High-purified cannabidiol efficacy and safety in a cohort of adult patients with various types of drug-resistant epilepsies.

About 30% of patients with epilepsy are drug resistant. Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC) are diseases for which high-purified-cannabidiol (CBD) known as Epidiolex® (GW pharma) can be prescribed in add-on of other medications in case of drug-resistance. Currently, there are only a few recent data in the literature about the efficacy and safety of CBD in other forms of refractory epilepsies especially focal epilepsies in adults. We report retrospectively the experience of high-purified-CBD use in two French reference medical centers for epilepsy in various forms of drug-resistant epilepsy. We distinguished two groups of patients: group A with epileptic encephalopathies and group B with focal or multifocal epilepsy. Safety and efficacy (% of responder patients) were evaluated. Finally, 73 patients (51 in group A and 22 in group B) used high-purified CBD as an add-on treatment for their drug-resistant epilepsy. Patients in group A were significantly younger (P=0.0155), with a longer exposition of treatment (P=0.0497) than group B and with higher doses (P=0.0300). Respectively, 15 patients (29.4%) and five patients (22.7%) were responders during the follow-up period (P=0.552). The association with clobazam was more frequent in responders than in non-responder patients (16 patients [80%] versus four [20%]). The most frequent side effect was somnolence. At the end of follow-up, 15 patients in group A (29.4%) and nine patients in group B (40.1%) had stopped the high-purified-CBD treatment due to aggravation of seizure, absence of positive effects, or adverse events. This study showed no significant difference regarding the type of drug-resistant epilepsy and suggests that this treatment may be of interest for all types of drug-resistant epilepsy.

The role of SEEG in the presurgical decision-making process in MRI-normal mesial temporal lobe epilepsy.

OBJECTIVES: In patients with mesial temporal lobe epilepsy (mTLE) and normal MRI, anterior temporal lobectomy sparing the hippocampus might be considered because of the risk of post-operative memory deficit. However, it is unclear whether some patients with normal MRI and non-invasive EEG and semiological pattern highly suggestive of mesial temporal seizures demonstrate a seizure onset network sparing the hippocampus, potentially warranting surgery. METHODS: A retrospective study of 17 patients with mTLE epilepsy and normal MRI who underwent SEEG. Only patients whose non-invasive presurgical data suggested an unilateral mesial temporal epileptogenic zone (EZ), as defined by combination of ictal semiology and ictal EEG during scalp video-EEG, were included. SEEG data were analyzed using both visual and quantitative approaches. Two EZ organization were defined: (i) EZ involved the hippocampus at the onset of the ictal discharge (HIP group): (ii) patients in whom a delay>1sec was observed between the seizure onset and the involvement of the hippocampus (nHIP group). Non-invasive clinical and functional imaging data, as well as post-operative outcomes, were compared across groups. RESULTS: Eleven patients were included in HIP group and 6 in the nHIP group. In the nHIP group, the maximal epileptogenicity was in the amygdala in five patients and in the entorhinal cortex in one. The hippocampus normalized interictal spiking activity was not different between groups. None of the patients characteristics collected during the non-invasive presurgical workup was associated with the SEEG-based organization of the EZ. Twelve patients underwent a surgical resection, including temporal cortectomy sparing hippocampus in six. Seizure and neuropsychological post-operative outcomes were similar. CONCLUSION: In patients with MRI-normal mTLE, SEEG should be included in the surgical decision-making process because seizure organization cannot be predicted from non-invasive investigations. When hippocampus is not included in the EZ, temporal resection sparing the hippocampus can be considered.

Relationships between migraine and epilepsy: Pathophysiological mechanisms and clinical implications.

