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OBJECTIVES: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS). METHODS: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively. RESULTS: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003). DISCUSSION: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.
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Avaliação da Deficiência , Progressão da Doença , Esclerose Múltipla Recidivante-Remitente , Humanos , Masculino , Feminino , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Adulto , Pessoa de Meia-Idade , Sistema de Registros , Recidiva , Itália/epidemiologia , SeguimentosRESUMO
Thrombotic microangiopathy (TMA) has been observed in some patients receiving interferon beta (IFNß) therapy for relapsing-remitting multiple sclerosis, but little is known about its clinical features and outcomes. We searched the literature to identify cases with IFNß-related TMA and assessed their pattern of organ involvement, the presence of prodromal manifestations, the treatments used, and the outcomes. Thirty-five articles met the inclusion criteria, and data of 67 patients were collected. The median duration of IFNß therapy before the diagnosis of TMA was 8 years, and 56/67 (84%) presented with acute kidney injury (AKI), of which 33 required acute dialysis. All but three patients had manifestations during the four weeks before TMA onset, including flu-like symptoms, headache, and worsening blood pressure control. In only two patients, ADAMTS13 activity was reduced, while 27% had low C3 levels. However, none showed causative genetic mutations associated with development of atypical hemolytic uremic syndrome. All patients discontinued IFNß, 34 (55%) also received plasma exchange, and 12 (18%) received eculizumab. Complete renal recovery was achieved by 20 patients (30%), while 13 (20%) developed end-stage renal disease. Among those with AKI requiring dialysis, eculizumab therapy was associated with a significantly reduced risk of ESRD compared with plasma exchange. Therefore, TMA with features of aHUS mainly occurs after prolonged treatment with IFNß and is preceded by prodromes, which may lead to an early diagnosis before life-threatening complications occur. Eculizumab appears beneficial in cases with severe kidney involvement, which supports a role of the complement system in the pathogenesis of these forms.
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Importance: Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair. Objective: To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS). Design, Setting, and Participants: This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73â¯564 patients from 120 MS centers were available in the register. Main Outcomes and Measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors. Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT. Results: After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001). Conclusions and Relevance: PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adulto , Criança , Humanos , Feminino , Masculino , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/epidemiologia , Estudos de Coortes , Progressão da Doença , Doença Crônica , Recidiva , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/epidemiologiaRESUMO
BACKGROUND: COVID-19 vaccination is highly recommended to multiple sclerosis (MS) patients. Little is known about the role of patients' clinical and demographic characteristics in determining antibody response. METHODS: We evaluated safety and efficacy of anti-SARS-CoV-2 vaccines on 143 included MS patients. Then, we analyzed antibody titer in a subgroup, assessing clinical and demographic variables associated with protection and antibody titer. RESULTS: After completing the vaccination cycle, the rate of local adverse events was similar after the first and second dose. A higher proportion of systemic AEs was reported after the second dose (65.7% vs 24.5% after the first dose). Antibody response was evaluated in 97 patients. Higher EDSS (OR 0.6, 95% CI 0.4-0.9, p = 0.006) and treatment with antiCD20 (OR 0.02, 95% CI 0.003-0.098, p 0.001) were associated with a lower chance of having an efficacious response. Higher weight was associated with higher Ab titer (ß = 15.2, 95% CI 2.8-27.6, p = 0.017), while treatment with antiCD20 with lower titers (ß = - 1092.3, 95% CI - 1477.4 to - 702.2, p < 0.001). In patients treated with antiCD20, hypogammaglobulinemia (ß - 543, 95% CI - 1047.6 to - 39.1, p = 0.036) and treatment duration (ß - 182, 95% CI - 341.4 to - 24.3, p = 0.027) were associated with lower Ab titer. CONCLUSION: Our study confirms that COVID-19 vaccination in MS patient is safe and effective in preventing symptomatic COVID-19 and should be recommended to all patients. Moreover, we suggest a possible role of hypogammaglobulinemia in reducing Ab response in patients treated with antiCD20 therapies.
