Literature review and protocol for a prospective multicentre cohort study on multimodal prediction of seizure recurrence after unprovoked first seizure.

INTRODUCTION: Epilepsy is a common neurological disorder characterised by recurrent seizures. Almost half of patients who have an unprovoked first seizure (UFS) have additional seizures and develop epilepsy. No current predictive models exist to determine who has a higher risk of recurrence to guide treatment. Emerging evidence suggests alterations in cognition, mood and brain connectivity exist in the population with UFS. Baseline evaluations of these factors following a UFS will enable the development of the first multimodal biomarker-based predictive model of seizure recurrence in adults with UFS. METHODS AND ANALYSIS: 200 patients and 75 matched healthy controls (aged 18-65) from the Kingston and Halifax First Seizure Clinics will undergo neuropsychological assessments, structural and functional MRI, and electroencephalography. Seizure recurrence will be assessed prospectively. Regular follow-ups will occur at 3, 6, 9 and 12 months to monitor recurrence. Comparisons will be made between patients with UFS and healthy control groups, as well as between patients with and without seizure recurrence at follow-up. A multimodal machine-learning model will be trained to predict seizure recurrence at 12 months. ETHICS AND DISSEMINATION: This study was approved by the Health Sciences and Affiliated Teaching Hospitals Research Ethics Board at Queen's University (DMED-2681-22) and the Nova Scotia Research Ethics Board (1028519). It is supported by the Canadian Institutes of Health Research (PJT-183906). Findings will be presented at national and international conferences, published in peer-reviewed journals and presented to the public via patient support organisation newsletters and talks. TRIAL REGISTRATION NUMBER: NCT05724719.

Development and Validation of the 5-SENSE Score to Predict Focality of the Seizure-Onset Zone as Assessed by Stereoelectroencephalography.

Importance: Stereoelectroencephalography (SEEG) has become the criterion standard in case of inconclusive noninvasive presurgical epilepsy workup. However, up to 40% of patients are subsequently not offered surgery because the seizure-onset zone is less focal than expected or cannot be identified. Objective: To predict focality of the seizure-onset zone in SEEG, the 5-point 5-SENSE score was developed and validated. Design, Setting, and Participants: This was a monocentric cohort study for score development followed by multicenter validation with patient selection intervals between February 2002 to October 2018 and May 2002 to December 2019. The minimum follow-up period was 1 year. Patients with drug-resistant epilepsy undergoing SEEG at the Montreal Neurological Institute were analyzed to identify a focal seizure-onset zone. Selection criteria were 2 or more seizures in electroencephalography and availability of complete neuropsychological and neuroimaging data sets. For validation, patients from 9 epilepsy centers meeting these criteria were included. Analysis took place between May and July 2021. Main Outcomes and Measures: Based on SEEG, patients were grouped as focal and nonfocal seizure-onset zone. Demographic, clinical, electroencephalography, neuroimaging, and neuropsychology data were analyzed, and a multiple logistic regression model for developing a score to predict SEEG focality was created and validated in an independent sample. Results: A total of 128 patients (57 women [44.5%]; median [range] age, 31 [13-58] years) were analyzed for score development and 207 patients (97 women [46.9%]; median [range] age, 32 [16-70] years) were analyzed for validation. The score comprised the following 5 predictive variables: focal lesion on structural magnetic resonance imaging, absence of bilateral independent spikes in scalp electroencephalography, localizing neuropsychological deficit, strongly localizing semiology, and regional ictal scalp electroencephalography onset. The 5-SENSE score had an optimal mean (SD) probability cutoff for identifying a focal seizure-onset zone of 37.6 (3.5). Area under the curve, specificity, and sensitivity were 0.83, 76.3% (95% CI, 66.7-85.8), and 83.3% (95% CI, 72.30-94.1), respectively. Validation showed 76.0% (95% CI, 67.5-84.0) specificity and 52.3% (95% CI, 43.0-61.5) sensitivity. Conclusions and Relevance: High specificity in score development and validation confirms that the 5-SENSE score predicts patients where SEEG is unlikely to identify a focal seizure-onset zone. It is a simple and useful tool for assisting clinicians to reduce unnecessary invasive diagnostic burden on patients and overutilization of limited health care resources.

