Novel noninvasive identification of patient-specific epileptic networks in focal epilepsies: Linking single-photon emission computed tomography perfusion during seizures with resting-state magnetoencephalography dynamics.

Single-photon emission computed tomography (SPECT) during seizures and magnetoencephalography (MEG) during the interictal state are noninvasive modalities employed in the localization of the epileptogenic zone in patients with drug-resistant focal epilepsy (DRFE). The present study aims to investigate whether there exists a preferentially high MEG functional connectivity (FC) among those regions of the brain that exhibit hyperperfusion or hypoperfusion during seizures. We studied MEG and SPECT data in 30 consecutive DRFE patients who had resective epilepsy surgery. We parcellated each ictal perfusion map into 200 regions of interest (ROIs) and generated ROI time series using source modeling of MEG data. FC between ROIs was quantified using coherence and phase-locking value. We defined a generalized linear model to relate the connectivity of each ROI, ictal perfusion z score, and distance between ROIs. We compared the coefficients relating perfusion z score to FC of each ROI and estimated the connectivity within and between resected and unresected ROIs. We found that perfusion z scores were strongly correlated with the FC of hyper-, and separately, hypoperfused ROIs across patients. High interictal connectivity was observed between hyperperfused brain regions inside and outside the resected area. High connectivity was also observed between regions of ictal hypoperfusion. Importantly, the ictally hypoperfused regions had a low interictal connectivity to regions that became hyperperfused during seizures. We conclude that brain regions exhibiting hyperperfusion during seizures highlight a preferentially connected interictal network, whereas regions of ictal hypoperfusion highlight a separate, discrete and interconnected, interictal network.

Using magnetic resonance fingerprinting to characterize periventricular nodular heterotopias in pharmacoresistant epilepsy.

OBJECTIVE: We aimed to use a novel magnetic resonance fingerprinting (MRF) technique to examine in vivo tissue property characteristics of periventricular nodular heterotopia (PVNH). These characteristics were further correlated with stereotactic-electroencephalographic (SEEG) ictal onset findings. METHODS: We included five patients with PVNH who had SEEG-guided surgery and at least 1 year of seizure freedom or substantial seizure reduction. High-resolution MRF scans were acquired at 3 T, generating three-dimensional quantitative T1 and T2  maps. We assessed the differences between T1 and T2  values from the voxels in the nodules located in the SEEG-defined seizure onset zone (SOZ) and non-SOZ, on -individual and group levels. Receiver operating characteristic analyses were performed to obtain the optimal classification performance. Quantification of SEEG ictal onset signals from the nodules was performed by calculating power spectrum density (PSD). The association between PSD and T1 /T2  values was further assessed at different frequency bands. RESULTS: Individual-level analysis showed T1 was significantly higher in SOZ voxels than non-SOZ voxels (p < .05), with an average 73% classification accuracy. Group-level analysis also showed higher T1 was significantly associated with SOZ voxels (p < .001). At the optimal cutoff (normalized T1 of 1.1), a 76% accuracy for classifying SOZ nodules from non-SOZ nodules was achieved. T1  values were significantly associated with ictal onset PSD at the ultraslow, θ, ß, γ, and ripple bands (p < .05). T2  values were significantly associated with PSD only at the ultraslow band (p < .05). SIGNIFICANCE: Quantitative MRF measures, especially T1 , can provide additional noninvasive information to separate nodules in SOZ and non-SOZ. The T1 and T2 tissue property changes carry electrophysiological underpinnings relevant to the epilepsy, as shown by their significant positive associations with power changes during the SEEG seizure onset. The use of MRF as a supplementary noninvasive tool may improve presurgical evaluation for patients with PVNH and pharmacoresistant epilepsy.

Neurovascular networks in epilepsy: Correlating ictal blood perfusion with intracranial electrophysiology.

