found in the right auditory and sensory-motor networks. Progressive increase of slow theta-delta activity related to drowsiness was found in all conditions, but was significantly higher for fMRI . Theta-delta significantly and positively correlated with variations of cortical connectivity. DISCUSSION: rs-fMRI connectivity is biased by unavoidable environmental factors during scanning, which warrant more careful control and improved experimental designs. MEG is free from acoustic noise and allows a sensitive estimation of resting state connectivity in cortical areas. Although underutilized, MEG could overcome issues related to noise during fMRI, in particular when investigation of motor and auditory networks is needed.

High-yielding, automated radiosynthesis of [11 C]martinostat using [11 C]methyl triflate.

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [11 C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug-occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [11 C]martinostat using [11 C]methyl triflate in ethanol, as opposed to the originally described synthesis using [11 C]methyl iodide and DMSO. [11 C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 µl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5-1.8 GBq (41-48 mCi; n = 3) of formulated [11 C]martinostat was obtained from solid-phase extraction using a hydrophilic-lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [11 C]MeI), with a molar activity of 369 ± 53 GBq/µmol (9.97 ± 1.3 Ci/µmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [11 C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing.

How cerebral cortex protects itself from interictal spikes: The alpha/beta inhibition mechanism.

Interactions between interictal epileptiform discharges (IEDs) and distant cortical regions subserve potential effects on cognition of patients with focal epilepsy. We hypothesize that "healthy" brain areas at a distance from the epileptic focus may respond to the interference of IEDs by generating inhibitory alpha and beta oscillations. We predict that more prominent alpha-beta oscillations can be found in patients with less impaired neurocognitive profile. We performed a source imaging magnetoencephalography study, including 41 focal epilepsy patients: 21 with frontal lobe epilepsy (FLE) and 20 with mesial temporal lobe epilepsy. We investigated the effect of anterior (i.e., frontal and temporal) IEDs on the oscillatory pattern over posterior head regions. We compared cortical oscillations (5-80 Hz) temporally linked to 3,749 IEDs (1,945 frontal and 1,803 temporal) versus an equal number of IED-free segments. We correlated results from IED triggered oscillations to global neurocognitive performance. Only frontal IEDs triggered alpha-beta oscillations over posterior head regions. IEDs with higher amplitude triggered alpha-beta oscillations of higher magnitude. The intensity of posterior head region alpha-beta oscillations significantly correlated with a better neuropsychological profile. Our study demonstrated that cerebral cortex protects itself from IEDs with generation of inhibitory alpha-beta oscillations at distant cortical regions. The association of more prominent oscillations with a better cognitive status suggests that this mechanism might play a role in determining the cognitive resilience in patients with FLE.

Patient specific prediction of temporal lobe epilepsy surgical outcomes.

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) is the most common type of epilepsy for which patients undergo surgery. Despite the best clinical judgment and currently available prediction algorithms, surgical outcomes remain variable. We aimed to build and to evaluate the performance of multidimensional Bayesian network classifiers (MBCs), a type of probabilistic graphical model, at predicting probability of seizure freedom after TLE surgery. METHODS: Clinical, neurophysiological, and imaging variables were collected from 231 TLE patients who underwent surgery at the University of California, San Francisco (UCSF) or the Montreal Neurological Institute (MNI) over a 15-year period. Postsurgical Engel outcomes at year 1 (Y1), Y2, and Y5 were analyzed as primary end points. We trained an MBC model on combined data sets from both institutions. Bootstrap bias corrected cross-validation (BBC-CV) was used to evaluate the performance of the models. RESULTS: The MBC was compared with logistic regression and Cox proportional hazards according to the area under the receiver-operating characteristic curve (AUC). The MBC achieved an AUC of 0.67 at Y1, 0.72 at Y2, and 0.67 at Y5, which indicates modest performance yet superior to what has been reported in the state-of-the-art studies to date. SIGNIFICANCE: The MBC can more precisely encode probabilistic relationships between predictors and class variables (Engel outcomes), achieving promising experimental results compared to other well-known statistical methods. Multisite application of the MBC could further optimize its classification accuracy with prospective data sets. Online access to the MBC is provided, paving the way for its use as an adjunct clinical tool in aiding pre-operative TLE surgical counseling.

