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Objective: This study was undertaken to develop a standardized grading system based on expert consensus for evaluating the level of confidence in the localization of the epileptogenic zone (EZ) as reported in published studies, to harmonize and facilitate systematic reviews in the field of epilepsy surgery. Methods: We conducted a Delphi study involving 22 experts from 18 countries, who were asked to rate their level of confidence in the localization of the EZ for various theoretical clinical scenarios, using different scales. Information provided in these scenarios included one or several of the following data: magnetic resonance imaging (MRI) findings, invasive electroencephalography summary, and postoperative seizure outcome. Results: The first explorative phase showed an overall interrater agreement of.347, pointing to large heterogeneity among experts' assessments, with only 17% of the 42 proposed scenarios associated with a substantial level of agreement. A majority showed preferences for the simpler scale and single‐item scenarios. The successive Delphi voting phases resulted in a majority consensus across experts, with more than two thirds of respondents agreeing on the rating of each of the tested single‐item scenarios. High or very high levels of confidence were ascribed to patients with either an Engel class I or class IA postoperative seizure outcome, a well‐delineated EZ according to all available invasive EEG (iEEG) data, or a well‐delineated focal epileptogenic lesion on MRI. MRI signs of hippocampal sclerosis or atrophy were associated with a moderate level of confidence, whereas a low level was ascribed to other MRI findings, a poorly delineated EZ according to iEEG data, or an Engel class II–IV postoperative seizure outcome. Significance: The proposed grading system, based on an expert consensus, provides a simple framework to rate the level of confidence in the EZ reported in published studies in a structured and harmonized way, offering an opportunity to facilitate and increase the quality of systematic reviews and guidelines in the field of epilepsy surgery. [ABSTRACT FROM AUTHOR]

Objective: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE. Methods: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations ("temporal lobe epilepsy [TLE] surgery") or multilobar interventions including the temporal lobe ("TPE surgery"), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow‐up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson χ2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t‐test for each continuous variable of interest, when appropriate. Results: Twenty‐one patients underwent TPE surgery and 17 underwent TLE surgery with a follow‐up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB–IV outcome, with a steadily worsening trend from 5‐year follow‐up onward. TPE surgery was associated with better results than TLE surgery. Significance: This study suggests that surgical outcome in patients with TPE can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a TPE is suspected. [ABSTRACT FROM AUTHOR]

Objective: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers. Methods: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed‐effect models corrected for multiple comparisons. Results: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow‐up (FU) was significantly higher in children (P =.006 and <.0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short‐ vs long‐term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P =.023, Q = 0.046 vs normal, at 2‐year FU and abnormal, improved, OR = 0.301, P =.001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P =.001, Q = 0.003, at 2‐year FU and OR = 45.03, P <.0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group. Significance: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long‐term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome. [ABSTRACT FROM AUTHOR]

Objective: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. Methods: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. Results: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P <.0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend =.0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend =.0047) and a significant decrease in unilobar temporal surgeries (P for trend =.0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo‐electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. Significance: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures. [ABSTRACT FROM AUTHOR]

Objective To analyze the attitude and results of Italian epilepsy surgery centers in the surgical management of 'low grade epilepsy associated neuroepithelial tumors' ( LEATs). Methods We conducted a retrospective study enrolling 339 consecutive patients with LEATs who underwent surgery between January 2009 and June 2015 at eight Italian epilepsy surgery centers. We compared demographic, clinical, pathologic, and surgical features of patients with favorable (Engel class I) and unfavorable (Engel class II, III, and IV) seizure outcome. In addition, we compared patients with tumor-associated focal cortical dysplasia (FCD) and patients with solitary tumors to identify factors correlated with FCD diagnosis. Results Fifty-five (98.2%) of 56 patients with medically controlled epilepsy were seizure-free after surgery, compared to 249 (88.0%) of 283 patients with refractory epilepsy. At multivariate analysis, three variables independently predict unfavorable seizure outcome in the drug-resistant group. Age at surgery is largely the most significant (p = 0.001), with an odds ratio (OR) of 1.04. This means that the probability of seizure recurrence grows by 4% for every waited year. The resection site is also significant (p = 0.039), with a relative risk (RR) of 1.99 for extratemporal tumors. Finally, the completeness of tumor resection has a trend toward significance (p = 0.092), with an RR of 1.82 for incomplete resection. Among pediatric patients, a longer duration of epilepsy was significantly associated with preoperative neuropsychological deficits (p < 0.001). A statistically significant association was observed between FCD diagnosis and the following variables: tailored surgery (p < 0.001), temporal resection (p = 0.001), and surgical center (p = 0.012). Significance Our nationwide LEATs study gives important insights on factors predicting seizure outcome in refractory epilepsy and determining variability in FCD detection. Timely surgery, regardless of pharmacoresistance and oriented to optimize epileptologic, neuropsychological, and oncologic outcomes should be warranted. [ABSTRACT FROM AUTHOR]

