Clinical and radiological correlates of apathy in multiple sclerosis.

BACKGROUND: Although apathy has been associated with fronto-striatal dysfunction in several neurological disorders, its clinical and magnetic resonance imaging (MRI) correlates have been poorly investigated in people with multiple sclerosis (PwMS). OBJECTIVES: To evaluate clinical variables and investigate microstructural integrity of fronto-striatal grey matter (GM) and white matter (WM) structures using diffusion tensor imaging (DTI). METHODS: A total of 123 PwMS (age: 40.25 ± 11.5; female: 60.9%; relapsing-remitting multiple sclerosis: 75.6%) were prospectively enrolled and underwent neurological and neuropsychological evaluation, including Expanded Disability Status Scale (EDSS), Apathy Evaluation Scale (AES-S), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and brain 3T-MRI volumes of whole brain, frontal/prefrontal cortex (PFC) and subcortical regions were calculated. DTI-derived metrics were evaluated in the same GM regions and in connecting WM tracts. RESULTS: Apathetic PwMS (32.5%) showed lower education levels, higher HADS, MFIS scores and WM lesions volume than nonapathetic PwMS. Significant differences in DTI metrics were found in middle frontal, anterior cingulate and superior frontal PFC subregions and in caudate nuclei. Significant alterations were found in the right cingulum and left striatal-frontorbital tracts. CONCLUSIONS: Apathy in PwMS is associated with higher levels of physical disability, depression, anxiety and fatigue together with lower educational backgrounds. Microstructural damage within frontal cortex, caudate and fronto-striatal WM bundles is a significant pathological substrate of apathy in multiple sclerosis (MS).

An aggressive form of MOGAD treated with aHSCT: A case report.

BACKGROUND: Although myelin-oligodendrocyte-glycoprotein (MOG)-antibody-associated disease (MOGAD) has been considered a more favorable demyelinating central nervous system disorder, recent data evidence that some patients might experience severe relapses and high disability. Actual treatment-options are acquired mostly from anti-aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder and rely on clinical experience. Therefore, treatment of aggressive forms of MOGAD can be challenging. OBJECTIVES AND METHODS: To describe a patient with an aggressive MOGAD treated with autologous hematopoietic stem cell transplantation (aHSCT). RESULTS: A 56-year-old man was diagnosed with MOGAD in 2017 because of right optic-neuritis and anti-MOG-antibody positivity. In the following 2 years, he experienced two optic neuritis with good recovery after high-dose steroid. At the end of 2019, he presented sensory and motor impairment at lower limbs with evidence of several spinal, longitudinally extended, tumefactive inflammatory lesions. Despite sequential treatment with rituximab and tocilizumab alongside high-dose steroid, intravenous immunoglobulins and plasma-exchange, he experienced several clinical relapses and exhibited persistent magnetic resonance activity. He was finally addressed to intense immunosuppression with myeloablative conditioning regimen followed by autologous hematopoietic stem cell transplantation (aHSCT). After 2 years follow-up, he is free from disease-activity. CONCLUSIONS: In a patient affected by aggressive, treatment-refractory MOGAD, aHSCT resulted as safe and was able to suppress disease-activity for over 2 years.

Embracing resilience in multiple sclerosis: a new perspective from COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) resulted in several psychological consequences. Past epidemiological experiences already showed the deep albeit heterogeneous psychological repercussions of pandemics. Nevertheless, little is known about COVID-19 outbreak and the possible strategies for boosting resilience in patients with chronic diseases such as Multiple Sclerosis (MS). Therefore, we designed a study aiming to assess the changes in mental distress during COVID-19 outbreak in patients with MS and to identifyfactors contributing to resilience's development.We enrolled 106 patients (69 relapsing-remitting, 20 secondary-progressive, and 17 primary-progressive) whose neuropsychological assessment before the COVID-19 pandemic (1 January 2019-1 March 2020) was available. It consisted of Brief International Cognitive Assessment for MS (BICAMS), Hospital Anxiety and Depression Scale (HADS) and patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P). All patients were re-tested during Italian lockdown through an online survey, comprehensive of sociodemographic information, HADS self-rating Scale, MSNQ-P Questionnaire and finally Connor-Davidson Resilience self-rating Scale (CD-RISC 25), in order to evaluate resilience.No significant changes in HADS and MSNQ-P scores were detected during COVID-19 pandemic in our population. Though, pre-existing lower HADS and MSNQ-P scores but not demographic, disease- and treatment-related elements were found significantly (p < 0.0001) and independently associated with a better resilience attitude.

