Frailty and brain changes in older adults without cognitive impairment: A scoping review.

Little is known about changes in the brain associated with frailty, in particular, which brain areas could be related to frailty in older people without cognitive impairment. This scoping review mapped evidence on functional and/or structural brain changes in frail older adults without cognitive impairment. The methodology proposed by the JBI® was used in this study. The search in PubMed, PubMed PMC, BVS/BIREME, EBSCOHOST, Scopus, Web of Science, Embase, and PROQUEST was conducted up to January 2023. Studies included following the population, concepts, context and the screening and data extraction were performed by two independent reviewers. A total of 9,912 records were identified, 5,676 were duplicates and were excluded. The remaining articles were screened; 31 were read in full and 17 articles were included. The results showed that lesions in white matter hyperintensities, reduced volume of the hippocampus, cerebellum, middle frontal gyrus, low gray matter volume, cortical atrophy, decreased connectivity of the supplementary motor area, presence of amyloid-beta peptide (aß) in the anterior and posterior putamen and precuneus regions were more frequently observed in frail older adults, compared with non-frail individuals. Studies have suggested that such findings may be of neurodegenerative or cerebrovascular origin. The identification of these brain alterations in frail older adults through neuroimaging studies contributes to our understanding of the underlying mechanisms of frailty. Such findings may have implications for the early detection of frailty and implementation of intervention strategies.

Practices in the prescription of antiseizure medications: is it time to change?

The treatment of epilepsy has advanced over the past 30 years through the development of new antiseizure medications (ASMs). Unfortunately, not all of them have been approved yet in Brazil, and many are still underused. When comparing new ASMs to older ones, they are generally not more effective in treating epilepsy. However, they offer better tolerability, with fewer interactions and long-term side effects, especially for patients with comorbidities or those requiring polytherapy. Enzyme induction caused by older ASMs is associated with increased cholesterol levels, drug interactions with decreased effects of statins and other cardiovascular medications, anticoagulants, chemotherapy, immunosuppressors, anti-infective agents (including HIV treatment), antidepressants, and contraceptives. Additionally, they can reduce levels of vitamin D and sex hormones, as well as decrease bone density. The increasing concern about these effects during life, especially after prolonged exposure, has led most developed countries to change prescription patterns in favor of new ASMs, particularly levetiracetam and lamotrigine. Both are also considered the safest options for women of childbearing age. Regrettably, the prescription trends in Brazil have remained largely unchanged over time. This can be partially attributed to the slower approval process of ASM and the reluctance of general physicians and neurologists to embrace these new concepts. In this concise review, we highlight the various advantages linked to the new ASM, aiming to promote a shift in the prescription pattern for ASM. The selection of ASM should be customized according to individual characteristics, and practical suggestions for choosing ASMs are provided in this paper.

O tratamento da epilepsia avançou nos últimos 30 anos com o desenvolvimento de novos medicamentos anticrise (MAC). Infelizmente, nem todos estão aprovados no Brasil e muitos ainda são subutilizados. Os novos MAC não são mais eficazes que os antigos, mas apresentam melhor tolerabilidade, menos interações e efeitos colaterais a longo prazo, especialmente para pacientes com comorbidades ou que necessitam de politerapia. A indução enzimática causada pelos MAC antigos está associada ao aumento dos níveis de colesterol, interações medicamentosas com redução do efeito das estatinas e outros medicamentos cardiovasculares, anticoagulantes, quimioterapia, imunossupressores, agentes anti-infecciosos (incluindo tratamento do HIV), antidepressivos e contraceptivos. Além disso, podem reduzir os níveis de vitamina D e hormônios sexuais, podendo afetar a massa óssea. A crescente preocupação sobre estes efeitos ao longo da vida, com a exposição prolongada, levou a maioria dos países desenvolvidos a modificar o padrão de prescrição com maior uso dos novos MAC, especialmente levetiracetam e lamotrigina. Ambos são considerados as opções mais seguras para mulheres em idade fértil. Infelizmente, as tendências de prescrição no Brasil permaneceram praticamente inalteradas ao longo do tempo. Isto pode ser parcialmente explicado pela lentidão no processo de aprovação dos MAC e à resistência dos médicos generalistas e neurologistas em adotar estes novos conceitos. Nesta revisão, destacamos as vantagens dos novos MAC e a necessidade da mudança no padrão de prescrição também no Brasil. A escolha do MAC deve ser feita de acordo com as características individuais dos pacientes e sugestões práticas são apresentadas.

Disruption of Resting-State Functional Connectivity in Acute Ischemic Stroke: Comparisons Between Right and Left Hemispheric Insults.