Migraine and epilepsy are distinct neurological diseases with specific clinical features and underlying pathophysiological mechanisms. However, numerous studies have highlighted the complex and multifaceted relationships between the two conditions. The relationships between headache and epilepsy manifest themselves in different ways. Firstly, the clinical diagnosis of these disorders may be challenging in view of possible overlapping. While post-ictal headache is a frequent condition, ictal epileptic headache is a rare but challenging diagnosis. Both situations raise the question of the pathophysiological mechanism of headache triggered by seizures. Migraine aura and epilepsy can also exhibit overlapping symptoms leading to their misdiagnosis, in particular in the case of visual aura. Secondly, migraine with aura and epilepsy can occur as a co-morbid condition, particularly in familial hemiplegic migraine (FHM). From a pathophysiological perspective, the identification of genetic mutations in FHM has brought significant advances in the understanding of dysfunctions of neuronal networks leading to hyperexcitability. The purpose of this review is to present clinical situations encompassing headache and epilepsy that can be challenging in neurological practice and to discuss the underlying pathophysiological mechanism of such interactions.

A real-time marker of object-based attention in the human brain. A possible component of a "gate-keeping mechanism" performing late attentional selection in the Ventro-Lateral Prefrontal Cortex.

The decision to process an incoming stimulus attentively - and to trigger a follow-up cascade of high-level processes - is strategic for the human brain as it becomes transiently unavailable to subsequent stimulus processing. In this study, we set to identify brain networks that carry out such evaluations. We therefore assessed the time-course of neural responses with intracerebral EEG in human patients during an attentional reading task, contrasting to-be-attended vs. to-be-ignored items. We measured High-Frequency Activity [50-150 â€‹Hz] as a proxy of population-level spiking activity and we identified a crucial component of a Gate-Keeping Mechanism bilateral in the mid-Ventro-Lateral Prefrontal Cortex (VLPFC), at the interplay of the Ventral and Dorsal Attention Networks, that selectively reacts before domain specialized cortical regions that engage in full stimulus analysis according to task demands.

Wearable devices for seizure detection: Is it time to translate into our clinical practice?

With the exponential development of mobile health technologies over the past ten years, there has been a growing interest in the potential applications in the field of epilepsy, and specifically for seizure detection. Better detection of seizures is probably one of the best ways to improve patient safety. Overall, we are observing an exponential increase in the number of non-EEG based seizure detection systems and a progressive homogenization of their evaluation procedures. Most importantly, the properties of these devices for detection of tonic-clonic seizures are now very interesting, both in terms of sensitivity and in terms of false-alarm rates. Accordingly, we might expect that these be used in clinical practice in the near future, especially in patients at high risk of seizure-related injuries or sudden unexpected death in epilepsy (SUDEP).

Malformations of cortical development: New surgical advances.

Epilepsy related to malformations of cortical development is frequently drug resistant or requires heavy medication, therefore surgery is key in their management. The role of stereotactic surgery has recently changed the diagnosis and treatment of focal cortical dysplasias (FCD), hypothalamic hamartomas (HH) and periventricular nodular heterotopias (PNH). In HH, radiosurgery using Gammaknife® leads to 60 % of seizure control and is associated with excellent neuropsychological results without significant endocrine function impairment. The seizure control rate is even higher (more than 80 %) with monopolar multiple stereotactic thermocoagulations and Laser interstitial Thermal Therapy (LiTT). While the first technique is associated with a 2 % complications rate (but with excellent neuropsychological outcomes), the latest has up to 22 % side effects in some series. All three of these techniques have encouraging results, but controlled studies are still lacking to provide evidence-based new therapeutic algorithms. With regard to the PNH, surgical management has long been limited by the depth of the lesions and their close anatomical relations with the functional brain connectome. Stereotactic approaches required to perform a SEEG, to locate the part of the PNH responsible for the seizure onset, are later followed by a stereotactic lesioning procedure, therefore doubling the bleeding risk. That is why SEEG-guided radiofrequency-thermocoagulation (SEEG guided-RF-TC), which makes it possible to perform these two steps in a single procedure, was considered as a promising option. A recent meta-analysis confirmed this intuition and reported 38 % of seizure-free patients and 81 % of responders with only 0.3 % of complications, making this approach the first treatment line, followed by LiTT. Among the multiple advances in the FCD identification by non-invasive investigations, a new modality of per-operative diagnostic procedure, the three-dimensional electrocorticography may lead to simplify the preoperative investigation and enhance the accuracy of FCD delineation. Evidence is nevertheless still insufficient to validate this promising concept. Conventional surgical resection has also been concerned by significant conceptual advances during the past few years, in particular with the development of the hodotopic approach, initially in oncologic surgery. Associated with a better understanding of neuroplasticity in epilepsy and the setting up of functional mapping during SEEG or during awake surgery, the possibility of surgical resections grew up. A short-term perspective in this field, when surgical resection remains impossible, would be to target crucial nodes of the epileptic network, distinct from the core functional connectome.