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Agamaglobulinemia , Vacinas contra COVID-19 , COVID-19 , Esclerose Múltipla , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Agamaglobulinemia/etiologia , Formação de Anticorpos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Esclerose Múltipla/tratamento farmacológico , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/fisiologia , Vacinação/efeitos adversosRESUMO
Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking. Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS. Design, Setting, and Participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up. Main Outcomes and Measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models. Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective). Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data. Conclusions and Relevance: Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adulto , Progressão da Doença , Feminino , Humanos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (MS) can be especially vulnerable to cognitive impairment (CI) due to the onset of MS during a critical period for CNS development and maturation. The objective of this longitudinal study was to assess long-term cognitive functioning and socioprofessional attainment in the Italian pediatric MS cohort, previously assessed at baseline and 2 and 5 years. METHODS: The 48 patients evaluated at the 5-year assessment were screened for inclusion. All participants were assessed with a cognitive test battery exploring 4 different cognitive abilities. Depression, fatigue, and socioprofessional attainment were also assessed. Mean cognitive z scores were calculated for the whole cohort, and their evolution over time was analyzed with an analysis of variance for repeated measurements test. Predictors of cognitive worsening or improvement were assessed with a linear mixed-model analysis. RESULTS: Thirty-three participants were included (mean follow-up 12.8 ± 0.8 years). The global cognitive performance worsened at year 2 and improved at year 5, although the z score remained significantly lower than at baseline (-0.9 ± 1.2 vs -0.3 ± 0.9, p = 0.002). There was no significant variation between years 5 and 12 (-0.7 ± 1.1, p = 0.452). Higher IQ (>90) at baseline (effect 0.3, 95% CI 0.1-0.5, p = 0.017) and lower number of relapses in the 2 years before baseline (effect -0.1, 95% CI -0.1 to 0.1, p = 0.025) predicted better cognitive performances. Eighteen (54.5%) patients failed at least 2 tests compared with healthy controls and were defined as cognitively impaired. The presence of CI predicted worse socioprofessional attainment (ß = 4.8, 95% CI 1.4-8.2, p = 0.008). DISCUSSION: The longitudinal cognitive trajectory in pediatric-onset MS has a heterogeneous course over time, with a decline in the first years followed by a partial recovery over the long term. However, at the last follow-up evaluation, the proportion of impaired patients was more than double compared with baseline, with a negative impact on the individual's socioprofessional attainment in adulthood. This study underscores how cognitive reserve may partially mitigate the negative effects of brain damage, highlighting the critical importance of intellectual enrichment early during the disease course.
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Disfunção Cognitiva , Reserva Cognitiva , Esclerose Múltipla , Adulto , Criança , Cognição , Disfunção Cognitiva/etiologia , Humanos , Estudos Longitudinais , Esclerose Múltipla/complicações , Esclerose Múltipla/psicologia , Testes NeuropsicológicosRESUMO
OBJECTIVES: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS). METHODS: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery ("treatment approach," (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery ("conservative approach," (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire. RESULTS: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6-10.6, p = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4-7.9 p = 0.007). We found no major development abnormalities in children. DISCUSSION: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Criança , Avaliação da Deficiência , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Lactente , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/efeitos adversos , Gravidez , RecidivaRESUMO
Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up ≥5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Doença Crônica , Estudos de Coortes , Progressão da Doença , Humanos , Recidiva , Estudos RetrospectivosRESUMO
Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was shown to strongly affect BDNF function, but its role in modulating gray matter damage in multiple sclerosis (MS) patients is still not clear. Given BDNF relevance on the hippocampus, we aimed to explore BDNF Val66Met polymorphism effect on hippocampal subfield volumes and its role in cognitive functioning in MS patients. Using a 3T scanner, we obtained dual-echo and 3DT1-weighted sequences from 50 MS patients and 15 healthy controls (HC) consecutively enrolled. MS patients also underwent genotype analysis of BDNF, neurological and neuropsychological evaluation. Hippocampal subfields were segmented by using Freesurfer. The BDNF Val66Met polymorphism was found in 22 MS patients (44%). Compared to HC, MS patients had lower volume in: bilateral hippocampus-amygdala transition area (HATA); cornus ammonis (CA)1, granule cell layer of dentate gyrus (GCL-DG), CA4 and CA3 of the left hippocampal head; molecular layer (ML) of the left hippocampal body; presubiculum of right hippocampal body and right fimbria. Compared to BDNF Val66Val, Val66Met MS patients had higher volume in bilateral hippocampal tail; CA1, ML, CA3, CA4, and GCL-DG of left hippocampal head; CA1, ML, and CA3 of the left hippocampal body; left HATA and presubiculum of the right hippocampal head. In MS patients, higher lesion burden was associated with lower volume of presubiculum of right hippocampal body; lower volume of left hippocampal tail was associated with worse visuospatial memory performance; lower volume of left hippocampal head with worse performance in semantic fluency. Our findings suggest the BNDF Val66Met polymorphism may have a protective role in MS patients against both hippocampal atrophy and cognitive impairment. BDNF genotype might be a potential biomarker for predicting cognitive prognosis, and an interesting target to study for neuroprotective strategies.