Few resting-state functional magnetic resonance imaging (RS-fMRI) studies evaluated the impact of acute ischemic changes on cerebral functional connectivity (FC) and its relationship with functional outcomes after acute ischemic stroke (AIS), considering the side of lesions. To characterize alterations of FC of patients with AIS by analyzing 12 large-scale brain networks (NWs) with RS-fMRI. Additionally, we evaluated the impact of the side (right (RH) or left (LH) hemisphere) of insult on the disruption of brain NWs. 38 patients diagnosed with AIS (17 RH and 21 LH) who performed 3T MRI scans up to 72 h after stroke were compared to 44 healthy controls. Images were processed and analyzed with the software toolbox UF2C with SPM12. For the first level, we generated individual matrices based on the time series extraction from 70 regions of interest (ROIs) from 12 functional NWs, constructing Pearson's cross-correlation; the second-level analysis included an analysis of covariance (ANCOVA) to investigate differences between groups. The statistical significance was determined with p < 0.05, after correction for multiple comparisons with false discovery rate (FDR) correction. Overall, individuals with LH insults developed poorer clinical outcomes after six months. A widespread pattern of lower FC was observed in the presence of LH insults, while a contralateral pattern of increased FC was identified in the group with RH insults. Our findings suggest that LH stroke causes a severe and widespread pattern of reduction of brain networks' FC, presumably related to the impairment in their long-term recovery.

Practices in the prescription of antiseizure medications: is it time to change? / Práticas na prescrição de medicamentos anticrise: está na hora de mudar?

Abstract The treatment of epilepsy has advanced over the past 30 years through the development of new antiseizure medications (ASMs). Unfortunately, not all of them have been approved yet in Brazil, and many are still underused. When comparing new ASMs to older ones, they are generally not more effective in treating epilepsy. However, they offer better tolerability, with fewer interactions and long-term side effects, especially for patients with comorbidities or those requiring polytherapy. Enzyme induction caused by older ASMs is associated with increased cholesterol levels, drug interactions with decreased effects of statins and other cardiovascular medications, anticoagulants, chemotherapy, immunosuppressors, anti-infective agents (including HIV treatment), antidepressants, and contraceptives. Additionally, they can reduce levels of vitamin D and sex hormones, as well as decrease bone density. The increasing concern about these effects during life, especially after prolonged exposure, has led most developed countries to change prescription patterns in favor of new ASMs, particularly levetiracetam and lamotrigine. Both are also considered the safest options for women of childbearing age. Regrettably, the prescription trends in Brazil have remained largely unchanged over time. This can be partially attributed to the slower approval process of ASM and the reluctance of general physicians and neurologists to embrace these new concepts. In this concise review, we highlight the various advantages linked to the new ASM, aiming to promote a shift in the prescription pattern for ASM. The selection of ASM should be customized according to individual characteristics, and practical suggestions for choosing ASMs are provided in this paper.

Resumo O tratamento da epilepsia avançou nos últimos 30 anos com o desenvolvimento de novos medicamentos anticrise (MAC). Infelizmente, nem todos estão aprovados no Brasil e muitos ainda são subutilizados. Os novos MAC não são mais eficazes que os antigos, mas apresentam melhor tolerabilidade, menos interações e efeitos colaterais a longo prazo, especialmente para pacientes com comorbidades ou que necessitam de politerapia. A indução enzimática causada pelos MAC antigos está associada ao aumento dos níveis de colesterol, interações medicamentosas com redução do efeito das estatinas e outros medicamentos cardiovasculares, anticoagulantes, quimioterapia, imunossupressores, agentes anti-infecciosos (incluindo tratamento do HIV), antidepressivos e contraceptivos. Além disso, podem reduzir os níveis de vitamina D e hormônios sexuais, podendo afetar a massa óssea. A crescente preocupação sobre estes efeitos ao longo da vida, com a exposição prolongada, levou a maioria dos países desenvolvidos a modificar o padrão de prescrição com maior uso dos novos MAC, especialmente levetiracetam e lamotrigina. Ambos são considerados as opções mais seguras para mulheres em idade fértil. Infelizmente, as tendências de prescrição no Brasil permaneceram praticamente inalteradas ao longo do tempo. Isto pode ser parcialmente explicado pela lentidão no processo de aprovação dos MAC e à resistência dos médicos generalistas e neurologistas em adotar estes novos conceitos. Nesta revisão, destacamos as vantagens dos novos MAC e a necessidade da mudança no padrão de prescrição também no Brasil. A escolha do MAC deve ser feita de acordo com as características individuais dos pacientes e sugestões práticas são apresentadas.

Cognitive impairment in post-acute COVID-19 syndrome: a scoping review.

