Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults.

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.

Microclimate, airborne particles, and microbiological monitoring protocol for conservation of rock-art caves: The case of the world-heritage site La Garma cave (Spain).

Cave heritage is often threatened by tourism or even scientific activities, which can lead to irreversible deterioration. We present a preventive conservation monitoring protocol to protect caves with rock art, focusing on La Garma Cave (Spain), a World Heritage Site with valuable archaeological materials and Palaeolithic paintings. This study assessed the suitability of the cave for tourist use through continuous microclimate and airborne particles monitoring, biofilm analysis, aerobiological monitoring and experimental visits. Our findings indicate several factors that make it inadvisable to adapt the cave for tourist use. Human presence and transit within the cave cause cumulative effects on the temperature of environmentally very stable and fragile sectors and significant resuspension of particles from the cave sediments. These environmental perturbations represent severe impacts as they affect the natural aerodynamic control of airborne particles and determine bacterial dispersal throughout the cave. This monitoring protocol provides part of the evidence to design strategies for sustainable cave management.

Histopathological characterization of cerebral small vessel disease in epilepsy patients with temporal lobe epilepsy submitted to surgery: A case-control study.

BACKGROUND: Cerebrovascular disease (CVD) is a major contributor to epilepsy; however, patients with epilepsy also have a significantly increased risk of stroke. The way in which epilepsy contributes to the increased risk of stroke is still uncertain and is ill-characterized in neuropathological studies. A neuropathological characterization of cerebral small vessel disease (cSVD) in patients with chronic epilepsy was performed. METHODS: Thirty-three patients with refractory epilepsy and hippocampal sclerosis (HS) submitted to epilepsy surgery from a reference center were selected between 2010 and 2020 and compared with 19 autopsy controls. Five randomly selected arterioles from each patient were analyzed using a previously validated scale for cSVD. The presence of CVD disease imaging markers in pre-surgical brain magnetic resonance imaging (MRI) was studied. RESULTS: There were no differences in age (43.8 vs. 41.6 years; p = 0.547) or gender distribution (female gender 60.6% vs. male gender 52.6%; p = 0.575) between groups. Most CVD findings in brain MRI were mild. Patients had a mean time between the epilepsy onset and surgery of 26 ± 14.7 years and were medicated with a median number of three antiseizure medication (ASMs) [IQR 2-3]. Patients had higher median scores in arteriolosclerosis (3 vs. 1; p < 0.0001), microhemorrhages (4 vs. 1; p < 0.0001) and total score value (12 vs. 8.9; p = 0.031) in comparison with controls. No correlation was found between age, number of years until surgery, number of ASMs or cumulative defined daily dosage of ASM. CONCLUSION: The present study provides evidence supporting the increased burden of cSVD in the neuropathological samples of patients with chronic epilepsy.

First Insights into the Bacterial Diversity of Mount Etna Volcanic Caves.

While microbial communities in limestone caves across the world are relatively understood, knowledge of the microbial composition in lava tubes is lagging behind. These caves are found in volcanic regions worldwide and are typically lined with multicolored microbial mats on their walls and ceilings. The Mount Etna (Sicily, S-Italy) represents one of the most active volcanos in the world. Due to its outstanding biodiversity and geological features, it was declared Natural Heritage of Humanity by the UNESCO in 2013. Despite the presence of more than 200 basaltic lava tubes, the microbial diversity of these hypogean systems has never been investigated so far. Here, we investigated bacterial communities in four lava tubes of Mount Etna volcano. Field emission scanning electron microscopy (FESEM) was carried out for the morphological characterization and detection of microbial features. We documented an abundant presence of microbial cells with different morphotypes including rod-shaped, filamentous, and coccoidal cells with surface appendages, resembling actinobacteria reported in other lava tubes across the world. Based on 16S rRNA gene analysis, the colored microbial mats collected were mostly composed of bacteria belonging to the phyla Actinomycetota, Pseudomonadota, Acidobacteriota, Chloroflexota, and Cyanobacteria. At the genus level, the analysis revealed a dominance of the genus Crossiella, which is actively involved in biomineralization processes, followed by Pseudomonas, Bacillus, Chujaibacter, and Sphingomonas. The presence of these taxa is associated with the carbon, nitrogen, and ammonia cycles, and some are possibly related to the anthropic disturbance of these caves. This study provides the first insight into the microbial diversity of the Etna volcano lava tubes, and expands on previous research on microbiology of volcanic caves across the world.

