Organization of the epileptogenic zone and signal analysis at seizure onset in patients with drug-resistant epilepsy due to focal cortical dysplasia with mTOR pathway gene mutations-An SEEG study.

Epilepsy surgery in genetic drug-resistant epilepsy is a debated subject as more histological and molecular data are available. We retrospectively collected data from focal drug-resistant epilepsy patients that underwent stereoelectroencephalography (SEEG) invasive recordings. Patients with nonlesional brain imaging or in whom a first epilepsy surgery failed to control seizures were selected. We computed and displayed the intracranial ictal onset activity pattern on structural imaging. Patients underwent epilepsy gene panel testing, next generation sequencing-NGS. Of 113 patients, 13 underwent genetic testing, and in 6 patients, a mechanistic target of rapamycin pathway gene germline mutation (mTOR) was identified. Brain imaging was nonlesional except for one patient in whom two abnormalities suggestive of focal cortical dysplasia (FCD) were found. Patients underwent tailored brain surgery based on SEEG data, tissue analysis revealed FCD and postsurgical outcome was favorable. Our findings are similar to previous case series suggesting that epilepsy surgery can be a treatment option in patients with mTOR pathway mutation. In patients with mTOR pathway mutation, the postsurgical outcome is favorable if complete resection of the epileptogenic zone is performed. Electrophysiological seizure onset patterns in FCDs associated with mTOR pathway mutations display low-voltage fast activity as previously described.

Accuracy and Safety of Customized Stereotactic Fixtures for Stereoelectroencephalography in Pediatric Patients.

Stereoelectroencephalography (SEEG) in children with intractable epilepsy presents particular challenges. Their thin and partially ossified cranium, specifically in the temporal area, is prone to fracture while attaching stereotactic systems to the head or stabilizing the head in robot's field of action. Postponing SEEG in this special population of patients can have serious consequences, reducing their chances of becoming seizure-free and impacting their social and cognitive development. This study demonstrates the safety and accuracy offered by a frameless personalized 3D printed stereotactic implantation system for SEEG investigations in children under 4 years of age. SEEG was carried out in a 3-year-old patient with drug-resistant focal epilepsy, based on a right temporal-perisylvian epileptogenic zone hypothesis. Fifteen intracerebral electrodes were placed using a StarFix patient-customized stereotactic fixture. The median lateral entry point localization error of the electrodes was 0.90 mm, median lateral target point localization error was 1.86 mm, median target depth error was 0.83 mm, and median target point localization error was 1.96 mm. There were no perioperative complications. SEEG data led to a tailored right temporal-insular-opercular resection, with resulting seizure freedom (Engel IA). In conclusion, patient-customized stereotactic fixtures are a safe and accurate option for SEEG exploration in young children.

Sleep modulates effective connectivity: A study using intracranial stimulation and recording.

OBJECTIVE: Sleep is an active process with an important role in memory. Epilepsy patients often display a disturbed sleep architecture, with consequences on cognition. We aimed to investigate the effect of sleep on cortical networks' organization. METHODS: We analyzed cortico-cortical evoked responses elicited by single pulse electrical stimulation (SPES) using intracranial depth electrodes in 25 patients with drug-resistant focal epilepsy explored using stereo-EEG. We applied the SPES protocol during wakefulness and NREM - N2 sleep. We analyzed 31,710 significant responses elicited by 799 stimulations covering most brain structures, epileptogenic or non-epileptogenic. We analyzed effective connectivity between structures using a graph-theory approach. RESULTS: Sleep increases excitability in the brain, regardless of epileptogenicity. Local and distant connections are differently modulated by sleep, depending on the tissue epileptogenicity. In non-epileptogenic areas, frontal lobe connectivity is enhanced during sleep. There is increased connectivity between the hippocampus and temporal neocortex, while perisylvian structures are disconnected from the temporal lobe. In epileptogenic areas, we found a clear interhemispheric difference, with decreased connectivity in the right hemisphere during sleep. CONCLUSIONS: Sleep modulates brain excitability and reconfigures functional brain networks, depending on tissue epileptogenicity. SIGNIFICANCE: We found specific patterns of information flow during sleep in physiologic and pathologic structures, with possible implications for cognition.

