Nonlesional Focal Epilepsy Research Articles

MRI-negative PET-negative epilepsy long-term surgical outcomes: A single-institution retrospective review

PurposeSurgical planning for people with drug resistant non-lesional focal epilepsy can be challenging. Prior studies focus on cases that are only MRI-negative or MRI-negative with PET-positive imaging, but little is known about outcomes in patients with non-lesional findings on both MRI and PET imaging. In this study, we investigate 5-year surgical outcomes in patients who underwent epilepsy surgery for drug resistant MRI/PET-negative focal epilepsy. MethodsWe collected clinical and testing data on 131 consecutive patients with drug resistant non-lesional epilepsy who were presented at a multidisciplinary epilepsy surgery conference at the New York University Comprehensive Epilepsy Center between 2010 and 2014, and identified those who underwent epilepsy surgery in order to review 5-year surgical outcomes. ResultsThere were 103 with non-lesional MRI studies, and of these, 22 had corresponding non-lesional PET imaging. 14 MRI/PET-negative patients pursued a surgical treatment option and 9 underwent resections after intracranial EEG. At 5 years, 77.8 % of patients had favorable (ILAE class 1 and 2) outcomes. Most (77.8 %) had focal cortical dysplasia type Ia (FCDIa) on pathology. ConclusionThese findings suggest that with careful planning and patient selection, surgery for patients with drug resistant MRI/PET-negative focal epilepsy can be successful.

Utility of magnetic source imaging in nonlesional focal epilepsy: a prospective study

For patients with nonlesional refractory focal epilepsy (NLRFE), localization of the epileptogenic zone may be more arduous than for other types of epilepsy and frequently requires information from multiple noninvasive presurgical modalities and intracranial EEG (icEEG). In this prospective, blinded study, the authors assessed the clinical added value of magnetic source imaging (MSI) in the presurgical evaluation of patients with NLRFE. This study prospectively included 57 consecutive patients with NLRFE who were considered for epilepsy surgery. All patients underwent noninvasive presurgical evaluation and then MSI. To determine the surgical plan, discussion of the results of the presurgical evaluation was first undertaken while discussion participants were blinded to the MSI results. MSI results were then presented. MSI influence on the initial management plan was assessed. MSI results influenced patient management in 32 patients. MSI results led to the following changes in surgical strategy in 14 patients (25%): allowing direct surgery in 6 patients through facilitating the detection of subtle cortical dysplasia in 4 patients and providing additional concordant diagnostic information to other presurgical workup in another 2 patients; rejection of surgery in 3 patients originally deemed surgical candidates; change of plan from direct surgery to icEEG in 2 patients; and allowing icEEG in 3 patients deemed not surgical candidates. MSI results led to changed electrode locations and contact numbers in another 18 patients. Epilepsy surgery was performed in 26 patients influenced by MSI results and good surgical outcome was achieved in 21 patients. This prospective, blinded study showed that information provided by MSI allows more informed icEEG planning and surgical outcome in a significant percentage of patients with NLRFE and should be included in the presurgical workup in those patients.

Acute knockdown of Depdc5 leads to synaptic defects in mTOR-related epileptogenesis

DEP-domain containing 5 (DEPDC5) is part of the GATOR1 complex that functions as key inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1). Loss-of-function mutations in DEPDC5 leading to mTOR hyperactivation have been identified as the most common cause of either lesional or non-lesional focal epilepsy. However, the precise mechanisms by which DEPDC5 loss-of-function triggers neuronal and network hyperexcitability are still unclear. In this study, we investigated the cellular mechanisms of hyperexcitability by comparing the constitutive heterozygous Depdc5 knockout mouse versus different levels of acute Depdc5 deletion (≈40% and ≈80% neuronal knockdown of Depdc5 protein) by RNA interference in primary cortical cultures. While heterozygous Depdc5+/− neurons have only a subtle phenotype, acutely knocked-down neurons exhibit a strong dose-dependent phenotype characterized by mTOR hyperactivation, increased soma size, dendritic arborization, excitatory synaptic transmission and intrinsic excitability. The robust synaptic phenotype resulting from the acute knockdown Depdc5 deficiency highlights the importance of the temporal dynamics of Depdc5 knockdown in triggering the phenotypic changes, reminiscent of the somatic second-hit mechanism in patients with focal cortical dysplasia. These findings uncover a novel synaptic phenotype that is causally linked to Depdc5 knockdown, highlighting the developmental role of Depdc5. Interestingly, the synaptic defect appears to affect only excitatory synapses, while inhibitory synapses develop normally. The increased frequency and amplitude of mEPSCs, paralleled by increased density of excitatory synapses and expression of glutamate receptors, may generate an excitation/inhibition imbalance that triggers epileptogenesis.

