Assessing robustness and generalization of a deep neural network for brain MS lesion segmentation on real-world data.

OBJECTIVES: Evaluate the performance of a deep learning (DL)-based model for multiple sclerosis (MS) lesion segmentation and compare it to other DL and non-DL algorithms. METHODS: This ambispective, multicenter study assessed the performance of a DL-based model for MS lesion segmentation and compared it to alternative DL- and non-DL-based methods. Models were tested on internal (n = 20) and external (n = 18) datasets from Latin America, and on an external dataset from Europe (n = 49). We also examined robustness by rescanning six patients (n = 6) from our MS clinical cohort. Moreover, we studied inter-human annotator agreement and discussed our findings in light of these results. Performance and robustness were assessed using intraclass correlation coefficient (ICC), Dice coefficient (DC), and coefficient of variation (CV). RESULTS: Inter-human ICC ranged from 0.89 to 0.95, while spatial agreement among annotators showed a median DC of 0.63. Using expert manual segmentations as ground truth, our DL model achieved a median DC of 0.73 on the internal, 0.66 on the external, and 0.70 on the challenge datasets. The performance of our DL model exceeded that of the alternative algorithms on all datasets. In the robustness experiment, our DL model also achieved higher DC (ranging from 0.82 to 0.90) and lower CV (ranging from 0.7 to 7.9%) when compared to the alternative methods. CONCLUSION: Our DL-based model outperformed alternative methods for brain MS lesion segmentation. The model also proved to generalize well on unseen data and has a robust performance and low processing times both on real-world and challenge-based data. CLINICAL RELEVANCE STATEMENT: Our DL-based model demonstrated superior performance in accurately segmenting brain MS lesions compared to alternative methods, indicating its potential for clinical application with improved accuracy, robustness, and efficiency. KEY POINTS: • Automated lesion load quantification in MS patients is valuable; however, more accurate methods are still necessary. • A novel deep learning model outperformed alternative MS lesion segmentation methods on multisite datasets. • Deep learning models are particularly suitable for MS lesion segmentation in clinical scenarios.

Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T-cell subsets in multiple sclerosis patients.

Excessive levels of proinflammatory cytokines in the CNS are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with MS, a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8+ T cells. By contrast, 5-HT increased IL-10 production by CD4+ T cells from MS patients. A more accurate analysis of these IL-10-secreting CD4+ T cells revealed that 5-HT favors the expansion of FoxP3+ CD39+ regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in upregulating CD39+ Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS.

Different interleukin-17-secreting Toll-like receptor+ T-cell subsets are associated with disease activity in multiple sclerosis.

Signalling through Toll-like receptors (TLRs) may play a role in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). In the present study, the expression of TLR-2, -4 and -9 was significantly higher on CD4+ and CD8+ T-cells from MS patients compared to healthy individuals. Following in-vitro activation, the proportion of interleukin (IL)-17+ and IL-6+ CD4+ and CD8+ T-cells was higher in the patients. In addition, the proportion of IFN-γ-secreting TLR+ CD8+ T-cells was increased in MS patients. Among different IL-17+ T-cell phenotypes, the proportion of IL-17+ TLR+ CD4+ and CD8+ T-cells producing IFN-γ or IL-6 were positively associated with the number of active brain lesions and neurological disabilities. Interestingly, activation of purified CD4+ and CD8+ T-cells with ligands for TLR-2 (Pam3Csk4), TLR-4 [lipopolysaccharide (LPS)] and TLR-9 [oligodeoxynucleotide (ODN)] directly induced cytokine production in MS patients. Among the pathogen-associated molecular patterns (PAMPs), Pam3Csk4 was more potent than other TLR ligands in inducing the production of all proinflammatory cytokines. Furthermore, IL-6, IFN-γ, IL-17 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels produced by Pam3Csk4-activated CD4+ cells were directly associated with disease activity. A similar correlation was observed with regard to IL-17 levels released by Pam3Csk4-stimulated CD8+ T-cells and clinical parameters. In conclusion, our data suggest that the expansion of different T helper type 17 (Th17) phenotypes expressing TLR-2, -4 and -9 is associated with MS disease activity, and reveals a preferential ability of TLR-2 ligand in directly inducing the production of cytokines related to brains lesions and neurological disabilities.

Quantitative Susceptibility Mapping Indicates a Disturbed Brain Iron Homeostasis in Neuromyelitis Optica - A Pilot Study.