In vivo hippocampal cornu ammonis 1-3 glutamatergic abnormalities are associated with temporal lobe epilepsy surgery outcomes.

OBJECTIVE: Previous positron emission tomography (PET) studies using [11 C]ABP688 show reduced metabotropic glutamate receptor type 5 (mGluR5) allosteric binding site availability in the epileptogenic hippocampus of mesial temporal lobe epilepsy (MTLE) patients. However, the link between mGluR5 abnormalities and postsurgical outcomes remains unclear. Here, we test whether reduced PET [11 C]ABP688 binding in cornu ammonis (CA) sectors more vulnerable to glutamatergic excitotoxicity relates to surgical outcomes. METHODS: We obtained magnetic resonance imaging (MRI) and [11 C]ABP688-PET from 31 unilateral MTLE patients and 30 healthy controls. MRI hippocampal subfields were segmented using FreeSurfer. To respect the lower PET special resolution, MRI-derived anatomical subfields were combined into CA1-3, CA4/dentate gyrus, and Subiculum. Partial volume corrected [11 C]ABP688 nondisplaceable binding potential (BPND ) values were averaged across each subfield, and Z-scores were calculated. Subfield [11 C]ABP688-BPND was compared between seizure-free and non-seizure-free patients. In addition, we also assessed subfield volumes and [18 F]fluorodeoxyglucose (FDG) uptake in each clinical group. RESULTS: MTLE [11 C]ABP688-BPND was reduced in ipsilateral (epileptogenic) CA1-3 and CA4/dentate-gyrus (p < .001, 95% confidence interval [CI] = .29-.51) compared to controls, with no difference in Subiculum. [11 C]ABP688-BPND and subfield volumes were compared between seizure-free (Engel IA, n = 13) and non-seizure-free patients (Engel IC-III, n = 10). In ipsilateral CA1-3 only, [11 C]ABP688-BPND was lower in seizure-free patients than in non-seizure-free patients (p = .012, 95% CI = 1.46-11.0) independently of volume. A subset analysis of 12 patients with [11 C]ABP688-PET+[18 F]FDG-PET showed no between-group significant difference in [18 F]FDG uptake, whereas CA1-3 [11 C]ABP688-BPND remained significantly lower in the seven of 12 seizure-free patients (p = .03, 95% CI = -3.13 to -.21). SIGNIFICANCE: Reduced mGluR5 allosteric site availability in hippocampal CA1-3, measured in vivo by [11 C]ABP688-PET, is associated with postsurgery seizure freedom independent of atrophy or hypometabolism. Information derived from hippocampal CA1-3 [11 C]ABP688-PET is a promising imaging biomarker potentially impactful in surgical decisions for MRI-negative/PET-negative MTLE patients.

Accuracy and spatial properties of distributed magnetic source imaging techniques in the investigation of focal epilepsy patients.

Source localization of interictal epileptiform discharges (IEDs) is clinically useful in the presurgical workup of epilepsy patients. We aimed to compare the performance of four different distributed magnetic source imaging (dMSI) approaches: Minimum norm estimate (MNE), dynamic statistical parametric mapping (dSPM), standardized low-resolution electromagnetic tomography (sLORETA), and coherent maximum entropy on the mean (cMEM). We also evaluated whether a simple average of maps obtained from multiple inverse solutions (Ave) can improve localization accuracy. We analyzed dMSI of 206 IEDs derived from magnetoencephalography recordings in 28 focal epilepsy patients who had a well-defined focus determined through intracranial EEG (iEEG), epileptogenic MRI lesions or surgical resection. dMSI accuracy and spatial properties were quantitatively estimated as: (a) distance from the epilepsy focus, (b) reproducibility, (c) spatial dispersion (SD), (d) map extension, and (e) effect of thresholding on map properties. Clinical performance was excellent for all methods (median distance from the focus MNE = 2.4 mm; sLORETA = 3.5 mm; cMEM = 3.5 mm; dSPM = 6.8 mm, Ave = 0 mm). Ave showed the lowest distance between the map maximum and epilepsy focus (Dmin lower than cMEM, MNE, and dSPM, p = .021, p = .008, p < .001, respectively). cMEM showed the best spatial features, with lowest SD outside the focus (SD lower than all other methods, p < .001 consistently) and high contrast between the generator and surrounding regions. The average map Ave provided the best localization accuracy, whereas cMEM exhibited the lowest amount of spurious distant activity. dMSI techniques have the potential to significantly improve identification of iEEG targets and to guide surgical planning, especially when multiple methods are combined.

