Successful epilepsy surgery in two cases with multiple sclerosis

Brain surgery is the only curative treatment for people with focal epilepsy, but it is unclear whether this induces active disease in multiple sclerosis (MS). This creates a barrier to evaluate MS patients for epilepsy surgery. We present two cases of successful epilepsy surgery in patients with pharmacoresistant epilepsy and stable MS and give an overview of the existing literature. (1) a 28-year-old woman with seizures arising from a right basal temporo-occipital ganglioglioma was seizure-free after surgery, without MS relapse but with one new MS lesion postsurgically. (2) a 46-year-old woman with seizures arising from a natalizumab-associated progressive multifocal leukoencephalopathy (PML) lesion in the right frontal lobe was seizure-free after surgery preceded by extraoperative subdural electrocorticography, with new subclinical MS lesions. We are the first to report brain surgery in a PML survivor. Both patients stabilized radiologically after initiating second-line therapies. Successful epilepsy surgery can substantially increase the quality of life in patients with pharmacoresistant epilepsy and MS. With increasing survival rates of brain tumors and PML, the risk–benefit ratio of epilepsy surgery compared to a potential MS relapse after surgery becomes critically important. Shared decision-making is valuable for balancing the risks related to both diseases

The value of intra-operative electrographic biomarkers for tailoring during epilepsy surgery: from group-level to patient-level analysis

Signal analysis biomarkers, in an intra-operative setting, may be complementary tools to guide and tailor the resection in drug-resistant focal epilepsy patients. Effective assessment of biomarker performances are needed to evaluate their clinical usefulness and translation. We defined a realistic ground-truth scenario and compared the effectiveness of different biomarkers alone and combined to localize epileptogenic tissue during surgery. We investigated the performances of univariate, bivariate and multivariate signal biomarkers applied to 1 min inter-ictal intra-operative electrocorticography to discriminate between epileptogenic and non-epileptogenic locations in 47 drug-resistant people with epilepsy (temporal and extra-temporal) who had been seizure-free one year after the operation. The best result using a single biomarker was obtained using the phase-amplitude coupling measure for which the epileptogenic tissue was localized in 17 out of 47 patients. Combining the whole set of biomarkers provided an improvement of the performances: 27 out of 47 patients. Repeating the analysis only on the temporal-lobe resections we detected the epileptogenic tissue in 29 out of 30 combining all the biomarkers. We suggest that the assessment of biomarker performances on a ground-truth scenario is required to have a proper estimate on how biomarkers translate into clinical use. Phase-amplitude coupling seems the best performing single biomarker and combining biomarkers improves localization of epileptogenic tissue. Performance achieved is not adequate as a tool in the operation theater yet, but it can improve the understanding of pathophysiological process

The spatial relationship between the MRI lesion and intraoperative electrocorticography in focal epilepsy surgery.

MRI and intraoperative electrocorticography are often used in tandem to delineate epileptogenic tissue in resective surgery for focal epilepsy. Both the resection of the MRI lesion and tissue with high rates of electrographic discharges on electrocorticography, e.g. spikes and high-frequency oscillations (80-500 Hz), lead to a better surgical outcome. How MRI and electrographic markers are related, however, is currently unknown. The aim of this study was to find the spatial relationship between MRI lesions and spikes/high-frequency oscillations. We retrospectively included 33 paediatric and adult patients with lesional neocortical epilepsy who underwent electrocorticography-tailored surgery (14 females, median age = 13.4 years, range = 0.6-47.0 years). Mesiotemporal lesions were excluded. We used univariable linear regression to find correlations between pre-resection spike/high-frequency oscillation rates on an electrode and its distance to the MRI lesion. We tested straight lines to the centre and the edge of the MRI lesion, and the distance along the cortical surface to determine which of these distances best reflects the occurrence of spikes/high-frequency oscillations. We conducted a moderator analysis to investigate the influence of the underlying pathology type and lesion volume on our results. We found spike and high-frequency oscillation rates to be spatially linked to the edge of the MRI lesion. The underlying pathology type influenced the spatial relationship between spike/high-frequency oscillation rates and the MRI lesion (P spikes < 0.0001, P ripples < 0.0001), while the lesion volume did not (P spikes = 0.64, P ripples = 0.89). A higher spike rate was associated with a shorter distance to the edge of the lesion for cavernomas [F(1,64) = -1.37, P < 0.0001, η 2 = 0.22], focal cortical dysplasias [F(1,570) = -0.25, P < 0.0001, η 2 = 0.05] and pleomorphic xanthoastrocytomas [F(1,66) = -0.18, P = 0.01, η 2 = 0.09]. In focal cortical dysplasias, a higher ripple rate was associated with a shorter distance [F(1,570) = -0.35, P < 0.0001, η 2 = 0.05]. Conversely, low-grade gliomas showed a positive correlation; the further an electrode was away from the lesion, the higher the rate of spikes [F(1,75) = 0.65, P < 0.0001, η 2 = 0.37] and ripples [F(1,75) = 2.67, P < 0.0001, η 2 = 0.22]. Pathophysiological processes specific to certain pathology types determine the spatial relationship between the MRI lesion and electrocorticography results. In our analyses, non-tumourous lesions (focal cortical dysplasias and cavernomas) seemed to intrinsically generate spikes and high-frequency oscillations, particularly at the border of the lesion. This advocates for a resection of this tissue. Low-grade gliomas caused epileptogenicity in the peritumoural tissue. Whether a resection of this tissue leads to a better outcome is unclear. Our results suggest that the underlying pathology type should be considered when intraoperative electrocorticography is interpreted