Emerging studies indicate the persistence of symptoms beyond the acute phase of COVID-19. Cognitive impairment has been observed in certain individuals for months following infection. Currently, there is limited knowledge about the specific cognitive domains that undergo alterations during the post-acute COVID-19 syndrome and the potential impact of disease severity on cognition. The aim of this review is to examine studies that have reported cognitive impairment in post-acute COVID-19, categorizing them into subacute and chronic phases. The methodology proposed by JBI was followed in this study. The included studies were published between December 2019 and December 2022. The search was conducted in PubMed, PubMed PMC, BVS - BIREME, Embase, SCOPUS, Cochrane, Web of Science, Proquest, PsycInfo, and EBSCOHost. Data extraction included specific details about the population, concepts, context, and key findings or recommendations relevant to the review objectives. A total of 7,540 records were identified and examined, and 47 articles were included. The cognitive domains most frequently reported as altered 4 to 12 weeks after acute COVID-19 were language, episodic memory, and executive function, and after 12 weeks, the domains most affected were attention, episodic memory, and executive function. The results of this scoping review highlight that adults with post-acute COVID-19 syndrome may have impairment in specific cognitive domains.

Estudos emergentes indicam a persistência dos sintomas além da fase aguda da COVID-19. O comprometimento cognitivo foi observado em alguns indivíduos durante meses após a infecção. Atualmente, há pouco conhecimento sobre os domínios cognitivos específicos que sofrem alterações durante a síndrome pós-aguda da COVID-19 e o possível impacto da gravidade da doença na cognição. O objetivo desta revisão é examinar estudos que relataram comprometimento cognitivo na COVID-19 pós-aguda, categorizando-os em fases subaguda e crônica. A metodologia proposta pela Joanna Briggs Institute foi seguida neste estudo. Os estudos incluídos foram publicados entre dezembro de 2019 e dezembro de 2022. A busca foi realizada no PubMed, PubMed PMC, BVS ­ BIREME, Embase, SCOPUS, Cochrane, Web of Science, Proquest, PsycInfo e EBSCOHost. A extração de dados incluiu detalhes específicos sobre a população, os conceitos, o contexto e as principais descobertas ou recomendações relevantes para os objetivos da revisão. Um total de 7.540 registros foi identificado e examinado, e 47 artigos foram incluídos. Os domínios cognitivos mais frequentemente relatados como alterados de 4 a 12 semanas após a COVID-19 aguda foram linguagem, memória episódica e função executiva e, após 12 semanas, os domínios mais afetados foram atenção, memória episódica e função executiva. Os resultados dessa revisão de escopo destacam que adultos com síndrome pós-aguda da COVID-19 podem apresentar comprometimento em domínios cognitivos específicos.

Cognitive impairment in post-acute COVID-19 syndrome: a scoping review / Comprometimento cognitivo na síndrome pós-COVID-19 aguda: uma revisão de escopo

Abstract Emerging studies indicate the persistence of symptoms beyond the acute phase of COVID-19. Cognitive impairment has been observed in certain individuals for months following infection. Currently, there is limited knowledge about the specific cognitive domains that undergo alterations during the post-acute COVID-19 syndrome and the potential impact of disease severity on cognition. The aim of this review is to examine studies that have reported cognitive impairment in post-acute COVID-19, categorizing them into subacute and chronic phases. The methodology proposed by JBI was followed in this study. The included studies were published between December 2019 and December 2022. The search was conducted in PubMed, PubMed PMC, BVS - BIREME, Embase, SCOPUS, Cochrane, Web of Science, Proquest, PsycInfo, and EBSCOHost. Data extraction included specific details about the population, concepts, context, and key findings or recommendations relevant to the review objectives. A total of 7,540 records were identified and examined, and 47 articles were included. The cognitive domains most frequently reported as altered 4 to 12 weeks after acute COVID-19 were language, episodic memory, and executive function, and after 12 weeks, the domains most affected were attention, episodic memory, and executive function. The results of this scoping review highlight that adults with post-acute COVID-19 syndrome may have impairment in specific cognitive domains.

Resumo Estudos emergentes indicam a persistência dos sintomas além da fase aguda da COVID-19. O comprometimento cognitivo foi observado em alguns indivíduos durante meses após a infecção. Atualmente, há pouco conhecimento sobre os domínios cognitivos específicos que sofrem alterações durante a síndrome pós-aguda da COVID-19 e o possível impacto da gravidade da doença na cognição. O objetivo desta revisão é examinar estudos que relataram comprometimento cognitivo na COVID-19 pós-aguda, categorizando-os em fases subaguda e crônica. A metodologia proposta pela Joanna Briggs Institute foi seguida neste estudo. Os estudos incluídos foram publicados entre dezembro de 2019 e dezembro de 2022. A busca foi realizada no PubMed, PubMed PMC, BVS - BIREME, Embase, SCOPUS, Cochrane, Web of Science, Proquest, PsycInfo e EBSCOHost. A extração de dados incluiu detalhes específicos sobre a população, os conceitos, o contexto e as principais descobertas ou recomendações relevantes para os objetivos da revisão. Um total de 7.540 registros foi identificado e examinado, e 47 artigos foram incluídos. Os domínios cognitivos mais frequentemente relatados como alterados de 4 a 12 semanas após a COVID-19 aguda foram linguagem, memória episódica e função executiva e, após 12 semanas, os domínios mais afetados foram atenção, memória episódica e função executiva. Os resultados dessa revisão de escopo destacam que adultos com síndrome pós-aguda da COVID-19 podem apresentar comprometimento em domínios cognitivos específicos.