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Disfunção Cognitiva , Esclerose Múltipla , Atrofia/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Disfunção Cognitiva/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/genética , Esclerose Múltipla/patologiaRESUMO
BACKGROUND: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial. OBJECTIVE: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy. METHODS: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model. RESULTS: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06-2.84; p = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12-1.74; p = 0.003), younger age (aHR = 0.95; 95% CI 0.91-0.99; p = 0.022) and shorter DMD exposure over the follow-up (p < 0.008). CONCLUSION: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity.
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Pessoas com Deficiência , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Itália/epidemiologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Gravidez , RecidivaRESUMO
The presence of intrathecal IgM synthesis (ITMS) has been associated with an aggressive multiple sclerosis (MS) clinical course. In the present systematic review, we aimed at assessing the prevalence of ITMS among different MS phenotypes. Moreover, we aimed at quantifying the risk of a second relapse in ITMS positive and oligoclonal IgG bands (OCGBs)-positive patients. We selected clinical studies reporting the ITMS prevalence assessed as oligoclonal IgM Bands (OCMBs), lipid-specific OCMBs (LS-OCMBs), and/or as an intrathecal IgM production > 0% (IgMLoc, Reiber formula). The overall prevalence of ITMS was higher in relapsing-remitting (RR) than clinically isolated syndrome (CIS) patients (40.1% versus 23.8%, p < 0.00001), while was in line with that detected in primary progressive MS (PPMS, 26.7%). Almost all patients (98%) with ITMS had also OCGBs. The risk of having a second relapse was higher in OCGBs positive patients (HR = 2.18, p = 0.007) but much higher in ITMS positive patients (HR = 3.62, p = 0.0005). This study revealed that the prevalence of ITMS is higher in RRMS patients. It suggests that the risk of having a second relapse, previously ascribed to OCGBs, may, to a certain extent, be related to the presence of intrathecal IgM.
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Introduction: Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, involved in neuronal survival and synaptic plasticity. The BDNF Val66Met polymorphism is known to reduce BDNF expression and secretion; its role in multiple sclerosis (MS) is poorly investigated. Objectives and Methods: In this multicenter, retrospective study, we assessed the role of BDNF Val66Met polymorphism on cognitive and motor disability in MS patients consecutively referred to the University of Florence and the Hospital of Barletta. All patients underwent a genetic analysis for the presence of Val66Met polymorphism and a comprehensive neuropsychological examination on the Rao's Brief Repeatable Battery and the Stroop Color Word Test. Possible predictors of the Expanded Disability Status Scale (EDSS) score and number of failed neuropsychological tests were assessed through linear multivariable regression models. Results: Ninety-eight patients were recruited. Patients with the BDNF Val66Met polymorphism (35.7%) were more frequently males (p = 0.020), more disabled (p = 0.026) and, marginally, older (p = 0.064). In the multivariable analysis, BDNF Val66Met polymorphism was associated with a better cognitive performance (B = -1.1 ± 0.5, p = 0.027). Higher EDSS score was associated with a progressive disease course (B = 3.4, p < 0.001) and, marginally, with the presence of the BDNF Val66Met polymorphism (B = 0.56, p = 0.066). Discussion: Our results preliminarily suggest a protective role of BDNF Val66Met polymorphism against cognitive impairment in MS patients, possibly related to a detrimental effect of increased BDNF concentration in a neuroinflammatory environment.