Dysregulation of brain iron homeostasis is a hallmark of many neurodegenerative diseases and can be associated with oxidative stress. The objective of this study was to investigate brain iron in patients with Neuromyelitis Optica (NMO) using quantitative susceptibility mapping (QSM), a quantitative iron-sensitive MRI technique. 12 clinically confirmed NMO patients (6 female and 6 male; age 35.4y±14.2y) and 12 age- and sex-matched healthy controls (7 female and 5 male; age 33.9±11.3y) underwent MRI of the brain at 3 Tesla. Quantitative maps of the effective transverse relaxation rate (R2*) and magnetic susceptibility were calculated and a blinded ROI-based group comparison analysis was performed. Normality of the data and differences between patients and controls were tested by Kolmogorov-Smirnov and t-test, respectively. Correlation with age was studied using Spearman's rank correlation and an ANCOVA-like analysis. Magnetic susceptibility values were decreased in the red nucleus (p<0.01; d>0.95; between -15 and -22 ppb depending on reference region) with a trend toward increasing differences with age. R2* revealed significantly decreased relaxation in the optic radiations of five of the 12 patients (p<0.0001; -3.136±0.567 s(-1)). Decreased relaxation in the optic radiation is indicative for demyelination, which is in line with previous findings. Decreased magnetic susceptibility in the red nucleus is indicative for a lower brain iron concentration, a chemical redistribution of iron into less magnetic forms, or both. Further investigations are necessary to elucidate the pathological cause or consequence of this finding.

Interleukin-17- and interleukin-22-secreting myelin-specific CD4(+) T cells resistant to corticoids are related with active brain lesions in multiple sclerosis patients.

Multiple sclerosis (MS) is thought to be an autoimmune disorder. It is believed that immunological events in the early stages have great impact on the disease course. Therefore, we aimed to evaluate the cytokine profile of myelin basic protein (MBP)-specific T cells from MS patients in the early phase of the disease and correlate it to clinical parameters, as well as to the effect of in vitro corticoid treatment. Peripheral T cells from MS patients were stimulated with MBP with our without hydrocortisone for 5 days. The cytokines level were determined by ELISA. The number of active brain lesions was determined by MRI scans, and the neurological disabilities were assessed by Expanded Disability Status Scale scores. Our results demonstrated that MS-derived T cells responded to MBP by producing high levels of T helper type 1 (Th1) and Th17 cytokines. Although the production of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, IL-17 and IL-22 was less sensitive to hydrocortisone inhibition, only IL-17 and IL-22 levels correlated with active brain lesions. The ability of hydrocortisone to inhibit IL-17 and IL-22 production by MBP-specific CD4(+) T cells was inversely related to the number of active brain lesions. Finally, the production of both cytokines was significantly higher in cell cultures from Afrodescendant patients and it was less sensitive to hydrocortisone inhibition. In summary, our data suggest that IL-17- and IL-22-secreting CD4(+) T cells resistant to corticoids are associated with radiological activity of the MS in early stages of the disease, mainly among Afrodescendant patients who, normally, have worse prognosis.

In vivo assessment of white matter damage in neuromyelitis optica: a diffusion tensor and diffusion kurtosis MR imaging study.

BACKGROUND AND PURPOSE: In patients with neuromyelitis optica (NMO), damage to extensive regions of normal-appearing WM has been observed. To investigate the possibility that microstructural alterations are present in these WM tracts, DTI and diffusion kurtosis imaging (DKI) techniques were applied and compared. MATERIAL AND METHODS: Thirteen patients with NMO and 13 demographically and gender-matched controls underwent MRI using a 3T MR scanner, with DTI/DKI sequence acquired jointly fitted. Parametric fractional anisotropy maps were derived from diffusion tensor (FADTI) values using b-values of 0s/mm(2) and 1000s/mm(2). Parametric fractional anisotropy maps derived from diffusion kurtosis tensor (FADKI) values were also acquired using b-values of 0, 1000, and 2000s/mm(2). Mean FADTI and FADKI values were also calculated. A ROI analysis of the genu and splenium of the corpus callosum (CC), cerebral peduncle (CP), and optic radiation (OR) was also performed. Student's t-test and corrections for multiple comparisons were used to evaluate the data obtained. RESULTS: A significant decrease in the FADTI values obtained for NMO patients versus controls was observed for the splenium of the CC and the left OR (p<0.05). However, just a positive trend was observed for the FADKI values associated with the same WM tracts. CONCLUSIONS: To our knowledge, this is the first study to analyze WM tracts of NMO patients using DTI and DKI. These data indicate that DKI could have limitations in evaluating the WM integrity in NMO patients. Furthermore, the results obtained are consistent with the hypothesis that diffuse brain involvement characterizes NMO.