Perfusion patterns observed in Subtraction Ictal SPECT Co-registered to MRI (SISCOM) assist in focus localization and surgical planning for patients with medically intractable focal epilepsy. While the localizing value of SISCOM has been widely investigated, its relationship to the underlying electrophysiology has not been extensively studied and is therefore not well understood. In the present study, we set to investigate this relationship in a cohort of 70 consecutive patients who underwent ictal and interictal SPECT studies and subsequent stereo-electroencephalography (SEEG) monitoring for localization of the epileptogenic focus and surgical intervention. Seizures recorded during SEEG evaluation (SEEG seizures) were matched to semiologically-similar seizures during the preoperative ictal SPECT evaluation (SPECT seizures) by comparing the semiological changes in the course of each seizure. The spectral changes of the ictal SEEG with respect to interictal ones over 7 traditional frequency bands (0.1 to 150Hz) were analyzed at each SEEG site. Neurovascular (SEEG/SPECT) relations were assessed by comparing the estimated spectral power density changes of the SEEG at each site with the perfusion changes (SISCOM z-scores) estimated from the acquired SISCOM map at that site. Across patients, a significant correlation (p<0.05) was observed between spectral changes during the SEEG seizure and SISCOM perfusion z-scores. Brain sites with high perfusion z-score exhibited higher increased SEEG power in theta to ripple frequency bands with concurrent suppression in delta and theta frequency bands compared to regions with lower perfusion z-score. The dynamics of the correlation of SISCOM perfusion and SEEG spectral power from ictal onset to seizure end and immediate postictal period were also derived. Forty-six (46) of the 70 patients underwent resective epilepsy surgery. SISCOM z-score and power increase in beta to ripple frequency bands were significantly higher in resected than non-resected sites in the patients who were seizure-free following surgery. This study provides for the first time concrete evidence that both hyper-perfusion and hypo-perfusion patterns observed in SISCOM maps have strong electrophysiological underpinnings, and that integration of the information from SISCOM and SEEG can shed light on the location and dynamics of the underlying epileptic brain networks, and thus advance our anatomo-electro-clinical understanding and approaches to targeted diagnostic and therapeutic interventions.

Value of 7T MRI and post-processing in patients with nonlesional 3T MRI undergoing epilepsy presurgical evaluation.

OBJECTIVE: Ultra-high-field 7-Tesla (7T) magnetic resonance imaging (MRI) offers increased signal-to-noise and contrast-to-noise ratios, which may improve visualization of cortical malformations. We aim to assess the clinical value of in vivo structural 7T MRI and its post-processing for the noninvasive identification of epileptic brain lesions in patients with pharmacoresistant epilepsy and nonlesional 3T MRI who are undergoing presurgical evaluation. METHODS: Sixty-seven patients were included who had nonlesional 3T MRI by official radiology report. Epilepsy protocols were used for the 3T and 7T acquisitions. Post-processing of the 7T T1-weighted magnetization-prepared two rapid acquisition gradient echoes sequence was performed using the morphometric analysis program (MAP) with comparison to a normal database consisting of 50 healthy controls. Review of 7T was performed by an experienced board-certified neuroradiologist and at the multimodal patient management conference. The clinical significance of 7T findings was assessed based on intracranial electroencephalography (ICEEG) ictal onset, surgery, postoperative seizure outcomes, and histopathology. RESULTS: Unaided visual review of 7T detected previously unappreciated subtle lesions in 22% (15/67). When aided by 7T MAP, the total yield increased to 43% (29/67). The location of the 7T-identified lesion was identical to or contained within the ICEEG ictal onset in 13 of 16 (81%). Complete resection of the 7T-identified lesion was associated with seizure freedom (P = .03). Histopathology of the 7T-identified lesions encountered mainly focal cortical dysplasia (FCD). 7T MAP yielded 25% more lesions (6/24) than 3T MAP, and showed improved conspicuity in 46% (11/24). SIGNIFICANCE: Our data suggest a major benefit of 7T with post-processing for detecting subtle FCD lesions for patients with pharmacoresistant epilepsy and nonlesional 3T MRI.

Development of high-resolution 3D MR fingerprinting for detection and characterization of epileptic lesions.