Semiology of insular lobe seizures.

After the early attempts of intra-operative electrocorticography and insulectomy in the 1950s, the notion of insular lobe seizures was largely forgotten for decades. It is only since the late 1990s that the recent technique of stereo-electroencephalography (SEEG) enabled preoperative diagnosis of insular origin seizures and thus gave rise to a renewed interest for this ill-defined electroclinical entity. Owing to the multiple functional roles of insula and its extensive connectivity with adjacent as well as distant brain structures, insular lobe seizures present with a combination or series of diverse subjective and objective symptoms. In this review, we summarize current knowledge on the semiology of insular origin seizures. The following two distinct forms of clinical presentation have been recognized: 1) Seizures with predominant insulo-perisylvian symptoms, most notably paraesthesia and cervico-laryngeal discomfort. The former typically involves a large/bilateral cutaneous territory and can be perceived as cold, hot, or painful sensations. The latter ranges from slight dyspnea to strong sensation of strangulation. Other symptoms include epigastric discomfort/nausea, hypersalivation, auditory, vestibular, gustatory, and aphasic symptoms. 2) Nocturnal hyperkinetic seizures with/without tonic elevation of upper limbs, masquerading as fronto-mesial seizures. Patients are usually not fully aware of their symptoms despite preserved contact and organized behavior to others. Ipsilateral eye blinking can be observed. These two patterns often occur in succession or simultaneously. This characteristic combination and progression of ictal symptoms orients us strongly towards an insular origin of seizure, a better understanding of which is a crucial key to further optimize modern SEEG strategy.

Resective surgery in tuberous Sclerosis complex, from Penfield to 2018: A critical review.

Medically treated patients suffering from tuberous sclerosis complex (TSC) have less than 30% chance of achieving a sustained remission. Both the international TSC consensus conference in 2012, and the panel of European experts in 2012 and 2018 have concluded that surgery should be considered for medically refractory TSC patients. However, surgery remains currently underutilized in TSC. Case series, meta-analyses and guidelines all agree that a 50 to 60% chance of long-term seizure freedom can be achieved after surgery in TSC patients and a presurgical work-up should be done as early as possible after failure of two appropriate AEDs. The presence of infantile spasms, the second most common seizure type in TSC, had initially been a barrier to surgical planning but is now no longer considered a contraindication for surgery in TSC patients. TSC patients undergoing presurgical evaluation range from those with few tubers and good anatomo-electro-clinical correlations to patients with a significant "tuber burden" in whom the limits of the epileptogenic zone is much more difficult to define. Direct surgery is often possible in patients with a good electro-clinical and MRI correlation. For more complex cases, invasive monitoring is often mandatory and bilateral investigations can be necessary. Multiple non-invasive tools have been shown to be helpful in determining the placement of these invasive electrodes and in planning the resection scheme. Additionally, at an individual level, multimodality imaging can assist in identifying the epileptogenic zone. Increased availability of investigations that can be performed without sedation in young and/or cognitively impaired children such as MEG and HR EEG would most probably be of great benefit in the TSC population. Of those selected for invasive EEG, rates of seizure freedom following surgery are close to cases where invasive monitoring is not required, strengthening the important and efficient role of intracranial investigations in drug-resistant TSC associated epilepsy.

Single and paired-pulse electrical stimulation during invasive EEG recordings.