The lack of influence of IVS5-91 G>A polymorphism of the SCN1A gene on efficacy of lamotrigine in patients with focal epilepsy

ABSTRACTBackground: IVS5-91G>A (rs3812718) polymorphism of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene has been associated with inadequate responsiveness to common antiepileptic drugs which act as sodium channel blockers. This study was performed to investigate the effect of IVS5-91G>A (rs3812718) polymorphism on lamotrigine (LTG) efficacy in a cohort of patients with non-lesional focal epilepsy taking LTG as monotherapy.Methods: A total of 100 of patients with non-lesional focal epilepsy on LTG monotherapy was included in this prospective interventional study. After reaching a stable dose of LTG patients were followed-up for 12 consecutive months. LTG responsiveness was defined as a 75% or more reduction in seizure frequency on a stable dose of LTG. Genotyping was performed at the end of the study using standard procedures and data were correlated with clinical data.Results: There were no significant differences in the prevalence of responsiveness to LTG between carriers of different genotypes. Average maintenance LTG doses in the responder group differed by genotype in the order AA>GA>GG, but these differences did not reach statistical significance.Conclusion: Our data suggest lack of association between SCN1A IVS5-91G>A (rs3812718) polymorphism and response to LTG.

Functional Connectivity Associated with Health-Related Quality of Life in Children with Focal Epilepsy.

Although functional connectivity has been linked to cognitive function in epilepsy, its relationship with physical, psychological, or social dysfunction is unknown. This study aimed to assess the relationship between network architecture from resting-state fMRI and health-related quality of life in children with medically intractable focal epilepsy. Forty-seven children with nonlesional focal epilepsy were included; 22 had frontal lobe epilepsy and 15 had temporal lobe epilepsy. We computed graph metrics of functional connectivity, including network segregation (clustering coefficient and modularity) and integration (characteristic path length and participation coefficient). Health-related quality of life was measured using the Quality of Life in Childhood Epilepsy questionnaire. We examined the associations between graph metrics and the Quality of Life in Childhood Epilepsy total and domains scores, with age, sex, age at seizure onset, fMRI motion, and network density as covariates. There was a negative relationship between the clustering coefficient and total Quality of Life in Childhood Epilepsy score [t(40) = -2.0; P = .04] and social function [t(40) = -2.9; P = .005]. There was a positive association between the mean participation coefficient and total Quality of Life in Childhood Epilepsy score [t(40) = 2.2; P = .03] and cognition [t(40) = 3.8; P = .0004]. In temporal lobe epilepsy, there was a negative relationship between the clustering coefficient and total Quality of Life in Childhood Epilepsy score [t(8) = -2.8; P = .02] and social function [t(8) = -3.6; P = .0075] and between modularity and total Quality of Life in Childhood Epilepsy score [t(8) = -2.5; P = .04] and social function [t(8) = -4.4; P = .0021]. In frontal lobe epilepsy, there was no association between network segregation and integration and Quality of Life in Childhood Epilepsy total or domain scores. Our findings indicate that there are other higher order brain functions beyond cognition, which may be linked with functional connectivity of the brain.

Higher nicotinic receptor availability in the cingulo-insular network is associated with lower cardiac parasympathetic tone.

