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Management of MRI-negative patients with intractable focal epilepsy after failed surgery is particularly challenging. In this study, we aim to investigate whether MRI post-processing could identify relevant targets for the re-evaluation of MRI-negative patients who failed the initial resective surgery. We examined a consecutive series of 56 MRI-negative patients who underwent resective surgery and had recurring seizures at 1-year follow-up. T1-weighted volumetric sequence from the pre-surgical MRI was used for voxel-based MRI post-processing which was implemented in a morphometric analysis program (MAP). MAP was positive in 15 of the 56 patients included in this study. In 5 patients, the MAP+ regions were fully resected. In 10 patients, the MAP+ regions were not or partially resected: two out of the 10 patients had a second surgery including the unresected MAP+ region, and both became seizure-free; the remaining 8 patients did not undergo further surgery, but the unresected MAP+ regions were concordant with more than one noninvasive modality in 7. In the 8 patients who had unresected MAP+ regions and intracranial-EEG before the previous surgery, the unresected MAP+ regions were concordant with ictal onset in 6. Our data suggest that scrutiny of the presurgical MRI guided by MRI post-processing may reveal relevant targets for reoperation in nonlesional epilepsies. MAP findings, when concordant with the patient's other noninvasive data, should be considered when planning invasive evaluation/reoperation for this most challenging group of patients.

OBJECT The frontal and insular fiber network in humans remains largely unknown. This study investigated the connectivity of the frontal and anterior insular network in humans using cortico-cortical evoked potential (CCEP). METHODS This retrospective analysis included 18 patients with medically intractable focal epilepsy who underwent stereoelectroencephalography and CCEP. Alternating 1-Hz electrical stimuli were delivered to parts of the frontal lobe and anterior insula (prefrontal cortex [PFC], ventrolateral and dorsolateral premotor area [vPM and dPM, respectively], presupplementary motor area [pre-SMA], SMA, frontal operculum, and anterior insula). A total of 40-60 stimuli were averaged in each trial to obtain CCEP responses. The distribution of CCEP was evaluated by calculating the root mean square of CCEP responses. RESULTS Stimulation of the PFC elicited prominent CCEP responses in the medial PFC and PMs over the ipsilateral hemisphere. Stimulation of the vPM and dPM induced CCEP responses in the ipsilateral frontoparietal areas. Stimulation of the pre-SMA induced CCEP responses in the ipsilateral medial and lateral frontal areas and contralateral pre-SMA, whereas stimulation of the SMA induced CCEP responses in the bilateral frontoparietal areas. Stimulation of the frontal operculum induced CCEP responses in the ipsilateral insula and temporal operculum. CCEPs were observed in the ipsilateral medial, lateral frontal, and frontotemporal operculum in the anterior insular stimulation. Stimulation of the vPM and SMA led to the network in the dominant hemisphere being more developed. CONCLUSIONS Various regions within the frontal lobe and anterior insula were linked to specific ipsilateral and contralateral regions, which may reflect distinct functional roles.

Purpose: Infraslow activity (ISA) occurring during the interictal state in focal epilepsy is largely unstudied. In this exploratory analysis, the authors aimed to characterize features of interictal ISA in a cohort of patients studied by stereoelectroencephography., Methods: The interictal stereoelectroencephography records for 15 consecutive adult patients were retrospectively analyzed, after application of both conventional (1.6-70 Hz) and infraslow (0.01-0.1 Hz) bandpass filters. Visual analysis was complemented by time-frequency analysis to quantify the change in ISA power over hours. Linear correlation coefficient (R) calculations were used to map interictal connectivity in the infraslow band., Results: Interictal ISA background fluctuations were present throughout the interictal state in all patients, manifesting as recurrent and stereotyped oscillations. These oscillations had an apparent modulatory effect on conventional-band activities and spikes ("spike-crested oscillations"). In the infraslow band, the correlations between electrode contacts were shown to have a stable structure over time., Conclusions: Infraslow activity exists as a fundamental component of wideband cortical dynamics in focal epilepsy, with features suggestive of scale-free (1/f) dynamics: evidence of phase-amplitude coupling and functional connectivity in the infraslow band. Rather than viewed as a focal paroxysmal activity, interictal ISA may be better understood as a network process, although this requires further study.

