Source reconstruction based on subdural EEG recordings adds to the presurgical evaluation in refractory frontal lobe epilepsy

ObjectiveIn presurgical investigations of refractory frontal lobe epilepsy, subdural EEG recordings offer extensive cortical coverage, but may overlook deep sources. Electrical Source Localization (ESL) from subdural recordings could overcome this sampling limitation. This study aims to assess the clinical relevance of this new method in refractory frontal lobe epilepsy associated with focal cortical dysplasia.MethodsIn 14 consecutive patients, we retrospectively compared: (i) the ESL of interictal spikes to the conventional irritative and seizure onset zones; (ii) the surgical outcome of cases with congruent ESL and resection volume to cases with incongruent ESL and resection volume. Each spike type was averaged to serve as a template for ESL by the MUSIC and sLORETA algorithms. Results were superimposed on the corresponding pre and post-surgical MRI.ResultsBoth ESL methods were congruent and consistent with conventional electroclinical analysis in all patients. In 7 cases, ESL identified a common deep source for spikes of different 2D localizations. The inclusion of ESL in the resection volume correlated with seizure freedom.ConclusionsESL from subdural recordings provided clinically relevant results in patients with refractory frontal lobe epilepsy.SignificanceESL complements the conventional analysis of subdural recordings. Its potential in improving tailored resections and surgical outcomes should be prospectively assessed.     

Clinical utility of current-generation dipole modelling of scalp EEG.

OBJECTIVE: To investigate the clinical utility of current-generation dipole modelling of scalp EEG in focal epilepsies seen commonly in clinical practice. METHODS: Scalp EEG recordings from 10 patients with focal epilepsy, five with Benign Focal Epilepsy of Childhood (BFEC) and five with Mesial Temporal Lobe Epilepsy (MTLE), were used for interictal spike dipole modelling using Scan 4.3 and CURRY 5.0. Optimum modelling parameters for EEG source localisation (ESL) were sought by the step-wise application of various volume conductor (forward) and dipole (inverse) models. Best-fit ESL solutions (highest explained forward-fit to measured data variance) were used to characterise best-fit forward and inverse models, regularisation effect, additional electrode effect, single-to-single spike and single-to-averaged spike variability, and intra- and inter-operator concordance. Inter-parameter relationships were examined. Computation times and interface problems were recorded. RESULTS: For both BFEC and MTLE, the best-fit forward model was the finite element method interpolated (FEMi) model, while the best-fit single dipole models were the rotating non-regularised and the moving regularised models. When combined, these forward-inverse models appeared to offer clinically meaningful ESL results when referenced to an averaged cortex overlay, best-fit dipoles localising to the central fissure region in BFEC and to the basolateral temporal region in MTLE. Single-to-single spike and single-to-averaged spike measures of concordance for dipole location and orientation were stronger for BFEC versus MTLE. The use of an additional pair of inferior temporal electrodes in MTLE directed best-fit dipoles towards the basomesial temporal region. Inverse correlations were noted between unexplained variance (RD) and dipole strength (Amp), RD and signal to noise ratio (SNR), and SNR and confidence ellipsoid (CE) volume. Intra- and inter-operator levels of agreement were relatively robust for dipole location and orientation. Technical problems were infrequent and modelling operations were performed within 5min. CONCLUSIONS: The optimal forward-inverse single dipole modelling set-up for BFEC and MTLE interictal spike analysis is the FEMi model using the combination of rotating non-regularised and moving regularised dipoles. Dipole modelling of single spikes characterises best-fit dipole location and orientation more reliably in BFEC than in MTLE for which spike averaging is recommended. SIGNIFICANCE: The clinical utility of dipole modelling in two common forms of focal epilepsy strengthens the case for its place in the routine clinical work-up of patients with localisation-related epilepsy syndromes.     

