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Background: Cladribine, a selective immune reconstitution therapy, is approved for the treatment of adult patients with highly active multiple sclerosis (MS). Objectives: Provide experience with cladribine therapy in a real-world setting. Methods: This is a registry-based retrospective observational cohort study. First, using data from the Czech nationwide registry ReMuS, we analysed patients who initiated cladribine from September 1, 2018 to December 31, 2021. Second, we analysed a subgroup of patients who initiated cladribine between September 1, 2018 to June 30, 2020, thus possessing a follow-up period of at least 2 years. We evaluated demographic and MS characteristics including disease-modifying therapies (DMTs) before and after cladribine administration, relapses, Expanded Disability Status Scale (EDSS), and adherence. Results: In total, 617 patients (335 with follow-up of at least 2 years) started cladribine therapy in the study period (mean age 37.0, mean disease duration 8.4 years, 74.1% females). In most cases, cladribine was administered as a second-line drug, a total of 80.7% had been escalated from a platform DMT. During 2 years before cladribine initiation, the average annualised relapse rate (ARR) was .67. Following cladribine initiation, the ARR decreased to .28 in the first year and .22 in the second year. Overall, across the entire two-year treatment period, 69.0% of patients were relapse-free and the average ARR was .25. As for EDSS development, the median baseline EDSS was 2.5 and remained stable even after 24 months. The adherence to treatment ranged of around 90%. Conclusion: This nationwide study confirms the efficacy of cladribine in real-world settings, especially in patients who are not treatment-naïve. In addition, the study shows an exceptionally high adherence rate, a finding that underscores the invaluable role of cladribine, but also the value of registry-based studies in capturing real-world clinical practice.
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INTRODUCTION: Plasma exchange (PE) is considered a Category II option for the treatment of acute attacks and relapse cases of neuromyelitis optica spectrum disorder (NMOSD). However, neurologists are also considering intravenous immunoglobulins (IVIg) as an add-on therapy for this disorder. AIMS: The aim of this study is to evaluate the efficacy of PE in acute attacks of NMOSD when compared with IVIg, in terms of improvement in the Expanded disability status scale (EDSS) and activities of daily living (ADL) scale score and levels of anti-Aquaporin P4 (AQP4) antibody in seropositive patients. METHODS: We enrolled 43 NMOSD patients in two groups: Group 1 (n = 29) received steroids and PE, and Group 2 (n = 14) received steroids with IVIg. The baseline EDSS and ADL scores were recorded and compared with scores at the end of therapy, 4 weeks, and 3 months after. Also, anti-AQP4 antibody was measured at baseline and post-therapy in seropositive patients of both groups. RESULTS: We observed a significant difference in EDSS (p = 0.00) and ADL score (p = 0.00) at day 10 and 3 months in both groups. However, no significant difference in EDSS, as well as ADL score from baseline (p = 0.83; p = 0.25) to 3 months (p = 0.85; p = 0.19), was observed when delta change of score at 3 months was compared across the two groups (p = 0.39; p = 0.52). We observed improved visual acuity in both groups with mild improvement in findings of magnetic resonance imaging at 3 months. We observed a significant decline in AQP4 antibody concentration (at day 10) in group 1 seropositive patients (p = 0.013) with improved EDSS (p = 0.027) and ADL scores (p = 0.026) of these patients. CONCLUSIONS: PE should be considered as a choice of an add-on therapy in anti-AQP4 antibody-positive NMOSD patients compared with IVIg as it is more effective in reducing antibody concentrations.
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Aquaporina 4 , Imunoglobulinas Intravenosas , Neuromielite Óptica , Troca Plasmática , Humanos , Neuromielite Óptica/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas Intravenosas/administração & dosagem , Troca Plasmática/métodos , Feminino , Adulto , Masculino , Aquaporina 4/imunologia , Pessoa de Meia-Idade , Atividades Cotidianas , Resultado do Tratamento , Autoanticorpos/sangueRESUMO
The Expanded Disability Status Scale (EDSS) is the most popular method to assess disease progression and treatment effectiveness in patients with multiple sclerosis (PwMS). One of the main problems with the EDSS method is that different results can be determined by different physicians for the same patient. In this case, it is necessary to produce autonomous solutions that will increase the reliability of the EDSS, which has a decision-making role. This study proposes a machine learning approach to predict EDSS scores using aerobic capacity data from PwMS. The primary goal is to reduce potential complications resulting from incorrect scoring procedures. Cardiovascular and aerobic capacity parameters of individuals, including aerobic capacity, ventilation, respiratory frequency, heart rate, average oxygen density, load, and energy expenditure, were evaluated. These parameters were given as input to CatBoost, gradient boosting (GBM), extreme gradient boosting (XGBoost), and decision tree (DT) machine learning methods. The most significant EDSS results were determined with the XGBoost algorithm. Mean absolute error, root mean square error, mean square error, mean absolute percent error, and R square values were obtained as 0.26, 0.4, 0.26, 16, and 0.68, respectively. The XGBoost based machine learning technique was shown to be effective in predicting EDSS based on aerobic capacity and cardiovascular data in PwMS.