Illusory own body perceptions mapped in the cingulate cortex-An intracranial stimulation study.

Body awareness is the result of sensory integration in the posterior parietal cortex; however, other brain structures are part of this process. Our goal is to determine how the cingulate cortex is involved in the representation of our body. We retrospectively selected patients with drug-resistant epilepsy, explored by stereo-electroencephalography, that had the cingulate cortex sampled outside the epileptogenic zone. The clinical effects of high-frequency electrical stimulation were reviewed and only those sites that elicited changes related to body perception were included. Connectivity of the cingulate cortex and other cortical structures was assessed using the h2 coefficient, following a nonlinear regression analysis of the broadband EEG signal. Poststimulation changes in connectivity were compared between two sets of stimulations eliciting or not eliciting symptoms related to body awareness (interest and control groups). We included 17 stimulations from 12 patients that reported different types of body perception changes such as sensation of being pushed toward right/left/up, one limb becoming heavier/lighter, illusory sensation of movement, sensation of pressure, sensation of floating or detachment of one hemi-body. High-frequency stimulation in the cingulate cortex (1 anterior, 15 middle, 1 posterior part) elicits body perception changes, associated with a decreased connectivity of the dominant posterior insula and increased coupling between other structures, located particularly in the nondominant hemisphere.

Functional mapping and effective connectivity of the human operculum.

The operculum, defined as the cortex adjacent to the insula, is a large structure encompassing three lobes, with a recognized role in a variety of neurologic and psychiatric conditions. Its complex functions include sensory, motor, autonomic and cognitive processing. In humans, these are extended with the addition of language. These functions are implemented by highly specialized neuronal populations and their widespread connections, which our study aims at mapping in detail. We studied a group of 31 patients that were explored with intracranial electrodes during the pre-surgical workup for drug-resistant epilepsy. We have selected the subset of contacts implanted in non-epileptogenic opercular cortex and we analyzed the neurophysiological and behavioral responses to direct electrical stimulation. The functional mapping was performed by applying 1 Hz and 50 Hz electrical stimulation on 252 contact pairs and recording the threshold for evoking clinical effects. The effective connectivity was assessed using cortico-cortical evoked potentials elicited by single-pulse electrical stimulation in a subset of 19 patients. The locations of the effects grouped in twelve distinct semiological classes were analyzed. The most frequent effects evoked by stimulation of the frontal operculum were language related (29%). The Rolandic area produced most often oropharyngeal symptoms (47%), the parietal operculum produced somatosensory effects (67%), while the temporal evoked auditory (58%) semiology. The connectivity pattern was complex, with these structures having widespread ipsilateral and contralateral projections. The local connections between the opercular subregions and with the insula, as well as with more distant areas like the cingulate gyrus, were distinguished by strength and between-subjects consistency. In conclusion, we demonstrate specific opercular functionality, distinct from the one of the insular cortex. The study is complemented by a literature review on the opercular functional connectome in human and non-human primates.

Co-occurrence of high-frequency oscillations and delayed responses evoked by intracranial electrical stimulation in stereo-EEG studies.

OBJECTIVE: To perform a side-by-side comparison of two epileptogenicity biomarkers, high frequency oscillations (HFOs) and delayed responses (DRs), as a result of single-pulse electrical stimulation. METHODS: We have recorded stimulation-evoked HFOs and DRs in 16 epileptic patients undergoing presurgical evaluation using the stereoelectroencephalographic method. To evaluate converging and complementary information provided by the biomarkers, we analyzed them individually and for logical "and"/"or" combinations between them. 3D maps of the biomarkers' distributions by recording location (inbound maps) and by stimulation location (outbound maps) were created to analyze their relationship with the epileptogenic structures. RESULTS: HFOs occur less frequently than DRs, by 18.7%, when counting by recording contacts, and more frequently, by 7.4%, when counting by stimulation contacts. 40.6% of the contacts exhibiting HFOs also exhibit DRs, and 44.1% of the contacts exhibiting DRs also exhibit HFOs. When combining biomarkers, there was a tradeoff between increased seizure onset zone (SOZ) sensitivity, from 21.3% to 73%, and decreased specificity, from 87.2% to 34.3%. CONCLUSIONS: There is a moderate similarity in the information provided by the DRs and HFOs. SIGNIFICANCE: The biomarkers complement each other, but there is a tradeoff between different metrics for SOZ localization.