In vivo metabotropic glutamate receptor type 5 abnormalities localize the epileptogenic zone in mesial temporal lobe epilepsy.

OBJECTIVE: Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole-brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [11 C]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site. METHODS: Thirty-one unilateral MTLE patients and 30 healthy controls underwent [11 C]ABP688 PET. We compared partial volume corrected [11 C]ABP688 nondisplaceable binding potentials (BPND ) between groups using region-of-interest and whole-brain voxelwise analyses. [18 F]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [11 C]ABP688 BPND and [18 F]FDG uptake to compare lateralization and localization differences. RESULTS: [11 C]ABP688 BPND was focally reduced in the epileptogenic hippocampal head and amygdala (p < 0.001). Patients with hippocampal atrophy showed more extensive abnormalities, including the ipsilateral temporal neocortex (p = 0.006). [11 C]ABP688 BPND showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [18 F]FDG uptake, which showed more widespread hypometabolism. Among 23 of 25 operated patients with >1 year of follow-up, 13 were seizure-free (Engel Ia) and showed significantly lower [11 C]ABP688 BPND in the ipsilateral entorhinal cortex. INTERPRETATION: [11 C]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [18 F]FDG PET. Focally reduced mGluR5 availability in the EZ might reflect receptor internalization or conformational changes in response to excessive extracellular glutamate, supporting a potential role for mGluR5 as therapeutic target in human MTLE. Ann Neurol 2019; 1-11 ANN NEUROL 2019;85:218-228.

A simplified radiosynthesis of [18 F]MK-6240 for tau PET imaging.

[18 F]MK-6240 (6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [18 F]MK-6240 was synthesized in one step from its bis-Boc protected precursor N-[(tert-butoxy)carbonyl]-N-(6-nitro-3-[1H-pyrrolo[2,3-c]pyridin-1-yl]isoquinolin-5-yl) carbamate in DMSO using [18 F] fluoride with TEA HCO3 with step-wise heating up to 150°C, resulting in an isolated radiochemical yield of 9.8% ± 1.8% (n = 3) calculated from the end of bombardment (5.2% ± 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis-Boc 18 F-labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses, which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single-use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [18 F]MK-6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies.

Clinical yield of magnetoencephalography distributed source imaging in epilepsy: A comparison with equivalent current dipole method.

OBJECTIVE: Source localization of interictal epileptic discharges (IEDs) is clinically useful in the presurgical workup of epilepsy patients. It is usually obtained by equivalent current dipole (ECD) which localizes a point source and is the only inverse solution approved by clinical guidelines. In contrast, magnetic source imaging using distributed methods (dMSI) provides maps of the location and the extent of the generators, but its yield has not been clinically validated. We systematically compared ECD versus dMSI performed using coherent Maximum Entropy on the Mean (cMEM), a method sensitive to the spatial extent of the generators. METHODS: 340 source localizations of IEDs derived from 49 focal epilepsy patients with foci well-defined through intracranial EEG, MRI lesions, and surgery were analyzed. The comparison was based on the assessment of the sublobar concordance with the focus and of the distance between the source and the focus. RESULTS: dMSI sublobar concordance was significantly higher than ECD (81% vs 69%, P < 0.001), especially for extratemporal lobe sources (dMSI = 84%; ECD = 67%, P < 0.001) and for seizure free patients (dMSI = 83%; ECD = 70%, P < 0.001). The median distance from the focus was 4.88 mm for ECD and 3.44 mm for dMSI (P < 0.001). ECD dipoles were often wrongly localized in deep brain regions. CONCLUSIONS: dMSI using cMEM exhibited better accuracy. dMSI also offered the advantage of recovering more realistic maps of the generator, which could be exploited for neuronavigation aimed at targeting invasive EEG and surgical resection. Therefore, dMSI may be preferred to ECD in clinical practice. Hum Brain Mapp 39:218-231, 2018. © 2017 Wiley Periodicals, Inc.