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We aimed to compare the ability of diffusion tensor imaging and multi-compartment spherical mean technique to detect focal tissue damage and in distinguishing between different connectivity patterns associated with varying clinical outcomes in multiple sclerosis (MS). Seventy-six people diagnosed with MS were scanned using a SIEMENS Prisma Fit 3T magnetic resonance imaging (MRI), employing both conventional (T1w and fluid-attenuated inversion recovery) and advanced diffusion MRI sequences from which fractional anisotropy (FA) and microscopic FA (µFA) maps were generated. Using automated fiber quantification (AFQ), we assessed diffusion profiles across multiple white matter (WM) pathways to measure the sensitivity of anisotropy diffusion metrics in detecting localized tissue damage. In parallel, we analyzed structural brain connectivity in a specific patient cohort to fully grasp its relationships with cognitive and physical clinical outcomes. This evaluation comprehensively considered different patient categories, including cognitively preserved (CP), mild cognitive deficits (MCD), and cognitively impaired (CI) for cognitive assessment, as well as groups distinguished by physical impact: those with mild disability (Expanded Disability Status Scale [EDSS] <=3) and those with moderate-severe disability (EDSS >3). In our initial objective, we employed Ridge regression to forecast the presence of focal MS lesions, comparing the performance of µFA and FA. µFA exhibited a stronger association with tissue damage and a higher predictive precision for focal MS lesions across the tracts, achieving an R-squared value of .57, significantly outperforming the R-squared value of .24 for FA (p-value <.001). In structural connectivity, µFA exhibited more pronounced differences than FA in response to alteration in both cognitive and physical clinical scores in terms of effect size and number of connections. Regarding cognitive groups, FA differences between CP and MCD groups were limited to 0.5% of connections, mainly around the thalamus, while µFA revealed changes in 2.5% of connections. In the CP and CI group comparison, which have noticeable cognitive differences, the disparity was 5.6% for FA values and 32.5% for µFA. Similarly, µFA outperformed FA in detecting WM changes between the MCD and CI groups, with 5% versus 0.3% of connections, respectively. When analyzing structural connectivity between physical disability groups, µFA still demonstrated superior performance over FA, disclosing a 2.1% difference in connectivity between regions closely associated with physical disability in MS. In contrast, FA spotted a few regions, comprising only 0.6% of total connections. In summary, µFA emerged as a more effective tool than FA in predicting MS lesions and identifying structural changes across patients with different degrees of cognitive and global disability, offering deeper insights into the complexities of MS-related impairments.