George Marinesco in the Constellation of Modern Neuroscience.

George Marinesco is the founder of Romanian School of Neurology and one of the most remarkable neuroscientists of the last century. He was the pupil of Jean-Martin Charcot in Salpêtrière Hospital in Paris, France, but visited many other neurological centers where he met the entire constellation of neurologists of his time, including Camillo Golgi and Santiago Ramón y Cajal. The last made the preface of Nervous Cell, written in French by Marinesco. The original title was "La Cellule Nerveuse" and is considered even now a basic reference book for specialists in the field. He was a refined clinical observer with an integrative approach, as could be seen from the multitude of his discoveries. The descriptions of the succulent hand in syringomyelia, senile plaque in old subjects, palmar jaw reflex known as Marinesco-Radovici sign, or the application of cinematography in medicine are some of his important contributions. He was the first who described changes of locus niger in a patient affected by tuberculosis, as a possible cause in Parkinson disease. Before modern genetics, Marinesco and Sjögren described a rare and complex syndrome bearing their names. He was a hardworking man, focused on his scientific research, did not accepted flattering of others and was a great fighter against the injustice of the time.

Intrusive Thoughts Elicited by Direct Electrical Stimulation during Stereo-Electroencephalography.

Cortical direct electrical stimulation (DES) is a method of brain mapping used during invasive presurgical evaluation of patients with intractable epilepsy. Intellectual auras like intrusive thoughts, also known as forced thinking (FT), have been reported during frontal seizures. However, there are few reports on FT obtained during DES in frontal cortex. We report three cases in which we obtained intrusive thoughts while stimulating the dorsolateral prefrontal cortex and the white matter in the prefrontal region. In order to highlight the effective connectivity that might explain this clinical response, we have analyzed cortico-cortical potentials evoked by single pulse electrical stimulation.

A comparative study of the effects of pulse parameters for intracranial direct electrical stimulation in epilepsy.

OBJECTIVES: Intracranial direct electrical stimulation (iDES) uses different parameters for mapping the epileptogenic and functional areas in patients with drug-resistant epilepsy. We aim at finding the common factor driving the electrographic responses to various iDES protocols reported in the literature. METHODS: We recorded early responses to single-pulse iDES in 11 subjects undergoing stereoelectroencephalographic presurgical evaluation. We systematically explored the role of several pulse parameters in evoking responses: monophasic versus biphasic pulses, current intensity, and pulse duration. We performed a correlation and regression analysis between responses to different protocols by amplitude, duration, and charge per phase. RESULTS: Regression analysis revealed that the responses were similar for the same charge per phase, regardless of their pulse duration and amplitude. Over eighty percent (82.8%) of the responses to variable pulse duration biphasic stimulation and between 58.6% and 81.9% of the responses to monophasic stimulation, depending on pulse polarity, were correlated to the responses evoked by the variable amplitude biphasic protocol, when expressing stimulus strength in terms of charge per phase. CONCLUSIONS: Regardless of the combination of different stimulation currents, it is the underlying charge per phase parameter that determines the magnitude of the responses to single-pulse electrical stimulation. SIGNIFICANCE: Our results provide a unifying method for comparing iDES protocols.

Successful epilepsy surgery in frontal lobe epilepsy with startle seizures: a SEEG study.

Pre-surgical assessment and surgical management of frontal epilepsy with normal MRI is often challenging. We present a case of a 33-year-old, right-handed, educated male. During childhood, his seizures presented with mandibular myoclonus and no particular trigger. As a young adult, he developed seizures with a startle component, triggered by unexpected noises. During his ictal episodes, he felt fear and grimaced with sudden head flexion and tonic axial posturing. Similar seizures also occurred without startle. Neuropsychological assessment showed executive dysfunction and verbal memory deficit. The cerebral MRI was normal. Electro-clinical reasoning, investigations performed, the results obtained and follow-up are discussed in detail. [Published with video sequence].

