Occurrence and microstructural features of slowly expanding lesions on fingolimod or natalizumab treatment in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), up to 57% of white matter lesions are chronically active. These slowly expanding lesions (SELs) contribute to disability progression. OBJECTIVE: The aim of this study is to compare fingolimod and natalizumab effects on progressive linearly enlarging lesions (i.e. SELs), a putative biomarker of smouldering inflammation. METHODS: Relapsing-remitting MS patients starting fingolimod (n = 24) or natalizumab (n = 28) underwent 3T brain magnetic resonance imaging (MRI) at baseline, months 6, 12 and 24. SELs were identified among baseline-visible lesions showing ⩾ 12.5% of annual increase, calculated by linearly fitting the Jacobian of the nonlinear deformation field between timepoints obtained combining T1- and T2-weighted scans. SEL burden, magnetization transfer ratio (MTR) and T1 signal intensity were compared using linear models. RESULTS: The prevalences of fingolimod (75%) and natalizumab patients (46%) with ⩾ 1 SEL were not significantly different (adjusted-p = 0.08). Fingolimod group had higher SEL number and volume (adjusted-p ⩽ 0.047, not false discovery rate (FDR) survived). In both groups, SELs versus non-SELs showed lower MTR and T1 signal intensity (adjusted-p ⩽ 0.01, FDR-survived). Longitudinally, non-SEL MTR increased in both treatment groups (adjusted-p ⩽ 0.005, FDR-survived). T1 signal intensity decreased in SELs with both treatments (adjusted-p ⩽ 0.049, FDR-survived in fingolimod group) and increased in natalizumab non-SELs (adjusted-p = 0.03, FDR-survived). CONCLUSION: The effects of natalizumab and fingolimod on SEL occurrence seem modest, with natalizumab being slightly more effective. Both treatments may promote reparative mechanisms in stable or chronic inactive lesions.

Two-year macular volume assessment in multiple sclerosis patients treated with fingolimod.

BACKGROUND: Fingolimod (FNG) is associated with the development of symptomatic macular edema (ME) in a small subset of multiple sclerosis (MS) patients. By using spectral domain optical coherence tomography (SD-OCT), an increase in the total macular volume (TMV) was rarely detected during the first months of treatment. OBJECTIVES: The objective of this study is to assess whether FNG treatment leads to long-term macular changes in a real-life setting. METHODS: Sixty RRMS patients starting FNG, according to therapeutic indication, were enrolled at three Italian MS centers and followed for 2 years. RESULTS: The mean TMV did not change between baseline and the follow-up. No patients experienced visual acuity drop during the follow-up. CONCLUSIONS: Initiation of FNG in MS is associated with a modest, not significant, increase in macular volume followed by no further significant changes over 2 years, highlighting the good safety profile of such treatment in MS.

Two-year regional grey and white matter volume changes with natalizumab and fingolimod.

OBJECTIVE: To compare the efficacy of fingolimod and natalizumab in preventing regional grey matter (GM) and white matter (WM) atrophy in relapsing-remitting multiple sclerosis (RRMS) over 2 years. METHODS: Patients with RRMS starting fingolimod (n=25) or natalizumab (n=30) underwent clinical examination and 3T MRI scans at baseline (month (M) 0), M6, M12 and M24. Seventeen healthy controls were also scanned at M0 and M24. Tensor-based morphometry and SPM12 were used to assess the longitudinal regional GM/WM volume changes. RESULTS: At M0, no clinical or GM/WM volume differences were found between treatment groups. At M24, both drugs reduced relapse rate (p<0.001 for both) and stabilised disability. At M6 vs M0, both groups experienced significant atrophy of several areas in the cortex, deep GM nuclei and supratentorial WM. Significant bilateral cerebellar GM and WM atrophy occurred in fingolimod patients only. At M12 vs M6 and M24 vs M12, further supratentorial GM and WM atrophy occurred in both groups. Bilateral GM/WM cerebellar atrophy continued to progress in fingolimod patients only. Compared with natalizumab, fingolimod-treated patients showed a significant cerebellar GM/WM atrophy, mainly at M6 vs M0, but still occurring up to M24. Compared with fingolimod, natalizumab-treated patients had a small number of areas of GM atrophy in temporo-occipital regions at the different time-points. CONCLUSIONS: Natalizumab and fingolimod are associated with heterogeneous temporal and regional patterns of GM and WM atrophy progression. Compared with natalizumab, fingolimod-treated patients experience accelerated GM and WM atrophy in the cerebellum, while both drugs show minimal regional volumetric differences in supratentorial regions.