Autologous hematopoietic stem cell transplantation following alemtuzumab therapy in aggressive multiple sclerosis: A report of three cases.

The management of multiple sclerosis patients with persistent disease activity under alemtuzumab treatment is not established yet. Concerns have been raised on the safety of autologous haematopoietic stem cell transplantation (aHSCT) after alemtuzumab treatment because of the risk of serious infectious adverse events. We report short-term safety and efficacy data from three patients treated with aHSCT following alemtuzumab treatment. Early adverse events were consistent with expected transplant toxicities. All patients were free of disease activity at the last follow-up. Our data suggest that aHSCT can be considered as a rescue treatment strategy for MS patients with persistent disease activity during alemtuzumab treatment.

Menstrual cycle resumption and female fertility after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Data on fertility after autologous hematopoietic stem cell transplantation (aHSCT) in women with multiple sclerosis (MS) are inconclusive. This study aims to report on post-aHSCT menstrual resumption in a multi-center MS-women cohort. Out of 43 women, 30 (70%) recovered menses after a mean time of 6.8 months. Older age (odds ratio (OR) = 0.5, p < 0.0001) and previous pulsed cyclophosphamide (OR = 0.44, p = 0.005) were independently associated with a reduced menstrual recovery probability. Conditioning regimens' intensity resulted not associated with post-procedure amenorrhea. Our results highlight younger age as significantly associated with menses recovery; proper fertility counseling for MS women candidated to aHSCT both prior- and post-transplantation is therefore warranted.

Relationship Between Retinal Layer Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis.

BACKGROUND: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS. METHODS: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively. RESULTS: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-µm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS. CONCLUSIONS: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.

A novel SPAST gene splicing variant (c.1617-2A>C) in a heterozygous carrier with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of genetically heterogenous neurodegenerative disorders characterized by progressive spasticity and weakness of lower limbs. We report a novel splicing variant (c.1617-2A>C) of the SPAST gene in a heterozygous carrier from an Italian family with autosomal dominant HSP. The case study describes a pure form of spastic paraparesis with the cardinal clinical features of SPG4. The novel variant affects a canonical splice site and is likely to disrupt RNA splicing. We conclude that the c.1617-2A>C substitution is a null variant, which could be classified as pathogenic; its penetrance should be further investigated.

In-vivo characterization of macro- and microstructural injury of the subventricular zone in relapsing-remitting and progressive multiple sclerosis.

Introduction: The subventricular zone (SVZ) represents one of the main adult brain neurogenesis niche. In-vivo imaging of SVZ is very challenging and little is known about MRI correlates of SVZ macro- and micro-structural injury in multiple sclerosis (MS) patients. Methods: The aim of the present study is to evaluate differences in terms of volume and microstructural changes [as assessed with the novel Spherical Mean Technique (SMT) model, evaluating: Neurite Signal fraction (INTRA); Extra-neurite transverse (EXTRATRANS) and mean diffusivity (EXTRAMD)] in SVZ between relapsing-remitting (RR) or progressive (P) MS patients and healthy controls (HC). We are also going to explore whether SVZ microstructural injury correlate with caudate (a nucleus that is in the vicinity of the SVZ) or thalamus (another well-defined grey matter area which is further from SVZ than caudate) volume and clinical disability. Clinical and brain MRI data were prospectively acquired from 20 HC, 101 RRMS, and 50 PMS patients. Structural and diffusion metrics inside the global SVZ, normal appearing (NA-) SVZ, caudate and thalamus were collected. Results: We found a statistically significant difference between groups in terms of NA-SVZ EXTRAMD (PMS>RRMS>HC; p = 0.002), EXTRATRANS (PMS>RRMS>HC; p<0.0001), and INTRA (HC>RRMS>PMS; p = 0.009). Multivariable models showed that NA-SVZ metrics significantly predicted caudate (R 2 = 0.21, p < 0.0001), but not thalamus, atrophy. A statistically significant correlation between EXTRAMD and EXTRATRANS of the NA-SVZ and EDSS (r=0.25, p=0.003 and r=0.24, p = 0.003, respectively) was found. These findings were confirmed in analyses restricted to RRMS, but not to PMS patients. Discussion: In conclusion, the microstructural damage we observed within the NA-SVZ of MS patients - reflecting higher free water content (higher EXTRAMD), cytoarchitecture disruption and astrogliosis (higher EXTRATRANS and lower INTRA) - was more evident in the progressive as compared to the relapsing phases of MS. These abnormalities were significantly associated with a more pronounced caudate atrophy and higher clinical disability scores. Our findings may support the neuroprotective role of SVZ in MS patients.

