Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials.

INTRODUCTION: Despite the existence of over 30 anti-seizure medications (ASM), including 20 over the last 30 years, a third of patients with epilepsy remain refractory to treatment, with no disease-modifying or preventive therapies until very recently. The development of new ASMs with new mechanisms of action is therefore critical. Recent clinical trials of new treatments have shifted focus from traditional common epilepsies to rare, genetic epilepsies with known mechanistic targets for treatment and disease-specific animal models. AREAS COVERED: ASMs in phase 2a/b-3 clinical trials target cholesterol, serotonin, sigma-1 receptors, potassium channels and metabotropic glutamate receptors. Neuroinflammation, protein misfolding, abnormal thalamocortical firing, and molecular deficiencies are among the targeted pathways. Clinically, the current phase 2a/b-3 agents hold promise for variety of epilepsy conditions, from developmental epileptic encephalopathies (Dravet Syndrome, Lennox-Gastaut syndrome, CDKL5 and PCDH19, Rett's Syndrome), infantile spasms, tuberous sclerosis as well as focal and idiopathic generalized epilepsies and acute rescue therapy for cluster seizures. EXPERT OPINION: New delivery mechanisms increase potency and site-specificity of existing drugs. Novel mechanisms of action involve cholesterol degradation, mitochondrial pathways, anti-inflammation, and neuro-regeneration. Earlier identification of genetic conditions through genetic testing will allow for earlier use of disease specific and disease-modifying therapies.

Memory outcomes of temporal lobe surgery in adults aged over 45 years.

OBJECTIVE: It is assumed that temporal lobe resection in older people is associated with worse seizure outcomes and potential postsurgical memory decline. We studied postsurgical memory development and surgical efficacy in patients over 45 years of age compared with younger patients. METHODS: We studied 88 patients (51 male and 37 female) after temporal lobe surgery, which involved hippocampal resection. The patients were evaluated before surgery and in the first (72 patients) and/or third (57 patients) postsurgical year. The Wechsler Memory Scale III test was performed to evaluate the MQ postsurgical development. Engel's classification was used to evaluate the postsurgical seizure outcome. RESULTS: The presurgical MQ (median 88) in ≥45 years age group was significantly lower than in both younger groups (median MQ = 100 for ≤30 years age group, p = 0.002; median MQ = 107 for 31-44 years age group, p = 0.002). Three years after the surgery, the MQ decreased significantly in ≤30 years age group (p = 0.012), while only non-significant MQ decline was observed in both older groups. We found no significant impact of age on the surgical outcome. CONCLUSION: Higher age at the time of surgery does not significantly increase the risk for postsurgical memory decline; however, older patients are more likely to have lowered presurgical MQ. We did not find significant differences in the impact of surgery on seizure outcome among the age groups. Epilepsy surgery appears to be a safe and effective method in the age over 45 years even though an earlier surgery should be preferred.

Prevention of epilepsy: Should we be avoiding clinical trials?

Epilepsy prevention is one of the great unmet needs in epilepsy. Approximately 15% of all epilepsy is caused by an acute acquired CNS insult such as traumatic brain injury (TBI), stroke or encephalitis. There is a latent period between the insult and epilepsy onset that presents an opportunity to intervene with preventive treatment that is unique in neurology. Yet no phase 3 epilepsy prevention studies, and only 2 phase 2 studies have been initiated in the last 16years. Current prevailing opinion is that the research community is not ready for clinical preventive epilepsy studies, and that animal models should first be refined and biomarkers of epileptogenesis and of epilepsy discovered before clinical studies are embarked upon. We review data to suggest that there is basis to do epilepsy prevention studies now with the current knowledge and available drugs, and that those studies are feasible with currently available tools. We suggest that a different approach is needed from the past in order to maximize chances of success, minimize the cost, and set up platform for future preventive treatment development. That approach should include close coordination of preclinical and clinical development programs in a combined PTE prevention strategy, consideration of polytherapy, and simultaneous, combined clinical development of preventive treatment and of biomarker discovery. We argue that the currently favored approach of eschewing clinical studies until biomarkers are available will delay the discovery of epilepsy prevention treatment by at least 10 years and significantly increase the cost of such discovery.