Structural connectivity in multiple sclerosis and modeling of disconnection.

BACKGROUND: Multiple sclerosis (MS) is characterized by focal white matter damage, and when the brain is modeled as a network, lesions can be treated as disconnection events. OBJECTIVE: To evaluate whether modeling disconnection caused by lesions helps explain motor and cognitive impairment in MS. METHODS: Pathways connecting 116 cortical regions were reconstructed with magnetic resonance imaging (MRI) tractography from diffusion tensors averaged across healthy controls (HCs); maps of pathways were applied to 227 relapse-onset MS patients and 50 HCs to derive structural connectivity. Then, the likelihood of individual connections passing through lesions was used to model disconnection. Patients were grouped according to clinical phenotype (113 relapsing-remitting multiple sclerosis (RRMS), 69 secondary progressive multiple sclerosis (SPMS), 45 benign MS), and then network metrics were compared between groups (analysis of variance (ANOVA)) and correlated with motor and cognitive scores (linear regression). RESULTS: Global metrics differentiated RRMS from SPMS and benign MS patients, but not benign from SPMS patients. Nodal connectivity strength replicated global results. After disconnection, few nodes were significantly different between benign MS and RRMS patients. Correlations revealed nodes pertinent to motor and cognitive dysfunctions; these became slightly stronger after disconnection. CONCLUSION: Connectivity did not change greatly after modeled disconnection, suggesting that the brain network is robust against damage caused by MS lesions.

Imaging patterns of gray and white matter abnormalities associated with PASAT and SDMT performance in relapsing-remitting multiple sclerosis.

OBJECTIVES: To map the regional patterns of white matter (WM) microstructural abnormalities and gray matter (GM) atrophy exclusively associated with reduced performance in the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting (RR) multiple sclerosis (MS) patients. METHODS: In all, 177 RRMS patients and 80 healthy controls (HC) were studied. WM microstructural abnormalities were investigated on diffusion tensor images using tract-based spatial statistics analysis, and regional GM atrophy was estimated on three-dimensional (3D) T1-weighted images using voxel-based morphometry. RESULTS: Compared to HC, RRMS patients showed the expected pattern of cortical-subcortical GM atrophy and WM microstructural abnormalities. In patients, diffusivity abnormalities of supratentorial WM tracts correlated with both SDMT and PASAT scores. Lower SDMT performance was also associated with WM damage in several infratentorial WM tracts. Lower SDMT scores correlated with atrophy of the right anterior cingulate cortex, left postcentral gyrus, and right middle temporal gyrus, whereas lower PASAT scores correlated with atrophy of the deep GM nuclei, bilaterally, and several fronto-temporo-occipital regions. CONCLUSION: In RRMS patients, regional damage of different neural systems helps explaining reduced performance in SDMT and PASAT. WM microstructural damage typified reduced SDMT performance, whereas atrophy of several GM regions distinguished reduced PASAT performance.

Hippocampal-related memory network in multiple sclerosis: A structural connectivity analysis.