Distinct Patterns of Brain Metabolism in Patients at Risk of Sudden Unexpected Death in Epilepsy.

Objective: To characterize regional brain metabolic differences in patients at high risk of sudden unexpected death in epilepsy (SUDEP), using fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Methods: We studied patients with refractory focal epilepsy at high (n = 56) and low (n = 69) risk of SUDEP who underwent interictal 18FDG-PET as part of their pre-surgical evaluation. Binary SUDEP risk was ascertained by thresholding frequency of focal to bilateral tonic-clonic seizures (FBTCS). A whole brain analysis was employed to explore regional differences in interictal metabolic patterns. We contrasted these findings with regional brain metabolism more directly related to frequency of FBTCS. Results: Regions associated with cardiorespiratory and somatomotor regulation differed in interictal metabolism. In patients at relatively high risk of SUDEP, fluorodeoxyglucose (FDG) uptake was increased in the basal ganglia, ventral diencephalon, midbrain, pons, and deep cerebellar nuclei; uptake was decreased in the left planum temporale. These patterns were distinct from the effect of FBTCS frequency, where increasing frequency was associated with decreased uptake in bilateral medial superior frontal gyri, extending into the left dorsal anterior cingulate cortex. Significance: Regions critical to cardiorespiratory and somatomotor regulation and to recovery from vital challenges show altered interictal metabolic activity in patients with frequent FBTCS considered to be at relatively high-risk of SUDEP, and shed light on the processes that may predispose patients to SUDEP.

Localisation in focal epilepsy: a practical guide.

The semiology of epileptic seizures reflects activation, or dysfunction, of areas of brain (often termed the symptomatogenic zone) as a seizure begins and evolves. Specific semiologies in focal epilepsies provide an insight into the location of the seizure onset zone, which is particularly important for presurgical epilepsy assessment. The correct diagnosis of paroxysmal events also depends on the clinician being familiar with the spectrum of semiologies. Here, we summarise the current literature on localisation in focal epilepsies using illustrative cases and discussing possible pitfalls in localisation.

A prospective pilot study of cognitive impairment and mood in adults with first seizure, new-onset epilepsy, and newly diagnosed epilepsy at time of initial seizure presentation.

INTRODUCTION: This is an observational prospective cohort study of cognition and mood in individuals presenting to a tertiary neurology clinic with first unprovoked seizure (FS), new-onset epilepsy (NOE), and newly diagnosed epilepsy (NDE). Our aim was to understand the cognitive profile of these three diagnostic groups at the time of first presentation. Follow-up was obtained to evaluate any association between cognition at presentation and subsequent clinical course. METHODS: Forty-three participants (age: 18-60 years) were recruited with FS (n = 17), NOE (n = 16), and NDE (n = 10). Clinical details, neuropsychological testing, and screening for mood disorders were obtained at the time of presentation to clinic. Seizure recurrence was evaluated at clinic follow-up at least 6-12 months following the initial presentation. RESULTS: In all groups, general intelligence (intelligence quotient [IQ]) was consistent with population norms, but more than half of participants (55.8%) were impaired in at least one cognitive domain. The most commonly impaired domain in all diagnostic groups was visuospatial and visuoconstruction suggesting that it may be a sensitive marker of early cognitive impairment. Those with epilepsy (NOE and NDE) at initial presentation were more likely to be impaired than those with FS, particularly on tests of attention, working memory, and processing speed. Seven participants with FS converted to NOE (FSNOE) at follow-up. They were more likely to be impaired on tests of memory than those with FS who did not convert to NOE. On mood screening, 21% of participants scored moderate or severe for depressive symptoms, and 25.6% of participants scored moderate or severe for anxiety symptoms. DISCUSSION: Cognitive impairment and mood changes are common at first seizure presentation and mirror the pattern seen in chronic epilepsy. This cooccurrence of symptomatology at disease onset prior to prolonged antiepilepsy drug exposure suggests a shared underlying disease mechanism and carries important clinical implications for effective diagnosis and management of epilepsy. Furthermore, early cognitive testing may become a clinical biomarker and enable the prediction of an individual's clinical course.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

Seizures as a complication of recreational drug use: Analysis of the Euro-DEN Plus data-set.