The dorsal anterior cingulate cortex (dACC) and the anterior insula (AI) constitute the salience network and form as well the major cortical components of the central autonomic nervous system. These two cortical regions have the highest density in α4β2 nicotinic acetylcholine receptors (nAChRs) within the whole cortex.The aim of the study was to test the association between nAChRs density/availability in the salience network and the heart rate variability in humans. We selected subjects from a previous positron emission tomography (PET) imaging study in epilepsy with 18F-FA-85380, a specific marker for α4β2 nAChRs, including 10 healthy controls, 10 patients with nonlesional focal epilepsy and 8 patients with idiopathic generalized epilepsy. Participants underwent a 10 min-resting electrocardiogram as they were lying still in a semi-supine position while watching an emotionally neutral video. We tested the association between parasympathetic tone and the regional brain nAChR availability, as measured by 18F-F-A-85380 binding potential (BP), using linear regression. We observed an association between higher nAChRs availability in the bilateral dACC and the right dorsal AI/frontal operculum and a lower parasympathetic tone, without significant effect of the clinical group on this relation. Our study is the first one to show a neurochemical correlate to the parasympathetic role of the anterior cingulate cortex and the AI. The nicotinic system, which plays a major role in the peripheral autonomic nervous system intervening both in the parasympathetic and sympathetic chains, seems also to play a role in the central autonomic nervous system.

Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci.

Despite tremendous progress through next generation sequencing technologies, familial focal epilepsies are insufficiently understood. We sought to identify the genetic basis in multiplex Palestinian families with familial focal epilepsy with variable foci (FFEVF). Family I with 10 affected individuals and Family II with five affected individuals underwent detailed phenotyping over three generations. The phenotypic spectrum of the two families varied from nonlesional focal epilepsy including nocturnal frontal lobe epilepsy to severe structural epilepsy due to hemimegalencephaly. Whole-exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38-kb deletion encompassing eight exons (exons 8-15) and the 3'-untranslated region of the NPRL3 gene in Family I, and a de novo nonsense variant c.1063C>T, p.Gln355* in Family II. Furthermore, we identified a truncating variant in the PDCD10 gene in addition to the NPRL3 variant in a patient with focal epilepsy from Family I. The individual also had developmental delay and multiple cerebral cavernomas, possibly demonstrating a digenic contribution to the individual's phenotype. Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants.

Cerebrovascular disease burden in late-onset non-lesional focal epilepsy

PurposeLate-onset non-lesional focal epilepsy, defined as new-onset seizures in patients older than 60 years, is diagnosed increasingly more often in relation to aging of the population. It has been attributed mainly to occult cerebral small vessel disease (SVD), although high levels of evidence to support this notion are lacking. This study aimed to evaluate the burden of leukoaraiosis, a marker of cerebral SVD, and hippocampal atrophy in patients with late-onset epilepsy (LOE). MethodsBrain magnetic resonance imaging (MRI) studies were retrospectively analyzed by two blinded radiologists. The Fazekas and Scheltens scales were used to assess the degree of leukoaraiosis and hippocampal atrophy in 33 patients with non-lesional LOE, 41 patients with clinical signs of SVD (eg, recent history of transient ischemic attack [TIA] or lacunar stroke), and 26 healthy controls, all >60 years of age. ResultsMean age in epilepsy patients was 70.9 (±6.6) years; 57.6% were men. The history of vascular risk factors was similar in all groups. Median (interquartile range) Fazekas score was 1 (0–1) in the epilepsy group, 1 (0–2) in TIA/lacunar stroke patients, and 0 (0–1) in the healthy group. Degree of leukoaraiosis was milder in epilepsy patients compared to the TIA/lacunar stroke group (p = 0.004), and similar to that of healthy controls (p = 0.593). Hippocampal atrophy was significantly greater in patients with epilepsy (p < 0.005). ConclusionThese findings suggest that the etiology of LOE is not exclusively related to cerebrovascular disease. Hippocampal atrophy may contribute to the origin of the seizures.

Therapeutic effect of repetitive transcranial magnetic stimulation on non-lesional focal refractory epilepsy

The effects of repetitive transcranial magnetic stimulation (rTMS) on epilepsy remain unclear. This study was performed to investigate the effects of low-frequency rTMS on non-lesional focal epilepsy.This was a prospective open-label longitudinal study with four patients with multi-drug-resistant non-lesional focal epilepsy and no control group. The patients received daily doses of 900 pulses of 0.5-Hz stimulation for 10 days over the epileptic foci in neocortical areas determined by electrical source analysis. The outcomes were measured in terms of seizure reduction. The incidences of seizures were measured at baseline (4 weeks), intervention (2 weeks), and follow up (8 weeks).Seizure reduction was observed in three of four subjects. The effects of rTMS persisted over a follow-up period of 8 weeks. One of the four patients did not respond to rTMS and showed no seizure reduction.The low frequency rTMS would be an effective treatment for non-lesional focal refractory epilepsy, may be an adjunctive treatment with conventional medical treatment for refractory epilepsy. These results are therefore useful for planning treatment strategies for patients with refractory epilepsy, as well as for treatment of epilepsy.