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Imagem de Tensor de Difusão , Esclerose Múltipla , Substância Branca , Humanos , Feminino , Masculino , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Anisotropia , Adulto , Imagem de Tensor de Difusão/métodos , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/etiologiaRESUMO
Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune inflammatory disease of the central nervous system, (CNS) different from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). While numerous studies have delved into the involvement of thyroid antibodies (ATAbs) and thyroid function in NMOSD and MS. The objective of this study is to explore the clinical significance of thyroid dysfunction and ATAbs abnormalities in adult patients with MOGAD. Methods: 36 adult inpatients diagnosed with MOGAD and 47 sex- and age-matched healthy controls were enrolled. Patients were divided into two groups based on the presence or absence of low T3 syndrome. Demographics, clinical characteristics, and results of auxiliary examinations were compared across the subgroups. Moreover, an analysis was conducted to explore the correlations between thyroid hormone levels and Expanded Disability Status Scale (EDSS) scores. Results: Thyroid dysfunction was notably more frequent in MOGAD patients than healthy controls (p < 0.0001), particularly low T3 syndrome (p=0.03). Furthermore, subgroup analyses revealed that the low T3 syndrome group exhibited higher EDSS scores and a higher proportion of individuals with EDSS scores > 3, in comparison to the non-low T3 syndrome group (p = 0.014, p = 0.046). However, no significant differences were observed in demographic characteristics, annual relapse rates, clinical phenotypes, laboratory and MRI results, and EEG abnormalities between the two groups. Additional Spearman's analysis showed significantly negative correlations between the TT3 and FT3 levels with EDSS scores (r = -0.367, p = 0.028; r = -0.377, p = 0.024). Typical brain lesions and paralateral ventricle lesions were significantly rare in patients with positive ATAbs compared to those with negative ATAbs (p = 0.0001, p = 0.03), although the incidence of ATAbs abnormalities did not differ significantly between MOGAD patients and healthy controls. Conclusions: Overall, this study confirmed thyroid dysfunction, especially low T3 syndrome, is frequent in adult MOGAD patients. Patients with low T3 syndrome exhibited elevated EDSS scores and a significantly higher incidence of unfavorable condition. additionally, the correlation analysis model manifests that FT3 and TT3 levels were negatively correlated with EDSS scores. These evidences indicate that low T3 syndrome is associated with the severity of MOGAD exacerbation.
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INTRODUCTION: Examining the safety of theBNT162b2 mRNA vaccine in multiple sclerosis (MS) patients remains inconclusive, particularly regarding the potential for disease exacerbations. This study aims to assess the effects of BNT162b2 COVID-19 vaccination on disease activity in MS patients through sequential MRI imaging. METHODS: A retrospective study of 84 MS patients from five Israeli hospitals was conducted. MS lesion load was determined from three brain MRI scans, one postvaccination and two prevaccination scans. A post hoc analysis compared subgroups featuring vaccinated and unvaccinated patients respectively, with early onset MS. RESULTS: The cohort included 70 women with early onset (mean age 16.4 ± 0.8 years) and adult onset (mean age 34.9 ± 1.1 years) MS. Among the early onset group, vaccinated patients showed an increased risk of new lesions (p = .00026), while there was no increased risk among adult-onset patients. Additionally, a comparison between early onset vaccinated and nonvaccinated groups revealed a higher risk of increased lesions in the vaccinated group (p = .024). DISCUSSION: Overall, the study suggests that the BNT162b2 vaccine is generally safe in MS patients, with no association found between vaccination and new lesions in most patients. However, close MRI follow-up is recommended for early-onset MS cases to monitor lesion development.
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Vacina BNT162 , Vacinas contra COVID-19 , COVID-19 , Imageamento por Ressonância Magnética , Esclerose Múltipla , Humanos , Feminino , Imageamento por Ressonância Magnética/métodos , Adulto , Esclerose Múltipla/diagnóstico por imagem , Estudos Retrospectivos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/administração & dosagem , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Israel/epidemiologia , Masculino , Vacinação/efeitos adversos , Adulto JovemRESUMO
PURPOSE: This study analyzes the main changes in retinal microcirculation in patients with multiple sclerosis (MS) and their relationship with the type of disease course. MATERIAL AND METHODS: 159 patients (318 eyes) were examined. The groups were formed according to the type of course and duration of MS: group 1 - 37 patients (74 eyes; 23.27%) with relapsing-remitting MS (RRMS) less than 1 year; group 2 - 47 patients (94 eyes; 29.56%) with RRMS from 1 year to 10 years; group 3 - 44 patients (86 eyes; 27.05%) with RRMS >10 years; group 4 - 32 patients (64 eyes; 20.12%) with secondary progressive MS (SPMS). Subgroups A and B were allocated within each group depending on the absence or presence of optic neuritis (ON). Patients underwent standard ophthalmological examination, including optical coherence tomography angiography (OCTA). RESULTS: A decrease in the vessel density (wiVD) and perfusion density (wiPD) in the macular and peripapillary regions was revealed, progressing with the duration of the disease and with its transition to the progressive type. The minimum values were observed in patients with SPMS (group 4), with the most pronounced in the subgroup with ON (wiVD = 16.06±3.65 mm/mm2, wiPD = 39.38±9.46%, ppwiPD = 44.06±3.09%, ppwiF = 0.41±0.05). CONCLUSION: OCTA provides the ability to detect subclinical vascular changes and can be considered a comprehensive, reliable method for early diagnosis and monitoring of MS progression.