BACKGROUND: We used graph theoretical analysis to quantify structural connectivity of the hippocampal-related episodic memory network and its association with memory performance in multiple sclerosis (MS) patients. METHODS: Brain diffusion and T1-weighted sequences were obtained from 71 MS patients and 50 healthy controls (HCs). A total of 30 gray matter regions (selected a priori) were used as seeds to perform probabilistic tractography and create connectivity matrices. Global, nodal, and edge graph theoretical properties were calculated. In patients, verbal and visuospatial memory was assessed. RESULTS: MS patients showed decreased network strength, assortativity, transitivity, global efficiency, and increased average path length. Several nodes had decreased strength and communicability in patients, whereas insula and left temporo-occipital cortex increased communicability. Patients had widespread decreased streamline count (SC) and communicability of edges, although a few ones increased their connectivity. Worse memory performance was associated with reduced network efficiency, decreased right hippocampus strength, and reduced SC and communicability of edges related to medial temporal lobe, thalamus, insula, and occipital cortex. CONCLUSION: Impaired structural connectivity occurs in the hippocampal-related memory network, decreasing the efficiency of information transmission. Network connectivity measures correlate with episodic memory, supporting the relevance of structural integrity in preserving memory processes in MS.

Functional network connectivity abnormalities in multiple sclerosis: Correlations with disability and cognitive impairment.

OBJECTIVE: To investigate resting state (RS) functional connectivity (FC) abnormalities within the principal brain networks in a large cohort of multiple sclerosis (MS) patients, to define the trajectory of FC changes over disease stages and their relation with clinical and structural magnetic resonance imaging (MRI) measures. METHODS: RS functional magnetic resonance imaging (fMRI), clinical, and neuropsychological evaluation were obtained from 215 MS patients and 98 healthy controls. Connectivity abnormalities and correlations with clinical/neuropsychological/imaging measures were evaluated. We analyzed seed-voxel FC with seven major hubs, producing one visual/sensory, one motor, two cognitive, one cerebellar, and two subcortical networks. RESULTS: MS patients showed reduced network average RS FC versus controls in the default-mode network. At regional level, a complex pattern of decreased and increased RS FC was found. Reduced RS FC mainly involved sensorimotor, cognitive, thalamic, and cerebellar networks, whereas increased RS FC involved visual/sensory and subcortical networks. Reduced RS FC correlated with T2 lesions. Reduced thalamic RS FC correlated with better neuropsychological performance, whereas for all remaining networks reduced FC correlated with more severe clinical/cognitive impairment. CONCLUSION: Increased and decreased RS FC occurs in MS and contributes to a wide spectrum of clinical manifestations. RS FC reduction is related to T2 lesions. Such a paradigm is inverted for the thalamic network.

Abnormal functional connectivity of thalamic sub-regions contributes to fatigue in multiple sclerosis.

OBJECTIVE: To investigate sub-regional thalamic resting-state (RS) functional connectivity (FC) abnormalities in multiple sclerosis (MS) and their correlation with fatigue and its subcomponents (physical, cognitive, and psychosocial). METHODS: From 122 MS patients and 94 healthy controls, 5 thalamic sub-regions (frontal, motor, postcentral, occipital, temporal) were parcellated based on their cortico-thalamic structural connectivity and used for a seed-based RS FC analysis. Abnormalities of thalamic RS FC in MS patients and their correlation with Modified Fatigue Impact Scale (MFIS) were assessed. RESULTS: Compared to controls and non-fatigued MS ( n = 86), fatigued MS patients ( n = 36) showed thalamic RS FC abnormalities with middle frontal gyrus, sensorimotor network, precuneus, insula, and cerebellum, which correlated with global MFIS. Higher thalamic RS FC with precuneus and lower RS FC with posterior cerebellum correlated with cognitive MFIS. Higher thalamic RS FC with sensorimotor network in frontal-, motor-, and temporal thalamic sub-regions correlated with physical and psychosocial MFIS. Reduced thalamic RS FC with right insula in motor-, postcentral-, and occipital thalamic sub-regions correlated with psychosocial fatigue. CONCLUSION: Regional thalamic RS FC abnormalities with different cortical regions, including the frontal lobe, sensorimotor network, precuneus, insular cortices, and cerebellum contribute to fatigue in MS. Abnormal RS FC of selected thalamo-cortical connections explains different components of fatigue.