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BACKGROUND: There is emerging evidence that intrathecal IgM synthesis (ITMS) is a risk factor for conversion to clinically defined multiple sclerosis (CDMS) in clinically isolated syndrome (CIS) patients. OBJECTIVES: The objective of this study is to verify the prognostic role of ITMS as a risk factor for the second clinical attack in patients after the first demyelinating event. METHODS: Monocentric observational study performed on prospectively acquired clinical data and retrospective evaluation of magnetic resonance imaging (MRI) data. ITMS was assessed according to Reiber's non-linear function. We compared time to the second attack by using Kaplan-Meier curves and performed adjustment by Cox regression analysis. RESULTS: Demographics and clinical data were collected prospectively in a cohort of 68 patients. ITMS occurred in 40% (27/68) of patients who had a higher T1-hypointense lesion load at brain MRI (p = 0.041). In multivariate Cox regression analysis (adjusted for age, sex, baseline Expanded Disability Status Scale, IgG oligoclonal bands and disease-modifying treatment exposure), relapsing-remitting multiple sclerosis (MS) patients with ITMS were at higher risk to experience a second clinical attack (adjusted hazard ratio (aHR) = 6.3, 95% confidence interval (CI) = 2.1-18.4, p = 0.001). CONCLUSION: Together with previous studies, our findings support the role of ITMS as a prognostic biomarker in MS.
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Esclerose Múltipla , Progressão da Doença , Humanos , Imunoglobulina M , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Bandas Oligoclonais , Prognóstico , Estudos RetrospectivosRESUMO
An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% conï¬dence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.
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Antirreumáticos/uso terapêutico , Pessoas com Deficiência , Progressão da Doença , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Primary progressive multiple sclerosis (PPMS) presents with clinical signs of slowly progressive long tract dysfunction that can overlap with neurodegenerative disorders, such as hereditary spastic paraplegia (HSP). Herein, we present two siblings in whom we have identified a novel mutation in the paraplegin (SPG7) gene. The proband, a 49-year-old woman, presented with a five-year history of progressive spastic paraparesis and ataxia. Brain MRI showed mild cerebellar atrophy. The genetic study revealed a homozygous mutation in the SPG7 gene, that led to the diagnosis of HSP. Four years previously, the younger brother had complained of slowly progressive spastic-ataxic gait, that started one year before; MRI had disclosed multiple areas of white matter hyperintensity with contrast enhancement. A diagnosis of active PPMS was made, and the patient started Disease-Modifying Therapy with further clinical and radiological stability. Once a genetic diagnosis was achieved in his sister, the patient underwent SPG7 testing, which disclosed the same mutation. Whether MS is a mimicry of HSP or it represents "double trouble" condition in this patient, it remains undetermined.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , ATPases Associadas a Diversas Atividades Celulares , Feminino , Humanos , Masculino , Metaloendopeptidases/genética , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/genética , MutaçãoRESUMO
BACKGROUND: Multiple sclerosis (MS) is an autoimmune, neuroinflammatory, and neurodegenerative disease of the central nervous system. B cells have recently emerged as a promising target to significantly reduce inflammatory disease activity in MS, with successful trial studies using antiCD20 therapies. However, real-life data about safety and efficacy are limited. OBJECTIVES: To analyze the clinical and radiological inflammatory activity, adherence to therapy, and safety of rituximab (RTX) in an MS patients' sample, treated from 2015 to 2018 in our center PATIENTS AND METHODS: Retrospective study on prospectively collected data about relapses, disability progression, and radiological activity (new T2 lesions and Gd-enhancing lesions) were recorded and used to assess no evidence of disease activity (NEDA) at 12 months. RTX-related adverse events were recorded. RTX was administered intravenously at a dosage of 1000 mg twice 2 weeks apart, then every 6 months. RESULTS: Sixty-nine patients were included. Fifty-three (76.8%) had a relapsing-remitting, two a primary progressive course, and 14 a secondary progressive course. The mean follow-up period was 16 ± 9.7 months. Thirty-five (50.7%) patients had relapses in the year prior to RTX therapy, with a mean annualized relapse rate of 0.75, significantly reduced to 0.36 at 12 months (p < 0.001). Among the 36 patients included in the study who had an MRI available at 12 months, MRI activity was reduced from 88% (n = 32) to 8.3% (n = 3) at follow-up (p < 0.001). Twelve (17.4%) patients suspended RTX during the study. CONCLUSIONS: Our real-life experience confirms that off-label therapy with RTX may represent a valid, cost-effective therapeutic option in MS.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Doenças Neurodegenerativas , Humanos , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos Retrospectivos , Rituximab/efeitos adversosRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0222929.].