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., (© 2015 American Neurological Association.)

Papez proposed a network for higher brain function, which is termed the limbic network. However, the in vivo human limbic network has not been established. We investigated the connectivity of the human limbic system using corticocortical evoked potential (CCEP). This retrospective analysis included 28 patients with medically intractable focal epilepsy who underwent stereoelectroencephalography (SEEG) and CCEP. Alternating 1 Hz electrical stimuli were delivered to parts of the limbic system [anterior and posterior hippocampus, temporal pole, parahippocampal gyrus (PHG), amygdala, anterior (ACG) and posterior cingulate gyrus (PCG), medial and lateral orbitofrontal cortex (OF)]. A total of 40-60 stimuli were averaged in each trial to obtain CCEP responses. CCEP distributions were evaluated by calculating the root mean square (RMS) of CCEP responses. Anterior hippocampal stimulation elicited prominent CCEP responses in medial and lateral temporal structures, PCG, medial OF and insula over the ipsilateral hemisphere. Posterior hippocampal stimulation induced CCEP responses in the ipsilateral medial and lateral temporal structures and PCG. The findings also revealed connections from temporal pole to the ipsilateral medial temporal structures, and connections from PHG to the ipsilateral hippocampus and PCG. The amygdala projected to broad areas including the ipsilateral medial and lateral temporal structures, medial and lateral frontal areas, the cingulate gyrus, insula and inferior parietal lobule. ACG and PCG showed connections to the ipsilateral medial fronto-parietal areas and connections to bilateral medial temporo-parieto-occipital and lateral parieto-occipital areas, respectively. Medial and lateral OF stimulation induced responses in the adjacent cortices. This study revealed that various regions within the limbic network are intimately connected in reverberating circuits and are linked to specific ipsilateral and contralateral regions, which may reflect distinct functional roles., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To investigate the human limbic system using cortico-cortical evoked potential (CCEP), which reveals the brain networks., Methods: Five patients with nonlesional medically intractable focal epilepsy with ictal onset outside the limbic system were enrolled. All patients underwent stereoelectroencephalogram electrode implantation in order to delineate the epileptogenic zone. Alternating 1Hz electrical stimuli were delivered to the hippocampus and posterior cingulate gyrus. A total of sixty stimuli were averaged in each trial to obtain CCEP responses., Results: Hippocampal stimulation elicited prominent CCEP responses in the posterior cingulate gyrus. The latencies of early (N1) and late (N2) negative peak ranged 20-60 ms and 102-175 ms respectively. In addition, CCEP responses were observed in the posterior parahippocampal gyrus, medial superior frontal gyrus (SFG) and orbitofrontal cortex. Stimulation of posterior cingulate contacts induced CCEPs in the hippocampus with N1 and N2 latencies of 25-43 ms and 90-234 ms respectively in all five patients., Conclusion: This finding supports the assertion that the hippocampus is connected with the posterior cingulate gyrus, posterior parahippocampal gyrus, medial SFG and orbitofrontal cortex. The hippocampus and posterior cingulate gyrus have a bidirectional network through the cingulum., Significance: The present study provides new insight into the human limbic network., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to experience epileptic seizures and the neurobiological, cognitive, psychological, and social difficulties relating to the condition. An epileptic spasm (ES) is a type of seizure characterized by clusters of short contractions involving axial muscles and proximal segments. However, the precise mechanism of ESs remains unknown. Despite the potential of magnetoencephalography (MEG) as a tool for investigating the neurophysiological mechanism of ESs, it has been difficult to use this methodology due to magnetic artifacts attributable to patient movement. We report on an 8-year-old girl suffering from intractable epileptic spasms from the age of 7 months. She was diagnosed with possible Aicardi syndrome [corrected] (AGS), characterized by the triad of callosal agenesis, infantile spasms, and chorioretinal lacunae. She is now intellectually delayed and suffers from intractable ES. We used both MEG and electroencephalography to investigate her epilepsy. The recording captured two series of spasm clusters. Spikes were clearly identified with MEG in about four-fifths of all spasms but were identified poorly or not at all in the remainder. MEG findings support previous studies that used intracranial electrodes to analyze patients with ESs and that showed variability in ES-associated spikes in terms of manner of cortical involvement and magnitude. Given the limitations of intracranial electrodes, such as sampling restrictions and invasiveness, MEG may be a helpful tool for non-invasively investigating the unique pathophysiological profile of focal-onset ESs.