Case report: Granzyme-B expression by T- and B- cells during severe AQP4-positive Neuromyelitis Optica spectrum disorder with fatal venous thromboembolism outcome.

Background: The expression of serine protease granzyme-B (GzmB) by circulating CD8+ T lymphocytes has been recently suggested as a biomarker for poor immunotherapy response and severe disability in patients with Neuromyelitis Optica spectrum disorders (NMOSD). In parallel, venous thromboembolism (VTE) has been reported mainly in NMOSD patients exhibiting transverse myelitis. Case presentation: Here, we describe an Aquaporin-4 positive (AQP4-positive) NMOSD patient who showed short myelitis (SM) and experienced a fatal pulmonary thromboembolism/lower extremity deep vein thrombosis during anti-CD20 treatment. Flow cytometry analyses from the peripheral blood revealed an enhanced cytotoxic behavior through circulating CD8+GzmB+ T, CD4+GzmB+ T lymphocytes, and residual CD19+GzmB+ B cells. Conclusions: Fatal VTE may be a rare outcome, particularly in patients exhibiting SM, and may share poorly understood immunological mechanisms with AQP4-positive NMOSD severity.

Brain volumes and white matter diffusion across the adult lifespan in temporal lobe epilepsy.

OBJECTIVE: Typical aging is associated with gradual cognitive decline and changes in brain structure. The observation that cognitive performance in mesial temporal lobe epilepsy (TLE) patients diverges from controls early in life with subsequent decline running in parallel would suggest an initial insult but does not support accelerated decline secondary to seizures. Whether TLE patients demonstrate similar trajectories of age-related gray (GM) and white matter (WM) changes as compared to healthy controls remains uncertain. METHODS: 3D T1-weighted and diffusion tensor images were acquired at a single site in 170 TLE patients (aged 23-74 years) with MRI signs of unilateral hippocampal sclerosis (HS, 77 right) and 111 healthy controls (aged 26-80 years). Global brain (GM, WM, total brain, and cerebrospinal fluid) and regional volumes (ipsi- and contralateral hippocampi), and fractional anisotropy (FA) of 10 tracts (three portions of corpus callosum, inferior longitudinal, inferior fronto-occipital and uncinate fasciculi, body of fornix, dorsal and parahippocampal-cingulum, and corticospinal tract) were compared between groups as a function of age. RESULTS: There were significant reductions of global brain and hippocampi volumes (greatest ipsilateral to HS), and FA of all 10 tracts in TLE versus controls. For TLE patients, regression lines run in parallel to those from controls for brain volumes and FA (for all tracts except the parahippocampal-cingulum and corticospinal tract) versus age across the adult lifespan. INTERPRETATION: These results imply a developmental hindrance occurring earlier in life (likely in childhood/neurodevelopmental stages) rather than accelerated atrophy/degeneration of most brain structures herein analyzed in patients with TLE.

Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II: Insights into pathophysiology and tissue characterization.

Introduction: Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. Methods: We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. Results: We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. Cholesterol biosynthesis was among the main enriched cellular pathways in both IIa and IIb gray matter. Particularly, the genes HMGCS1, HMGCR, and SQLE were upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Discussion: Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gray or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.

Magnetic resonance imaging texture analysis to differentiate ameloblastoma from odontogenic keratocyst.

The differentiation between ameloblastoma (AB) and odontogenic keratocyst (OKC) is essential for the formulation of the surgical plan, especially considering the biological behavior of these two pathological entities. Therefore, developing means to increase the accuracy of the diagnostic process is extremely important for a safe treatment. The aim of this study was to use magnetic resonance imaging (MRI) based on texture analysis (TA) as an aid in differentiating AB from OKC. This study comprised 18 patients; eight patients with AB and ten with OKC. All diagnoses were determined through incisional biopsy and later through histological examination of the surgical specimen. MRI was performed using a 3 T scanner with a neurovascular coil according to a specific protocol. All images were exported to segmentation software in which the volume of interest (VOI) was determined by a radiologist, who was blind to the histopathological results. Next, the textural parameters were computed by using the MATLAB software. Spearman's correlation coefficient was used to assess the correlation between texture parameters and the selected variables. Differences in TA parameters were compared between AB and OKC by using the Mann-Whitney test. Mann-Whitney test showed a statistically significant difference between AB and OKC for the parameters entropy (P = 0.033) and sum average (P = 0.033). MRI texture analysis has the potential to discriminate between AB and OKC as a noninvasive method. MRI texture analysis can be an additional tool to differentiate ameloblastoma from odontogenic keratocyst.