Invasive EEG recordings are frequently required during the presurgical exploration of patients with drug-resistant focal epilepsy in order to clarify the epileptic zone location. Intracranial direct electrical stimulations (DES) induce EEG and/or clinical responses that participate in this evaluation. Clinical DES protocols (1Hz and/or 50Hz) trigger massive cortical activation that can elicit seizures, after-discharges or complex clinical signs. In contrast, low-energy (<1Hz) protocols activate more localized cortical regions using single-pulse electrical stimulations (SPES). SPES can elicit two main types of responses. Cortico-cortical evoked potentials (CCEPs) correspond to highly consistent early responses, appearing before 100ms after stimulation, with fixed latency; they are considered physiological and assess the effective connectivity between the recorded regions. Late responses appear after 100ms; they are rare, inconsistent with variable latency and are suggestive of an underlying epileptogenic cortex. Paired-pulse stimulation paradigm associates a conditioning and a test stimulation to induce intracortical inhibition or facilitation by modifying the response amplitude. Largely used in transcranial magnetic stimulation, it has rarely been applied to CCEP although the mechanisms put in place seem highly similar. Low frequency intracerebral stimulations allow analysing brain connectivity and cortical excitability with a high temporal and spatial resolution. The development of new stimulation protocols and the combination with imaging or statistical techniques recently offered promising results.

The concept of temporal 'plus' epilepsy.

The concept of temporal 'plus' epilepsy (T+E) is not new, and a number of observations made by means of intracerebral electrodes have illustrated the complexity of neuronal circuits that involve the temporal lobe. The term T+E was used to unify and better individualize these specific forms of multilobar epilepsies, which are characterized by electroclinical features primarily suggestive of temporal lobe epilepsy, MRI findings that are either unremarkable or show signs of hippocampal sclerosis, and intracranial recordings which demonstrate that seizures arise from a complex epileptogenic network including a combination of brain regions located within the temporal lobe and over closed neighbouring structures such as the orbitofrontal cortex, the insulo-opercular region, and the temporo-parieto-occipital junction. We will review here how the term of T+E has emerged, what it means, and which practical consideration it raises.

Publication bias in pharmacogenetics of adverse reaction to antiseizure drugs: An umbrella review and a meta-epidemiological study.

Publication bias may lead to a misestimation in the association between pharmacogenetic biomarkers (PGx) and antiseizure drug's adverse effects (AEs). We aimed to assess its prevalence in this field. We searched for systematic reviews assessing PGx of antiseizure drug's AEs. For each unique association between a PGx, a drug and its AE, we used the available odds ratio (ORs) to generate corresponding funnel plots. We estimated the prevalence of publication bias using visual inspections and asymmetry tests. We explored the impact of publication bias using ORs adjusted for potential publication bias. Twenty-two associations were available. Our visual analysis suggested a publication bias in five out twenty-two funnel plots (23% [95%CI: 8; 45]). The Egger's test showed a significant publication bias in one (HLA-B*15:02 and phenytoin-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, p = 0.03) out of nine (11% [95%CI: 0; 48]) and the Begg's test in one (HLA-B*15:02 and carbamazepine-induced serious cutaneous reactions, p = 0.02) out of ten (10% [95%CI: 0; 45]) assessable funnel plots. Adjusting for publication bias may reduce by half the ORs of the pharmacogenetics associations. Publication bias in the pharmacogenetic of antiseizure drug's AEs is not uncommon and may affect the estimation of the effect of such biomarkers. When conducting pharmacogenetic studies, it is critical to publish also the negative one.

Can you guess the colour of this moving object? A dissociation between colour and motion in blindsight.

Blindsight has been primarily and extensively studied by Lawrence Weiskrantz. Residual visual abilities following a hemispheric lesion leading to homonymous hemianopia encompass a variety of visual-perceptual and visuo-motor functions. Attention blindsight produces the more salient subjective experiences, especially for motion (Riddoch phenomenon). Action blindsight illustrates visuo-motor abilities despite the patients' feeling that they produce random movements. Perception blindsight seems to be the weakest residual function observed in blindsight, e.g. for wavelength sensitivity. Discriminating motion produced by isoluminant colours does not give rise to blindsight for motion but the outcome of the reciprocal test is not known. Here we tested whether moving stimuli could give rise to colour discrimination in a patient with homonymous hemianopia. It was found that even though the patient exhibited nearly perfect performances for motion direction discrimination his colour discrimination for the same moving stimulus remained at chance level. It is concluded that easily discriminated moving stimuli do not give rise to colour discrimination and implications for the 3 levels of blindsight taxonomy are discussed.