Outcome after individualized stereoelectroencephalography (sEEG) implantation and navigated resection in patients with lesional and non-lesional focal epilepsy.

Refined localization of the epileptogenic zone (EZ) in patients with pharmacoresistant focal epilepsy proceeding to resective surgery might improve postoperative outcome. We here report seizure outcome after stereo EEG (sEEG) evaluation with individually planned stereotactically implanted depth electrodes and subsequent tailored resection. A cohort of consecutive patients with pharmacoresistant focal epilepsy, evaluated with a non-invasive evaluation protocol and invasive monitoring with personalized, stereotactically implanted depth electrodes for sEEG was analyzed. Co-registration of post-implantation CT scan to presurgical MRI data was used for 3D reconstructions of the patients' brain surface and mapping of neurophysiology data. Individual multimodal 3D maps of the EZ were used to guide subsequent tailored resections. The outcome was rated according to the Engel classification. Out of 914 patients who underwent non-invasive presurgical evaluation, 85 underwent sEEG, and 70 were included in the outcome analysis. Median follow-up was 31.5months. Seizure-free outcome (Engel class I A-C, ILAE class 1-2) was achieved in 83% of the study cohort. Patients exhibiting lesional and non-lesional (n = 42, 86% vs. n = 28, 79%), temporal and extratemporal (n = 45, 80% vs. n = 25, 84%), and right- and left-hemispheric epilepsy (n = 44, 82% vs. n = 26, 85%) did similarly well. This remains also true for those with an EZ adjacent to or distant from eloquent cortex (n = 21, 86% vs. n = 49, 82%). Surgical outcome was independent of resected tissue volume. Favourable post-surgical outcome can be achieved in patients with resistant focal epilepsy, using individualized sEEG evaluation and tailored navigated resection, even in patients with non-lesional or extratemporal focal epilepsy.

Brainstem atrophy in focal epilepsy destabilizes brainstem-brain interactions: Preliminary findings

BackgroundMR Imaging has shown atrophy in brainstem regions that were linked to autonomic dysfunction in epilepsy patients. The brainstem projects to and modulates the activation state of several wide-spread cortical/subcortical regions. The goal was to investigate 1. Impact of brainstem atrophy on gray matter connectivity of cortical/subcortical structures and autonomic control. 2. Impact on the modulation of cortical/subcortical functional connectivity.Methods11 controls and 18 patients with non-lesional focal epilepsy (FE) underwent heart rate variability (HRV) measurements and a 3 T MRI (T1 in all subjects, task-free fMRI in 7 controls/ 12 FE). The brainstem was extracted, and atrophy assessed using deformation-based-morphometry. The age-corrected z-scores of the mean Jacobian determinants were extracted from 71 5x5x5 mm grids placed in brainstem regions associated with autonomic function. Cortical and non-brainstem subcortical gray matter atrophy was assessed with voxel-based-morphometry and mean age corrected z-scores of the modulated gray matter volumes extracted from 380 cortical/subcortical rois. The profile similarity index was used to characterize the impact of brainstem atrophy on gray matter connectivity. The fMRI was preprocessed in SPM12/Conn17 and the BOLD signal extracted from 398 ROIs (16 brainstem). A dynamic task-free analysis approach was used to identify activation states. Connectivity HRV relationship were assessed with Spearman rank correlations.ResultsHRV was negatively correlated with reduced brainstem right hippocampus/parahippocampus gray matter connectivity in controls (p < .05, FDR) and reduced brainstem to right parietal cortex, lingual gyrus, left hippocampus/amygdala, parahippocampus, temporal pole, and bilateral anterior thalamus connectivity in FE (p < .05, FDR). Dynamic task-free fMRI analysis identified 22 states. The strength of the functional brainstem/cortical connectivity of state 15 was negatively associated with HRV (r = −0.5, p = .03) and positively with decreased brainstem-cortical (0.49, p = .03) gray matter connectivity.ConclusionThe findings of this small pilot study suggest that impaired brainstem-cortex gray matter connectivity in FE negatively affects the brainstem's ability to control cortical activation.