BACKGROUND: Conventional MRI can be limited in detecting subtle epileptic lesions or identifying active/epileptic lesions among widespread, multifocal lesions. PURPOSE: We developed a high-resolution 3D MR fingerprinting (MRF) protocol to simultaneously provide quantitative T1 , T2 , proton density, and tissue fraction maps for detection and characterization of epileptic lesions. STUDY TYPE: Prospective. POPULATION: National Institute of Standards and Technology (NIST) / International Society for Magnetic Resonance in Medicine (ISMRM) phantom, five healthy volunteers and 15 patients with medically intractable epilepsy undergoing presurgical evaluation with noninvasive or invasive electroclinical data. FIELD STRENGTH/SEQUENCE: 3D MRF scans and routine clinical epilepsy MR protocols were acquired at 3 T. ASSESSMENT: The accuracy of the T1 and T2 values were first evaluated using the NIST/ISMRM phantom. The repeatability was then estimated with both phantom and volunteers based on the coefficient of variance (CV). For epilepsy patients, all the maps were qualitatively reviewed for lesion detection by three independent reviewers (S.E.J., M.L., I.N.) blinded to clinical data. Region of interest (ROI) analysis was performed on T1 and T2 maps to quantify the multiparametric signal differences between lesion and normal tissues. Findings from qualitative review and quantitative ROI analysis were compared with patients' electroclinical data to assess concordance. STATISTICAL TESTS: Phantom results were compared using R-squared, and patient results were compared using linear regression models. RESULTS: The phantom study showed high accuracy with the standard values, with an R2 of 0.99. The volunteer study showed high repeatability, with an average CV of 4.3% for T1 and T2 in various tissue regions. For the 15 patients, MRF showed additional findings in four patients, with the remaining 11 patients showing findings consistent with conventional MRI. The additional MRF findings were highly concordant with patients' electroclinical presentation. DATA CONCLUSION: The 3D MRF protocol showed potential to identify otherwise inconspicuous epileptogenic lesions from the patients with negative conventional MRI diagnosis, as well as to correlate with different levels of epileptogenicity when widespread lesions were present. LEVEL OF EVIDENCE: 3. Technical Efficacy Stage: 3. J. Magn. Reson. Imaging 2019;49:1333-1346.

New onset epilepsy among patients with periodic discharges on continuous electroencephalographic monitoring.

OBJECTIVE: To evaluate the incidence of new onset epilepsy and associated risk factors in patients with periodic patterns on continuous electroencephalography (cEEG) during critical illness. METHODS: The local cEEG database and then medical records were reviewed from January 1, 2013 to June 30, 2013 to find adult patients with no history of epilepsy who had periodic discharges-either lateralized (LPDs) or generalized (GPDs)-or nonperiodic/nonepileptogenic (NP/NE) findings on cEEG and ≥3 months of clinical follow-up. Clinical seizure after discharge was the primary outcome. Chi-square test, Kruskal-Wallis test, and Cox proportional hazards models were used for statistical analysis. RESULTS: A total of 195 patients (median age = 67.8 years) were included. There were 53 (27%), 73 (37%), and 69 (35%) patients with LPDs, GPDs, and NP/NE findings on cEEG, respectively. These three groups did not differ by demographic or clinical variables. A total of 29 (15%) patients (LPDs = 20 [38%], GPDs = 4 [6%], and NP/NE = 5 [7%]) developed epilepsy during a median follow-up of 32.1 (95% confidence interval [CI] = 13.2-42.8) months. The hazard ratio for epilepsy development among LPD patients was 7.7 (95% CI = 2.9-20.7) times compared to the NP/NE group, and the risk further increased to 11.4 (95% CI = 4-31.4) times if they also had electrographic seizures. This association remained significant despite adjusting for each covariate at a time. SIGNIFICANCE: Patients with LPDs on cEEG during critical illness are at least seven times more likely to develop epilepsy compared to patients with NP/NE findings. This risk is further increased if patients with LPDs have electrographic seizures. In comparison, the presence of GPDs does not seem to impact the risk for developing epilepsy. cEEG findings at the time of acute insult have potential to serve as prognostic biomarkers for epilepsy development.

Insulo-opercular cortex generates oroalimentary automatisms in temporal seizures.

OBJECTIVE: Oroalimentary automatisms (OAAs) resembling normal alimentary behavior are stereotyped complex movements that may occur during epileptic seizures. They are considered common clinical signs in temporal lobe seizures, but their anatomofunctional mechanisms are not established. We took the opportunity of presurgical intracerebral recordings to study the relations between the occurrence of OAAs and temporal/spatial features of ictal activities. METHODS: We retrospectively reviewed patients with medically intractable medial temporal lobe epilepsy who underwent stereoelectroencephalography (SEEG) at Cleveland Clinic between 2009 and 2016. Patients presenting oroalimentary automatisms during seizures, with intracerebral electrodes spanning temporal and extratemporal areas, were selected. SEEG-clinical correlations with latency measurements were done. Coherence analyses were performed on regions of interest as defined by the areas involved at the onset of oroalimentary automatisms. RESULTS: Fifteen patients (115 seizures) were analyzed. Sixty-nine seizures exhibited overt oroalimentary automatisms. Only insulo-opercular cortex ictal involvement was consistently related to the occurrence of OAAs, with a linear correlation between OAA onset and ictal oscillatory activity onset in the insulo-opercular cortex. SEEG signal processing showed an increase in theta coherence preceding oroalimentary automatism onset between mediobasal-temporal structures and insulo-opercular cortex, as well as between the 2 insulo-opercular regions. SIGNIFICANCE: The underlying mechanism for the production of oroalimentary automatisms in medial temporal seizures is based on temporal-insulo-opercular theta coherence leading to a synchronous state generating rhythmic patterned outputs from the cortical masticatory area.