Seizures are a recognized and potentially serious complication of recreational drug use. This study examined a large international data set of presentations to Emergency Departments with acute recreational drug toxicity, the European Drug Emergencies Plus (Euro-DEN Plus) Network, to compare presentations with and without seizures and estimate incidence and associated drugs. Amongst 23,947 presentations between January 2014 and December 2017, there were 1013 (4.2%) with reported seizures. Clinical and demographic features were similar between individuals who had a seizure and those who did not, although rates of coma, cardiac arrest, intubation, intensive care admission, and death were significantly higher in those with seizures. There was a significant association between specific drugs and a higher seizure incidence, including fentanyl (odds ratio 2.63, 95% confidence interval 1.20-5.80), and synthetic cannabinoids (OR 2.90, 95% CI 2.19-3.84). Other drugs were associated with a lower seizure incidence, including heroin (OR 0.46, 95% CI 0.35-0.61), clonazepam (OR 0.22, 95% CI 0.06-0.91), and cannabis (OR 0.65, 95% CI 0.50-0.86). This substantiates observations that the synthetic cannabinoids as a group of novel psychoactive substances are clinically different in consequence of intoxication than cannabis, and that individuals who suffer a seizure in the context of recreational drug intoxication are likely to have worse outcomes overall. Utilising this information of what substances have a greater risk of seizures, could provide tailored harm reduction and education strategies to users to reduce the risk of seizures and their associated complications.

Case Studies in Neuroscience: Evidence of motor thalamus reorganization following bilateral forearm amputations.

Following injury, functional improvement can result from central nervous system plasticity. Use-dependent plasticity of motor systems is evident, for example, in recovery of function resulting from rehabilitative interventions. Here, we present a single patient who underwent bilateral microelectrode-guided stereotactic implantation of deep brain stimulating leads for the treatment of essential tremor 52 yr following bilateral arm amputations. The tremor affected his upper extremities and had rendered him unable to perform fine motor tasks with his prostheses, significantly reducing his independence. We found a large territory of neurons in the ventral intermediate nucleus of his thalamus that responded to shoulder protraction, the movement that he used to control fine motor movements of his terminal hook prostheses. We propose that reorganization of this motor nucleus may have occurred secondary to a use-dependent gain of function in neurons that were previously involved in hand movement. NEW & NOTEWORTHY We had a unique opportunity to record neurons in the ventrointermediate (Vim) motor nucleus of thalamus in a patient with essential tremor, decades following bilateral forearm amputations. We demonstrate that a large region of Vim is active during shoulder protraction-the movement used to operate the patient's mechanical prostheses. We suggest that this provides evidence of human motor thalamic plasticity.

Intracortical inhibition abnormality during the remission phase of multiple sclerosis is related to upper limb dexterity and lesions.

OBJECTIVE: The impact of inhibitory cortical activity on motor impairment of people with relapsing-remitting multiple sclerosis (RRMS) has not been fully elucidated despite its relevance to neurorehabilitation. The present study assessed the extent to which transcranial magnetic stimulation (TMS)-based metrics of intracortical inhibition are related to motor disability and brain damage. METHODS: Participants included forty-three persons with RRMS in the remitting phase and twenty-nine healthy controls. We stimulated the dominant hemisphere and recorded from the dominant hand to assess short-interval intracortical inhibition (SICI) and cortical silent period (CSP) duration. Disability was evaluated with the Multiple Sclerosis Functional Composite (MSFC). Regional cortical thickness and lesion volume were measured. RESULTS: RRMS participants with dominant upper limb dexterity impairments had prolonged CSP, but equivalent SICI, compared to participants with preserved function. CSP was not related to walking or cognitive performance. Higher normalized lesion volume correlated with longer CSP duration. When adjusting for normalized lesion volume, longer CSP significantly predicted worse dominant upper extremity impairment. CONCLUSIONS: High intracortical inhibition possibly contributes to (or prevents remission from) motor impairment. Lesions may be associated with intracortical inhibition shifts. SIGNIFICANCE: CSP duration and lesion burden should be considered when developing interventions aiming to mitigate motor impairment.