RESUMO
BACKGROUND: Many potentially modifiable risk factors for MS are investigated. It is not known, however, if these factors also apply to MS-related cognitive impairment (CI), a frequent consequence of MS. OBJECTIVE: The aim of our study was to assess risk factors for CI in MS patients, focusing on environmental exposures, lifestyle and comorbidities. METHODS: We included MS patients referring to MS Centers in Florence and Barletta between 2014 and 2017. Neuropsychological performance was assessed through the Rao's battery and Stroop test, cognitive reserve (premorbid intelligence quotient-IQ) was evaluated using the National Adult Reading Test (NART). Potential risk factors were investigated through a semi-structured questionnaire. RESULTS: 150 patients were included. CI was detected in 45 (30%) subjects and was associated with older age (p<0.005), older age at MS onset (p = 0.016), higher EDSS score (p<0.005), progressive disease course (p = 0.048) and lower premorbid IQ score (p<0.005). As for risk factors, CI was related with lower physical activity in childhood-adolescence (p<0.005). In women, hormonal therapy resulted to be protective against CI (p = 0.041). However, in the multivariable analysis, the only significant predictors of CI were older age (p<0.05; OR 1.06, 95% CI 1.02-1.10) and lower premorbid IQ (p<0.05; OR 0.93, 95% CI: 0.88-0.98). Removing IQ from the model, CI was associated with higher EDSS (p = 0.030; OR 1.25, 95% CI 1.02-1.53) and, marginally, previous physical activity (p = 0.066; OR 0.49, 95% CI: 0.23-1.05). CONCLUSIONS: Our findings suggest that physical activity in childhood-adolescence could be a contributor to cognitive reserve building, thus representing a potential protective factors for MS-related CI susceptible to preventive strategies.
Assuntos
Cannabis/efeitos adversos , Disfunção Cognitiva/tratamento farmacológico , Exercício Físico/fisiologia , Esclerose Múltipla/tratamento farmacológico , Adulto , Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/fisiopatologia , Reserva Cognitiva/fisiologia , Progressão da Doença , Feminino , Humanos , Testes de Inteligência , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/fisiopatologia , Testes Neuropsicológicos , Fatores de Risco , Fumar/efeitos adversos , Escalas de WechslerRESUMO
BACKGROUND: Definition of benign multiple sclerosis (BMS) remains controversial. Moreover, a sizeable proportion of classically defined BMS patients may be no longer benign (NLB) when re-assessed in the long-term. In a previous work, we found that after a five-year follow-up, a clinical score was able to identify patients at risk of losing their benign status. OBJECTIVES: In this 12-year reappraisal of the same cohort, we aimed at assessing the predictive value of the same score in the long-term. METHODS: After a mean follow-up of 12.6â¯+â¯0.4 years, patients still having an EDSS scoreâ¯<3.0 were classified as "still benign" (SB), whereas patients having an EDSS scoreâ¯≥3.5 were defined as NLB. The predictive value of the mentioned score was re-assessed using survival analysis. RESULTS: By the end of the follow-up, 20 (32.8%) were classified as NLB. Patients were grouped on the basis of the above mentioned score. Patients with score 2-3 were at higher risk of NLB status at the follow-up (HRâ¯=â¯3.5; 95%CI 1.5-8.6; pâ¯=â¯0.005, accuracyâ¯=â¯70.5%). CONCLUSIONS: In patients with established BMS, prognostic prediction of longer-term disease course remains of critical value. In this study, a clinical score was able to predict disease evolution in the long term.