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Progressão da Doença , Esclerose Múltipla , Vasos Retinianos , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/fisiopatologia , Vasos Retinianos/diagnóstico por imagem , Angiofluoresceinografia/métodos , Microcirculação/fisiologia , Neurite Óptica/diagnóstico , Neurite Óptica/etiologia , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/fisiopatologia , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: Depression and the presence of a disability emerge as noteworthy predictors of the quality of life (QoL) in patients with multiple sclerosis (MS). In this article, we explore the relationship between disability status, depression, and quality of life in individuals with multiple sclerosis. METHODS: A total of 150 patients participated in this cross-sectional study. A Persian translation of the Multiple Sclerosis Quality of Life-54 questionnaire was utilized to assess their health-related quality of life (QoL), while the patients' disability levels were measured using the Expanded Disability Status Scale. Additionally, we assessed patients' depression levels using the 21-item BDI-II scale. The questionnaire data were analyzed using SPSS version 25. RESULTS: A total of 150 MS patients participated in the study, with a mean age of 33.4 years (SD = 3.1). The majority were female (n = 71.2 %). The mean EDSS score was 3.7 (SD = 1.8). In the correlation analysis, we found that EDSS scores were not significantly correlated with mental QoL (r = -0.180, p = 0.109), but were significantly correlated with lower physical QoL (r = -0.393, p 0.001). Depression scores were significantly correlated with mental QoL (r = -0.776, P 0.001) and physical QoL (r = -0. 726, P 0.001). The results reveal that both EDSS and Beck scores significantly affect mental and physical health, explaining 62 % and 60 % of their variances, respectively. CONCLUSION: Our findings indicate a significant relationship between physical quality of life and EDSS scores in MS patients. Higher EDSS scores consistently corresponded to more significant physical impact, as evidenced by higher impact ratings. Conversely, there was no clear association between EDSS scores and mental quality of life. Furthermore, increased depression levels were linked to reduced levels of both mental and physical well-being. These results emphasize the intricate interplay between the physical aspects of quality of life and their implications for the progression and severity of MS in patients.
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Depressão , Esclerose Múltipla , Qualidade de Vida , Humanos , Feminino , Masculino , Adulto , Estudos Transversais , Esclerose Múltipla/psicologia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/complicações , Índice de Gravidade de Doença , Avaliação da Deficiência , Pessoa de Meia-IdadeRESUMO
Verbal fluency (VF) evaluates language and cognitive abilities. This study compared VF in Relapsing-Remitting Multiple Sclerosis (RRMS) and healthy controls (HC), examining variables including correct responses (CR), mean cluster size (MCS), switches (S), and fluency difference score (FDS). RRMS participants were subgrouped by Expanded Disability Status Scale (EDSS), to explore the relationship between MS severity and VF. Twenty-four RRMS participants and matched HCs underwent Mini-Mental State Exam and VF Test. Statistical analysis compared VF between RRMS subgroups based on severity levels, and in HC. RRMS significantly impacted the CR, and S (CRSF p = 0.01, SSF p = 0.002; CRPF=0.002, SPF p = 0.002), while there was no significant difference in FDS between RRMS groups (p = 0.9). No significant relationship was found between EDSS scores, and VF subtests (CRSF p = 0.061, MCSSF p = 0.46, SSF p = 0.051, CRPF p = 0.521, MCSPF p = 0.966, SPF p = 0.599). In RRMS, our results demonstrate impairments in all VF parameters except the MCSSF+PF, and FDS. This study suggests that intact MCSSF+PF may reflect preserved verbal memory and word recall, while significant switching differences may indicate impaired cognitive flexibility. Similar FDS to those of HC suggest that no performance discrepancy in subtests in RRMS. Intact MCS might be a distinctive pattern in the early clinical stage of MS.