Role of cerebral glutamate in post-stroke epileptogenesis.

Stroke is one of the most important causes of acquired epilepsy in the adult population. While factors such as cortical involvement and haemorrhage have been associated with increased seizure risk, the mechanisms underlying the development of epilepsy after stroke remain unclear. One hypothesised mechanism is an excitotoxic effect of abnormal glutamate release following a stroke. Cerebral extracellular glutamate levels are known to rise in the setting of acute stroke, and numerous studies have implicated glutamate in the pathogenesis of seizures and epilepsy, both through direct measurement of glutamate from the epileptic brain and by analysis of receptors and transporters central to glutamate homeostasis. While experimental evidence suggests the cellular injury induced by glutamate exposure may lead to development of an epileptic phenotype, there is little direct data linking the rise in glutamate during stroke with the later development of epilepsy. Clinical research in this field has been hampered by the lack of non-invasive methods to measure cerebral glutamate. However, with the increasing availability of 7T MRI technology, Magnetic Resonance Spectroscopy is able to better resolve glutamate from other chemical species at this field strength, and Glutamate Chemical Exchange Saturation Transfer (GluCEST) imaging has been applied to localise epileptic foci in non-lesional focal epilepsy. This review outlines the evidence implicating a pivotal role for cerebral glutamate in the development of post-stroke epilepsy, and exploring the role of MRI in studying glutamate as a biomarker and therefore its suitability as a molecular target for anti-epileptogenic therapies. We hypothesise that the rise in glutamate levels in the setting of acute stroke is a clinically relevant biomarker for the development of post-stroke epilepsy.

Brain somatic mutations in SLC35A2 cause intractable epilepsy with aberrant N-glycosylation.

ObjectiveTo identify whether somatic mutations in SLC35A2 alter N-glycan structures in human brain tissues and cause nonlesional focal epilepsy (NLFE) or mild malformation of cortical development (mMCD).MethodsDeep whole exome and targeted sequencing analyses were conducted for matched brain and blood tissues from patients with intractable NLFE and patients with mMCD who are negative for mutations in mTOR pathway genes. Furthermore, tissue glyco-capture and nanoLC/mass spectrometry analysis were performed to examine N-glycosylation in affected brain tissue.ResultsSix of the 31 (19.3%) study patients exhibited brain-only mutations in SLC35A2 (mostly nonsense and splicing site mutations) encoding a uridine diphosphate (UDP)-galactose transporter. Glycome analysis revealed the presence of an aberrant N-glycan series, including high degrees of N-acetylglucosamine, in brain tissues with SLC35A2 mutations.ConclusionOur study suggests that brain somatic mutations in SLC35A2 cause intractable focal epilepsy with NLFE or mMCD via aberrant N-glycosylation in the affected brain.

Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy

Mutations of cholinergic neuronal nicotinic receptors have been identified in the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), associated with changes on PET images using [18F]-F-85380-A (F-A-85380), an α4β2 nicotinic receptor ligand. The aim of the present study was to evaluate potential changes in nicotinic receptor availability in other types of epilepsy. We included 34 male participants, 12 patients with idiopathic generalized epilepsy (IGE), 10 with non-lesional diurnal focal epilepsy, and 12 age-matched healthy controls. All patients underwent PET/CT using F-A-85380 and [18F]-fluorodeoxyglucose (FDG), 3D T1 MRI and diffusion tensor imaging (DTI). F-A-85380 and FDG images were compared with the control group using a voxel-wise (SPM12) and a volumes of interest (VOI) analysis. In the group of patients with IGE, the voxel-wise and VOI analyses showed a significant increase of F-A-85380 ratio index of binding potential (BPRI, corresponding to the receptor availability) in the anterior cingulate cortex (ACC), without structural changes on MRI. At an individual level, F-A-85380 BPRI increase in the ACC could distinguish IGE patients from controls and from patients with focal epilepsy with good accuracy. We observed focal changes of density/availability of nicotinic receptors in IGE, namely an increase in the ACC. These data suggest that the modulation of α4β2 nicotinic receptors plays a role not only in ADNFLE, but also in other genetic epileptic syndromes such as IGE and could serve as a biomarker of epilepsy syndromes with a genetic background.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Effect of Levetiracetam Monotherapy in Nonlesional Focal Childhood Epilepsy