Endovascular treatment for intracranial infectious aneurysms.

OBJECTIVE: To re-enforce an alternative, less aggressive treatment modality in the management of intracranial infectious aneurysms. METHOD: We present a series of five patients with infectious endocarditis and intracranial infectious aneurysms (mycotic aneurysms) managed by means of endovascular treatment. RESULTS: Endovascular treatment was executed technically uneventfully in all patients. Three patients had favorable clinical outcome: two were classified as Glasgow Outcome Scale 4/5, and one had total neurological recovery (GOS 5/5). Two patients died (GOS 1/5), one in consequence of the initial intracranial bleeding and the other after cardiac complications from endocarditis and open-heart surgery. CONCLUSION: Endovascular techniques are an expanding option for the treatment of IIAs. It has been especially useful for infectious endocarditis patients with IIA, who will be submitted to cardiac surgery with cardiopulmonary bypass and anticoagulation, with the risk of intracranial bleeding.

Endovascular treatment for intracranial infectious aneurysms / Tratamento endovascular de aneurismas infecciosos intracranianos

OBJETIVE: To re-enforce an alternative, less aggressive treatment modality in the management of intracranial infectious aneurysms. METHOD: We present a series of five patients with infectious endocarditis and intracranial infectious aneurysms (mycotic aneurysms) managed by means of endovascular treatment. RESULTS: Endovascular treatment was executed technically uneventfully in all patients. Three patients had favorable clinical outcome: two were classified as Glasgow Outcome Scale 4/5, and one had total neurological recovery (GOS 5/5). Two patients died (GOS 1/5), one in consequence of the initial intracranial bleeding and the other after cardiac complications from endocarditis and open-heart surgery. CONCLUSION: Endovascular techniques are an expanding option for the treatment of IIAs. It has been especially useful for infectious endocarditis patients with IIA, who will be submitted to cardiac surgery with cardiopulmonary bypass and anticoagulation, with the risk of intracranial bleeding.

OBJETIVO: Enfatizar o método endovascular como uma opção de tratamento alternativa e menos agressiva no tratamento de aneurismas infecciosos intracranianos. MÉTODO: Apresentamos uma série de cinco pacientes com endocardite infecciosa e aneurismas infecciosos intra-cranianos (aneurismas micóticos) tratados através da via endovascular. RESULTADOS: O tratamento endovascular teve sucesso técnico e sem intercorrências relacionadas ao cateterismo em todos os casos. Três pacientes tiveram desfecho clínico favorável: dois com escala de regeneração de Glasgow 4/5 e um com recuperação neurológica completa (GOS 5/5). Dois pacientes tiveram desfecho desfavorável (GOS 1/5), um devido às conseqüências do sangramento intracraniano inicial e outro devido a complicações cardíacas da endocardite e cirurgia de troca valvar. CONCLUSÃO: As técnicas endovasculares são uma nova opção de tratamento dos aneurismas infecciosos intracranianos. Ela é especialmente útil em pacientes que serão submetidos à cirurgia cardíaca com circulação extra-corpórea e anticoagulação, com o conseqüente risco de hemorragia intracraniana.

Diffusion tensor MR imaging evaluation of the corpus callosum of patients with multiple sclerosis.

OBJECTIVE: To evaluate the fractional anisotropy (FA) values of the normal-appearing white matter of the corpus callosum (CC) in patients with relapsing-remitting multiple sclerosis (MS). METHOD: Fifty-seven patients with diagnosis of relapsing-remitting MS and 47 age- and gender-matched controls were studied. A conventional MR imaging protocol and a DTI sequence were performed. One neuroradiologist placed the regions of interest (ROIs) in the FA maps in five different portions of the normal-appearing CC (rostrum, genu, anterior and posterior portion of the body and splenium) in all cases. The statistical analysis was performed with the Mann-Whitney U test and p<0.05 was considered statistically significant. RESULTS: The FA values were lower in the MS patients compared with the controls (p<0.05) in the following CC regions: rostrum (0.720 vs 0.819), anterior body (0.698 vs 0.752), posterior body (0.711 vs 0.759) and splenium (0.720 vs 0.880). CONCLUSION: In this series, there was a robust decrease in the FA in all regions of the normal-appearing CC, being significant in the rostrum, body and splenium. This finding suggests that there is a subtle and diffuse abnormality in the CC, which could be probably related to myelin content loss, axonal damage and gliosis.