Automated detection of focal cortical dysplasia type II with surface-based magnetic resonance imaging postprocessing and machine learning.

OBJECTIVE: Focal cortical dysplasia (FCD) is a major pathology in patients undergoing surgical resection to treat pharmacoresistant epilepsy. Magnetic resonance imaging (MRI) postprocessing methods may provide essential help for detection of FCD. In this study, we utilized surface-based MRI morphometry and machine learning for automated lesion detection in a mixed cohort of patients with FCD type II from 3 different epilepsy centers. METHODS: Sixty-one patients with pharmacoresistant epilepsy and histologically proven FCD type II were included in the study. The patients had been evaluated at 3 different epilepsy centers using 3 different MRI scanners. T1-volumetric sequence was used for postprocessing. A normal database was constructed with 120 healthy controls. We also included 35 healthy test controls and 15 disease test controls with histologically confirmed hippocampal sclerosis to assess specificity. Features were calculated and incorporated into a nonlinear neural network classifier, which was trained to identify lesional cluster. We optimized the threshold of the output probability map from the classifier by performing receiver operating characteristic (ROC) analyses. Success of detection was defined by overlap between the final cluster and the manual labeling. Performance was evaluated using k-fold cross-validation. RESULTS: The threshold of 0.9 showed optimal sensitivity of 73.7% and specificity of 90.0%. The area under the curve for the ROC analysis was 0.75, which suggests a discriminative classifier. Sensitivity and specificity were not significantly different for patients from different centers, suggesting robustness of performance. Correct detection rate was significantly lower in patients with initially normal MRI than patients with unequivocally positive MRI. Subgroup analysis showed the size of the training group and normal control database impacted classifier performance. SIGNIFICANCE: Automated surface-based MRI morphometry equipped with machine learning showed robust performance across cohorts from different centers and scanners. The proposed method may be a valuable tool to improve FCD detection in presurgical evaluation for patients with pharmacoresistant epilepsy.

Connectivity in ictal single photon emission computed tomography perfusion: a cortico-cortical evoked potential study.

Subtraction ictal and interictal single photon emission computed tomography can demonstrate complex ictal perfusion patterns. Regions with ictal hyperperfusion are suggested to reflect seizure onset and propagation pathways. The significance of ictal hypoperfusion is not well understood. The aim of this study was to verify whether ictal perfusion changes, both hyper- and hypoperfusion, correspond to electrically connected brain networks. A total of 36 subtraction ictal and interictal perfusion studies were analysed in 31 consecutive medically refractory focal epilepsy patients, evaluated by stereo-electroencephalography that demonstrated a single focal onset. Cortico-cortical evoked potential studies were performed after repetitive electrical stimulation of the ictal onset zone. Evoked responses at electrode contacts outside the stimulation site were used as a measure of connectivity. The evoked responses at these electrodes were compared to ictal perfusion values noted at these locations. In 67% of studies, evoked responses were significantly larger in hyperperfused compared to baseline-perfused areas. The majority of hyperperfused contacts also had significantly increased evoked responses relative to pre-stimulus electroencephalogram. In contrast, baseline-perfused and hypoperfused contacts mainly demonstrated non-significant evoked responses. Finally, positive significant correlations (P < 0.05) were found between perfusion scores and evoked responses in 61% of studies. When the stimulated ictal onset area was hyperperfused, 82% of studies demonstrated positive significant correlations. Following stimulation of hyperperfused areas outside seizure onset, positive significant correlations between perfusion changes and evoked responses could be seen, suggesting bidirectional connectivity. We conclude that strong connectivity was demonstrated between the ictal onset zone and hyperperfused regions, while connectivity was weaker in the direction of baseline-perfused or hypoperfused areas. In trying to understand a patient's epilepsy, one should consider the contribution of all hyperperfused regions, as these are likely not random, but represent an electrically connected epileptic network.

Voxel-based morphometric magnetic resonance imaging (MRI) postprocessing in MRI-negative epilepsies.