Sudden Unexpected Death in Epilepsy During Ambulatory Video-EEG Monitoring at Home.

BACKGROUND AND OBJECTIVES: We report the recording of sudden unexpected death in epilepsy (SUDEP) in a 68-year-old man with recent onset cryptogenic epilepsy, captured by video-EEG monitoring, at home in the company of his wife while sitting in a chair. This was only the third seizure of his life, the first 2 occurring 19 days previously. This rare event is a novel case of SUDEP recorded with ambulatory video EEG at home. The video is included by permission. METHODS: Electroclinical seizure and cardiorespiratory analysis was ascertained using a combination of video, EEG (Natus, standard 10-20 electrode), ECG, and sound. Respiratory rate was ascertained based on chest, abdominal, and facial respiratory movements, together with video and audio. RESULTS: The unique video-EEG recording illustrates the time course of apnea and bradycardia leading to terminal apnea in conjunction with prolonged postictal generalized EEG suppression. DISCUSSION: This case is illustrative of a wide spectrum of SUDEP cases, ranging from the highly intractable to the patient with newly diagnosed epilepsy with very few seizures. It illustrates that patients can succumb to SUDEP while awake and in the sitting position (1) very early in their epilepsy course, (2) without recognized risk factors other than generalized convulsive seizures, (3) even when accompanied.

Epilepsy, behavior, and art (Epilepsy, Brain, and Mind, part 1).

Epilepsy is both a disease of the brain and the mind. Brain diseases, structural and/or functional, underlie the appearance of epilepsy, but the notion of epilepsy is larger and cannot be reduced exclusively to the brain. We can therefore look at epilepsy from two angles. The first perspective is intrinsic: the etiology and pathophysiology, problems of therapy, impact on the brain networks, and the "mind" aspects of brain functions - cognitive, emotional, and affective. The second perspective is extrinsic: the social interactions of the person with epilepsy, the influence of the surrounding environment, and the influences of epilepsy on society. All these aspects reaching far beyond the pure biological nature of epilepsy have been the topics of two International Congresses of Epilepsy, Brain, and Mind that were held in Prague, Czech Republic, in 2010 and 2012 (the third Congress will be held in Brno, Czech Republic on April 3-5, 2014; www.epilepsy-brain-mind2014.eu). Here, we present the first of two papers with extended summaries of selected presentations of the 2012 Congress that focused on epilepsy, behavior, and art.

Syncope with atypical trunk convulsions in a patient with malignant arrhythmia.

Syncope is a condition often misdiagnosed as epilepsy. Syncope caused by cardiac disturbance is a life-threatening condition and accurate diagnosis is crucial for patient outcome. We present a case study of a 71-year-old woman who was referred to our epilepsy centre with a diagnosis of refractory epilepsy. We diagnosed convulsive syncope caused by malignant cardiac arrhythmia based on the presence of cardiac asystole lasting for 20-30 seconds, which was caused by sick sinus syndrome combined with third-degree atrioventricular block. The most prominent feature of this syncope was atypical trunk (abdominal or thoracoabdominal) convulsions, which were accompanied by other motor signs (head and eye deviation and brief jerks of the extremities). In the periods between attacks, all investigations, including standard 12-lead ECG and 24-hour ECG monitoring, were normal. This case study highlights the challenge in differential diagnosis of sudden loss of consciousness. [Published with video sequences].

The role of voxel-based morphometry in the detection of cortical dysplasia within the temporal pole in patients with intractable mesial temporal lobe epilepsy.