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Non-invasive and effective differentiation along with determining the degree of deviations compared to the healthy cohort is important in the case of various brain disorders, including multiple sclerosis (MS). Evaluation of the effectiveness of diffusion tensor metrics (DTM) in 3T DTI for recording MS-related deviations was performed using a time-acceptable MRI protocol with unique comprehensive detection of systematic errors related to spatial heterogeneity of magnetic field gradients. In a clinical study, DTMs were acquired in segmented regions of interest (ROIs) for 50 randomly selected healthy controls (HC) and 50 multiple sclerosis patients. Identical phantom imaging was performed for each clinical measurement to estimate and remove the influence of systematic errors using the b-matrix spatial distribution in the DTI (BSD-DTI) technique. In the absence of statistically significant differences due to age in healthy volunteers and patients with multiple sclerosis, the existence of significant differences between groups was proven using DTM. Moreover, a statistically significant impact of spatial systematic errors occurs for all ROIs and DTMs in the phantom and for approximately 90 % in the HC and MS groups. In the case of a single patient measurement, this appears for all the examined ROIs and DTMs. The obtained DTMs effectively discriminate healthy volunteers from multiple sclerosis patients with a low mean score on the Expanded Disability Status Scale. The magnitude of the group differences is typically significant, with an effect size of approximately 0.5, and similar in both the standard approach and after elimination of systematic errors. Differences were also observed between metrics obtained using these two approaches. Despite a small alterations in mean DTMs values for groups and ROIs (1-3 %), these differences were characterized by a huge effect (effect size â¼0.8 or more). These findings indicate the importance of determining the spatial distribution of systematic errors specific to each MR scanner and DTI acquisition protocol in order to assess their impact on DTM in the ROIs examined. This is crucial to establish accurate DTM values for both individual patients and mean values for a healthy population as a reference. This approach allows for an initial reliable diagnosis based on DTI metrics.
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Encefalopatias , Esclerose Múltipla , Humanos , Imagem de Tensor de Difusão/métodos , Esclerose Múltipla/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND AND PURPOSE: Higher latitude has been associated with increased occurrence of multiple sclerosis (MS) and with more severe disease. The aim was to study the impact of sun exposure habits on MS disease progression and health-related quality of life. METHODS: Patients from a population-based case-control study were categorized based on sun exposure habits at diagnosis and were followed up to 15 years post-diagnosis through the Swedish MS registry (n = 3314) with regard to changes in Expanded Disability Status Scale (EDSS). Linear mixed models were used to analyse long-term changes, while Cox regression models, with 95% confidence intervals, were used to investigate outcomes, including 24-week confirmed diasability worsening, EDSS3, EDSS4, and physical worsening as measured by the physical component of the Multiple Sclerosis Impact Scale 29. RESULTS: Compared to average sun exposure (median value), low exposure to sunlight was associated with faster EDSS progression, increased risk of confirmed disability worsening (hazard ratio [HR] 1.48, 95% CI 1.21-1.81), increased risk of reaching EDSS 3 (HR 1.35, 95% CI 1.02-1.79), EDSS 4 (HR 1.47, 95% CI 1.01-2.20) and self-reported physical worsening (HR 1.27, 95% CI 1.00-1.62). Significant trends revealed a lower risk of unfavourable outcomes with increasing sun exposure. CONCLUSIONS: Very low levels of sun exposure are associated with worse disease progression and health-related quality of life in patients with MS.
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Progressão da Doença , Esclerose Múltipla , Qualidade de Vida , Sistema de Registros , Luz Solar , Humanos , Masculino , Feminino , Adulto , Esclerose Múltipla/epidemiologia , Pessoa de Meia-Idade , Estudos de Casos e Controles , Suécia/epidemiologia , Hábitos , Avaliação da DeficiênciaRESUMO
BACKGROUND: Paramagnetic rim lesions (PRLs) have been linked to higher clinical disease severity and relapse frequency. However, it remains unclear whether PRLs predict future, long-term disease progression. OBJECTIVES: The study aimed to assess whether baseline PRLs were associated with subsequent long-term (10 years) Expanded Disability Status Scale (EDSS) increase and relapse frequency and, if so, whether PRL-associated EDSS increase was mediated by relapse. METHODS: This retrospective analysis included 172 people with multiple sclerosis (pwMS) with 1868 yearly clinical visits over a mean follow-up time of 10.2 years. 3T magnetic resonance imaging (MRI) was acquired at baseline and PRLs were assessed on quantitative susceptibility mapping (QSM) images. The associations between PRLs, relapse, and rate of EDSS change were assessed using linear models. RESULTS: PRL+ pwMS had greater overall annual relapse rate (ß = 0.068; p = 0.010), three times greater overall odds of relapse (exp(ß) = 3.472; p = 0.009), and greater rate of yearly EDSS change (ß = 0.045; p = 0.010) than PRL- pwMS. Greater PRL number was associated with greater odds of at least one progression independent of relapse activity (PIRA) episode over follow-up (exp(ß) = 1.171, p = 0.009). Mediation analysis showed that the association between PRL presence (yes/no) and EDSS increase was 96.7% independent of relapse number. CONCLUSION: PRLs are a marker of aggressive ongoing disease inflammatory activity, including more frequent future clinical relapses and greater long-term, relapse-independent disability progression.