Identification and accurate localization of seizure foci is vital in patients with medically-intractable focal epilepsy, who may be candidates for potentially curative resective epilepsy surgery. We present a patient with difficult-to-control seizures associated with an occult focal cortical dysplasia residing within the deeper left parietal operculum and underlying posterior insula, which was not detected by conventional MRI analysis. Propagated activities from this deeper generator produced misleading EEG patterns both on surface and subdural electrode recordings suggesting initial activation of the perirolandic and mesial frontal regions. However, careful spatio-temporal analysis of stereotyped interictal activities recorded during MEG, using sequential dipole modeling, revealed a consistent pattern of epileptic propagation originating from the deeper source and propagating within few milliseconds to the dorsal convexity. In this instance, careful dissection of noninvasive investigations (interictal MEG along with ictal SPECT findings) allowed clinicians to dismiss the inaccurate and misleading findings of the traditional "gold-standard" intracranial EEG. In fact, this multimodal noninvasive approach uncovered a subtle dysplastic lesion, resection of which rendered the patient seizure-free. This case highlights the potential benefits of dynamic analysis of interictal MEG in the appropriate clinical context. Pathways of interictal spike propagation may help elucidate essential neural networks underlying focal epilepsy., (Copyright © 2011 Wiley Periodicals, Inc.)

A movement compensation (MC) algorithm may help to evaluate seizure focus in magnetoencephalography despite patient movement. We report a boy whose ictal MEG focus was localized to the same sublobar region before and after head turning when MC was applied, but which was erroneously localized to a different area without MC. This study provides the first clinical evidence for utility of MC in magnetoencephalography for localizing focal seizures., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To investigate the utility of magnetic source imaging (MSI) for localizing the epileptogenic zone (EZ) and predicting epilepsy surgery outcome in non-lesional neocortical focal epilepsy (NLNE) patients., Methods: Data from 18 consecutive patients with NLNE who underwent presurgical evaluation including intracranial electroencephalography (ICEEG) and MSI were studied. Follow-up after epilepsy surgery was ≥24 months. Intracranial electroencephalography and MSI results were classified using a sublobar classification., Results: Sublobar ICEEG focus was completely resected in 15 patients; seizure-free rate was 60%. Eight patients showed sublobar-concordant ICEEG/MSI results and complete resection of both regions; seizure-free rate was 87.5%. Seizure-free rate in cases not matching these criteria was only 30% (p=0.013)., Conclusions: Magnetoencephalography is a useful tool to localize the EZ and determine the site of surgical resection in NLNE patients. When sublobar concordance with ICEEG is observed, MSI increases the predictive value for a seizure-free epilepsy surgery outcome in these patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report an unusual case of Parry-Romberg syndrome in which medically refractory focal epilepsy with ongoing epilepsia partialis continua (EPC) arose from the hemisphere contralateral to the side of facial atrophy. Unilateral cerebral involvement was confirmed by multi-modal brain imaging, as well as by electroencephalography (EEG) and magnetoencephalography (MEG). While in many cases of Parry-Romberg syndrome, the side of cerebral involvement is ipsilateral to that of the cutaneous lesion, these "discordant" exceptions imply that other yet undefined mechanisms may be responsible for the distribution of the cutaneous and cerebral pathologies.