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response.

Increased expression of complement components in tuberous sclerosis complex and focal cortical dysplasia type 2B brain lesions.

OBJECTIVE: Increasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well-characterized patients with TSC and FCD2B. METHODS: We applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed. RESULTS: Protein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns. SIGNIFICANCE: Our results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies.

Intelligence quotient (IQ) as a predictor of epilepsy surgery outcome.

INTRODUCTION: About one-third of patients with epilepsy have a refractory form which is associated with important economic and psychosocial burden. Most of these patients also suffer from comorbidities. One of the most frequent is cognitive impairment. Resective surgery or neuromodulation techniques may improve seizure control. Several factors have been proposed as potential predictors of the success of surgery regarding seizure frequency. We aimed to study preoperative cognitive performance as a predictor of the epilepsy surgery outcome. METHODS: In this ambispective study we studied total intelligence quotients (IQ) measured before surgery with the Wechsler Adult Intelligence Scale (WAIS) as a potential predictor of Engel Class at 1 year after surgery. Then we included IQ in a multivariate model and tested its performance. RESULTS: Preoperative IQ was a significant and independent predictor of the Engel Class at 1 year after surgery (OR 0.94; CI 0.90-0.98; p = 0.007). The multivariate model including the age at epilepsy onset, education level, sex, and the type of surgery (resective versus palliative surgery) showed an area under the ROC curve of 0.85. CONCLUSIONS: A low intelligence level may constitute a marker of worse prognosis after epilepsy surgery. However, other predictors should also be considered when evaluating surgical candidates.

Anterior Nucleus of Thalamus Deep Brain Stimulation: A Clinical-Based Analysis of the Ideal Target in Drug-Resistant Epilepsy.

INTRODUCTION: Deep brain stimulation of the anterior nucleus of thalamus (ANT-DBS) is an approved procedure for drug-resistant epilepsy. However, the preferred location inside ANT is not well known. In this study, we investigated the relationship between stereotactical coordinates of stimulated contacts and clinical improvement, in order to define the ideal target for ANT-DBS. METHODS: Individual contact's coordinates were obtained in the Montreal Neurological Institute (MNI) 152 space, with the utilization of advanced normalization tools and co-registration of pre- and postoperative MRI and CT images in open-source toolbox lead-DBS with the "Atlas of the Human Thalamus." Each contact's pair was either classified as a responder (≥50% seizure reduction and absence of intolerable adverse effects) or nonresponder, with a minimum follow-up of 11 continuous months of stimulation. RESULTS: A total of 19 contacts' pairs were tested in 14 patients. The responder rate was 9 out of 14 patients (64.3%). In 4 patients, a change in contacts' pairs was needed to achieve this result. A highly encouraging location inside ANT (HELIA) was delimited in MNI space, corresponding to an area in the anterior and inferior portion of the anteroventral (AV) nucleus, medially to the endpoint of the mammillothalamic tract (ANT-mtt junction) (x [3.8; 5.85], y [-2.1; -6.35] and z [6.2; 10.1] in MNI space). Statistically significant difference was observed between responders and nonresponders, in terms of the number of coordinates inside this volume. Seven responders and two nonresponders had at least 5 of 6 coordinates (2 electrodes) inside HELIA (77.8% sensitivity and 80% specificity). In 3 patients, changing to contacts that were better placed inside HELIA changed the status from nonresponder to responder. CONCLUSIONS: A relationship between stimulated contacts' coordinates and responder status was observed in drug-resistant epilepsy. The possibility to target different locations inside HELIA may help surpass anatomical variations and eventually obtain increased clinical benefit.

Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors.

Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

Paracoccus onubensis sp. nov., a novel alphaproteobacterium isolated from the wall of a show cave.

A novel facultatively anaerobic, non-motile, Gram-stain-negative, non-endospore-forming alphaproteobacterium, strain 1011MAR3C25T, was isolated from a white biofilm colonizing the walls of the Andalusian show cave Gruta de las Maravillas (Huelva, Spain). Strain 1011MAR3C25T grew at 8-42 °C (optimum, 20-30 °C), at pH 5.0-9.0 (optimum, pH 5.0-6.0) and in the presence of 0-12 % (w/v) NaCl (optimum 3-5 %). Cells were catalase- and oxidase-positive. The strain grew heterotrophically with various carbon sources and chemoautotrophically with thiosulfate under aerobic conditions. Results of phylogenetic analysis showed that strain 1011MAR3C25T was related to Paracoccus saliphilus DSM 18447T and Paracoccus alkanivorans LMG 30882T (97.90 % and 97.32 % 16S rRNA sequence identity values, respectively). The major respiratory quinone was ubiquinone Q-10 and the predominant fatty acid was C18 : 1 ω7c. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, an unidentified aminolipid, an unidentified glycolipid and an unidentified polar lipid. The DNA G+C content was 60.3 mol%. Based on a polyphasic taxonomic study it is proposed that strain 1011MAR3C25T (=CECT 9092T=LMG 29414T) represents a novel species of the genus Paracoccus, for which the name Paracoccus onubensis sp. nov. is proposed.

Environment-driven control of fungi in subterranean ecosystems: the case of La Garma Cave (northern Spain).

Airborne microorganisms can cause important conservation problems in caves with Paleolithic art and therefore the knowledge of cave aerodynamic is essential. La Garma Cave (Cantabria, Spain), an exceptional archaeological site with several levels of galleries interconnected and two entrances, presents a complex atmospheric dynamics. An approach including aerobiological sampling together with microclimate monitoring was applied to assess the factors controlling the origin of airborne fungi. Here we show that winter ventilation is critical for the increasing of Basidiomycota spores in the cave air and the highest concentrations were found in the most ventilated areas. On the contrary, Ascomycota spores prevailed in absence of ventilation. Besides, most Ascomycota were linked to insects and bats that visit or inhabit the cave. The combination of aerobiological and microclimate data constitutes a good approach to evaluate the influence of external climatic conditions and design the most suitable strategies for the conservation of cultural heritage in the cave environment.

Microbial Community Characterizing Vermiculations from Karst Caves and Its Role in Their Formation.

The microbiota associated with vermiculations from karst caves is largely unknown. Vermiculations are enigmatic deposits forming worm-like patterns on cave walls all over the world. They represent a precious focus for geomicrobiological studies aimed at exploring both the microbial life of these ecosystems and the vermiculation genesis. This study comprises the first approach on the microbial communities thriving in Pertosa-Auletta Cave (southern Italy) vermiculations by next-generation sequencing. The most abundant phylum in vermiculations was Proteobacteria, followed by Acidobacteria > Actinobacteria > Nitrospirae > Firmicutes > Planctomycetes > Chloroflexi > Gemmatimonadetes > Bacteroidetes > Latescibacteria. Numerous less-represented taxonomic groups (< 1%), as well as unclassified ones, were also detected. From an ecological point of view, all the groups co-participate in the biogeochemical cycles in these underground environments, mediating oxidation-reduction reactions, promoting host rock dissolution and secondary mineral precipitation, and enriching the matrix in organic matter. Confocal laser scanning microscopy and field emission scanning electron microscopy brought evidence of a strong interaction between the biotic community and the abiotic matrix, supporting the role of microbial communities in the formation process of vermiculations.

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.

The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.

May the right-side epileptogenic zone be a predictor of psychiatric comorbidity in people with refractory epilepsy?