OBJECTIVE: In the presurgical workup of magnetic resonance imaging (MRI)-negative (MRI(-) or "nonlesional") pharmacoresistant focal epilepsy (PFE) patients, discovering a previously undetected lesion can drastically change the evaluation and likely improve surgical outcome. Our study utilizes a voxel-based MRI postprocessing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle abnormalities in a consecutive cohort of MRI(-) surgical candidates. METHODS: Included in this retrospective study was a consecutive cohort of 150 MRI(-) surgical patients. MAP was performed on T1-weighted MRI, with comparison to a scanner-specific normal database. Review and analysis of MAP were performed blinded to patients' clinical information. The pertinence of MAP(+) areas was confirmed by surgical outcome and pathology. RESULTS: MAP showed a 43% positive rate, sensitivity of 0.9, and specificity of 0.67. Overall, patients with the MAP(+) region completely resected had the best seizure outcomes, followed by the MAP(-) patients, and patients who had no/partial resection of the MAP(+) region had the worst outcome (p < 0.001). Subgroup analysis revealed that visually identified subtle findings are more likely correct if also MAP(+) . False-positive rate in 52 normal controls was 2%. Surgical pathology of the resected MAP(+) areas contained mainly non-balloon-cell focal cortical dysplasia (FCD). Multiple MAP(+) regions were present in 7% of patients. INTERPRETATION: MAP can be a practical and valuable tool to: (1) guide the search for subtle MRI abnormalities and (2) confirm visually identified questionable abnormalities in patients with PFE due to suspected FCD. A MAP(+) region, when concordant with the patient's electroclinical presentation, should provide a legitimate target for surgical exploration.

Measurable transitions during seizures in intracranial EEG: A stereoelectroencephalography and SPECT study.

OBJECTIVE: Ictal Single Photon Emission Computed Tomography (SPECT) and stereo-electroencephalography (SEEG) are diagnostic techniques used for the management of patients with drug-resistant focal epilepsies. While hyperperfusion patterns in ictal SPECT studies reveal seizure onset and propagation pathways, the role of ictal hypoperfusion remains poorly understood. The goal of this study was to systematically characterize the spatio-temporal information flow dynamics between differently perfused brain regions using stereo-EEG recordings. METHODS: We identified seizure-free patients after resective epilepsy surgery who had prior ictal SPECT and SEEG investigations. We estimated directional connectivity between the epileptogenic-zone (EZ), non-resected areas of hyperperfusion, hypoperfusion, and baseline perfusion during the interictal, preictal, ictal, and postictal periods. RESULTS: Compared to the background, we noted significant information flow (1) during the preictal period from the EZ to the baseline and hyperperfused regions, (2) during the ictal onset from the EZ to all three regions, and (3) during the period of seizure evolution from the area of hypoperfusion to all three regions. CONCLUSIONS: Hypoperfused brain regions were found to indirectly interact with the EZ during the ictal period. SIGNIFICANCE: Our unique study, combining intracranial electrophysiology and perfusion imaging, presents compelling evidence of dynamic changes in directional connectivity between brain regions during the transition from interictal to ictal states.

Effective connectivity relates seizure outcome to electrode placement in responsive neurostimulation.

Responsive neurostimulation is a closed-loop neuromodulation therapy for drug resistant focal epilepsy. Responsive neurostimulation electrodes are placed near ictal onset zones so as to enable detection of epileptiform activity and deliver electrical stimulation. There is no standard approach for determining the optimal placement of responsive neurostimulation electrodes. Clinicians make this determination based on presurgical tests, such as MRI, EEG, magnetoencephalography, ictal single-photon emission computed tomography and intracranial EEG. Currently functional connectivity measures are not being used in determining the placement of responsive neurostimulation electrodes. Cortico-cortical evoked potentials are a measure of effective functional connectivity. Cortico-cortical evoked potentials are generated by direct single-pulse electrical stimulation and can be used to investigate cortico-cortical connections in vivo. We hypothesized that the presence of high amplitude cortico-cortical evoked potentials, recorded during intracranial EEG monitoring, near the eventual responsive neurostimulation contact sites is predictive of better outcomes from its therapy. We retrospectively reviewed 12 patients in whom cortico-cortical evoked potentials were obtained during stereoelectroencephalography evaluation and subsequently underwent responsive neurostimulation therapy. We studied the relationship between cortico-cortical evoked potentials, the eventual responsive neurostimulation electrode locations and seizure reduction. Directional connectivity indicated by cortico-cortical evoked potentials can categorize stereoelectroencephalography electrodes as either receiver nodes/in-degree (an area of greater inward connectivity) or projection nodes/out-degree (greater outward connectivity). The follow-up period for seizure reduction ranged from 1.3-4.8 years (median 2.7) after responsive neurostimulation therapy started. Stereoelectroencephalography electrodes closest to the eventual responsive neurostimulation contact site tended to show larger in-degree cortico-cortical evoked potentials, especially for the early latency cortico-cortical evoked potentials period (10-60 ms period) in six out of 12 patients. Stereoelectroencephalography electrodes closest to the responsive neurostimulation contacts (≤5 mm) also had greater significant out-degree in the early cortico-cortical evoked potentials latency period than those further away (≥10 mm) (P < 0.05). Additionally, significant correlation was noted between in-degree cortico-cortical evoked potentials and greater seizure reduction with responsive neurostimulation therapy at its most effective period (P < 0.05). These findings suggest that functional connectivity determined by cortico-cortical evoked potentials may provide additional information that could help guide the optimal placement of responsive neurostimulation electrodes.