Half-dose fingolimod for treating relapsing-remitting multiple sclerosis: Observational study.

OBJECTIVES: To investigate the efficacy and safety of fingolimod (FTY) 0.5 mg administered every other day (FTY-EOD) compared to every day (FTY-ED) in multiple sclerosis patients. METHODS: Multicentre retrospective observational study. Clinical, laboratory and neuroimaging data were consecutively collected from 60 FTY-EOD and 63 FTY-ED patients. Baseline characteristics were compared using logistic regression. Efficacy in preventing occurrence of relapses and demyelinating lesions was tested using propensity score-adjusted Cox and linear regressions. RESULTS: Weight was inversely associated with risk of switch to FTY-EOD because of any reason (odds ratio (OR) = 0.94, 95% confidence interval (95% CI) = 0.89-0.99, p = 0.026), and female sex and lower baseline lymphocyte count were positively associated with switch because of lymphopenia. Compared to FTY-ED patients, FTY-EOD patients were at higher risk of developing relapses (hazard ratio (HR) = 2.98, 95% CI = 1.07-8.27, p = 0.036) and either relapses or new magnetic resonance imaging (MRI) demyelinating lesions (combined outcome, HR = 2.07, 95% CI = 1.06-4.08, p = 0.034). Within FTY-EOD, treatment with natalizumab before FTY and lower age were positively associated with risk of developing relapses and combined outcome, respectively (HR = 25.71, 95% CI = 3.03-217.57, p = 0.002 and HR = 0.85, 95% CI = 0.77-0.96, p = 0.005). FTY-EOD was overall well tolerated. CONCLUSION: Disease reactivation was observed in a significant proportion of patients treated with FTY-EOD. Neurologists should be cautious when reducing FTY administration to every other day, especially in younger patients and those previously treated with natalizumab.

Assessing the role of innovative therapeutic paradigm on multiple sclerosis treatment response.

OBJECTIVE: Within the last decade, many changes have been made to the management of patients with multiple sclerosis (MS). The aim of our study was to investigate the global impact of all these changes on the disease's course. MATERIALS AND METHODS: This single-centre study was carried out on patients with multiple sclerosis (pwMS) who started treatment with first-line disease-modifying therapies. We have compared three large cohorts of patients with MS diagnosis, for three consecutive periods within July 2001, August 2001-December 2005, and January 2006-September 2011. RESULTS: A total of 1068 relapsing-remitting pwMS cases were included. Patients in the last cohort began treatment earlier (P < 0.0001), started more frequent treatment with high-dose interferon beta or glatiramer acetate (P < 0.0001), and had experienced a more frequent treatment escalation strategy (P = 0.004) than patients in other cohorts. The multivariate analysis adjusted for baseline characteristics showed that pwMS of the last cohort had a high probability of showing no evidence of disease activity (NEDA3) at 4 years (OR 3.22, 95% CIs 1.89-5.47; P < 0.0001). These results were confirmed in a propensity score analysis. CONCLUSIONS: Our study showed an improvement over the last 15 years in the treatment response; this observation can be associated to a paradigm shift in MS treatment strategies.

Structural connectivity-defined thalamic subregions have different functional connectivity abnormalities in multiple sclerosis patients: Implications for clinical correlations.

