Background

Background: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking, as randomized clinical trials failed to show efficacy in reducing disability progression in this patient population.

Objectives

Objective: To investigate the effectiveness of disease-modifying treatment (DMT) on hard disability outcomes (EDSS 6 and 7) in a real-life population of PPMS patients.

Methods

Methods: Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. The impact of DMT on the risk of reaching EDSS 6 and 7 was assessed as a dichotomous variable (yes versus no) and as a time-dependent covariate through multivariable Cox regression models (adjusted for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, annualized relapse rate). We compared outcomes with an as-treated analysis and used propensity-score matching (PSM) to select cohorts with comparable baseline characteristics. DMT-exposure was also evaluated in terms of quartiles of exposure.

Results

Results: Of the 1214 patients we included 671 females, mean ± Standard Deviation baseline age 48.7 ± 11.1 years, mean EDSS score 4.1 ± 1.8, 790 (65%) received a DMT during the follow-up (57% platform and 43% highly active treatments). In the whole sample, after a mean follow-up of 11.6 ± 6.3 years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not influence the risk of reaching EDSS 6 (aHR=1.1, 95% CI 0.95-1.28, p=0.181) and EDSS 7 (aHR = 0.93, 95% CI 0.77-1.12. p = 0.454). However, longer DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.73, 95% CI 0.56-0.95, p =0.021). Of note, patients in the upper quartile of DMT exposure compared with those with shorter DMT exposure were younger at baseline (mean age 44.1 ± 10.6 years; p < 0.001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years ± 6.1 ; p=0.002). All these findings were confirmed in the PSM analysis.

Conclusions

Conclusion: Our results suggest that longer exposure to DMT may delay time to wheelchair in PPMS patients. Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients’ long-term disability outcomes. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.

Background

Cognitive impairment (CI) affects nearly 30% of paediatric patients with Multiple Sclerosis (MS) and has a negative impact on school performance and participation in social activities. This study is a re-appraisal of cognitive functioning and socio-professional attainment in adulthood in an Italian cohort of paediatric MS patients after 10 years from baseline neuropsychological assessment.

Objectives

To re-assess cognitive performance and its impact on socio-professional attainment in our cohort of paediatric MS patients after 10 years from baseline evaluation and to determine predictors of the individual outcomes.

Methods

Sixty-three paediatric patients were assessed at baseline and 48 followed-up after five years. To date, 31 out of these 48 patients (17 females, mean age 27.9±2.5 years, mean EDSS 1.7±1.6) were reassessed on an extensive neuropsychological battery and compared with a matched group of 31 healthy controls. CI was defined as the failure of > 2 tests. Socio-professional attainment was evaluated on the Work and Social Assessment Scale (WSAS). Predictors of CI and WSAS score were assessed through multivariable logistic and linear models.

Results

After a mean follow-up of 12.5±2.3 years, 15 (54%) subjects were classified as cognitively impaired. Patients with CI compared with those cognitively preserved at follow-up had higher Expanded Disability Status Scale (EDSS) score (1.9±1.4 vs 1.0±0.7; p = 0.046), lower baseline intelligence quotient (IQ) (86.2±23.8 vs 103.6±14.7; p = 0.025) and were less frequently treated with disease modifying therapy (DMT) at baseline [6 (35.3%) vs 11 (78.6%); p = 0.016]. In the regression model, CI after 10 years was related to lower IQ (OR 0.93, 95% CI 0.87-0.99, p = 0. 027) and absence of DMT at baseline assessment (OR 17.78 95%; 1.72-183.65, p = 0.017).

Baseline predictors of worse socio-professional attainment on the WSAS in adulthood were CI (B=6.3, p=0.016), higher EDSS (B=2.2, p=0.023) and higher age at onset (B=0.6, p=0.041). As for 10-year correlates, only CI was associated to poor functional outcome (B=5.2, p=0.006).

Conclusions

Complete data collection is ongoing; available findings to date show that in paediatric onset subjects CI remains significant in adulthood, is related to lower cognitive reserve, higher levels of neurological impairment and delay in DMT initiation. Moreover, CI plays a key role in predicting the subject social performance and professional outcome. Early treatment and promotion of strategies aimed at enhancing cognitive reserve are recommended in paediatric patients with MS.

Background

Background: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking, as randomized clinical trials failed to show efficacy in reducing disability progression in this patient population.

Objectives

Objective: To investigate the effectiveness of disease-modifying treatment (DMT) on hard disability outcomes (EDSS 6 and 7) in a real-life population of PPMS patients.

Methods

Methods: Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. The impact of DMT on the risk of reaching EDSS 6 and 7 was assessed as a dichotomous variable (yes versus no) and as a time-dependent covariate through multivariable Cox regression models (adjusted for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, annualized relapse rate). We compared outcomes with an as-treated analysis and used propensity-score matching (PSM) to select cohorts with comparable baseline characteristics. DMT-exposure was also evaluated in terms of quartiles of exposure.