High-resolution electric source imaging for presurgical evaluation of tuberous sclerosis complex patients

Objective: We retrospectively assessed the localizing value of patient-history-based semiology (PHS), video-based semiology (VS), long-term monitoring video electroencephalography (LTM-VEEG) and interictal high resolution electric source imaging (HR-ESI) in the presurgical workup of patients with tuberous sclerosis complex (TSC). Methods: Data from 24 consecutive TSC surgical candidates who underwent both HR-ESI and LTM-VEEG was retrospectively collected. PHS and VS were analyzed to hypothesize the symptomatogenic zone localization. LTM-VEEG and HR-ESI localization results were extracted from the diagnostic reports. Localizing value was compared between modalities, taken the resected/disconnected area of surgical patients in consideration. HR-ESI's impact on the epileptogenic zone hypothesis and surgical workup was evaluated. Results: Semiology, interictal EEG, ictal EEG and HR-ESI were localizing in 25%, 54%, 63% and 79% of patients. Inter-modality concordance ranged between 33–89%. In good surgical outcome patients, PHS, VS, interictal EEG, ictal EEG and HR-ESI showed concordance with resected area in 1/9 (11%), 0/9 (0%), 4/9 (44%), 3/9 (33%) and 6/9 patients (67%). HR-ESI positively impacts clinical management in 50% of patients. Conclusions: In presurgical evaluation of TSC patients, semiology often has limited localizing value. Presurgical work-up benefits from HR-ESI. Significance: Our findings may advice future presurgical epilepsy workup of TSC patients with the ultimate aim to improve outcome

Sharon Macdonald – Memorylands: Heritage and Identity in Europe Today

Memorylands: Heritage and Identity in Europe Today é um livro de síntese que assinala o culminar de anos de trabalho da antropóloga britânica Sharon Macdonald sobre os temas relacionados do património, da memória e da identidade em contextos europeus. Em Reimagining Culture: Histories, Identities and the Gaelic Renaissance, de 1997, situava o eixo analítico entre o local e o global, focando o seu olhar na questão dos muitos “renascimentos identitários” de escala local e regional que à época –..

Intraoperative mapping of epileptogenic foci and tumor infiltration in neuro-oncology patients with epilepsy

BACKGROUND: Epileptogenesis and glioma growth have a bidirectional relationship. We hypothesized people with gliomas can benefit from the removal of epileptic tissue and that tumor-related epileptic activity may signify tumor infiltration in peritumoral regions. We investigated whether intraoperative electrocorticography (ioECoG) could improve seizure outcomes in oncological glioma surgery, and vice versa, what epileptic activity (EA) tells about tumor infiltration. METHODS: We prospectively included patients who underwent (awake) ioECoG-assisted diffuse-glioma resection through the oncological trajectory. The IoECoG-tailoring strategy relied on ictal and interictal EA (spikes and sharp waves). Brain tissue, where EA was recorded, was assigned for histopathological examination separate from the rest of the tumor. Weibull regression was performed to assess how residual EA and extent of resection (EOR) related to the time-to-seizure recurrence, and we investigated which type of EA predicted tumor infiltration. RESULTS: Fifty-two patients were included. Residual spikes after resection were associated with seizure recurrence in patients with isocitrate dehydrogenase (IDH) mutant astrocytoma or oligodendroglioma (HR = 7.6[1.4-40.0], P-value = .01), independent from the EOR. This was not observed in IDH-wildtype tumors. All tissue samples resected based on interictal spikes were infiltrated by tumor, even if the MRI did not show abnormalities. CONCLUSIONS: Complete resection of epileptogenic foci in ioECoG may promote seizure control in IDH-mutant gliomas. The cohort size of IDH-wildtype tumors was too limited to draw definitive conclusions. Interictal spikes may indicate tumor infiltration even when this area appears normal on MRI. Integrating electrophysiology guidance into oncological tumor surgery could contribute to improved seizure outcomes and precise guidance for radical tumor resection