Magnetic-directed patterning of cell spheroids.

We have described an approach to fabricate three-dimensional (3D) cell-based structures using functionalized super paramagnetic iron oxide nanoparticles (SPIONs) as patterning agents to guide the assembly of endothelial cell spheroids into 3D patterns using the magnetic forces generated by a prefabricated magnetic template. SPIONs were first uptaken by endothelial cells before they were assembled into uniform-sized spheroids through a home-made robotic spheroid maker. To guide the magnetic spheroids, a unique magnetic template was fabricated using computer-aided design and cut from a magnetic sheet. The spheroids were then guided to the prefabricated magnetic template through the attractive magnetic forces between the SPIONs inside the endothelial cells and the magnetic template. Fusion of endothelial cell spheroids over time while adhered to the magnetic template allowed for the formation of 3D cell-based structures. Subsequent removal of the prefabricated magnetic template left 3-D endothelial cell sheets, which may be stacked to fabricate complicated 3D multicellular tissue structures. To enhance the cytocompatibility, SPIONs were silica-coated before use. At low concentrations, the SPIONs did not adversely affect cell viability, proliferation, and phenotype stability. Light and confocal microscopy showed that endothelial cell spheroids could be reproducibly created with high uniformity. The endothelial cells were able to remain viable and maintain the 3D structure in vitro. We have proved the concept to use SPIONs as a patterning agent to direct the attachment and self assembly of SPION-loaded endothelial cell spheroids on a prefabricated magnetic template for the formation of 3D cell based structures. A magnetic-directed technique allows quick patterning of cell spheroids in accordance with desirable magnetic patterns, therefore, holding promise for scalable fabrication of complicated 3D multicellular tissue structures. By varying the cell types and the prefabricated magnetic patterns, this magnetic-directed patterning strategy may find use in bioprinting and multicellular tissue graft fabrication.

Fabrication of a biomimetic elastic intervertebral disk scaffold using additive manufacturing.

A custom-designed three-dimensional additive manufacturing device was developed to fabricate scaffolds for intervertebral disk (IVD) regeneration. This technique integrated a computer with a device capable of 3D movement allowing for precise motion and control over the polymer scaffold resolution. IVD scaffold structures were designed using computer-aided design to resemble the natural IVD structure. Degradable polyurethane (PU) was used as an elastic scaffold construct to mimic the elastic nature of the native IVD tissue and was deposited at a controlled rate using ultra-fine micropipettes connected to a syringe pump. The elastic PU was extruded directly onto a collecting substrate placed on a freezing stage. The three-dimensional movement of the computer-controlled device combined with the freezing stage enabled precise control of polymer deposition using extrusion. The addition of the freezing stage increased the polymer solution viscosity and hardened the polymer solution as it was extruded out of the micropipette tip. This technique created scaffolds with excellent control over macro- and micro-structure to influence cell behavior, specifically for cell adhesion, proliferation, and alignment. Concentric lamellae were printed at a high resolution to mimic the native shape and structure of the IVD. Seeded cells aligned along the concentric lamellae and acquired cell morphology similar to native tissue in the outer portion of the IVD. The fabricated scaffolds exhibited elastic behavior during compressive and shear testing, proving that the scaffolds could support loads with proper fatigue resistance without permanent deformation. Additionally, the mechanical properties of the scaffolds were comparable to those of native IVD tissue.