PURPOSE: To determine whether voxel-based morphometry (VBM) might contribute to the detection of cortical dysplasia within the temporal pole in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS). METHODS: Eighteen patients with intractable MTLE/HS and 30 sex- and age-matched healthy controls were included in the study. All of the patients fulfilled the diagnostic criteria for MTLE/HS and underwent anteromedial temporal resection. VBM without a modulation step was applied to the magnetic resonance (MR) images of the brain. Statistical parametric maps were used to compare structural characteristics such as gray matter concentration (GMC) within the temporal pole among patients and controls separately. The acquired data were then statistically analyzed to determine the congruency between visually inspected MR imaging (MRI) scans and VBM results in the detection of morphologic abnormalities in the temporal pole compared to postoperative histopathologic findings of cortical dysplasia. KEY FINDINGS: Histopathologic examination revealed cortical dysplasia within the temporal pole in 11 patients. In detail, according to Palmini's classification, mild malformations of cortical development (mMCDs) were disclosed in three patients, focal cortical dysplasia (FCD) type Ia in three patients, and FCD type Ib in five patients. Some type of structural temporal pole abnormality was suggested by VBM in 14 patients and by visually inspected MRI scans in 11 patients. The results of VBM were in agreement with the presence/absence of cortical dysplasia in 13 patients (72.2%); this correspondence was significant (p = 0.047). In one case, VBM was false negative and in four cases it was false positive. There was congruence between the results of visual analysis and histologic proof in 55.6% of examined patients, which was not significant. SIGNIFICANCE: We found that VBM made a superior contribution to the detection of temporopolar structural malformations (cortical dysplasia) compared to visual inspection. The agreement with postoperative histopathologic proof was clearly significant for VBM results and nonsignificant for visual inspection.

"MRI-negative PET-positive" temporal lobe epilepsy: invasive EEG findings, histopathology, and postoperative outcomes.

The aim of this retrospective study was to analyze invasive EEG findings, histopathology, and postoperative outcomes in patients with MRI-negative, PET-positive temporal lobe epilepsy (TLE) (MRI-/PET+TLE) who had undergone epilepsy surgery. We identified 20 patients with MRI-/PET+TLE (8.4% of all patients with TLE who had undergone surgery; 11 men, 9 women). Of the 20 patients, 16 underwent invasive EEG. The temporal pole and hippocampus were involved in the seizure onset zone in 62.5% of the patients. We did not identify a lateral temporal or extratemporal seizure onset in any patient. Of the 20 patients, 17 had follow-up periods >1 year (mean follow-up=3.3 years). At the final follow-up, 70.6% patients were classified as Engel I, 5.8% of patients as Engel II, and 11.8% of patients as Engel III and IV (11.8%). Histopathological evaluation showed no structural pathology in any resected hippocampus in 58% of all evaluated temporal poles. The most common pathology of the temporal pole was focal cortical dysplasia type IA or IB. MRI-/PET+TLE should be delineated from other "nonlesional TLE." The ictal onset in these patients was in each case in the temporal pole or hippocampus, rather than in the lateral temporal neocortex. Standard surgery produced a good postoperative outcome, comparable to that for patients with lesional TLE. Histopathological findings were limited: the most common pathology was focal cortical dysplasia type I.

Lateralized ictal dystonia of upper and lower limbs in patients with temporal lobe epilepsy.

PURPOSE: To perform a retrospective study to determine the incidence and lateralizing value of ictal dystonia in patients with temporal lobe epilepsy. METHODS: The study included 142 patients (76 males, 66 females) with temporal lobe epilepsy, aged from 19 to 58 years with an average age of 33.1 +/- 8.7 years. Overall, 454 seizures were analysed. The seizure onset zone was mesial in 112 patients (78.8%), and "non-mesial" in 30 patients (21.2%). RESULTS: Ictal dystonia was present in 68 of the 142 patients (47.9%), and in 186 of 454 total seizures (40.9%). Upper limb dystonia was present in 94 seizures (50.5%) of 32 patients; hemidystonia in 84 seizures (45.2%) of 30 patients; and lower limb dystonia in eight seizures (4.3%) of six patients. For all cases, all types of ictal dystonia were contralateral to the seizure onset zone. Ictal dystonia was significantly more frequent in patients with a mesial seizure onset zone than in "non-mesial" patients (58.1% vs 7.7%; p < 0.001). Within the mesial group, ictal dystonia was significantly more frequent in patients with hippocampal sclerosis than in those patients with other lesions (66.1% vs 41.1%; p = 0.023). CONCLUSION: Ictal dystonia in temporal lobe epilepsy is a reliable lateralizing ictal sign. During almost half of the seizures studied, ictal dystonia was present in the form of hemidystonia, and isolated involvement of the lower limbs also occurred. Combined data obtained from both noninvasive and invasive EEG showed that ictal dystonia tended to occur more often in mesial onset temporal lobe epilepsy, especially when hippocampal sclerosis was the epileptogenic lesion.