Equipment Setup and Artifact Removal for Simultaneous Electroencephalogram and Functional Magnetic Resonance Imaging for Clinical Review in Epilepsy.

Simultaneous electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) is a unique combined technique that provides synergy in the understanding and localization of seizure onset in epilepsy. However, reported experimental protocols for EEG-fMRI recordings fail to address details about conducting such procedures on epilepsy patients. In addition, these protocols are limited solely to research settings. To fill the gap between patient monitoring in an epilepsy monitoring unit (EMU) and conducting research with an epilepsy patient, we introduce a unique EEG-fMRI recording protocol of epilepsy during the interictal period. The use of an MR conditional electrode set, which can also be used in the EMU for a simultaneous scalp EEG and video recording, allows an easy transition of EEG recordings from the EMU to the scanning room for concurrent EEG-fMRI recordings. Details on the recording procedures using this specific MR conditional electrode set are provided. In addition, the study explains step-by-step EEG processing procedures to remove the imaging artifacts, which can then be used for clinical review. This experimental protocol promotes an amendment to the conventional EEG-fMRI recording for enhanced applicability in both clinical (i.e., EMU) and research settings. Furthermore, this protocol provides the potential to expand this modality to postictal EEG-fMRI recordings in the clinical setting.

Black Line Sign in Focal Cortical Dysplasia IIB: A 7T MRI and Electroclinicopathologic Study.

BACKGROUND AND OBJECTIVES: We aim to provide detailed imaging-electroclinicopathologic characterization of the black line sign, a novel MRI marker for focal cortical dysplasia (FCD) IIB. METHODS: 7T T2*-weighted gradient-echo (T2*w-GRE) images were retrospectively reviewed in a consecutive cohort of patients with medically intractable epilepsy with pathology-proven FCD II, for the occurrence of the black line sign. We examined the overlap between the black line region and the seizure-onset zone (SOZ) defined by intracranial EEG (ICEEG) and additionally assessed whether complete inclusion of the black line region in the surgical resection was associated with postoperative seizure freedom. The histopathologic specimen was aligned with the MRI to investigate the pathologic underpinning of the black line sign. Region-of-interest-based quantitative MRI (qMRI) analysis on the 7T T1 map was performed in the black line region, entire lesional gray matter (GM), and contralateral/ipsilateral normal gray and white matter (WM). RESULTS: We included 20 patients with FCD II (14 IIB and 6 IIA). The black line sign was identified in 12/14 (85.7%) of FCD IIB and 0/6 of FCD IIA on 7T T2*w-GRE. The black line region was highly concordant with the ICEEG-defined SOZ (5/7 complete and 2/7 partial overlap). Seizure freedom was seen in 8/8 patients whose black line region was completely included in the surgical resection; in the 2 patients whose resection did not completely include the black line region, both had recurring seizures. Inclusion of the black line region in the surgical resection was significantly associated with seizure freedom (p = 0.02). QMRI analyses showed that the T1 mean value of the black line region was significantly different from the WM (p < 0.001), but similar to the GM. Well-matched histopathologic slices in one case revealed accumulated dysmorphic neurons and balloon cells in the black line region. DISCUSSION: The black line sign may serve as a noninvasive marker for FCD IIB. Both MRI-pathology and qMRI analyses suggest that the black line region was an abnormal GM component within the FCD. Being highly concordant with ICEEG-defined SOZ and significantly associated with seizure freedom when included in resection, the black line sign may contribute to the planning of ICEEG/surgery of patients with medically intractable epilepsy with FCD IIB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in individuals with intractable focal epilepsy undergoing resection who have a 7T MRI with adequate image quality, the presence of the black line sign may suggest FCD IIB, be concordant with SOZ from ICEEG, and be associated with more seizure freedom if fully included in resection.