This article compares the efficacy and tolerability of carbamazepine (CBZ) and levetiracetam (LEV) when used as initial monotherapy in children with nonlesional focal epilepsy. Patients with nonlesional focal epilepsy were subdivided into two groups according to the initial monotherapy: a LEV group administered LEV at an initial dose of 5 mg/kg/day and a CBZ group. Seizure response, adverse events, medication dose, reasons for discontinuing medication, adherence, and random serum levels were recorded. The overall percentage of patients who failed initial treatment and reasons for each treatment failure were determined. Data were analyzed from 183 children who received CBZ monotherapy and 46 children who received LEV monotherapy for ≥12 months. Overall, 126 patients (68.9%) became seizure-free with CBZ, compared with 37 patients (80.4%) with LEV. Moreover, four patients in CBZ and four patients in LEV groups showed a >50% reduction in seizure frequency. The efficacy rate was significantly higher and the adverse event rate was significantly lower in the LEV group than in the CBZ group (p = 0.0129 and p = 0.0039, respectively). LEV may offer superior efficacy and a lower risk of adverse effects compared with CBZ. LEV as initial monotherapy may represent a valuable treatment option for children with nonlesional focal childhood epilepsy.

The clinical impact of integration of magnetoencephalography in the presurgical workup for refractory nonlesional epilepsy

ObjectiveFor patients with nonlesional refractory focal epilepsy (NLRFE), localization of the epileptogenic zone is more arduous, and intracranial electroencephalography (EEG) (icEEG) is frequently required. Planning for icEEG is dependent on combined data from multiple noninvasive modalities. We report the negative impact of lack of integration of magnetoencephalography (MEG) in the presurgical workup in NLRFE. MethodsObservational MEG case series involving 31 consecutive patients with NLRFE in an academic epilepsy center. For various reasons, MEG data were not analyzed in a timely manner to be included in the decision-making process. The presumed impact of MEG was assessed retrospectively. ResultsMagnetoencephalography would have changed the initial management in 21/31 (68%) had MEG results been available by reducing the number of intracranial electrodes, modifying their position, allowing for direct surgery, canceling the intracranial study, or providing enough evidence to justify one. Good surgical outcome was achieved in 11 out of 17 patients who proceeded to epilepsy surgery. Nine out of eleven had MEG clusters corresponding to the resection area, and MEG findings would have allowed for direct surgery (avoiding icEEG) in 2/11. Six patients had poor outcome including three patients where MEG would have significantly changed the outcome by modifying the resection margin. Magnetoencephalography provided superior information in 3 patients where inadequate coverage precluded accurate mapping of the epileptogenic zone. ConclusionIn this single center retrospective study, MEG would have changed patient management, icEEG planning, and surgical outcome in a significant percentage of patients with NLRFE and should be considered in the presurgical workup in those patients.

P 88 Good outcome of resective epilepsy surgery in patients with non-lesional focal epilepsy after invasive evaluation with stereotactically implanted depth electrodes

Background Resective surgery is an effective and safe treatment option for medically refractory focal epilepsy. Patients who require prior invasive EEG evaluation with intracranial electrodes are usually considered difficult candidates. The absence of an MRI-visible structural lesion and extratemporal seizure onset are also considered disadvantageous and some studies showed a lower seizure free outcome after surgery. Uncertainty in the identification of the epileptogenic zone, incomplete resection and smaller resection volumes have been discussed as possible explanations. Methods All patients had noninvasive Video-EEG-monitoring and MRI scans, some had additional ictal SPECT, FDG-PET and/or DTI scans. Implantation of electrodes was planned individually, based on the conclusive interpretation of all available clinical and imaging data. After invasive Video-EEG-monitoring tailored resections were planned individually and were aided by an MRI-guided navigation system where labeled electrode localizations were available for reference. Clinical characteristics, details of electrode implantation, resection volume and postsurgical outcome were determined. Chi-square/ Fisher’s exact test for categorical variables and Student’s t -test/ Mann-Whitney U test for continuous variables were used for statistical analysis to identify prognostic factors for postsurgical outcome. Results 70 patients were included (median age: 34.9 years). Structural MRI was non-lesional in 29 patients (41%) and showed a structural lesion in 41 (59%). 26 patients (37%) had temporal lobe seizure onset, 44 (63%) were extratemporal. Between 3 and 16 (median 9) depth electrodes were implanted. After a median follow up of 13.1 months 79% of the patients were free of all seizures (Engel IA). Another 17% were free or almost free of disabling seizures (Engel IB, IC and II). There was no significant difference between lesional (81% Engel IA) and non-lesional (77% Engel IA) patients ( p = 0.73), between temporal or extratemporal ( p = 0.81) and left- or right-sided ( p = 0.69) resection, nor between first resection and re-operation ( p = 0.78) or an effect of proximity to eloquent cortex ( p = 0.59). There was no difference in the average resection volume between lesional (28 cm 3 ) and non-lesional (26 cm 3 ) patients ( p = 0.64). Conclusion Resective epilepsy surgery after invasive EEG with depth electrodes can achieve as good an outcome in non-lesional as in lesional focal epilepsy with temporal and extra-temporal seizure onset. The patient specific approach with individually planned implantation schemes allowed identification of the seizure onset in all patients. Re-operation after prior failed surgery and resections close to eloquent cortex also have good chances for successful seizure free outcome.