No prevention or cure of epilepsy as yet.

Approximately 20% of all epilepsy is caused by acute acquired injury such as traumatic brain injury, stroke and CNS infection. The known onset of the injury which triggers the epileptogenic process, early presentation to medical care, and a latency between the injury and the development of clinical epilepsy present an opportunity to intervene with treatment to prevent epilepsy. No such treatment exists and yet there has been remarkably little clinical research during the last 20 years to try to develop such treatment. We review possible reasons for this, possible ways to rectify the situations and note some of the ways currently under way to do so. Resective surgical treatment can achieve "cure" in some patients but is sparsely utilized. In certain "self-limiting" syndromes of childhood and adolescence epilepsy remits spontaneously. In a proportion of patients who become seizure free on medications or with dietary treatment, seizure freedom persists when treatment is discontinued. We discuss these situations which can be considered "cures"; and note that at present we have little understanding of mechanism of such cures, and cannot therefore translate them into a treatment paradigm targeting a "cure" of epilepsy. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

Treatment of glioblastoma multiforme with "classic" 4:1 ketogenic diet total meal replacement.

INTRODUCTION: Glioblastoma (GBM) has poor survival with standard treatment. Experimental data suggest potential for metabolic treatment with low carbohydrate ketogenic diet (KD). Few human studies of KD in GBM have been done, limited by difficulty and variability of the diet, compliance, and feasibility issues. We have developed a novel KD approach of total meal replacement (TMR) program using standardized recipes with ready-made meals. This pilot study evaluated feasibility, safety, tolerability, and efficacy of GBM treatment using TMR program with "classic" 4:1 KD. METHOD: GBM patients were treated in an open-label study for 6 months with 4:1 [fat]:[protein + carbohydrate] ratio by weight, 10 g CH/day, 1600 kcal/day TMR. Patients were either newly diagnosed (group 1) and treated adjunctively to radiation and temozolomide or had recurrent GBM (group 2). Patients checked blood glucose and blood and urine ketone levels twice daily and had regular MRIs. Primary outcome measures included retention, treatment-emergent adverse events (TEAEs), and TEAE-related discontinuation. Secondary outcome measures were survival time from treatment initiation and time to MRI progression. RESULTS: Recruitment was slow, resulting in early termination of the study. Eight patients participated, 4 in group 1 and 4 in group 2. Five (62.5%) subjects completed the 6 months of treatment, 4/4 subjects in group 1 and 1/4 in group 2. Three subjects stopped KD early: 2 (25%) because of GBM progression and one (12.5%) because of diet restrictiveness. Four subjects, all group 1, continued KD on their own, three until shortly before death, for total of 26, 19.3, and 7 months, one ongoing. The diet was well tolerated. TEAEs, all mild and transient, included weight loss and hunger (n = 6) which resolved with caloric increase, nausea (n = 2), dizziness (n = 2), fatigue, and constipation (n = 1 each). No one discontinued KD because of TEAEs. Seven patients died. For these, mean (range) survival time from diet initiation was 20 months for group 1 (9.5-27) and 12.8 months for group 2 (6.3-19.9). Mean survival time from diagnosis was 21.8 months for group 1 (11-29.2) and 25.4 months for group 2 ( 13.9-38.7). One patient with recurrent GBM and progression on bevacizumab experienced a remarkable symptom reversal, tumor shrinkage, and edema resolution 6-8 weeks after KD initiation and survival for 20 months after starting KD. CONCLUSION: Treatment of GBM patients with 4:1 KD using total meal replacement program with standardized recipes was well tolerated. The small sample size limits efficacy conclusions. TRIAL REGISTRATION: NCT01865162 registered 30 May 2013, and NCT02302235 registered 26 November 2014, https://clinicaltrials.gov/.