Purpose: To determine reasons for neuroimaging and neuroimaging findings in children with benign focal epileptiform discharges (BFEDs)., Methods: We performed a retrospective chart review of children who had BFEDs on routine EEG and underwent brain MRI., Results: We identified 97 patients with BFEDs and MRI. Forty-five of these 97 patients also had seizures consistent with benign focal epilepsy of childhood with centrotemporal spikes (BECTS). Rationale for imaging in the 45 BECTS patients included historical features such as headaches (14), increase in seizure frequency (5), and new events (5). Nine MRIs were obtained prior to referral and 12 for unspecified reasons. MRI findings were not significantly different between BECTS and BFEDs patients. Fourty-one patients (42%) had abnormal findings on MRI, including T2 hyperintensities (10), hippocampal atrophy (6), malformation of cortical development (4), volume loss (5), Chiari malformation (4), and others (18)., Conclusion: MRIs are not routinely recommended in patients with BECTS unless atypical features are present. Atypical features which may prompt MRI include change in clinical seizure types or frequency, historical features such as headaches, abnormal neurological exam, and atypical EEG features. 42% of our selected patients had intracranial abnormalities, most of which were of unclear clinical significance. Remote infarcts and early lesions accounted for most MRI findings suggesting they may be related to BFEDs., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Purpose: To review the clinical, electrographic, radiological, and pathological findings of patients with coexistent idiopathic generalized and partial epilepsy syndromes., Methods: We performed a medical record review and a phone interview with all patients hospitalized to the Cleveland Clinic epilepsy monitoring unit (EMU) between 1992 and 2002 who fulfilled clinical and EEG criteria of coexistent partial and generalized epilepsy syndromes., Results: Seven patients were identified. Two (29%) were men with a mean age of 26 years. Four had a history of febrile seizures. Family history was positive in five. Mean duration of the generalized epilepsy syndrome was 11 years, and of the focal epilepsy 18 years. An equal number of patients developed focal versus generalized epilepsy first. Interictal EEG activity was predominantly generalized. Four had video-EEG documentation of both types of seizures. In the rest, only focal seizures were recorded but interictal activity strongly suggested a coexistent generalized epilepsy. MRI showed hippocampal atrophy in all, and hippocampal dysplasia in three. Five patients had PET imaging, all with hypometabolism in areas corresponding to the ictal onset on EEG. Four patients underwent epilepsy surgery with good surgical outcome and pathological confirmation of hippocampal sclerosis in all., Conclusion: We found a 0.2% incidence of coexistent focal and primary generalized epilepsy. Febrile seizures and a positive family history were common. Good seizure control was achieved after temporal lobectomy, even when interictal generalized activity predominated.

Purpose: Invasive ictal EEG recording is often necessary to delineate epileptogenic areas in patients with intractable partial epilepsy, but even intracranial ictal recordings often reveal ill-defined onset zones in neocortical epilepsy. We studied the physiologic significance of ictal direct current (DC) potentials recorded intracranially in human epilepsy., Methods: We made intracranial ictal EEG recordings in three patients with intractable partial seizures arising from frontal, lateral temporal, and parietal neocortical areas by using closely spaced subdural electrodes (platinum in two patients and stainless steel in one patient) with both standard (1.5 Hz) and open (0.016 Hz) low-frequency filter (LFF) settings., Results: The initial ictal pattern was localized to two to nine subdural electrodes and characterized by very low voltage and high-frequency rhythmic activity ("electrodecremental pattern"). A slow-rising negative potential (DC potential) was seen in a slightly more restricted area (two to six electrodes) and occurred 1-10 s before the initial ictal EEG discharges in two patients., Conclusions: These results agree with those of previous studies of ictal DC shifts in animals and suggest that ictal DC shifts may be helpful in delineating the epileptogenic area more precisely in human epilepsy.

To clarify the differences of movement-related potentials (MRPs) among ipsilateral, contralateral and simultaneous bilateral movements, MRPs with finger, thumb or foot movements were recorded from subdural electrodes chronically implanted on the supplementary motor area (SMA) in 3 patients, and also from the primary sensorimotor area in two of them being evaluated for epilepsy surgery. As a result: (1) SMA generated clear pre-movement potentials regardless of the type of movement. Its amplitude was almost identical between contralateral and bilateral movements except for the motor potential (MP). The pre-movement potentials associated with ipsilateral movements were relatively smaller than those with contralateral or bilateral movements. (2) The primary sensorimotor area generated clear pre-movement potentials in contralateral and bilateral movements with similar amplitude. With ipsilateral hand movements, however, only a small Bereitschaftspotential (BP) and no negative slope (NS') or MP was seen, and ipsilateral foot movements were not preceded by any BP. It is, therefore, most likely that, as far as the preparation for simple voluntary self-paced movement is concerned, the SMA plays an equally important role in unilateral and bilateral movements, whereas the primary sensorimotor area is involved predominantly in the preparation of contralateral movements.