Brain microstructural changes and fatigue after COVID-19.

Background: Fatigue and cognitive complaints are the most frequent persistent symptoms in patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to assess fatigue and neuropsychological performance and investigate changes in the thickness and volume of gray matter (GM) and microstructural abnormalities in the white matter (WM) in a group of patients with mild-to-moderate coronavirus disease 2019 (COVID-19). Methods: We studied 56 COVID-19 patients and 37 matched controls using magnetic resonance imaging (MRI). Cognition was assessed using Montreal Cognitive Assessment and Cambridge Neuropsychological Test Automated Battery, and fatigue was assessed using Chalder Fatigue Scale (CFQ-11). T1-weighted MRI was used to assess GM thickness and volume. Fiber-specific apparent fiber density (FD), free water index, and diffusion tensor imaging data were extracted using diffusion-weighted MRI (d-MRI). d-MRI data were correlated with clinical and cognitive measures using partial correlations and general linear modeling. Results: COVID-19 patients had mild-to-moderate acute illness (95% non-hospitalized). The average period between real-time quantitative reverse transcription polymerase chain reaction-based diagnosis and clinical/MRI assessments was 93.3 (±26.4) days. The COVID-19 group had higher total CFQ-11 scores than the control group (p < 0.001). There were no differences in neuropsychological performance between groups. The COVID-19 group had lower FD in the association, projection, and commissural tracts, but no change in GM. The corona radiata, corticospinal tract, corpus callosum, arcuate fasciculus, cingulate, fornix, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and uncinate fasciculus were involved. CFQ-11 scores, performance in reaction time, and visual memory tests correlated with microstructural changes in patients with COVID-19. Conclusions: Quantitative d-MRI detected changes in the WM microstructure of patients recovering from COVID-19. This study suggests a possible brain substrate underlying the symptoms caused by SARS-CoV-2 during medium- to long-term recovery.

My journey after a mild infection with COVID-19: I want my old brain back.

Although neurocognitive dysfunction has been observed after infection by SARS-CoV-2, few studies have detailed these alterations or demonstrated their impact on daily life activities and work. Here, I describe the sequence of events following a mild COVID-19 infection in August 2020 (which now is described as "post-COVID syndrome") and comment on my ensuing limitations associated with cognitive difficulties, headache, fatigue and sleepiness. Furthermore, I discuss the efforts that I have made to recover from my infection since its beginning and the strategies adopted for living with persistent restrictions in terms of cognitive performance.

My journey after a mild infection with COVID-19: I want my old brain back / Minha jornada após uma infecção leve por COVID-19: eu quero meu cérebro antigo de volta

ABSTRACT Although neurocognitive dysfunction has been observed after infection by SARS-CoV-2, few studies have detailed these alterations or demonstrated their impact on daily life activities and work. Here, I describe the sequence of events following a mild COVID-19 infection in August 2020 (which now is described as "post-COVID syndrome") and comment on my ensuing limitations associated with cognitive difficulties, headache, fatigue and sleepiness. Furthermore, I discuss the efforts that I have made to recover from my infection since its beginning and the strategies adopted for living with persistent restrictions in terms of cognitive performance.

RESUMO Embora a disfunção neurocognitiva tenha sido observada após a infecção por SARS-Cov2, poucos estudos detalharam essas alterações ou demonstraram seu impacto nas atividades de vida diária e trabalho. Aqui eu descrevo a sequência de eventos após uma infecção leve por COVID-19 em agosto de 2020 (agora considerada Síndrome pós-COVID) e comento as limitações associadas às dificuldades cognitivas, dor de cabeça, fadiga e sonolência. Além disso, eu caracterizo o esforço de recuperação desde o início e as estratégias para conviver com restrições persistentes em termos de desempenho cognitivo.

The Relationship Between Depression and Anxiety Symptoms of Adult PWE and Caregivers in a Tertiary Center.