Indications for vagus nerve stimulation ( VNS) therapy include focal, multifocal epilepsy, drop attacks (tonic/atonic seizures), Lennox-Gastaut syndrome, tuberous sclerosis complex ( TSC)-related multifocal epilepsy, and unsuccessful resective surgery. Surgical outcome is about 50-60% for seizures control, and may also improve mood, cognition, and memory. On this basis, VNS has also been proposed for the treatment of major depression and Alzheimer's' disease. The vagus nerve stimulator must be implanted with blunt technique on the left side to avoid cardiac side effects through the classic approach for anterior cervical discectomy. The actual device is composed of a wire with three helical contacts (two active contacts, one anchoring) and a one-pin battery. VNS is usually started 2 weeks after implantation with recommended settings of stimulation (1.0-2.0 mA; 500 μs pulse width; 20-30 Hz; 30 s ON, 5 min OFF). The complications of VNS therapy are early (related to surgery) and late (related to the device and to stimulation of the vagus nerve). Early complications include the following: intraoperative bradycardia and asystole during lead impedance testing, peritracheal hematoma, infections (3-8%), and vagus nerve injury followed by hoarseness, dyspnea, and dysphagia because of left vocal cord paralysis. Delayed morbidity due to the device includes late infections or problems in wound healing; other more rare events are due to late injury of the nerve. Late complications due to nerve stimulation include delayed arrhythmias, laryngopharyngeal dysfunction (hoarseness, dyspnea, and coughing), obstructive sleep apnea, stimulation of phrenic nerve, tonsillar pain mimicking glossopharyngeal neuralgia, and vocal cord damage during prolonged endotracheal intubation. The laryngopharyngeal dysfunction occurs in about 66% of patients and is usually transitory and due to the stimulation of the inferior (recurrent) laryngeal nerve. A true late paralysis of the left vocal cord is often partial and rare (1-2.7%), and usually transitory, and may be caused by previous surgical trauma (i.e., damage of nerve fibers and/or of their blood supply) or to a supposed chronic denervation during stimulation. Surgery for complete removal or revision and replacement of the device is to be considered in cases of device malfunction (4-16.8%), failure of VNS therapy, intolerable side effects, or because of patient's specific request. As described in the literature, the surgical techniques of lead revision and replacement are two: sharp and blunt dissection of helical electrodes and replacement; and blunt dissection combined with ultrasharp low-voltage cautery dissection. The incidence of left vocal cord palsy after vagus nerve stimulator replacement/revision is slightly higher than that of first implantation (4.9% vs. 3.8%). A de novo implantation in a naive segment of the left or right vagus nerve may be considered in specific cases; the use of the right vagus nerve is a rare exception that may be chosen with an acceptable result. [ABSTRACT FROM AUTHOR]

Objective To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance. Methods In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography ( EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses. Results Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging ( MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy. Significance In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone. [ABSTRACT FROM AUTHOR]

Objective To assess the diagnostic yield of 7T magnetic resonance imaging ( MRI) in detecting and characterizing structural lesions in patients with intractable focal epilepsy and unrevealing conventional (1.5 or 3T) MRI. Methods We conducted an observational clinical imaging study on 21 patients (17 adults and 4 children) with intractable focal epilepsy, exhibiting clinical and electroencephalographic features consistent with a single seizure-onset zone ( SOZ) and unrevealing conventional MRI. Patients were enrolled at two tertiary epilepsy surgery centers and imaged at 7T, including whole brain (three-dimensional [3D] T1-weighted [T1W] fast-spoiled gradient echo (FSPGR), 3D susceptibility-weighted angiography [ SWAN], 3D fluid-attenuated inversion recovery [ FLAIR]) and targeted imaging (2D T2*-weighted dual-echo gradient-recalled echo [ GRE] and 2D gray-white matter tissue border enhancement [ TBE] fast spin echo inversion recovery [FSE-IR]). MRI studies at 1.5 or 3T deemed unrevealing at the referral center were reviewed by three experts in epilepsy imaging. Reviewers were provided information regarding the suspected localization of the SOZ. The same team subsequently reviewed 7T images. Agreement in imaging interpretation was reached through consensus-based discussions based on visual identification of structural abnormalities and their likely correlation with clinical and electrographic data. Results 7T MRI revealed structural lesions in 6 (29%) of 21 patients. The diagnostic gain in detection was obtained using GRE and FLAIR images. Four of the six patients with abnormal 7T underwent epilepsy surgery. Histopathology revealed focal cortical dysplasia ( FCD) in all. In the remaining 15 patients (71%), 7T MRI remained unrevealing; 4 of the patients underwent epilepsy surgery and histopathologic evaluation revealed gliosis. Significance 7T MRI improves detection of epileptogenic FCD that is not visible at conventional field strengths. A dedicated protocol including whole brain FLAIR and GRE images at 7T targeted at the suspected SOZ increases the diagnostic yield. [ABSTRACT FROM AUTHOR]