The aim of this study was to determine the rate and types of lifetime psychiatric disorders, as well as their predictors, in a sample of people with refractory epilepsy. Demographic, neurological, psychiatric and neuropsychological data, from people with refractory epilepsy, were registered at the pre-surgical interview. Linear regression was used to determine predictors. One hundred and ninety-one participants were included. Forty-six percent of our sample had at least one previous psychiatric diagnosis, most frequently depressive (64%), anxiety (10%), substance use (10%) and psychotic disorders (6%). Patients with a right-side epileptogenic zone had an increased risk for these disorders (OR 2.36; CI 1.22-4.56; p = 0.01). Specific epilepsy-related factors may raise the risk of developing a psychiatric disorder. Our study adds evidence to support a bidirectional relationship between epilepsy and mental health.

Clinical determinants of psychopathological outcomes after epilepsy surgery.

OBJECTIVES: People with refractory epilepsy submitted to surgery may improve or deteriorate their cognitive and emotional functions. The aim of this study was to determine the predictors of longitudinal changes in psychopathological symptomatology, one year after epilepsy surgery, considering clinical and demographic characteristics. METHODS: People with refractory epilepsy referred to epilepsy surgery were included in this ambispective study. Psychiatric evaluations were made before surgery and one year after the procedure. Demographic, psychiatric, and neurological data were recorded. Linear regression was used to analyze longitudinal data regarding the Global Severity Index and 9 symptom dimensions of Symptom Checklist-90 (SCL-90). RESULTS: Seventy-six people were included. Bilateral epileptogenic zone, lack of remission of disabling seizures, and deep brain stimulation, targeting the anterior nucleus of the thalamus (ANT-DBS), were the most important predictors of an increase in SCL-90 scores, after surgery. CONCLUSION: Some individual factors may have an impact on the development or worsening of the previous psychopathology. This study identifies clinical aspects associated with greater psychological distress, after surgery. These patients may benefit from more frequent psychiatric routine assessments for early detection.

Psychiatric disorders as predictors of epilepsy surgery outcome.

OBJECTIVES: Our aim was to determine if a history of a mental disorder predicts a worst neurological outcome for patients undergoing epilepsy surgery. METHODS: We conducted an ambispective observational study including people with refractory epilepsy who underwent resective surgery. Demographic, psychiatric, and neurological data were collected, before and one year after surgery. Presurgical interviews included a psychiatric evaluation and the determination of prevalent and lifetime psychiatric diagnosis. The one-year postsurgical outcome was classified according to the Engel Outcome Scale. Predictors of postsurgical Engel class were determined using an ordered logistic regression model. RESULTS: A lifetime history of any mental disorder was a significant predictor of a higher Engel Class (p = 0.017). CONCLUSION: This study shows that psychiatric lifetime diagnoses are associated with worse surgical outcome and highlighted the importance of the inclusion of these diagnoses in the evaluation of the potential success of the surgery.

Predicting de novo psychopathology after epilepsy surgery: A 3-year cohort study.

OBJECTIVE: The aim of this study was to determine the potential risk factors for de novo psychiatric syndromes after epilepsy surgery. METHODS: Refractory epilepsy surgery candidates were recruited from our Refractory Epilepsy Reference Centre. Psychiatric evaluations were made before surgery and every year, during a 3-year follow-up period. Demographic, psychiatric, and neurological data were recorded. The types of surgeries considered were resective surgery (resection of the epileptogenic zone) and palliative surgery (deep brain stimulation of the anterior nuclei of the thalamus (ANT-DBS)). A survival analysis model was used to determine pre- and postsurgical predictors of de novo psychiatric events after surgery. RESULTS: One hundred and six people with refractory epilepsy submitted to epilepsy surgery were included. Sixteen people (15%) developed psychiatric disorders that were never identified before surgery. Multilobar epileptogenic zone (p = 0.001) and DBS of the ANT-DBS (p = 0.003) were found to be significant predictors of these events. CONCLUSION: People with more generalized epileptogenic activity and those who undergo ANT-DBS seem to present an increased susceptibility for the development of mental disorders, after neurosurgical interventions, for the treatment of refractory epilepsy. People considered to be at higher risk should be submitted to more frequent routine psychiatric assessments.