Background: Although several studies have emphasized the association between epilepsy and psychiatric disorders, fewer have investigated the impact of epilepsy on caregivers' emotional status, mainly in adult people with epilepsy (PWE). Here we investigated depressive symptoms, suicidal ideation, and anxiety symptoms in a large group of adult PWE and their caregivers. Methods: We analyzed symptoms of depression [with the Beck Depression Inventory-II (BDI-II)], suicidal ideation (with BDI-II item 9), and anxiety symptoms (with the Beck Anxiety Inventory) in a large group of adult PWE [N = 548 (60% women; median age 41)] and caregivers [N = 191 (72% women; median age 47)] from a Brazilian tertiary center, considering sociodemographic and clinical aspects. We also applied the Liverpool Adverse Events Profile to assess anti-seizure drugs adverse events. Results: While the presence (p = 0.026) (and intensity, p = 0.007) of depressive symptoms and suicidal ideation (p = 0.02) were higher in PWE compared to caregivers, the proportion of clinical anxiety symptoms (p = 0.32) (and the intensity, p = 0.13) was similar in both groups. Although the rates of suicidal ideation were higher in focal epilepsy (20%), both generalized genetic epilepsy and caregivers also presented elevated frequencies (11%) of suicidal ideation. The analyses of 120 patient-caregiver dyads revealed that the intensity of depressive symptoms in PWE (but not anxiety) correlated with the intensity of depressive (r = 0.35; p < 0.001) and anxiety (r = 0.25; p = 0.01) symptoms in their caregivers. In the multivariate analyses of PWE, focal epilepsy (compared to GGE) was associated with clinical depressive symptoms (odds ratio, OR 2.1) and suicidal ideation (OR 3.2), while recurrent seizures (compared to the seizure-free group) were associated with suicidal ideation (OR 2.6) and anxiety symptoms (OR 2.1). Also, caregivers with anxiety symptoms were 8 times more likely to exhibit depressive symptoms, and those with depressive symptoms were 8 times more likely to present anxiety symptoms. Conclusion: Our study suggests that specific attention for the caregivers' mental health is as essential as PWE. There is an urgent need for more studies involving caregivers to identify their emotional distress and provide adequate treatment.

Histopathological Correlations of Qualitative and Quantitative Temporopolar MRI Analyses in Patients With Hippocampal Sclerosis.

Hippocampal sclerosis (HS) is a common cause of pharmacoresistant focal epilepsy. Here, we (1) performed a histological approach to the anterior temporal pole of patients with HS to evaluate cortical and white matter (WM) cell populations, alteration of myelin integrity and markers of neuronal activity, and (2) correlated microscopic data with magnetic resonance imaging (MRI) findings. Our aim was to contribute with the understanding of neuroimaging and pathophysiological mechanisms of temporal lobe epilepsy (TLE) associated with HS. We examined MRIs and surgical specimens from the anterior temporal pole from TLE-HS patients (n = 9) and compared them with 10 autopsy controls. MRIs from healthy volunteers (n = 13) were used as neuroimaging controls. Histological techniques were performed to assess oligodendrocytes, heterotopic neurons, cellular proliferative index, and myeloarchitecture integrity of the WM, as well as markers of acute (c-fos) and chronic (ΔFosB) activities of neocortical neurons. Microscopic data were compared with neuroimaging findings, including T2-weighted/FLAIR MRI temporopolar blurring and values of fractional anisotropy (FA) from diffusion-weighed imaging (DWI). We found a significant increase in WM oligodendrocyte number, both in hematoxylin and eosin, and in Olig2-stained sections. The frequencies of oligodendrocytes in perivascular spaces and around heterotopic neurons were significantly higher in patients with TLE-HS compared with controls. The percentage of 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase; a marker of myeloarchitecture integrity) immunopositive area in the WM was significantly higher in TLE-HS, as well as the numbers of c-fos- and ΔFosB-immunostained neocortical neurons. Additionally, we demonstrated a decrease in axonal bundle integrity on neuroimaging, with a significant reduction in the FA in the anterior temporal pole. No differences were detected between individuals with and without temporopolar blurring on visual MRI analysis, considering the number of oligodendroglial cells and percentage of WM CNPase-positive areas. Also, there was no relationship between T2 relaxometry and oligodendrocyte count. In conclusion, our histopathological data support the following: (1) the hypothesis that repetitive neocortical neuronal activity could induce changes in the WM cellular constitution and myelin remodeling in the anterior temporal pole from patients with TLE-HS, (2) that oligodendroglial hyperplasia is not related to temporal blurring or T2 signal intensity on MRI, and (3) that reduced FA is a marker of increase in Olig2-immunopositive cells in superficial temporopolar WM from patients with TLE-HS.

Patterns of default mode network in temporal lobe epilepsy with and without hippocampal sclerosis.