Objective Mutations involving the cyclin-dependent kinase-like 5 ( CDKL5) gene cause an early onset epileptic encephalopathy ( EE) with severe neurologic impairment and a skewed 12:1 female-to-male ratio. To date, 18 mutations have been described in boys. We analyzed our cohort of boys with early onset EE to assess the diagnostic yield of our molecular approach. Methods We studied 74 boys who presented early onset severe seizures, including infantile spasms and developmental delay, in the setting of EE, using Sanger sequencing, next-generation sequencing ( NGS) and multiplex ligation-dependent probe amplification ( MLPA). Results We identified alterations involving CDKL5 in four boys (5.4%) using NGS in one and MLPA in three. Three of four mutations were indicative of somatic mosaicism. Significance CDKL5 gene mutations accounted for 5.4% of boys with early onset EE. Somatic mosaic mutations might be even more represented than germline mutations, probably because their less deleterious effect enhances viability of the male embryo. The molecular approach used for CDKL5 screening remarkably influences the diagnostic yield in boys. Diagnosis is optimized by Sanger sequencing combined with array-based methods or MLPA; alternatively, NGS targeted resequencing designed to also detect copy number alterations, may be performed. [ABSTRACT FROM AUTHOR]

Objective To report on six patients with SCN1A mutations and malformations of cortical development ( MCDs) and describe their clinical course, genetic findings, and electrographic, imaging, and neuropathologic features. Methods Through our database of epileptic encephalopathies, we identified 120 patients with SCN1A mutations, of which 4 had magnetic resonance imaging ( MRI) evidence of MCDs. We collected two further similar observations through the European Task-force for Epilepsy Surgery in Children. Results The study group consisted of five males and one female (mean age 7.4 ± 5.3 years). All patients exhibited electroclinical features consistent with the Dravet syndrome spectrum, cognitive impairment, and autistic features. Sequencing analysis of the SCN1A gene detected two missense, two truncating, and two splice-site mutations. Brain MRI revealed bilateral periventricular nodular heterotopia ( PNH) in two patients and focal cortical dysplasia ( FCD) in three, and disclosed no macroscopic abnormality in one. In the MRI-negative patient, neuropathologic study of the whole brain performed after sudden unexpected death in epilepsy ( SUDEP), revealed multifocal micronodular dysplasia in the left temporal lobe. Two patients with FCD underwent epilepsy surgery. Neuropathology revealed FCD type IA and type IIA. Their seizure outcome was unfavorable. All four patients with FCD exhibited multiple seizure types, which always included complex partial seizures, the area of onset of which co-localized with the region of structural abnormality. Significance MCDs and SCN1A gene mutations can co-occur. Although epidemiology does not support a causative role for SCN1A mutations, loss or impaired protein function combined with the effect of susceptibility factors and genetic modifiers of the phenotypic expression of SCN1A mutations might play a role. MCDs, particularly FCD, can influence the electroclinical phenotype in patients with SCN1A-related epilepsy. In patients with MCDs and a history of polymorphic seizures precipitated by fever, SCN1A gene testing should be performed before discussing any epilepsy surgery option, due to the possible implications for outcome. [ABSTRACT FROM AUTHOR]