Diagnostic accuracy of quantitative EEG to detect delayed cerebral ischemia after subarachnoid hemorrhage: A preliminary study.

OBJECTIVE: Delayed cerebral ischemia (DCI) is the most important and preventable morbidity cause after subarachnoid hemorrhage (SAH). Therefore, DCI early detection is a major challenge. Yet, neurological examination can be unreliable in poor grade SAH patients. EEG provides information from most superficial cortical area, with ischemia-related changes. This study aims at defining an alpha-theta/delta (AT/D) ratio decrease thresholds to detect DCI. METHODS: We used EEG with a montage matching vascular territories (right and left anterior central and posterior) and compared them to follow-up brain imaging. RESULTS: 15 SAH patients (Fischer ≥ 3, World Federation of Neurological Surgeons scale ≥4, 9 DCI) were monitored during 6.4 [4-8] days (min = 2d, max = 13d). AT/D changes could follow three different patterns: (1) prolonged or (2) transient decrease and (3) no decrease or progressive increase. A regional 30% decrease outlasting 3.7 h reached 100% sensitivity and 88.9% specificity to detect DCI. Only 22.6% were in a zone of uncertain diagnosis (3.7-8.04 h). These prolonged decreases, with a loss of transient changes, started in cortical areas evolving toward DCI, and preceded intracranial changes when available. CONCLUSION: Although this study has a small sample size, prolonged AT/D decrease seems to be a reliable biomarker of DCI. SIGNIFICANCE: cEEG changes are likely to precede cerebral infarction and could be useful at the bedside to detect DCI before irreversible damage.

Epileptic networks in patients with bitemporal epilepsy: the role of SEEG for the selection of good surgical candidates.

OBJECTIVE: In this study we investigated the electrical characteristics of seizures recorded by stereo-EEG (SEEG) in a cohort of patients with bitemporal lobe epilepsy (BTLE), in the attempt to verify the presence/absence of different seizure patterns and to identify good surgical candidates. METHODS: We retrospectively reviewed 14 consecutive patients with medically refractory BTLE confirmed by scalp video-EEG (VEEG) recording of bitemporal independent or non-lateralizing seizure onset. All patients had a comprehensive evaluation including history and neurologic examination, MRI, scalp VEEG and SEEG monitoring. Neuropsychological, Wada testing and FDG-PET were performed in most patients. When temporal lobe resection was performed (7 cases), the postoperative follow-up was of at least 1year. RESULTS: Intracranial EEG (SEEG) revealed that only 4/14 (29%) patients were suffering of unilateral TLE. Two groups of patients with distinct SEEG patterns of seizures were identified: a temporo-mesial origin of seizures was the only SEEG pattern observed in 8 patients (Group 1); in 6 patients seizures originated from multiple onset zones in mesial and lateral temporal cortex or from extra-temporal cortex (Group 2). All patients of group 1 (except one who refused surgery) underwent surgery and had a favorable outcome (6 Engel class I; one Engel's class II). The side of surgery was not necessarily the one responsible for the majority of recorded seizures. It was chosen on the basis of MRI findings and consistency of data from presurgical functional investigations, mostly memory assessment and Wada test. SIGNIFICANCE: In patients with suspected BTLE, SEEG proved to be useful in identifying the origin of seizures. Good surgical outcome can be obtained after unilateral resection in patients with bilateral independent seizure onsets or sequential mesial temporal involvement on SEEG if the side of surgery is chosen considering multimodal data.

Ipsilateral head deviation related to orbito-frontal and fronto-polar seizures.

The localizing and lateralizing values of eye and head ictal deviations during frontal lobe seizures are still matters of debate. In particular, no specific data regarding the origin of ipsilateral head turning in frontal lobe seizures are available. We report a patient with frontal lobe seizures associated with reproducible, early, ipsilateral head deviation, where imaging and video-stereo-electroencephalography data, as well as surgical outcome, demonstrated the fronto-polar and orbito-frontal origin of the epileptic discharge. We conclude that early ipsilateral head deviation, in the context of frontal lobe epilepsy, raises the possibility of fronto-polar or orbito-frontal seizure onset.[Published with video sequences].