A multimodal concept for invasive diagnostics and surgery based on neuronavigated voxel-based morphometric MRI postprocessing data in previously nonlesional epilepsy.

OBJECTIVE Diagnosis and surgical treatment of refractory and apparent nonlesional focal epilepsy is challenging. Morphometric MRI voxel-based and other postprocessing methods can help to localize the epileptogenic zone and thereby support the planning of further invasive electroencephalography (EEG) diagnostics, and maybe resective epilepsy surgery. METHODS The authors developed an algorithm to implement regions of interest (ROI), based on postprocessed MRI data, into a neuronavigation tool. This was followed by stereotactic ROI-guided implantation of depth electrodes and ROI-navigated resective surgery. Data on diagnostic yield, histology, and seizure outcome were collected and evaluated. RESULTS Fourteen consecutive patients with apparently nonlesional epilepsy were included in this study. Reevaluation of the MR images with the help of MRI postprocessing analysis led to the identification of probable subtle lesions in 11 patients. Additional information obtained by SPECT imaging and MRI reevaluation suggested possible lesions in the remaining 3 patients. The ROI-guided invasive implantation of EEG yielded interictal and ictal activity in 13 patients who were consequently referred to resective surgery. Despite the apparently negative MRI findings, focal cortical dysplasia was found in 64% of the patients (n = 9). At the last available outcome, 8 patients (57%) were completely seizure free (International League Against Epilepsy Class 1). CONCLUSIONS The results demonstrate the feasibility and usefulness of a robust and straightforward algorithm for implementation of MRI postprocessing-based targets into the neuronavigation system. This approach allowed the stereotactic implantation of a low number of depth electrodes only, which confirmed the seizure-onset hypothesis in 90% of the cases without causing any complications. Furthermore, the neuronavigated ROI-guided lesionectomy helped to perform resective surgery in this rather challenging subgroup of patients with apparent nonlesional epilepsy.

A method for u-fiber quantification from 7 T diffusion-weighted MRI data tested in patients with nonlesional focal epilepsy.

In this methods development, we present an ultra-high-field, diffusion-weighted MRI method to quantitatively assess u-fibers and use it to compare u-fiber counts in nonlesional epilepsy patients with controls. Emerging evidence implicates white matter abnormalities in nonlesional epilepsy, including the short-range, cortical-cortical connections, or u-fibers. Eight patients with nonlesional epilepsy and eight demographically matched controls underwent 7 T MRI consisting of a T1-weighted sequence (0.7 mm isotropic resolution) and high-angular-resolved diffusion-weighted MRI (1.05 mm isotropic resolution, 68 directions). MRI data were used to quantify u-fiber counts in known u-fiber populations on the basis of an atlas and fiber tractography. From tractography, connectivity matrices summarizing the u-fiber counts were computed. Quantitative group comparisons were performed on the connectivity matrices. U-fiber counts were found to be lower on average in patients with epilepsy than in healthy controls. The results indicate that the density or the number of u-fibers is reduced in patients with nonlesional epilepsy. Future work will focus on histological validation and determining whether differences in u-fiber counts can be used clinically to noninvasively identify seizure-onset zones.