Secondary generalization in seizures of temporal lobe origin: Ictal EEG pattern in a stereo-EEG study.

OBJECTIVE: We tested the hypothesis that secondary generalized seizures (SGS) are not truly generalized and may involve selective regions. METHODS: The spread from focal to generalized seizures in temporal lobe epilepsy (TLE) was studied in 20 SGS recorded via stereo-EEG (SEEG) in 15 candidates for surgery. Electrodes were assigned to fronto-orbital, prefrontal, and temporal cortex, cingulate, hippocampus, and amygdala. The onset of SGS was ascertained by behavioral analysis of the video recordings. EEG recordings were evaluated using the rating scale developed by Blumenfeld [Blumenfeld H, Rivera M, McNally KA, Davis K, Spencer DD, Spencer SS. Ictal neocortical slowing in temporal lobe epilepsy. Neurology 2004;63:1015-21]. The seizure rating in each region was compared with the rating in the hippocampus. RESULTS: Ranking significantly differed in the cingulate and fronto-orbital cortex; there was a trend toward significance in the prefrontal cortex. In these regions, slow activity dominated. CONCLUSION: The onset of secondary generalization, when the head, face and all limbs are involved, does not implicate global cortical involvement.

Perampanel as monotherapy and adjunctive therapy for focal onset seizures, focal to bilateral tonic-clonic seizures and as adjunctive therapy of generalized onset tonic-clonic seizures.

Introduction: Perampanel is an antiepileptic drug approved in the USA and Europe as monotherapy and adjunctive therapy for focal onset seizures and as adjunctive therapy for generalized tonic-clonic seizures. Areas covered: This an overview of animal data, pharmacokinetics, and clinical data published on Perampanel indexed in PubMed. Expert opinion: Pharmacological studies suggest that perampanel acts via noncompetitive antagonism of the ionotropic AMPA receptor of glutamate. The efficacy of perampanel has been shown in animal models of epilepsy and Phase II/III clinical trials. Efficacy and safety have been evaluated in the phase III trials of adjunctive treatment of focal epilepsy with median focal onset seizure reduction rates of 23% for 4 mg/d, 26-31% for 8 mg/day, and 18-35% for 12 mg/day. Fifty percent responder rates were 29% for 4 mg/day, 33-38% for 8 mg/day, and 34-36% for 12 mg/day. A pivotal Phase III trial in generalized onset tonic-clonic seizures showed a median seizure reduction by 76.5% (8 mg) versus 38.4% placebo and 50% seizure responder rate of 64.2% versus 30.9% placebo. Perampanel showed good safety and tolerability profile across 2-12 mg doses. Perampanel as a broad-spectrum antiepileptic drug has a potential to be an alternative treatment of multiple types of epileptic seizures.

Brivaracetam for the treatment of epilepsy.

INTRODUCTION: Approximately one third of patients with epilepsy fail to respond to existing medications. Levetiracetam is an effective antiepileptic drug (AED) postulated to act by binding to synaptic vesicle protein 2A. Brivaracetam is a novel high affinity SV2A ligand with approximately 20-fold higher affinity for SV2A protein than levetiracetam. It is at an advanced stage of clinical development for treatment of epilepsy. AREAS COVERED: This article reviews animal data, pharmacokinetics, and phase 1-3 data of Brivaracetam treatment of epilepsy. Brivaracetam has broad-spectrum anticonvulsant activity in animal models. EXPERT OPINION: Phase 1 studies indicated that single oral doses of 5-800 mg and repeated oral doses of up to 600 mg were well tolerated and showed favorable pharmacokinetic profile. Phase 2 studies indicated good safety and tolerability of brivaracetam in the dose range of 5-150 mg/day and provided proof of concept for efficacy in treating refractory partial onset seizures. Efficacy and safety have been evaluated in 4 phase 3 studies with dose range of 5-200 mg which have demonstrated efficacy in the range of 100-200 mg/day dose and, in most studies, also with 50 mg/day dose, and good safety and tolerability profile across 5-200 mg doses in adjunctive treatment of refractory partial onset seizures.