Diffusion tensor MR imaging evaluation of the corpus callosum of patients with multiple sclerosis / Avaliação do corpo caloso em pacientes com esclerose múltipla através de imagens de RM por tensor de difusão

OBJECTIVE: To evaluate the fractional anisotropy (FA) values of the normal-appearing white matter of the corpus callosum (CC) in patients with relapsing-remitting multiple sclerosis (MS). METHOD: Fifty-seven patients with diagnosis of relapsing-remitting MS and 47 age- and gender-matched controls were studied. A conventional MR imaging protocol and a DTI sequence were performed. One neuroradiologist placed the regions of interest (ROIs) in the FA maps in five different portions of the normal-apearing CC (rostrum, genu, anterior and posterior portion of the body and splenium) in all cases. The statistical analysis was performed with the Mann-Whitney U test and p<0.05 was considered statistically significant. RESULTS: The FA values were lower in the MS patients compared with the controls (p<0.05) in the following CC regions: rostrum (0.720 vs 0.819), anterior body (0.698 vs 0.752), posterior body (0.711 vs 0.759) and splenium (0.720 vs 0.880). CONCLUSION: In this series, there was a robust decrease in the FA in all regions of the normal-appearing CC, being significant in the rostrum, body and splenium. This finding suggests that there is a subtle and diffuse abnormality in the CC, which could be probably related to myelin content loss, axonal damage and gliosis.

OBJETIVO: Avaliar os valores da anisotropia fracionada (FA) da substância branca aparentemente normal do corpo caloso (CC) em pacientes com esclerose múltipla (EM) remitente recorrente. MÉTODO: 57 pacientes com diagnóstico de EM remitente recorrente e 47 controles pareados por sexo e idade foram estudados. O protocolo convencional de RM e imagens de tensor de difusão foram adquiridas. Um neurorradiologista posicionou as regiões de interesse nos mapas de FA em seis porções do CC aparentemente normal (rostro, joelho, anterior e posterior porções do corpo e esplênio) em todos os casos. A análise estatística foi realizada com o teste Mann-Whitney U e p<0,05 foi considerado estatisticamente significativo. RESULTADOS: Os valores de FA foram menores nos pacientes com EM comparados com os controles (p<0,05) nas seguintes porções do CC: rostro (0,720 vs 0,819), corpo anterior (0,698 vs 0,752), corpo posterior (0,711 vs 0,759) e esplênio (0,720 vs 0,880). CONCLUSÃO: Na presente série houve redução robusta na FA em todas as regiões aparentemente normais do CC, sendo significativa no rostro, corpo e esplênio. Este achado sugere que há alteração difusa no corpo caloso de pacientes com EM, provavelmente relacionada a perda da mielina, lesão axonal e gliose.

Diagnostico precoce da hanseniase: identificacao de lesao cutanea inicial pela populacao de regiao metropolitana do Rio de Janeiro / Early diagnosis on Hansen's disease: identification of skin lesions by a population in the metropolitan region of Rio de Janeiro State

A hanseniase continua sendo um importante problema de saude publica no Brasil. O objetivo deste estudo é avaliar o grau de conhecimento sobre a doenca na populacao de areas adstritas a 8 unidades basicas de saude de duas regioes metropolitanas do RJ, com enfoque na identificacao de seus sinais precoces. Ao longo de 2002, foram entrevistados 800 mulheres, e apresentadas quatro imagens de lesoes cutaneas (vitiligo, hanseniase indeterminada, mal perfurante plantar e hanseniase dimorfa) visando a sua impressao diagnostica. Observou-se que 54,9% dos entrevistados conheciam o termo hanseniase (particularmente os de escolaridade alta), enquanto 45,1% o termo lepra. A doenca foi reconhecida, na maior parte das vezes (23,4% dos casos) quando se encontrava em fase avancada. Apenas 5,9% identificaram a lesao precoce. Os resultados indicam desconhecimento da hanseniase por parte desta populacao, especialmente em suas manifestacoes iniciais. Observa-se ainda que as estrategias de difusao da nova terminologia hanseniase nao foram eficazes. Consideramos que a capacidade de suspeicao da doenca deve pertencer nao apenas ao profissional de saude, e sim a todos, na forma de um saber comum.