Reproducibility of EEG-MEG fusion source analysis of interictal spikes: Relevance in presurgical evaluation of epilepsy.

Fusion of electroencephalography (EEG) and magnetoencephalography (MEG) data using maximum entropy on the mean method (MEM-fusion) takes advantage of the complementarities between EEG and MEG to improve localization accuracy. Simulation studies demonstrated MEM-fusion to be robust especially in noisy conditions such as single spike source localizations (SSSL). Our objective was to assess the reliability of SSSL using MEM-fusion on clinical data. We proposed to cluster SSSL results to find the most reliable and consistent source map from the reconstructed sources, the so-called consensus map. Thirty-four types of interictal epileptic discharges (IEDs) were analyzed from 26 patients with well-defined epileptogenic focus. SSSLs were performed on EEG, MEG, and fusion data and consensus maps were estimated using hierarchical clustering. Qualitative (spike-to-spike reproducibility rate, SSR) and quantitative (localization error and spatial dispersion) assessments were performed using the epileptogenic focus as clinical reference. Fusion SSSL provided significantly better results than EEG or MEG alone. Fusion found at least one cluster concordant with the clinical reference in all cases. This concordant cluster was always the one involving the highest number of spikes. Fusion yielded highest reproducibility (SSR EEG = 55%, MEG = 71%, fusion = 90%) and lowest localization error. Also, using only few channels from either modality (21EEG + 272MEG or 54EEG + 25MEG) was sufficient to reach accurate fusion. MEM-fusion with consensus map approach provides an objective way of finding the most reliable and concordant generators of IEDs. We, therefore, suggest the pertinence of SSSL using MEM-fusion as a valuable clinical tool for presurgical evaluation of epilepsy.

Evaluation of the "non-epileptic" patient in a tertiary center epilepsy clinic.

PURPOSE: The epilepsy clinic at the Montreal Neurological Institute receives a high volume of referrals. Despite most patients assessed in the clinic eventually being diagnosed with epilepsy, other disorders causing alteration of consciousness or paroxystic symptoms that could be misdiagnosed as seizures are seen frequently. The incidence and clinical characteristics of such patients have not yet been determined. We aimed to determine the proportion and clinical characteristics of patients referred to our epilepsy clinic who had a final diagnosis other than epilepsy. METHODS: We performed a retrospective chart analysis of consecutive patient referrals to the epilepsy clinic from January 2013 to January 2015, inclusively. RESULTS: Four hundred four patient referrals were evaluated, 106 (or 26%) had a final diagnosis other than epilepsy. Referrals came primarily from general practitioners and nonneurology specialists. Although most patients had a normal routine electroencephalography (EEG) prior to the clinic visit, sleep-deprived EEG and cardiac investigations were rarely performed. Patients received a final diagnosis other than epilepsy after 1 to 2 visits in 92% of cases and with minimal paraclinical investigations. Prolonged video-EEG recording was required in 27% of patients. The most common diagnoses were syncope (33%), psychiatric symptoms (20%), followed by migraine (10%), and psychogenic nonepileptic seizures (9%). CONCLUSIONS: A significant proportion of patients seen in our tertiary care epilepsy clinic is in fact, not patients with epilepsy. Enhanced knowledge of these differential diagnosis and important anamnesis components to rule out seizures will help improve guidelines for referral to Epilepsy clinic and cost-effectively optimize the use of paraclinical investigations.

Psychogenic nonepileptic seizures in patients with surgically treated temporal lobe epilepsy: Presurgical and de novo postsurgical occurrence.