Dietary treatment in adults with refractory epilepsy: a review.

We review adjunctive ketogenic diet (KD) and modified Atkins diet (MAD) treatment of refractory epilepsy in adults. Only a few studies have been published, all open-label. Because of the disparate, uncontrolled nature of the studies, we analyzed all studies individually, without a meta-analysis. Across all studies, 32% of KD-treated and 29% of MAD-treated patients achieved ≥ 50% seizure reduction, including 9% and 5%, respectively, of patients with >90% seizure frequency reduction. The effect persists long term, but, unlike in children, may not outlast treatment. The 3:1 and 4:1 [fat]:[carbohydrate + protein] ratio KD variants and MAD are similarly effective. The anticonvulsant effect occurs quickly with both diets, within days to weeks. Side effects of both diets are benign and similar. The most serious, hyperlipidemia, reverses with treatment discontinuation. The most common, weight loss, may be advantageous in patients with obesity. Potential barriers to large-scale use of both diets in adults include low rate of diet acceptance and high rates of diet discontinuation. The eligible screened/enrolled subject ratios ranged from 2.9 to 7.2. Fifty-one percent of KD-treated and 42% of MAD-treated patients stopped the diet before study completion. Refusal to participate was due to diet restrictiveness and complexity, which may be greater for KD than MAD. However, long-term adherence is low for both diets. Most patients eventually stop the diet because of culinary and social restrictions. For treatment of refractory status epilepticus, only 14 adult cases of KD treatment have been published, providing insufficient data to allow evaluation. In summary, KD and MAD treatment show modest efficacy, although in some patients the effect is remarkable. The diets are well-tolerated, but often discontinued because of their restrictiveness. In patients willing to try dietary treatment, the effect is seen quickly, giving patients the option whether to continue the treatment.

Rhythmic ictal nonclonic hand (RINCH) motions in temporal lobe epilepsy: invasive EEG findings, incidence, and lateralizing value.

The main purpose of this retrospective analysis was to evaluate the incidence and lateralization value of rhythmic ictal nonclonic hand (RINCH) motions in patients with temporal lobe epilepsy (TLE), who were classified as Engel I at least 2 years after epilepsy surgery. We analyzed the distribution of ictal activity at the time of RINCH appearance in patients in whom RINCH motions were present during invasive EEG monitoring. A group of 120 patients was included in this study. In total, we reviewed 491 seizures: 277 seizures in patients with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (TLE-HS group) and 214 in TLE caused by other lesions (TLE-OTH group). We analyzed 29 patients (79 of the seizures) during invasive EEG monitoring. Fisher's exact test and binomial test were used for the statistical analysis. RINCH motions were observed in 24 out of 120 patients (20%) and in 48 out of 491 seizures (9.8%). There was no significant difference between the occurrence of RINCH motions in patients with TLE-HS and in patients with TLE-OTH, or between gender, right/left-sided TLE, and language dominant/nondominant TLE. RINCH motions were contralateral to the seizure onset in 83.3% of patients and 91.7% of seizures (p=0.0015; p<0.001, respectively). There were no differences in the lateralizing value of RINCH motions in patients with TLE-HS or TLE-OTH. We analyzed RINCH motions in 5 patients/7 seizures during invasive EEG. In all 7 seizures with RINCH motions, we observed the widespread activation of the temporal lobe (mesial and lateral, opercular and polar regions) contralateral to the side of RINCH motions. In all 7 seizures, we observed that at the time of RINCH motion onset, at least 1 explored region of the frontal lobe was affected by the ictal activity. In 3 seizures, we observed time-locked epileptic activation associated with the appearance of RINCH motions, i.e., in the orbitofrontal cortex in 2 seizures and in both the orbitofrontal cortex and anterior cingulate gyrus in 1 seizure. RINCH motions are a relatively frequent ictal sign in patients with TLE. They have a high lateralizing value in these patients, occurring contralateral to the ictal onset. RINCH motions usually occur after the spread of ictal activity beyond the temporal lobe, and their appearance is usually associated with the presence of ictal activity in various regions of the contralateral frontal lobe, mainly the orbitofrontal cortex and anterior cingulate gyrus. This is the first study analysing this phenomenon during invasive EEG recording.