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Encéfalo , Esclerose Múltipla , Humanos , Estudos Retrospectivos , Prognóstico , Encéfalo/patologia , Esclerose Múltipla/patologia , Imageamento por Ressonância Magnética , Doença Crônica , Progressão da Doença , RecidivaRESUMO
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neuroinflammatory disorder with a prevalence of 1-5/100,000 globally, characterized by attacks of the central nervous system including but not limited to optic neuritis, transverse myelitis and brainstem lesions, including area postrema lesions. These autoimmune attacks can lead to irreversible damage if left untreated, therefore strategies have been developed to prevent relapses. Initial off-label treatments have achieved variable levels of success in relapse prevention, but improved relapse prevention and quality of life remain a goal in the field. A better understanding of the underlying pathophysiology of NMOSD over the last 10 years has led to newer, more specific approaches in treatment, culminating in the first FDA approved treatments in the disease. In this review, we will discuss the seminal trials of PREVENT or Eculizumab in the treatment of aquaporin-4 (AQP4)-IgG positive NMOSD, N-Momentum or Inebilizumab in the study of NMOSD (both AQP4-IgG positive and negative) and SAkura Sky and SAkuraStar which studied satralizumab in AQP4-IgG seropositive and seronegative NMOSD patients. We will also discuss the extension trials of each of these medications and what lead to their approval in AQP4-IgG seropositive NMOSD patients. We will then examine treatments in the pipeline for adult and pediatric NMOSD patients and conclude with discussions on treatment considerations in pregnant patients and how to approach treatment of NMOSD patients during COVID.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare central nervous system inflammatory disorder caused by the aquaporin-4 antibody (AQP-4 IgG) labeling and immune system attack of astrocytes, and later downstream loss of myelin, the protective sheath surrounding neurons. It occurs in approximately 1-5 individuals per 100,000 globally and is characterized by attacks of the central nervous system including but not limited to optic neuritis, transverse myelitis and brainstem lesions, including area postrema lesions. These autoimmune attacks can lead to irreversible damage if left untreated, therefore strategies have been developed to prevent additional attacks. Initial off-label treatments have achieved variable levels of success in relapse prevention, but improved immune attack prevention and quality of life remain a goal in the field. A better understanding of the underlying causes of NMOSD over the last 10 years has led to newer, more specific approaches in treatment, culminating in the first FDA approved treatments in the disease. In this review, we will discuss the trials PREVENT or Eculizumab in the treatment of aquaporin-4 (AQP4)-IgG positive NMOSD, N-Momentum or Inebilizumab in the study of NMOSD (both AQP4-IgG positive and negative) and SAkura Sky and SAkuraStar which studied satralizumab in AQP4-IgG seropositive and seronegative NMOSD patients. We will also discuss the extension trials of each of these medications and what lead to their approval in AQP4-IgG seropositive NMOSD patients. We will then examine treatments in the pipeline for adult and pediatric NMOSD patients and conclude with discussions on treatment considerations in pregnant patients and how to approach treatment of NMOSD patients during COVID.
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PURPOSE: This study aimed to subtype multiple sclerosis (MS) patients using unsupervised machine learning on white matter (WM) fiber tracts and investigate the implications for cognitive function and disability outcomes. MATERIALS AND METHODS: We utilized the automated fiber quantification (AFQ) method to extract 18 WM fiber tracts from the imaging data of 103 MS patients in total. Unsupervised machine learning techniques were applied to conduct cluster analysis and identify distinct subtypes. Clinical and diffusion tensor imaging (DTI) metrics were compared among the subtypes, and survival analysis was conducted to examine disability progression and cognitive impairment. RESULTS: The clustering analysis revealed three distinct subtypes with variations in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Significant differences were observed in clinical and DTI metrics among the subtypes. Subtype 3 showed the fastest disability progression and cognitive decline, while Subtype 2 exhibited a slower rate, and Subtype 1 fell in between. CONCLUSIONS: Subtyping MS based on WM fiber tracts using unsupervised machine learning identified distinct subtypes with significant cognitive and disability differences. WM abnormalities may serve as biomarkers for predicting disease outcomes, enabling personalized treatment strategies and prognostic predictions for MS patients.