The default mode network (DMN) consists of the deactivation of specific regions during the performance of cognitive tasks and activation during resting or mind wandering. Several pieces of evidence indicate the impairment of DMN in patients with mesial temporal lobe epilepsy (MTLE). However, most of these studies combined different underlying etiologies, failing to disentangle the influence of seizures and presence and side of hippocampal sclerosis (HS). We included 119 patients with MTLE divided into right-HS (n = 42), left-HS (n = 46), and magnetic resonance imaging (MRI)-negative MTLE (n = 31) and controls (n = 59). All underwent resting-state seed-based functional connectivity (FC), with a seed placed at the posterior cingulate cortex (PCC), an essential node for the DMN. To access group inferences, we used an SPM (Statistical Parametric Mapping) full-factorial model to compare patterns of activation using pairwise comparisons among all groups. Our results indicate a different pattern of DMN FC when controlling for side and presence of HS. The group with right-HS had increased FC in the left angular gyrus and the left middle occipital gyrus, when compared to controls, and increased FC of the left hippocampus when compared to the group with left-HS. The MRI-negative group had increased FC of the left hippocampus, left ventral diencephalon, and left fusiform gyrus as compared to left-HS, but did not show any areas of reduced FC compared to controls. By contrast, the group with left-HS did not show areas of increased FC compared to controls or the right-HS and had reduced FC in the left hippocampus compared to controls. Hence, the right-HS presented increased FC in areas related to the DMN in the left hemisphere; the MRI-negative group also showed increased FC in left-sided structures close to temporal lobe when compared to left-HS, probably indicating engagement in a compensatory system. In a subanalysis considering only the MRI-negative with left-sided EEG (electroencephalogram) subgroup, we found differences against controls, with left angular gyrus more connected in the first group, but no significant differences when compared to the group with left-HS. We conclude that the origin of seizures on the left hemisphere seems to engender a less prominent capacity of recruiting other neighbor areas related to DMN as compared to right-HS and controls. Considering recent studies that have revealed the importance of DMN for cognitive skills and memory, our findings may indicate that deficiencies exhibited by patients with left-HS temporal lobe epilepsy (TLE) in connecting to the DMN could be a surrogate marker of their known worse neuropsychological performance. Further studies with direct comparisons between cognitive tests and FC within the DMN are needed to validate these findings, especially for MRI-negative patients. This article is part of the Special Issue "NEWroscience 2018".

Clinical Usefulness of SISCOM-SPM Compared to Visual Analysis to Locate the Epileptogenic Zone.

Introduction: Subtraction of ictal-interictal SPECT co-registered to MRI (SISCOM) is a quantification tool that can improve the sensitivity and specificity of the epileptogenic zone (EZ) localization. Commercially available image analysis software packages for SISCOM are costly, and Statistical Parametric Mapping (SPM) could be an alternative free software for the definition of the EZ. There are only a few studies that compare SISCOM using SPM (SISCOM-SPM) with visual analysis. Aim: To compare SISCOM-SPM vs. visual analysis for localization of the EZ in patients with pharmacoresistant focal epilepsies. Materials and methods: We evaluated all our patients with focal epilepsies that underwent ictal and interictal SPECT. We defined the reference standard to locate the EZ by pathology and follow-up (in patients submitted to surgery), or seizure semiology, serial EEG, long-term video-EEG, 18F-FDG PET/CT, and MRI (in patients who were not operated). We compared the location of the EZ by visual analysis of SPECT images and by SISCOM-SPM to the reference standard and classified as concordant, discordant, or partially concordant. Results: We included 23 patients. Visual analysis was concordant with the EZ reference standard in only 13 patients (56.5%), while SISCOM-SPM was concordant in 18 cases (78.3%), providing a 21.8% increase in the location of EZ. However, this difference was not significant due to the small sample size (p = 0.0856). Conclusion: Our preliminary results demonstrate that, in clinical practice, SISCOM-SPM has the potential to add information that might help localize the EZ compared to visual analysis. SISCOM-SPM has a lower cost than other commercially available SISCOM software packages, which is an advantage for developing countries. Studies with more patients are necessary to confirm our findings.

An adaptive probabilistic atlas for anomalous brain segmentation in MR images.

PURPOSE: Automated segmentation of brain structures (objects) in MR three-dimensional (3D) images for quantitative analysis has been a challenge and probabilistic atlases (PAs) are among the most well-succeeded approaches. However, the existing models do not adapt to possible object anomalies due to the presence of a disease or a surgical procedure. Post-processing operation does not solve the problem, for example, tissue classification to detect and remove such anomalies inside the resulting segmentation mask, because segmentation errors on healthy tissues cannot be fixed. Such anomalies very often alter the shape and texture of the brain structures, making them different from the appearance of the model. In this paper, we present an effective and efficient adaptive probabilistic atlas, named AdaPro, to circumvent the problem and evaluate it on a challenging task - the segmentation of the left hemisphere, right hemisphere, and cerebellum, without pons and medulla, in 3D MR-T1 brain images of Epilepsy patients. This task is challenging due to temporal lobe resections, artifacts, and the absence of contrast in some parts between the structures of interest. METHODS: In AdaPro, we first build one probabilistic atlas per object of interest from a training set with normal 3D images and the corresponding 3D object masks. Second, we incorporate a texture classifier based on convex optimization which dynamically indicates the regions of the target 3D image where the PAs (shape constraints) should be further adapted. This strategy is mathematically more elegant and avoids problems with post-processing. Third, we add a new object-based delineation algorithm based on combinatorial optimization and diffusion filtering. AdaPro can then be used to locate and delineate the objects in the coordinate space of the atlas or of the test image. We also compare AdaPro with three other state-of-the-art methods: an statistical shape model based on synergistic object search and delineation, and two methods based on multi-atlas label fusion (MALF). RESULTS: We evaluate the methods quantitatively on 3D MR-T1 brain images of 2T and 3T from epilepsy patients, before and after temporal lobe resections, and on the template and native coordinate spaces. The results show that AdaPro is considerably faster and consistently more accurate than the baselines with statistical significance in both coordinate spaces. CONCLUSION: AdaPro can be used as a fast and effective step for brain tissue segmentation and it can also be easily extended to segment subcortical brain structures. By choice of its components, probabilistic atlas, texture classifier, and delineation algorithm, it can also be extended to other organs and imaging modalities.