Study protocol for a multicenter randomised controlled trial on the (cost)effectiveness of biopsy combined with same-session MR-guided LITT versus biopsy alone in patients with primary irresectable glioblastoma (EMITT trial)

Background: Glioblastoma (GBM) is the most common primary, malignant brain tumour with a 5-year survival of 5%. If possible, a glioblastoma is resected and further treated with chemoradiation therapy (CRT), but resection is not feasible in about 30% of cases. Current standard of care in these cases is a biopsy followed by CRT. Magnetic resonance (MR) imaging-guided laser interstitial thermal therapy (LITT) has been suggested as a minimally invasive alternative when surgery is not feasible. However, high-quality evidence directly comparing LITT with standard of care is lacking, precluding any conclusions on (cost-)effectiveness. We therefore propose a multicenter randomized controlled study to assess the (cost-)effectiveness of MR-guided LITT as compared to current standard of care (EMITT trial). Methods and analysis: The EMITT trial will be a multicenter pragmatic randomized controlled trial in the Netherlands. Seven Dutch hospitals will participate in this study. In total 238 patients will be randomized with 1:1 allocation to receive either biopsy combined with same-session MR-guided LITT therapy followed by CRT or the current standard of care being biopsy followed by CRT. The primary outcomes will be health-related quality of life (HR-QoL) (non-inferiority) using EORTC QLQ-C30 + BN20 scores at 5 months after randomization and overall survival (superiority). Secondary outcomes comprise cost-effectiveness (healthcare and societal perspective) and HR-QoL of life over an 18-month time horizon, progression free survival, tumour response, disease specific survival, longitudinal effects, effects on adjuvant treatment, ablation percentage and complication rates. Discussion: The EMITT trial will be the first RCT on the effectiveness of LITT in patients with glioblastoma as compared with current standard of care. Together with the Dutch Brain Tumour Patient association, we hypothesize that LITT may improve overall survival without substantially affecting patients’ quality of life. Trial registration: This trial is registered at ClinicalTrials.gov (NCT05318612)

Developmental trajectory of transmission speed in the human brain

The structure of the human connectome develops from childhood throughout adolescence to middle age, but how these structural changes affect the speed of neuronal signaling is not well described. In 74 subjects, we measured the latency of cortico-cortical evoked responses across association and U-fibers and calculated their corresponding transmission speeds. Decreases in conduction delays until at least 30 years show that the speed of neuronal communication develops well into adulthood

Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology

Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis

Loss of maturity and homeostatic functions in Tuberous Sclerosis Complex-derived astrocytes

INTRODUCTION: Constitutive activation of the mTOR pathway, as observed in Tuberous Sclerosis Complex (TSC), leads to glial dysfunction and subsequent epileptogenesis. Although astrocytes are considered important mediators for synaptic clearance and phagocytosis, little is known on how astrocytes contribute to the epileptogenic network. METHODS: We employed singlenuclei RNA sequencing and a hybrid fetal calf serum (FCS)/FCS-free cell culture model to explore the capacity of TSC-derived astrocytes to maintain glutamate homeostasis and clear debris in their environment. RESULTS: We found that TSC astrocytes show reduced maturity on RNA and protein level as well as the inability to clear excess glutamate through the loss of both enzymes and transporters complementary to a reduction of phagocytic capabilities. DISCUSSION: Our study provides evidence of mechanistic alterations in TSC astrocytes, underscoring the significant impairment of their supportive functions. These insights enhance our understanding of TSC pathophysiology and hold potential implications for future therapeutic interventions