Central vein sign and diffusion MRI differentiate microstructural features within white matter lesions of multiple sclerosis patients with comorbidities.

Introduction: The Central Vein Sign (CVS) has been suggested as a potential biomarker to improve diagnostic specificity in multiple sclerosis (MS). Nevertheless, the impact of comorbidities on CVS performance has been poorly investigated so far. Despite the similar features shared by MS, migraine and Small Vessel Disease (SVD) at T2-weighted conventional MRI sequences, ex-vivo studies demonstrated their heterogeneous histopathological substrates. If in MS, inflammation, primitive demyelination and axonal loss coexist, in SVD demyelination is secondary to ischemic microangiopathy, while the contemporary presence of inflammatory and ischemic processes has been suggested in migraine. The aims of this study were to investigate the impact of comorbidities (risk factors for SVD and migraine) on the global and subregional assessment of the CVS in a large cohort of MS patients and to apply the Spherical Mean Technique (SMT) diffusion model to evaluate whether perivenular and non-perivenular lesions show distinctive microstructural features. Methods: 120 MS patients stratified into 4 Age Groups performed 3T brain MRI. WM lesions were classified in "perivenular" and "non-perivenular" by visual inspection of FLAIR* images; mean values of SMT metrics, indirect estimators of inflammation, demyelination and fiber disruption (EXTRAMD: extraneurite mean diffusivity, EXTRATRANS: extraneurite transverse diffusivity and INTRA: intraneurite signal fraction, respectively) were extracted. Results: Of the 5303 lesions selected for the CVS assessment, 68.7% were perivenular. Significant differences were found between perivenular and non-perivenular lesion volume in the whole brain (p < 0.001) and between perivenular and non-perivenular lesion volume and number in all the four subregions (p < 0.001 for all). The percentage of perivenular lesions decreased from youngest to oldest patients (79.7%-57.7%), with the deep/subcortical WM of oldest patients as the only subregion where the number of non-perivenular was higher than the number of perivenular lesions. Older age and migraine were independent predictors of a higher percentage of non-perivenular lesions (p < 0.001 and p = 0.013 respectively). Whole brain perivenular lesions showed higher inflammation, demyelination and fiber disruption than non perivenular lesions (p = 0.001, p = 0.001 and p = 0.02 for EXTRAMD, EXTRATRANS and INTRA respectively). Similar findings were found in the deep/subcortical WM (p = 0.001 for all). Compared to non-perivenular lesions, (i) perivenular lesions located in periventricular areas showed a more severe fiber disruption (p = 0.001), (ii) perivenular lesions located in juxtacortical and infratentorial regions exhibited a higher degree of inflammation (p = 0.01 and p = 0.05 respectively) and (iii) perivenular lesions located in infratentorial areas showed a higher degree of demyelination (p = 0.04). Discussion: Age and migraine have a relevant impact in reducing the percentage of perivenular lesions, particularly in the deep/subcortical WM. SMT may differentiate perivenular lesions, characterized by higher inflammation, demyelination and fiber disruption, from non perivenular lesions, where these pathological processes seemed to be less pronounced. The development of new non-perivenular lesions, especially in the deep/subcortical WM of older patients, should be considered a "red flag" for a different -other than MS- pathophysiology.

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. METHODS: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. RESULTS: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). DISCUSSION: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

The role of disconnection in explaining disability in multiple sclerosis.