Epilepsy surgery represents the main treatment option for epileptogenic brain tumors. Scalp video-electroencephalography ( EEG) and magnetic resonance imaging ( MRI) may suffice for defining lesional area and seizure-onset zone in discrete, surgically resectable lesions. The choice of timing for surgery requires a multidisciplinary evaluation, especially in children, when a 'wait and see' approach is chosen. Discordant electroclinical and neuroimaging data and an ill-defined epileptogenic lesion require invasive investigations. A multimodal integrated approach may maximize the extent of resection while preserving cerebral function in the eloquent cortex. Radical removal of the tumor is the most important predictor of seizure freedom. Additional predictors include histopathology, age at surgery, duration of epilepsy, and seizure type. Patients with brain tumors are highly vulnerable in relation to the frequent drug-resistance of seizures, the potential interactions between antiepileptic drugs ( AEDs) and chemotherapeutic agents ( CMTs), and the risk of AED-related cognitive adverse events (24% higher than in the rest of the epilepsy population), in addition to brain damage resulting from tumor itself, surgery, and radiotherapy. No robust, randomized, controlled evidence supports the choice of AEDs for the treatment of seizures in patients with brain tumors. Newer AEDs have limited or no enzyme-inducing profile, prevalent renal excretion, lower plasma protein binding and, consequently, fewer interactions with CMTs. Enzyme-inducing AEDs can lower serum levels of concomitantly administered CMTs. Class I evidence suggests that in patients with brain tumors who do not have a history of seizures, prophylactic use of AEDs is neutral or ineffective. [ABSTRACT FROM AUTHOR]

Surgery for seizures arising from the rolandic area can be performed effectively, and accurate mapping of eloquent regions may improve seizure and functional outcome. Noninvasive cortical mapping is, however, hardly feasible in young children. We studied two children with epileptogenic focal cortical dysplasia (FCD) type IIb in the rolandic area, in whom preoperative passive task functional MRI (fMRI) during sedation helped planning a tailored surgical approach. In one patient the dysplastic cortex was functionally activated. After complete lesionectomy both children exhibited motor impairment that readily improved. Repeat fMRI, performed after complete (Patient 1) or partial (Patient 2) recovery, demonstrated relocation of motor-related activations posterior to the area of resection. fMRI during sedation can be used to demonstrate postsurgical functional reorganization of the motor cortex in young children. There is interindividual variability in functional activation of FCD type IIb. [ABSTRACT FROM AUTHOR]

Summary Purpose:: To investigate whether children with epilepsy primarily affecting the occipital cortex exhibit impairment of visual object identification and to what extent such a hypothesized dysfunction is related to an interfering functional, rather than structural, process. Method:: We studied nine children with idiopathic childhood occipital epilepsy (ICOE) and compared them to eight children with lesional posterior cortex epilepsy (PCEs) and to 60 age-matched controls. We applied an 'ascendent' paradigm of object identification, using a coarse-to-fine order procedure, which gradually integrated spatial frequency information from the most blurred image to the complete figure. In children with ICOE, we explored how epilepsy-related variables might be related to object identification task. Key Findings:: Children with ICOE and those with PCEs needed more physical information than controls to identify visual stimuli. There was a decreasing accuracy from controls to children with ICOE and from children with ICOE to those with PCEs. Children with ICOE demonstrated slight selective impairment in visuospatial processing and those among them having experienced a higher number of seizures or in whom interictal electroencephalography (EEG) discharges had been present for a longer time, required a higher level of physical information to recognize objects. Significance:: The observation that children with ICOE performed worse than controls in object identification, although better than children with PCEs, might indicate that functional disruption caused by epileptiform EEG abnormalities and seizures, can interfere per se with perceptual processes, even in the absence of a lesion. This effect appears to be detected only by perceptual and cognitive screening. [ABSTRACT FROM AUTHOR]

Purpose: To correlate ictal hyperperfusion single-photon emission computed tomography (SPECT) area during provoked seizures to the epileptogenic zone (EZ), as defined by depth recordings in adult drug-resistant patients. Methods: We included in the study eight drug-resistant epilepsy patients, subjected to both noninvasive and invasive (stereo-electroencephalography, SEEG) presurgical evaluation in the Epilepsy Surgery Center of the Catholic University in Rome, from 2001 to 2003. All patients were subjected to interictal and provoked ictal SPECT scans during scalp video-EEG monitoring. The ictal hyperperfusion area assessed by visual image analysis and , when possible , by statistical parametric mapping (SPM), was compared with the EZ, as assessed by SEEG, to define whether they colocalized. Results: For each provoked seizure, we obtained a SPECT hyperperfusion area. In five patients, the SPECT hyperperfusion area was included in the EZ as assessed by SEEG. The effectiveness of provoked SPECT was confirmed by comparison with SEEG data, SPM analysis (four patients), and spontaneous ictal SPECT (two patients). Our data were obtained in adult drug-resistant epilepsy patients whose EZ was either located in or extended to extratemporal regions in all but two patients. Conclusions: Provoked ictal SPECT confirmed its efficacy and accuracy in the presurgical evaluation because of the colocalization to the EZ. Although the low number of patients precluded any statistical correlation with the surgical outcome, it is worth pointing out that the five patients in whom the hyperperfusion area was included in the EZ showed very satisfactory results. [ABSTRACT FROM AUTHOR]