Hippocampal atrophy disrupts the language network but not hemispheric language lateralization.

OBJECTIVE: It is still unclear how temporal lobe epilepsy (TLE) with and without hippocampal atrophy (HA) affects cortical language distribution. We aimed to investigate the role of the hippocampus on language lateralization, activation pattern, and functional connectivity (FC) in patients with TLE. METHODS: We investigated 93 patients with TLE-divided into right HA (RHA), left HA (LHA), and negative magnetic resonance imaging (MRI) (non-HA)-and 101 controls using a semantic-language functional MRI (fMRI) task and the Boston Naming Test (BNT). RESULTS: Groups did not differ in the frequency of atypical language lateralization (LL), which correlated differently with handedness in each brain region and group. Blood-oxygen-level dependend (BOLD) activation patterns and region of interest (ROI)-to-ROI FC differed between LHA and controls, as well as between LHA and non-HA patients. In the task activation pattern analysis, there was a decrease in the activation of patients with LHA relative to controls, exactly in the left hippocampus. However, non-HA patients had increased FC relative to controls in the left superior temporal gyrus region. Seed-to-voxel FC demonstrated greater differences between patients and controls and smaller differences among patient groups. The non-HA group was similar to controls, except for increased BOLD activation and increase FC in the superior temporal gyri. RHA and LHA differed from controls in BNT. BNT correlated with fMRI activation in RHA and non-HA groups. SIGNIFICANCE: LHA affected naming performance, fMRI semantic task activation pattern, and FC more than RHA and non-HA. Contrary to our expectations, LHA did not increase the frequency of atypical LL. Regardless of the side, HA impacts negatively on the language network but not on hemispheric language lateralization.

Major Depressive Disorder Associated With Reduced Cortical Thickness in Women With Temporal Lobe Epilepsy.

Background: Major Depressive Disorder (MDD) is highly prevalent in patients with mesial temporal lobe epilepsy (MTLE), especially in women, carrying significant morbidity. This study aimed to investigate the cortical thickness (CT) abnormalities associated with MDD in women with MTLE and hippocampal atrophy (HA). Also, we investigated the impact of MDD upon the volumes of the hippocampus and amygdala in these patients. Methods: We included 50 women with MTLE and HA (20 left, LMTLE; 30 right, RMTLE), 41 healthy women in the control group, and 15 women with MDD without epilepsy. MTLE patients were subdivided into three groups: MTLE-without-MDD (23 MTLE patients without MDD), MTLE-mild-MDD (nine MTLE patients with mild symptoms of MDD), and MTLE-severe-MDD (18 MTLE patients with moderate to severe symptoms of MDD). The five groups were balanced for age (p = 0.56). All participants had high-resolution 3D T1-weighted images in a 3T scanner. We used FreeSurfer 6.0 for volumetry and CT parcellation. All participants were submitted to a clinical psychological evaluation through the Structured Clinical Interview for DSM-IV (SCID-IV) and completed the Beck Depression Inventory (BDI-II). Results: We identified a smaller ipsilateral amygdala volume (p = 0.04) in the MTLE-severe-MDD group when compared to the control group. Our results presented a reduced ipsilateral lateral orbitofrontal cortex (p = 0.02) in the MTLE-severe-MDD in comparison to the MTLE-mild-MDD group. We also identified a thinner ipsilateral fusiform gyrus (p < 0.01) in the MTLE-severe-MDD compared to both MTLE-without-MDD and control groups. A reduced CT of the contralateral superior frontal gyrus (p = 0.02) was observed in the MTLE-severe-MDD in comparison to the MTLE-mild-MDD group. Conclusions: The identification of areas with reduced CT and atrophy of the ipsilateral amygdala in women with MTLE and MDD suggest that the cortical thinning in the network of the paralimbic system is related to the co-occurrence and intensity of depressive symptoms in this group.