BACKGROUND: In multiple sclerosis, the correlation between white matter lesion volumes (LV) and expanded disability status scale (EDSS) is at best moderate, leading to the "clinico-radiological paradox", influenced by many factors, including the lack of information on the spatial localisation of each lesion on synthetic metrics such as LV. We used a probabilistic approach to provide the volume of WM tracts that may be disconnected by lesions and to evaluate its correlation with EDSS. METHODS: Forty-five patients (aged 37.4 ± 6.8 years, mean ± standard deviation; 30 females; 29 relapsing-remitting, 16 progressive) underwent 3-T magnetic resonance imaging. Both LV and the volume of the tracts crossing the lesioned regions (disconnectome volume, DV) were calculated using BCBtoolkit and correlated with EDSS. RESULTS: T1-weighted LV and DV significantly correlated with EDSS (p ≤ 0.006 r ≥ 0.413) as it was for T2-weighted LV and T2-weighted DV (p ≤ 0.004 r ≥ 0.430), but only T1-weighetd and T2-weighted DVs were EDSS significant predictors (p ≤ 0.001). The correlations of T1-weighted and T2-weighted LV with EDSS were significantly mediated by DV, while no effect of LV on the EDSS-DV correlation was observed. CONCLUSION: The volume of disconnected WM bundles mediates the LV-EDSS correlation, representing the lonely EDSS predictor.

Vaccinations in patients with multiple sclerosis: a real-world, single-center experience.

Vaccines prevent infections in patients with multiple sclerosis (MS). Though recommendations regarding vaccinating patients with MS have been recently published, real-world data regarding vaccines' planning in patients receiving disease-modifying drugs (DMDs) for MS are missing. Our aim was, therefore, to describe vaccination coverage rates, timing-proposal and safety in real-life vaccinating patients with MS undergoing DMDs before the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination campaign. Patients followed at our MS-center were referred to individualized immunization-programs customized to Italian recommendations, patients' risks, immunity to exanthematic diseases, ongoing DMDs, or therapy-start urgency. Disease-activity stated the need for an essential immunization-cycle, whose core was composed by four vaccines: meningococcal-B, pneumococcal conjugated, Haemophilus influenzae B, and meningococcal-ACWY vaccines. Vaccines were administered prior to the planned DMD-start when possible, inactivated-vaccines >2 weeks and live-vaccines >4 weeks before treatment-start. Patients received a 6-months clinical-/radiological-follow-up after immunization. One-hundred and ninety-five patients were vaccinated between April 2017 and January 2021. 124/195 (63.6%) started a vaccination-program before therapy-start/-switch and 108/124 (87.1%) effectively completed immunization before new therapy-start without any delay. The time needed for immunization-conclusion reached a median of 27 (confidence interval 22) days in 2020. No increase in clinical-/radiological-activity 3-/6-months after immunization was noted. In conclusion, our study confirmed feasibility and safety of a vaccination-protocol in patients with MS whose duration resulted in a median of 27 days.

Occupational outcomes of people with multiple sclerosis: a scoping review.

OBJECTIVES: To update the knowledge on the occupational outcomes associated with multiple sclerosis (MS), systematically examine the extent, scope and nature of the pre-existing literature and identify research gaps in the existing literature. DESIGN: Scoping review. DATA SOURCES: A comprehensive database search of PubMed/MEDLINE, Scopus, SciVerse ScienceDirect and Web of Science was performed. There were no time limits. ELIGIBILITY CRITERIA: We included any peer-reviewed original article reporting the occupational outcomes of people with MS between the ages of 18 and 65 years. We excluded those off-topic and with insufficient information. METHODS: This review was conducted following the Joanna Briggs Institute recommendations and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping review checklist. Screening, reading of full-texts and data extraction was performed in a standardised way by expert reviewers from 14 July 2021 to 31 October 2021. We provided a narrative synthesis and an overview of findings. RESULTS: The initial systematic search yielded 104 228 results. After removing duplicates and applying the exclusion criteria, 403 articles were included in the review. In total, the studies evaluated 492 062 subjects with MS. One hundred fifty-four (38.2%) articles were published in the last 5 years, mostly from Europe and North America (50.9% and 33.0%, respectively). Concerning the occupational outcomes, studies mostly addressed unemployment (311, 77.2%), early retirement (120, 29.8%), disability pension (117, 29.0%), sick leave (77, 19.1%), the indirect cost of MS (74, 18.4%) and work characteristics (57, 14.1%). The results were categorised into seven subtopics: 'Changes in work and occupational status due to MS', 'work-related socio-economic consequences of MS', 'risk factors for unfavourable occupational outcomes', 'reported barriers to employment', 'reported job accommodations and vocational rehabilitation strategies', 'job satisfaction, stigma, and disclosing the diagnosis in the workplace' and 'rating clinical scales'. CONCLUSIONS: There are several issues that deserve further in-depth study by the scientific community in order to improve the occupational outcomes of people with MS.