Presurgical Evaluation and Epilepsy Surgery in MRI Negative Resistant Epilepsy of Childhood with Good Outcome.

Magnetic resonance imaging (MRI)-negative epilepsy may be successfully solved with a multidisciplinary approach using invasive recordings, image and signal analysis. The whole methodology used by the epilepsy surgery team is systematically described based on an resistant epilepsy case with all steps and rationale of choosing different investigation methods from surface electroencephalography (EEG) to invasive recordings. Due to negative MRI and non-concordant ictal surface EEG with clinical semiology, the patient was investigated with stereo- EEG (SEEG), aiming to delimitate epileptogenic and eloquent cerebral areas. Implantation strategy, seizures recordings, stimulation, resection planning using quantitative EEG analysis, and the surgery plan are presented. The patient has been seizure-free for 14 months so far, with improved behavior and daily life quality. Post-operative examination revealed focal cortical dysplasia type II B.

Atypical Bourneville sclerosis without epilepsy and mental retardation: case report and literature review.

Twenty-four-year-old woman without familiar detected signs of Bourneville's disease or tuberous sclerosis complex (TSC) was diagnosed with this disease by casual discovery on cerebral magnetic resonance imaging (MRI) of an intraventricular tumor, after symptoms consist in headache, equilibrium disturbances, and progressive loss of vision. MRI shows an intracranial mass, 33÷24÷30 mm in size, localized at the level of third ventricle and lateral ventricles, with irregular shape, interesting the foramen of Monroe. There are also nodular areas of calcification and a supratentorial hydrocephalus involving the lateral ventricles and the posterior part of the third ventricle. The patients present facial angiofibromas, but from the classical triad of the disease, the epilepsy and mental retardation were absent, the patient never presented seizures. The total removal of the tumor (peace to peace) was performed surgically, the macroscopic features of resected tumor (20/10/10 mm) was of white-gray color, elastic consistency, localized in the both lateral ventricles (left>right) and into the third ventricle, traversing the foramen Monroe. The histopatological examination associated with specific localization of tumor and the facial angiofibromas are very suggestive for subependimar giant cell astrocytoma (SEGA). We have a rare case of atypical or incomplete TSC in which the epileptic seizures and the mental retardation are absent, the intelligence is normal, but occur some psychical symptoms: anxiety, sleeplessness, and autism or behavior disturbances. The evolution of this case was marked by complications because of postoperative hydrocephalus and multiple shunt insertions and revisions were performed after the tumor resection.

A personalized stereotactic fixture for implantation of depth electrodes in stereoelectroencephalography.

BACKGROUND: The stereoelectroencephalographic (SEEG) implantation procedures still represent a challenge due to the intrinsic complexity of the method and the number of depth electrodes required. OBJECTIVES: We aim at designing and evaluating the accuracy of a custom stereotactic fixture based on the StarFix™ technology (FHC Inc., Bowdoin, ME) that significantly simplifies and optimizes the implantation of depth electrodes used in presurgical evaluation of patients with drug-resistant epilepsy. METHODS: Fiducial markers that also serve as anchors for the fixture are implanted into the patient's skull prior to surgery. A 3D fixture model is designed within the surgical planning software, with the planned trajectories incorporated in its design, aligned with the patient's anatomy. The stereotactic fixture is built using 3D laser sintering technology based on the computer-generated model. Bilateral rectangular grids of guide holes orthogonal to the midsagittal plane and centered on the midcommissural point are incorporated in the fixture design, allowing a wide selection of orthogonal trajectories. Up to two additional grids can be accommodated for targeting structures where oblique trajectories are required. The frame has no adjustable parts, this feature reducing the risk of inaccurate coordinate settings while simultaneously reducing procedure time significantly. RESULTS: We have used the fixture for the implantation of depth electrodes for presurgical evaluation of 4 patients with drug-resistant focal epilepsy, with nearly 2-fold reduction in the duration of the implantation procedure. We have obtained a high accuracy with a submillimetric mean positioning error of 0.68 mm for the anchor bolts placed at the trajectory entry point and 1.64 mm at target. CONCLUSIONS: The custom stereotactic fixture design greatly simplifies the planning procedure and significantly reduces the time in the operating room, while maintaining a high accuracy.