In spite of the well-known importance of thalami in multiple sclerosis (MS), only limited data on whole and subregional thalamic functional connectivity (FC) changes are available. Using diffusion tensor imaging, we performed a structural connectivity based thalamic parcellation and investigated subregional thalamic resting-state (RS) FC alterations and their relationship with clinical/cognitive measures in MS. MRI data from a reference set of healthy controls (HC) were used to parcellate the thalami into five subregions, according to their structural connectivity. For each thalamic subregion, a seed-based RS FC analysis was performed in 187 MS patients and 94 HC. Correlations between thalamic RS FC and clinical/cognitive variables were assessed. Compared to HC, MS patients showed increased intra- and inter-thalamic RS FC for almost all thalamic subregions, and increased RS FC between all thalamic subregions and the left insula. Frontal and motor thalamic subregions also showed reduced RS FC with the caudate nucleus. For the temporal thalamic subregion, we observed reduced RS FC with the ipsilateral thalamus, anterior and middle cingulate cortex, and cerebellum. Compared to cognitively preserved, cognitively impaired MS patients had higher thalamic RS FC with several temporal areas. In MS patients, lower RS FC between thalamic subregions and the caudate and cingulate cortex correlated with worse motor performance, whereas higher RS FC with the insula correlated with better motor performance. The main thalamic subregions have different RS-FC abnormalities in MS patients. Increased thalamic RS FC with the insula may have a compensatory role, whereas increased RS FC with temporal areas, observed in patients with cognitive impairment may reflect maladaptive mechanisms. Hum Brain Mapp 38:6005-6018, 2017. © 2017 Wiley Periodicals, Inc.

Slowly progressing varicella zoster brainstem encephalitis complicating Ramsay Hunt syndrome in an immunocompetent patient: case report and review of the literature.

A 56-year-old immunocompetent male developed brainstem encephalitis complicating Ramsay Hunt syndrome. The disease had a slowly progressing course of months after the triggering infection, much longer than previously reported. Furthermore, magnetic resonance imaging, physical-chemical, and cell count analyses on cerebrospinal fluid were normal, whereas polymerase chain reaction for varicella zoster virus DNA was positive. The simultaneous negativity of both imaging and basic CSF exams is very rare, although possible event which confirms the irreplaceable role of viral screening on CSF. A systematic review of similar reports with highlights on the unusual aspects of our case is also presented.

Working memory network dysfunction in relapse-onset multiple sclerosis phenotypes: A clinical-imaging evaluation.

OBJECTIVES: We investigated clinical, behavioural and functional magnetic resonance imaging (fMRI) correlates of working memory load in relapse-onset multiple sclerosis (MS) patients. METHODS: In total, 12 clinically isolated syndromes (CIS) patients at risk of MS, 38 relapsing-remitting multiple sclerosis (RRMS), 22 secondary progressive multiple sclerosis (SPMS) and 24 healthy controls (HC) performed an N-back fMRI task. Correlations between fMRI abnormalities and clinico-behavioural and structural magnetic resonance imaging (MRI) measures were assessed. RESULTS: Participants activated brain regions of the working memory network, especially in fronto-parietal lobes and cerebellum, and deactivated areas of the default mode network (DMN). During the N-back load contrast, compared to HC, the three groups of MS patients had a common pattern of decreased activation of the right superior parietal lobule, left inferior parietal lobule and left middle frontal gyrus. Areas specifically more active in CIS patients compared to the other study groups were found in the left medial superior frontal gyrus and right anterior cingulate cortex, whereas SPMS patients selectively activated the left parahippocampal gyrus and left superior temporal pole (STP). Worse accuracy and global cognitive scores correlated with increased STP activation. CONCLUSION: Load-dependent alterations of working memory network recruitment occur in MS. Frontal hyperactivation is maintained in CIS and lost in SPMS. Abnormal recruitment of DMN areas is related to worse cognitive and behavioural outcomes.

Cerebellar contribution to motor and cognitive performance in multiple sclerosis: An MRI sub-regional volumetric analysis.

OBJECTIVE: To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients. METHODS: Whole and sub-regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores. RESULTS: Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models. CONCLUSION: Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior-inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level.

A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity.

OBJECTIVE: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. METHODS: We performed a genome-wide association study in interferon-ß (IFNß)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. RESULTS: We found an association between rs9828519(G) and nonresponse to IFNß (pdiscovery = 4.43 × 10(-8)) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 × 10(-4)). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNγ, which is a proinflammatory molecule. INTERPRETATION: This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNß-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNß treatment.