Effect of Multiple Sclerosis and Its Treatments on Male Fertility: Cues for Future Research.

Multiple sclerosis is a chronic disease that may lead to different types of symptoms and disabilities. with the better quality of life and decreased disability due to early diagnosis and the availability of disease-modifying therapies (DMTs), the treating physician is increasingly asked to counsel patients on its effects on fertility and reproduction. In particular, reproductive issues are still scarcely studied and discussed in men. Among the still open questions are the following: (a) Does multiple sclerosis cause infertility per sè? (b) Is multiple sclerosis correlated with conditions that increase the risk of infertility? (c) Do DMTs or other therapies for multiple sclerosis impact gonadal function in men? The aim of this review is to provide an overview on the available literature data about the reproductive issues unique to men with multiple sclerosis, underlining the numerous areas where evidence is lacking and, therefore, the priorities for future research.

Predictors of Ocrelizumab Effectiveness in Patients with Multiple Sclerosis.

Data regarding effectiveness and safety of ocrelizumab in the post-marking setting are lacking. The aim of our study was to provide effectiveness and safety data of ocrelizumab treatment in patients with relapsing-remitting (RR-) and progressive multiple sclerosis (PMS) and to evaluate clinical and immunological predictors of early treatment response. In this single-center prospective observational study, we investigated effectiveness outcomes (time-to-confirmed disability worsening, time-to-first relapse, time-to-first evidence of MRI activity and time-to-first evidence of disease activity), clinical and immunological predictors of early treatment response, and incidence of adverse events (AEs). One hundred and fifty-three subjects were included (93 RRMS; 84 females). Median follow-up was 1.9 (1.3-2.7). At 2-year follow-up (FU), disability worsening-free survival were 90.5%, 64.7%, and 68.8% for RRMS, primary-progressive MS (PPMS), and secondary-progressive MS (SPMS) patients, respectively. At 2-year FU, 67.1%, 72.7%, and 81.3% of patients with RRMS, PPMS, and SPMS were free of MRI activity, with NEDA-3 percentages of 62.1%, 54.6%, and 55.1%, respectively. Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05-2.00), p = 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05-6.10), p = 0.039). At 6-month FU, CD8 + cell decrease was less pronounced in patients with inflammatory activity (p = 0.022). Six patients (3.9%) discontinued ocrelizumab due to severe AEs. Our findings suggest that ocrelizumab is an effective treatment in real-world patients with RRMS and PMS, with a manageable safety profile. Better outcomes were observed in treatment-naïve patients and in patients with a low baseline disability level. Depletion of CD8 + cells could underlie early therapeutic effects of ocrelizumab.

Fingolimod and Dimethyl-Fumarate-Derived Lymphopenia is not Associated with Short-Term Treatment Response and Risk of Infections in a Real-Life MS Population.