Resetting of brain dynamics: epileptic versus psychogenic nonepileptic seizures.

We investigated the possibility of differential diagnosis of patients with epileptic seizures (ES) and patients with psychogenic nonepileptic seizures (PNES) through an advanced analysis of the dynamics of the patients' scalp EEGs. The underlying principle was the presence of resetting of brain's preictal spatiotemporal entrainment following onset of ES and the absence of resetting following PNES. Long-term (days) scalp EEGs recorded from five patients with ES and six patients with PNES were analyzed. It was found that: (1) Preictal entrainment of brain sites was reset at ES (P<0.05) in four of the five patients with ES, and not reset (P=0.28) in the fifth patient. (2) Resetting did not occur (p>0.1) in any of the six patients with PNES. These preliminary results in patients with ES are in agreement with our previous findings from intracranial EEG recordings on resetting of brain dynamics by ES and are expected to constitute the basis for the development of a reliable and supporting tool in the differential diagnosis between ES and PNES. Finally, we believe that these results shed light on the electrophysiology of PNES by showing that occurrence of PNES does not assist patients in overcoming a pathological entrainment of brain dynamics. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction.

The Efficacy, Safety, and Outcomes of Brain-responsive Neurostimulation (RNS® System) therapy in older adults.

OBJECTIVES: The gold standard for the management of drug-resistant focal epilepsy (DRE) is resection of epileptogenic zone. However, some patients may not be candidates for resection. Responsive neurostimulation is approved in patients above 18 years of age for such patients. We aimed to investigate whether RNS outcomes and safety varied based on age. METHODS: We performed a single-center retrospective cohort study of patients with DRE who were treated with RNS between May 2008 and February 2020. We included patients who had been implanted with RNS for >6 months (N = 55), dividing them into older (N = 11) and younger adults (N = 44) depending on implantation age (≥50 and <50 years, respectively). RESULTS: Mean age at implantation in older adults was 54.9 ± 3.5 years. Seizure onset age, epilepsy duration, and comorbidities were significantly higher in older adults ( P < .01). Stimulation parameters, treatment duration, and median seizure frequency reduction (76% in older vs 50% in younger adults) were statistically comparable between the two cohorts. Posttreatment, antiseizure medication burden was significantly decreased in older compared with younger adults (P = .048). Postoperative and delayed adverse events among older adults were mild. Compared with three younger adults, none of the older adults required device explantation due to surgical site infection. CONCLUSION: Our study suggests that older adults treated with the RNS System achieve seizure outcomes comparable to younger adults with the additional benefit of a significant postimplantation medication reduction. With efficacy and safety similar to younger adults, brain-responsive neurostimulation was well-tolerated in older adults.

Epilepsy and Neurodevelopmental Comorbidities in Tuberous Sclerosis Complex: A Natural History Study.

BACKGROUND: We studied the natural history, genotype influence, and inter-relationship of epilepsy and neuropsychiatric disorders in tuberous sclerosis complex. METHODS: Patients were identified using the TSC Natural History Database, the largest repository of longitudinally studied patients enrolled by the TSC Clinics Consortium. RESULTS: A cohort of 1657 TSC Natural History Database patients was analyzed. Eighty-eight percent patients (91% TSC2 vs 82% TSC1; P = 0.002) had epilepsy; TSC2 was more frequent with epilepsy onset at age less than two years (TSC2 82% vs TSC1 54%; P < 0.001) and infantile spasms (TSC2 56% vs TSC1 27%; P < 0.001). Frequency of intellectual disability (intelligence quotient less than 70) was higher when epilepsy coexisted (P < 0.001), but was not impacted by genotype (P = 0.08). Severe intellectual disability (intelligence quotient less than 50) was associated with epilepsy onset at age less than two years (P = 0.007), but not with the epilepsy duration (P = 0.45). Autism was diagnosed in 23% and was associated with epilepsy (P < 0.001), particularly with epilepsy onset at age less than two years (P = 0.02) but not with genotype (P = 0.06). Attention-deficit/hyperactivity disorder (age greater than four years) was diagnosed in 18% and was associated with epilepsy (P < 0.001), but genotype made no difference. Nine percent had anxiety (age greater than seven years) and 6% had depression (age greater than nine years), but neither showed association with epilepsy or genotype. CONCLUSIONS: Epilepsy is associated with intellectual disability, and when epilepsy begins before age two years the frequency and severity of intellectual disability is much higher. Epilepsy is also associated with autism and attention-deficit/hyperactivity disorder but not with anxiety and depression. Additional trials, blinded, prospective, and adequately powered, will help clarify if early and effective treatment of epilepsy may also mitigate intellectual disability, autism, and attention-deficit/hyperactivity disorder.