Whether occurring before or after an epilepsy surgery, psychogenic nonepileptic seizures (PNES) impact treatment options and quality of life of patients with epilepsy. We investigated the frequency of pre- and postsurgical PNES, and the postsurgical Engel and psychiatric outcomes in patients with drug-resistant temporal lobe epilepsy (TLE). We reviewed 278 patients with mean age at surgery of 37.1±12.4years. Postsurgical follow-up information was available in 220 patients, with average follow-up of 4years. Nine patients (9/278 or 3.2%) had presurgical documented PNES. Eight patients (8/220 or 3.6%) developed de novo PNES after surgery. Pre- and postsurgery psychiatric comorbidities were similar to the patients without PNES. After surgery, in the group with presurgical PNES, five patients were seizure-free, and three presented persistent PNES. In the group with de novo postsurgery PNES, 62.5% had Engel II-IV, and 37.5% had Engel I. All presented PNES at last follow-up. Presurgical video-EEG monitoring is crucial in the diagnosis of coexisting PNES. Patients presenting presurgical PNES and drug-resistant TLE should not be denied surgery based on this comorbidity, as they can have good postsurgical epilepsy and psychiatric outcomes. Psychogenic nonepileptic seizures may appear after TLE surgery in a low but noteworthy proportion of patients regardless of the Engel outcome.

Metabotropic Glutamate Receptor Type 5 (mGluR5) Cortical Abnormalities in Focal Cortical Dysplasia Identified In Vivo With [11C]ABP688 Positron-Emission Tomography (PET) Imaging.

Metabotropic glutamate receptor type 5 (mGluR5) abnormalities have been described in tissue resected from epilepsy patients with focal cortical dysplasia (FCD). To determine if these abnormalities could be identified in vivo, we investigated mGluR5 availability in 10 patients with focal epilepsy and an MRI diagnosis of FCD using positron-emission tomography (PET) and the radioligand [11C]ABP688. Partial volume corrected [11C]ABP688 binding potentials (BPND) were computed using the cerebellum as a reference region. Each patient was compared to homotopic cortical regions in 33 healthy controls using region-of-interest (ROI) and vertex-wise analyses. Reduced [11C]ABP688 BPND in the FCD was seen in 7/10 patients with combined ROI and vertex-wise analyses. Reduced FCD BPND was found in 4/5 operated patients (mean follow-up: 63 months; Engel I), of whom surgical specimens revealed FCD type IIb or IIa, with most balloon cells showing negative or weak mGluR5 immunoreactivity as compared to their respective neuropil and normal neurons at the border of resections. [11C]ABP688 PET shows for the first time in vivo evidence of reduced mGluR5 availability in FCD, indicating focal glutamatergic alterations in malformations of cortical development, which cannot be otherwise clearly demonstrated through resected tissue analyses.

Intracranial EEG potentials estimated from MEG sources: A new approach to correlate MEG and iEEG data in epilepsy.

Detection of epileptic spikes in MagnetoEncephaloGraphy (MEG) requires synchronized neuronal activity over a minimum of 4cm2. We previously validated the Maximum Entropy on the Mean (MEM) as a source localization able to recover the spatial extent of the epileptic spike generators. The purpose of this study was to evaluate quantitatively, using intracranial EEG (iEEG), the spatial extent recovered from MEG sources by estimating iEEG potentials generated by these MEG sources. We evaluated five patients with focal epilepsy who had a pre-operative MEG acquisition and iEEG with MRI-compatible electrodes. Individual MEG epileptic spikes were localized along the cortical surface segmented from a pre-operative MRI, which was co-registered with the MRI obtained with iEEG electrodes in place for identification of iEEG contacts. An iEEG forward model estimated the influence of every dipolar source of the cortical surface on each iEEG contact. This iEEG forward model was applied to MEG sources to estimate iEEG potentials that would have been generated by these sources. MEG-estimated iEEG potentials were compared with measured iEEG potentials using four source localization methods: two variants of MEM and two standard methods equivalent to minimum norm and LORETA estimates. Our results demonstrated an excellent MEG/iEEG correspondence in the presumed focus for four out of five patients. In one patient, the deep generator identified in iEEG could not be localized in MEG. MEG-estimated iEEG potentials is a promising method to evaluate which MEG sources could be retrieved and validated with iEEG data, providing accurate results especially when applied to MEM localizations. Hum Brain Mapp 37:1661-1683, 2016. © 2016 Wiley Periodicals, Inc.