Intracerebrally recorded high frequency oscillations: simple visual assessment versus automated detection.

OBJECTIVE: We compared the possible contribution (in the detection of seizure onset zone - SOZ) of simple visual assessment of intracerebrally recorded high-frequency oscillations (HFO) with standard automated detection. METHODS: We analyzed stereo-EEG (SEEG) recordings from 20 patients with medically intractable partial seizures (10 temporal/10 extratemporal). Independently using simple visual assessment and automated detection of HFO, we identified the depth electrode contacts with maximum occurrences of ripples (R) and fast ripples (FR). The SOZ was determined by independent visual identification in standard SEEG recordings, and the congruence of results from visual versus automated HFO detection was compared. RESULTS: Automated detection of HFO correctly identified the SOZ in 14 (R)/10 (FR) out of 20 subjects; a simple visual assessment of SEEG recordings in the appropriate frequency ranges correctly identified the SOZ in 13 (R)/9 (FR) subjects. CONCLUSIONS: Simple visual assessment of SEEG traces and standard automated detection of HFO seem to contribute comparably to the identification of the SOZ in patients with focal epilepsies. When using macroelectrodes in neocortical extratemporal epilepsies, the SOZ might be better determined by the ripple range. SIGNIFICANCE: Standard automated detection of HFO enables the evaluation of HFO characteristics in whole data. This detection allows general purpose and objective evaluation, without any bias from the neurophysiologist's experiences and practice.

Grey-white matter abnormalities in temporal lobe epilepsy associated with hippocampal sclerosis: Inter-observer analysis, histopathological findings, and correlation with clinical variables.

This study was conducted to determine the incidence of grey-white matter abnormalities (GWMAs) on magnetic resonance images (MRIs) in patients with hippocampal sclerosis (HS), to assess the inter-observer reliability of this finding, and to establish a possible relationship between GWMA and histopathological findings in the anterior part of the temporal lobe, as well as its other relation to clinical variables. We established a group of 55 patients with histologically proven HS. Three observers independently reviewed the MRIs to assess whether GWMA was present. Substantial independent inter-observer agreement was reached for 44 of the 55 patients (80%) (Fleiss' kappa 0.732; p<0.0001). GWMAs were present in 38% of patients (HS+GWMA). Focal cortical dysplasia (FCD) of type IIIa (ILAE classification) was present in 31% of patients. FCD type IIIa was present in 52.4% with HS+GWMA, and in 17.6% without GWMA (HS-GWMA) (p=0.007). We did not find any statistically significant differences in the postoperative outcomes between HS+GWMA and HS-GWMA. We did not find any statistically significant differences in the presence or absence of GWMA and FCD of the temporal pole in relation to the onset of epilepsy, the duration of epilepsy, or the presence of potential epileptogenic insults. GWMA in the anterior part of temporal lobe in patients with HS is a reliable assessment sign for observers who are experienced in evaluating the MRIs of epilepsy patients. The presence of GWMA is significantly associated with the presence of FCD type IIIa in these patients. The presence or absence of GWMA and FCD type IIIa does not influence the postoperative outcome of HS patients.