Personality patterns of people with medically refractory epilepsy - Does the epileptogenic zone matter?

OBJECTIVES: The aims of this study were to determine the rate of dysfunctional personality patterns before and after epilepsy surgery, their types, and the importance of the epileptogenic zone in a sample of people with refractory epilepsy. METHODS: We conducted an ambispective observational study, including refractory epilepsy surgery candidates. Demographic, psychiatric, and neurological data were recorded. Evaluation of personality was made using the Millon Clinical Multiaxial Inventory-II (MCMI-II). Presurgical predictors of personality patterns were determined using a linear regression model. The proportion of patients with dysfunctional personality patterns, before and after surgery, was compared using the Mcnemar's test. Then a generalized estimating equation model was performed to include predictors of changes in this rate. RESULTS: One hundred and ninety-nine participants were included. Seventy percent had a dysfunctional personality pattern before surgery. After surgery, this percentage dropped to 58%. The difference was statistically significant after adjusting for potential confounders (p = 0.013). The most common types were Cluster C personality patterns. Temporal epileptogenic zone was a significant predictor of higher scores of the Avoidant (Coef. 11.8; Confidence Interval (CI) -0.59 23.7; p = 0.051) and Compulsive (Coef. 9.55; CI 2.48 16.6; p = 0.008) personality patterns and lower scores of Histrionic (Coef. -11.4; CI -21.2 -1.55; p = 0.024) and Antisocial (Coef. -8.4; CI -15.6 -1.25; p = 0.022) personality patterns, compared to extratemporal epileptogenic zone. CONCLUSION: People with refractory epilepsy have high rates of dysfunctional personality patterns. These patterns differ according to the epileptogenic zone.

BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions - Markers in the clinical stratification of pediatric gliomas.

BACKGROUND: Genetic alterations in pediatric primary brain tumors can be used as diagnostic and prognostic markers and are the basis for the development of new target therapies that, ideally, would be associated with lower mortality and morbidity. This study evaluates the incidence and interplay of the presence of BRAF V600E mutation and chromosomal 9p21 deletions in a series of 100 pediatric gliomas, aiming to determine the role of these alterations in recurrence and malignant transformation, and to verify if they could be used in the clinical set for stratifying patients for tailored therapies and surveillance. METHODS: Sanger sequencing was used for the assessment of BRAF mutations at exon 15 and Fluorescent In Situ Hybridization (FISH) with BAC: RP11-14192 for the detection of 9p21 alterations. Expression levels of the CDKN2A and MTAP by real-time PCR were evaluated in cases with 9p21 deletions. Statistical analysis of genetic and clinical data was performed using Graph Pad Prism 5 and SPSS Statistics 24 software. RESULTS: In our cohort it was observed that 7 /78 (8,9%) of the low-grade tumors recurred and 2 (2,6%) showed malignant transformation. BRAF V600E mutations were detected in 15 cases. No statistically significant correlations were found between the presence of BRAF V600E mutation and patient's morphologic or clinical features. Deletions at 9p21 abrogating the CDKN2A/B and MTAP loci were rare in grade I gliomas (12.2%, p = 0.0178) but frequent in grade IV gliomas (62.5%, p = 0.0087). Moreover it was found that deletions at these loci were correlated with a shorter overall survival (p = 0.011) and a shorter progression-free survival (p = 0.016). CONCLUSIONS: It was demonstrated that in these tumors BRAF V600E mutated and that CDKN2A/B MTAP co-deletions may be used for stratifying patients for a stricter surveillance. The Investigating and defining if glial tumors with CDKN2A/B and MTAP homozygous loss may be vulnerable to new forms of therapy, namely those affecting the methionine salvage pathway, was proven to be of importance.