Potential efficacy and safety of eslicarbazepine acetate oral loading in patients with epilepsy

Eslicarbazepine acetate (ESL) is a new antiseizure medication (ASM) approved as an adjunctive therapy or monotherapy for focal onset seizures. We performed this study to explore the potential efficacy and safety of ESL oral loading in selected patients with epilepsy. Thirty adult patients with status epilepticus or acute repetitive seizures were enrolled, and ESL was administered at a single loading dosage of 30 mg/kg. Plasma levels of an active metabolite of ESL, monohydroxy derivative (MHD), were measured at 2, 4, 6, 12, and 24 h after ESL oral loading. Two thirds of the patients reached a therapeutic level of MHD 2 h after ESL loading, and most of the patients achieved a therapeutic range within 12 h after loading. Plasma MHD levels did not rise above the supratherapeutic level in any patient throughout the study. The reported adverse effects included one patient with gaze-evoked nystagmus and another patient with a rash. No serious adverse events leading to drug discontinuation occurred. There was no discernible difference in sodium levels before and after ESL oral loading. Our study findings suggest that ESL oral loading could be a useful therapeutic option for patients with epilepsy who need rapid elevations in the therapeutic levels of ASMs.     

Automated interictal spike detection and source localization in magnetoencephalography using independent components analysis and spatio-temporal clustering.

OBJECTIVE: Magnetoencephalography (MEG) dipole localization of epileptic spikes is useful in epilepsy surgery for mapping the extent of abnormal cortex and to focus intracranial electrodes. Visually analyzing large amounts of data produces fatigue and error. Most automated techniques are based on matching of interictal spike templates or predictive filtering of the data and do not explicitly include source localization as part of the analysis. This leads to poor sensitivity versus specificity characteristics. We describe a fully automated method that combines time-series analysis with source localization to detect clusters of focal neuronal current generators within the brain that produce interictal spike activity. METHODS: We first use an ICA (independent components analysis) method to decompose the multichannel MEG data and identify those components that exhibit spike-like characteristics. From these detected spikes we then find those whose spatial topographies across the array are consistent with focal neural sources, and determine the foci of equivalent current dipoles and their associated time courses. We then perform a clustering of the localized dipoles based on distance metrics that takes into consideration both their locations and time courses. The final step of refinement consists of retaining only those clusters that are statistically significant. The average locations and time series from significant clusters comprise the final output of our method. RESULTS AND SIGNIFICANCE: Data were processed from 4 patients with partial focal epilepsy. In all three subjects for whom surgical resection was performed, clusters were found in the vicinity of the resectioned area. CONCLUSIONS: The presented procedure is promising and likely to be useful to the physician as a more sensitive, automated and objective method to help in the localization of the interictal spike zone of intractable partial seizures. The final output can be visually verified by neurologists in terms of both the location and distribution of the dipole clusters and their associated time series. Due to the clinical relevance and demonstrated promise of this method, further investigation of this approach is warranted.     

Clinical utility of distributed source modelling of interictal scalp EEG in focal epilepsy

Objective

Assess the clinical utility of non-invasive distributed EEG source modelling in focal epilepsy.

Methods

Interictal epileptiform discharges were recorded from eight patients – benign focal epilepsy of childhood (BFEC), four; mesial temporal lobe epilepsy (MTLE), four. EEG source localization (ESL) applied 48 forward–inverse–subspace set-ups: forward – standardized, leadfield-interpolated boundary element methods (BEMs, BEMi), finite element method (FEMi); inverse – minimum norm (MNLS), L1 norm (L1), low resolution electromagnetic tomography (LORETA), standardized LORETA (sLORETA); subspace– whole volume (3D), cortex with rotating sources (CxR), cortex with fixed sources (CxN), cortex with fixed extended sources (patch). Current density reconstruction (CDR) maxima defined ‘best-fit’.

Results

From 19,200 CDR parameter results and 2304 CDR maps, the dominant variables on best-fit were inverse model and subspace constraint. The most clinically meaningful and statistically robust results came with sLORETA–CxR/patch (lower Rolandic in BFEC, basal temporal lobe in MTLE). Computation time was inverse model dependent: sub-second (MNLS, sLORETA), seconds (L1), minutes (LORETA).