Results

Results: Of the 1214 patients we included 671 females, mean ± Standard Deviation baseline age 48.7 ± 11.1 years, mean EDSS score 4.1 ± 1.8, 790 (65%) received a DMT during the follow-up (57% platform and 43% highly active treatments). In the whole sample, after a mean follow-up of 11.6 ± 6.3 years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not influence the risk of reaching EDSS 6 (aHR=1.1, 95% CI 0.95-1.28, p=0.181) and EDSS 7 (aHR = 0.93, 95% CI 0.77-1.12. p = 0.454). However, longer DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.73, 95% CI 0.56-0.95, p =0.021). Of note, patients in the upper quartile of DMT exposure compared with those with shorter DMT exposure were younger at baseline (mean age 44.1 ± 10.6 years; p < 0.001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years ± 6.1 ; p=0.002). All these findings were confirmed in the PSM analysis.

Conclusions

Conclusion: Our results suggest that longer exposure to DMT may delay time to wheelchair in PPMS patients. Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients’ long-term disability outcomes. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.

Background

Restrictions imposed by the National and local authorities to mitigate the spread of Coronavirus disease-19 (COVID-19) posed unique challenges in the access to care and management of people with multiple sclerosis (PwMS).

Objectives

To collect data about the impact of the COVID-19 emergency on access to care for PwMS and analyze influence on treatment practices of MS neurologists worldwide.

Methods

Between March and July 2020 the European Committee for Treatment and Research in MS (ECTRIMS) promoted an online survey among Council members and MS specialists worldwide, covering five major areas: general information; MS patient access to care; management of relapses and visits; use of disease modifying therapy (DMT); experience with COVID-19 MS patients.

Results

Three-hundred-sixty neurologists (46% females, median age 48 years) from 52 countries (Europe 68%; Central/South America 17%; North America 10%, others 5%) completed the survey. Seventy-five percent worked within a specialized MS centre, 42% followed > 1000 patients. Ninety-eight percent of respondents reported COVID-19 pandemic had a negative impact on patients’ care. Routine MS clinical activities were suspended in 63% of cases and only urgent visits were guaranteed. Telemedicine services (mainly calls, video-calls, messaging) were provided by 90% of respondents: only in 20% of cases telemedicine was already in use in the practice. Forty-five percent revealed changes in relapse treatment: dosage and/or duration reduction 30%; treatment offered only for severe relapses 36%; treatment delivered at home 28%. As for DMT, 98% of respondents felt no modification was needed for interferons and glatiramer; 48-60% deemed no change was needed for dimethyl fumarate, teriflunomide, fingolimod and siponimod, while nearly 25% considered switching/suspending these agents based on lymphopenia. On the other hand, for natalizumab 31% applied an extended-dose regimen, for cladribine and alemtuzumab 42-52% considered postponing treatment in any case as the best choice. For anti-CD20 monoclonal antibodies, postponing treatment in any case (32%) or based on the patient immunophenotype (25%) were the preferred options. Sixty-one percent of respondents had at least one patient affected by COVID-19, 27% had at least one patient with severe infection; 70% of severe cases were on DMT. Finally, 11% of respondents reported at least one COVID-19 related death and 36% of fatal cases were on DMT.

Conclusions

While analysis of geographic differences is ongoing, the survey highlighted that COVID-19 pandemic is having a major impact on MS care worldwide. Telemedicine has a great potential to mitigate issues and needs to be potentiated/implemented de novo at most centres. As for DMT, major changes regarded cladribine, alemtuzumab and anti-CD20. Collecting standardized, reliable data on the potential impact of DMT on COVID-19 in PwMS is urgently needed to inform appropriate treatment decisions.

Background

Brain-derived neurotrophic factor (BDNF) can promote neuronal growth and repair, playing a key role in synaptic plasticity, especially in the hippocampus. The 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.

Objectives

Considering BDNF relevance on hippocampal function, we aimed to explore the effect of BDNF Val66Met polymorphism on the atrophy of hippocampal subfields and its role in cognitive functioning in MS patients.

Methods

Using a 3T scanner, we obtained dual-echo and 3DT1-weighted sequences from 50 MS patients and 15 healthy controls (HC). MS patients also underwent genotype analysis of BDNF and an extensive neuropsychological evaluation. Hippocampal subfields were segmented by using Freesurfer 7.0.1 software. Multiple linear regression models adjusted for age, sex and disease duration were used for between-group comparisons and analysis of associations.

Results

The BDNF Val66Met polymorphism was found in 22 MS patients (44%). Compared to HC, MS patients had reduced volumes of: bilateral hippocampus-amygdala transition area (HATA); left cornus ammonis (CA)1, CA3 and granule cell layer of dentate gyrus (GCL-DG); and right fimbria and presubiculum. BDNF Val66Met polymorphism carriers compared to wild-type (Val66Val) MS patients had higher volume of left hippocampal CA1, CA3, CA4, GCL-DG, molecular layer of subiculum and HATA; and of right hippocampal tail, fissure and presubiculum. In MS patients, higher volume in left CA3 and in right presubiculum correlated with better performance in semantic fluency, while higher volume in left GCL-DG correlated with better visuo-spatial memory performance.

Conclusions

The BNDF Val66Met polymorphism has a protective role in MS patients against both hippocampal atrophy and cognitive deterioration. BDNF genotype may be a potential biomarker for predicting cognitive prognosis, and an interesting target to study for neuroprotective strategies.