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Imagem de Tensor de Difusão , Esclerose Múltipla , Aprendizado de Máquina não Supervisionado , Substância Branca , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/classificação , Masculino , Feminino , Imagem de Tensor de Difusão/métodos , Adulto , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Pessoa de Meia-Idade , Progressão da DoençaRESUMO
BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. OBJECTIVE: This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. METHODS: This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica-immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). RESULTS: We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. CONCLUSIONS: This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46709.
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BACKGROUND: Isolated first episodes of longitudinally extensive transverse myelitis (LETM) have typically been associated with neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, in some cases, serological testing and screening for other aetiologies are negative, a condition referred to as double seronegative longitudinally extensive transverse myelitis (dsLETM). OBJECTIVE: The objective of this study was to evaluate comparative outcomes of dsLETM, MOGAD-LETM and NMOSD-LETM. METHODS: Cohort study of LETM cases seen in the UK NMOSD Highly Specialised Service between January 2008 and March 2022. RESULTS: LETM = 87 cases were identified (median onset age = 46 years (15-85); median follow-up = 46 months (1-144); 47% NMOSD-LETM = 41 (aquaporin-4 antibodies (AQP4-IgG) positive = 36), 20% MOGAD-LETM = 17 and 33% dsLETM = 29). Despite similar Expanded Disability Status Scale (EDSS) at nadir, last EDSS was higher in AQP4-IgG and seronegative NMOSD-LETM (sNMOSD) (p = 0.006). Relapses were less common in dsLETM compared to AQP4-IgG NMOSD-LETM and sNMOSD-LETM (19% vs 60% vs 100%; p = 0.001). Poor prognosis could be predicted by AQP4-IgG (odds ratio (OR) = 38.86 (95% confidence interval (CI) = 1.36-1112.86); p = 0.03) and EDSS 3 months after onset (OR = 65.85 (95% CI = 3.65-1188.60); p = 0.005). CONCLUSION: dsLETM remains clinically challenging and difficult to classify with existing nosological terminology. Despite a similar EDSS at nadir, patients with dsLETM relapsed less and had a better long-term prognosis than NMOSD-LETM.
Assuntos
Mielite Transversa , Neuromielite Óptica , Humanos , Pessoa de Meia-Idade , Estudos de Coortes , Aquaporina 4 , Recidiva Local de Neoplasia/complicações , Prognóstico , Autoanticorpos , Imunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Estudos RetrospectivosRESUMO
BACKGROUND: Most Multiple Sclerosis (MS) clinical trials fail to assess the long-term effects of disease-modifying therapies (DMT) or disability. METHODS: COLuMbus was a single-visit, cross-sectional study in Argentina in adult patients with ≥10 years of MS since first diagnosis. The primary endpoint was to determine patient disability using the Expanded Disability Status Scale (EDSS). The secondary endpoints were to evaluate the distribution of diagnoses between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS), patient demographics, disease history, and the risk of disability progression. The relationship between baseline characteristics and the current disability state and the risk of disability progression was assessed. RESULTS: Out of the 210 patients included, 76.7 % had a diagnosis of RRMS and 23.3 % had been diagnosed with SPMS, with a mean disease duration of 17.9 years and 20.5 years, respectively. The mean delay in the initial MS diagnosis was 2.6 years for the RRMS subgroup and 2.8 years for the SPMS subgroups. At the time of cut-off (28May2020), 90.1 % (RRMS) and 75.5 % (SPMS) of patients were receiving a DMT, with a mean of 1.5 and 2.0 prior DMTs, respectively. The median EDSS scores were 2.5 (RRMS) and 6.5 (SPMS). In the RRMS and SPMS subgroups, 23 % and 95.9 % of patients were at high risk of disability, respectively; the time since first diagnosis showed a significant correlation with the degree of disability. CONCLUSIONS: This is the first local real-world study in patients with long-term MS that highlights the importance of recognizing early disease progression to treat the disease on time and delay disability.
Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adulto , Humanos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/terapia , Estudos Transversais , Argentina/epidemiologia , Progressão da Doença , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/epidemiologia , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Esclerose Múltipla Recidivante-Remitente/terapiaRESUMO
BACKGROUND: The Expanded Disability Status Scale (EDSS) is widely used and accepted by regulatory agencies for the assessment of neurological disability secondary to Multiple Sclerosis. The "Expanded Disability Status Scale (EDSS) by phone" was developed to be a patient-reported telephone-based alternative for the assessment of EDSS functional system scores when a physical examination is not possible. The scale has been validated in multiple languages; however, its reliability has not been assessed in Brazilian Portuguese. METHODS: After cross-cultural translation and adaptation, 57 people with MS with a recent in-person visit (±6 months) were invited to answer the EDSS by phone scale on two occasions, 15 days apart. The agreement between scales (in-person and telephone-based) and between telephone-based assessments was evaluated using intraclass correlation coefficients (ICC) for absolute agreement and weighted Kappa coefficients. RESULTS: An excellent reliability was obtained for the agreement between the in-person and telephone assessments (ICC: 0.95, 95 %CI 0.92-0.97, Kappa: 0.83, 95 %CI 0.78-0.89) and between telephone-based assessments (ICC: 0.99, 95 %CI 0.98-0.99, Kappa: 0.93, 95 %CI 0.88-0.97). After stratification by disability level, the agreement between scales was less pronounced for subjects with an EDSS ≤ 4.0. CONCLUSION: this study offers evidence that supports the validity of the EDSS by phone questionnaire translated into Brazilian Portuguese, particularly for patients with higher EDSS scores.
Assuntos
Avaliação da Deficiência , Esclerose Múltipla , Humanos , Brasil , Reprodutibilidade dos Testes , Esclerose Múltipla/diagnóstico , TelefoneRESUMO
BACKGROUND AND PURPOSE: The validity, reliability, and longitudinal performance of the Patient-Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. METHODS: We included relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test-retest reliability was examined. Longitudinal data were analysed with mixed-effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). RESULTS: We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak (ρ = 0.45, p < 0.001). PDDS had stronger correlations with patient-reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test-retest reliability was good to excellent (concordance correlation coefficient = 0.73-0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. CONCLUSION: The PDDS has greater correlation with other PROs but less correlation with other MS-related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico , Reprodutibilidade dos Testes , Avaliação da Deficiência , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Background: The Expanded Disability Status Scale (EDSS) quantifies disability and measures disease progression in multiple sclerosis (MS), however is not available in administrative claims databases. Objectives: To develop a claims-based algorithm for deriving EDSS and validate it against a clinical dataset capturing true EDSS values from medical records. Methods: We built a unique linked dataset combining claims data from the German AOK PLUS sickness fund and medical records from the Multiple Sclerosis Management System 3D (MSDS3D). Data were deterministically linked based on insurance numbers. We used 69 MS-related diagnostic indicators recorded with ICD-10-GM codes within 3 months before and after recorded true EDSS measures to estimate a claims-based EDSS proxy (pEDSS). Predictive performance of the pEDSS was assessed as an eight-fold (EDSS 1.0-7.0, ≥8.0), three-fold (EDSS 1.0-3.0, 4.0-5.0, ≥6.0), and binary classifier (EDSS <6.0, ≥6.0). For each classifier, predictive performance measures were determined, and overall performance was summarized using a macro F1-score. Finally, we implemented the algorithm to determine pEDSS among an overall cohort of patients with MS in AOK PLUS, who were alive and insured 12 months prior to and after index diagnosis. Results: We recruited 100 people with MS insured by AOK PLUS who had ≥1 EDSS measure in MSDS3D between 01/10/2015 and 30/06/2019 (620 measurements overall). Patients had a mean rescaled EDSS of 3.2 and pEDSS of 3.0. The pEDSS deviated from the true EDSS by 1.2 points, resulting in a mean squared error of prediction of 2.6. For the eight-fold classifier, the macro F1-score of 0.25 indicated low overall predictive performance. Broader severity groupings were better performing, with the three-fold and binary classifiers for severe disability achieving a F1-score of 0.68 and 0.84, respectively. In the overall AOK PLUS cohort (3,756 patients, 71.9% female, mean 51.9 years), older patients, patients with progressive forms of MS and those with higher comorbidity burden showed higher pEDSS. Conclusion: Generally, EDSS was underestimated by the algorithm as mild-to-moderate symptoms were poorly captured in claims across all functional systems. While the proxy-based approach using claims data may not allow for granular description of MS disability, broader severity groupings show good predictive performance.