Investigation of networks underlying hyperkinetic seizures utilizing ictal SPECT.

OBJECTIVE: To study neural networks involved in hyperkinetic seizures (HKS) using ictal SPECT. METHODS: We retrospectively identified 18 patients with HKS evaluated at the Cleveland Clinic between 2005 and 2015 with video-EEG monitoring and ictal SPECT. Semiology was confirmed by the consensus of 2 epileptologists' independent reviews and classified as type 1, 2, or 3 HKS. SPECT data were analyzed by 2 independent physicians using a z score of 1.5. Ictal hyperperfusion patterns for each group were analyzed visually and with SPM. Spatial normalization to Montreal Neurological Institute space for each patient's data was performed, followed by flipping of data from patients with left-sided ictal onset to the right side. Finally, an average z score map for each group was calculated. RESULTS: Visual analysis and SPM identified different patterns of ictal hyperperfusion in the 3 subtypes of HKS. Type 1 seizures showed hyperperfusion in a more anteriorly located network involving the anterior insula, orbitofrontal cortex, cingulate, and anterior perisylvian region and rostral midbrain. Type 2 seizures were associated with hyperperfusion in a more caudally located network involving the orbitofrontal cortex, cingulate (middle and posterior), basal ganglia, thalami, and cerebellum. Type 3 seizures showed a mixed pattern of SPECT hyperperfusion involving the temporal pole and anterior perisylvian region. CONCLUSIONS: Each of the 3 different semiologic subtypes of HKS is associated with distinct patterns of hyperperfusion, providing further insight into the neural networks involved. This knowledge may inform placement of invasive EEG electrodes in patients with HKS semiology undergoing presurgical evaluation.

Perisylvian vulnerability to postencephalitic epilepsy.

OBJECTIVE: Postencephalitic epilepsy is often resistant to antiseizure medications, leading to evaluation for epilepsy surgery. Characterizing its localization carries implications for optimal surgical approach. We aimed to determine whether a prior history of encephalitis is associated with specific epileptogenic networks among patients with drug resistant epilepsy undergoing stereotactic EEG (SEEG). METHODS: We conducted a retrospective cohort study of drug resistant epilepsy, with and without a prior history of encephalitis. We analyzed SEEG recordings to identify patterns of seizure onset and organization. Seventeen patients with a history of encephalitis (of infectious etiology in two subjects) were identified from a database of patients undergoing SEEG and were compared to seventeen drug-resistant epilepsy controls without a history of encephalitis matched for confounding variables including pre-implantation hypotheses, epilepsy duration, age, and sex. RESULTS: Independent bilateral seizures were noted in 65% of the postencephalitic epilepsy cohort. We identified four SEEG-ictal patterns in patients with a prior history of encephalitis: (1) anteromesial temporal onset (24%), (2) anteromesial temporal onset with early spread to the perisylvian region (29%), (3) perisylvian (59%) and (4) synchronized anteromesial temporal and perisylvian (29%) onsets. Patterns 3 and 4, with perisylvian involvement at onset, were unique to the encephalitis group (p = 0.0003 and 0.04 respectively) and exhibited a "patchwork" organization. None of the encephalitis patients vs 5/7 matched controls had Engel I outcome (p = 0.0048). CONCLUSIONS: Postencephalitic epilepsies involve anteromesial temporal and perisylvian networks, often in a bilateral independent manner. Unique ictal patterns involving the perisylvian regions was identified in the encephalitis group, but not in the matched control group. SIGNIFICANCE: These findings may reflect a selective vulnerability of the perisylvian regions to epilepsy resulting from encephalitis, significantly mitigating the chances of success with SEEG-guided temporal resections.