BACKGROUND: The association between treatment-related lymphopenia in multiple sclerosis, drug efficacy and the risk of infections is not yet fully understood. OBJECTIVE: The objective of this study was to assess whether lymphopenia is associated with short-term treatment response and infection rate in a real-life multiple sclerosis population treated with fingolimod and dimethyl-fumarate. We assessed the associations between baseline absolute lymphocyte count and the lymphocyte mean percentage decrease at 6 and 12 months with treatment response and the occurrence of adverse events over 12 months in the entire cohort of patients and in the two treatment groups separately. METHODS: This is a retrospective observational real-world study of patients with multiple sclerosis treated with fingolimod and dimethyl-fumarate at the MS Center of the University of Genoa between 2011 and 2018. Patients with at least 12 months of follow-up were eligible if [1] they had an Expanded Disability Status Scale assessment at baseline and 12 months after treatment onset, [2] they had undergone brain magnetic resonance imaging at baseline and after 12 months, and [3] absolute lymphocyte counts were available at baseline, 6 and 12 months. Patients shifting from dimethyl-fumarate to fingolimod or vice versa were excluded from the analysis. RESULTS: In total, 137 and 75 patients treated with fingolimod and dimethyl-fumarate, respectively, were included in the analysis. At 12 months, fingolimod-treated patients were more likely to experience grade II and grade III lymphopenia compared with dimethyl-fumarate patients (p < 0.001, χ2 = 94) and had a higher lymphocyte mean percentage decrease (p < 0.001, U = 540). A higher number of previous therapies and a lower baseline absolute lymphocyte count were predictors of lymphopenia at 6 months (p = 0.047, odds ratio = 1.60 and p = 0.014, odds ratio = 1.1) and 12 months (p = 0.003, odds ratio = 1.97 and p = 0.023, odds ratio = 1.1). In fingolimod-treated patients only, female sex and a higher Expanded Disability Status Scale score were predictors of lymphopenia at 12 months (p = 0.006, odds ratio = 7.58 and p = 0.03, odds ratio = 1.56). Neither absolute lymphocyte count at 6 and 12 months nor the mean percentage decrease at 6 and 12 months predicted No Evidence of Disease Activity (NEDA-3) status at 1 year, the occurrence of relapses, disease activity on MRI or disability progression. CONCLUSIONS: Our findings suggest that peripheral blood lymphocyte changes are not associated with short-term treatment response and with the rate of infections during fingolimod and dimethyl-fumarate treatment in real-world patients. Higher treatment exposure and a lower baseline absolute lymphocyte count are risk factors for lymphopenia development during fingolimod and dimethyl-fumarate therapy.

Impact of treatment on cellular immunophenotype in MS: A cross-sectional study.

OBJECTIVE: To establish cytometry profiles associated with disease stages and immunotherapy in MS. METHODS: Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. RESULTS: In untreated patients with MS, significantly higher frequencies of Th17 cells in the RRMS population compared with HC and lower frequencies of B-memory/B-regulatory cells as well as higher percentages of B-mature cells in patients with PMS compared with HCs emerged. Overall, the greatest deviation in immunophenotype in MS was observed by treatment rather than disease course, with the strongest impact found in fingolimod-treated patients. Fingolimod induced a decrease in total CD4+ T cells and in B-mature and B-memory cells and increases in CD4+ and CD8+ T-regulatory and B-regulatory cells. CONCLUSIONS: Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals.

Relationship between retinal inner nuclear layer, age, and disease activity in progressive MS.

OBJECTIVE: To investigate whether inner nuclear layer (INL) thickness as assessed with optical coherence tomography differs between patients with progressive MS (P-MS) according to age and disease activity. METHODS: In this retrospective longitudinal analysis, differences in terms of peripapillary retinal nerve fiber layer (pRNFL), ganglion cell layer + inner plexiform layer (GCIPL), INL and T1/T2 lesion volumes (T1LV/T2LV) were assessed between 84 patients with P-MS and 36 sex- and age-matched healthy controls (HCs) and between patients stratified according to age (cut-off: 51 years) and evidence of clinical/MRI activity in the previous 12 months RESULTS: pRNFL and GCIPL thickness were significantly lower in patients with P-MS than in HCs (p = 0.003 and p < 0.0001, respectively). INL was significantly thicker in patients aged < 51 years compared to the older ones and HCs (38.2 vs 36.5 and 36.7 µm; p = 0.038 and p = 0.04, respectively) and in those who presented MRI activity (new T2/gadolinium-enhancing lesions) in the previous 12 months compared to the ones who did not and HCs (39.5 vs 36.4 and 36.7 µm; p = 0.003 and p = 0.008, respectively). Recent MRI activity was significantly predicted by greater INL thickness (Nagelkerke R2 0.36, p = 0.001). CONCLUSIONS: INL thickness was higher in younger patients with P-MS with recent MRI activity, a criterion used in previous studies to identify a specific subset of patients with P-MS who best responded to disease-modifying treatment. If this finding is confirmed, we suggest that INL thickness might be a useful tool in stratification of patients with P-MS for current and experimental treatment choice.