Conclusions

From the largest number of distributed ESL approaches compared in a clinical setting, an optimum modelling set-up for BFEC and MTLE incorporated sLORETA (inverse), CxR or patch (subspace), and either BEM or FEMi (forward). Computation is efficient and CDR results are reproducible.

Significance

Distributed source modelling demonstrates clinical utility for the routine work-up of unilateral BFEC of the typical Rolandic variety, and unilateral MTLE secondary to hippocampal sclerosis.     

Neuroimaging of epilepsy

Neuroimaging has an important role in the investigation and treatment of patients with epilepsy. Diagnosis of the underlying substrate in a given patient with epilepsy determines prognosis with higher accuracy than electroencephalography. Neuroimaging techniques include computed tomography (CT) and magnetic resonance imaging (MRI), although CT has a diminished role for diagnosis. MRI is the most appropriate imaging technique in the initial investigation of patients with epilepsy. MRI is the most sensitive technique for the diagnosis of hippocampal sclerosis, tumors, and malformations of cortical development. MRI is also critical for neurosurgical planning. Other imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography are reserved for patients with intractable epilepsy when surgery is contemplated. New developments such as MR spectroscopy, receptor PET, and magnetic source imaging are becoming clinical tools and have the promise of improving diagnosis.     

Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta‐analysis

Second and third generation AEDs have been directly compared to controlled‐release carbamazepine (CBZ‐CR) as initial monotherapy for new‐onset focal epilepsy. Conversely, no head‐to‐head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta‐analysis (NMA). Randomized, double‐blinded, parallel group, monotherapy studies comparing any AED to CBZ‐CR in adults with newly diagnosed untreated epilepsy with focal‐onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment‐emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ‐CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR‐CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6‐ and 12‐month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ‐CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ‐CR (OR 0.659, 95% CrI 0.428‐0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ‐CR     

Advances in MRI for 'cryptogenic' epilepsies

Nearly one-third of patients with focal epilepsy experience disabling seizures that are refractory to pharmacotherapy. Drug-resistant focal epilepsy is, however, potentially curable by surgery. Although lesions associated with the epileptic focus can often be accurately detected by MRI, in many patients conventional imaging based on visual evaluation is unable to pinpoint the surgical target. Patients with so-called cryptogenic epilepsy represent one of the greatest clinical challenges in many tertiary epilepsy centers. In recent years, it has become increasingly clear that epilepsies that are considered cryptogenic are not necessarily nonlesional, the primary histopathological substrate being subtle cortical dysplasia. This Review considers the application of new advances in brain imaging, such as MRI morphometry, computational modeling and diffusion tensor imaging. By revealing dysplastic lesions that previously eluded visual assessments, quantitative structural MRI methods such as these have clearly demonstrated an increased diagnostic yield of epileptic lesions, and have provided successful surgical options to an increasing number of patients with 'cryptogenic' epilepsy.     

Surgery for epilepsy: a review

This year marks the centennial of the first surgical resection for epilepsy performed by Horsley. While epilepsy is generally considered a disease best treated with anticonvulsant medications, surgical therapy is of significant benefit to some patients in whom medical therapy has proved ineffective. Anterior temporal lobectomy has been the single most successful operation commonly performed today. In this paper we review current techniques of preoperative evaluation, the role of scalp and intracranial electrophysiologic monitoring, as well as the contribution of PET and MRI scanning to improving the selection of patients for surgical therapy. The role of focal cortical excisions, hemispherectomy, and corpus callosotomy in the surgical armamentarium is also outlined. A plea is made for establishment of additional regionalized centers for epilepsy surgery in which close collaboration among neurologists, neuropsychologists, neurosurgeons and neurophysiologists can enhance patient care and advance our knowledge of the partial epilepsies and human cerebral function.