Abnormal adaptation over time of motor network recruitment in multiple sclerosis patients with fatigue.

OBJECTIVES: Using functional magnetic resonance imaging (fMRI) during a motor task, we investigated the functional correlates of central fatigue in multiple sclerosis (MS), and adaptation of motor network recruitment during a prolonged effort. METHODS: Motor fMRI was obtained from 79 MS patients (50 fatigued (F), 29 non-fatigued (nF)) and 26 matched healthy controls (HC). Cognitive and physical fatigue were rated using the Modified Fatigue Impact Scale (MFIS). RESULTS: Compared to HC and nF patients, F-MS patients experienced reduced activations of the left middle temporal gyrus, left supplementary motor area (SMA), bilateral superior frontal gyrus, left postcentral gyrus and basal ganglia regions. They also showed increased activation of the right middle frontal gyrus (MFG). Time-modulation analysis showed a reduced activity of the SMA and right precentral gyrus, and increased activity of the basal ganglia in HC. Such a trend was impaired in F-MS patients. In MS patients, increased MFG activity was related to MFIS scores. Physical MFIS score was related to a reduced recruitment of the right thalamus and SMA. CONCLUSIONS: Abnormalities and impaired timing of activation between different areas of the motor and executive networks occur in F-MS patients. The dysfunction of critical cortical areas contributes to the occurrence of central fatigue.

Natalizumab versus fingolimod in patients with relapsing-remitting multiple sclerosis non-responding to first-line injectable therapies.

BACKGROUND: Natalizumab and fingolimod have not been compared in controlled trials but only in observational studies, with inconclusive results. OBJECTIVES: The objective of this study is to compare the effect of natalizumab and fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). METHODS: We included all consecutive RRMS patients switched from first-line agents (glatiramer acetate/interferons) to natalizumab or fingolimod, with a follow-up of 24 months. Data of relapses, Expanded Disability Status Scale score and brain magnetic resonance imaging (MRI) scans were collected. We used propensity score (PS) matching and intention-to-treat analysis. RESULTS: We retained 102 patients in each cohort after PS matching, with similar baseline characteristics. More patients discontinued natalizumab compared to fingolimod (33% vs 11%, p < 0.001), mainly for progressive multifocal leukoencephalopathy (PML) concern. No serious adverse events occurred in the two cohorts. Compared to fingolimod, the natalizumab group presented a higher percentage of relapse-free patients (66% vs 80%, p = 0.015), a higher percentage of disability-improved patients (6% vs 15%, p = 0.033), a lower percentage of MRI-active patients (38% vs 14%, p = 0.001) and a higher percentage of patients with no evidence of disease activity (NEDA-3; 44% vs 70%, p < 0.001) after 2 years of follow-up. Disability worsening was not statistically different in the two groups. CONCLUSION: Natalizumab is superior to fingolimod in RRMS patients non-responding to first-line agents.

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.

Efficacy and safety of nabiximols (Sativex(®)) on multiple sclerosis spasticity in a real-life Italian monocentric study.

Multiple sclerosis (MS) patients frequently suffer from limb spasticity and pain despite antispastic treatments. To investigate nabiximols efficacy and safety in a real-world monocentric Italian cohort, the following data were collected at baseline, week 4, 14 and 48: Ambulation Index (AI), 10-min walking test (10MWT), combined Modified Ashworth scale (cMAS), scores at numerical rating scale for spasticity (sNRS) and pain (pNRS). Responder status was defined as a ≥20 % reduction in sNRS after 4 weeks of treatment. 144 MS patients (123 progressive and 21 relapsing-remitting) complaining of moderate-to-severe spasticity (mean sNRS: 7.5) were included: 138 (95.8 %) completed the first month of therapy and were classified as follows-23.2 % were non-responders, 5.1 % were responders but discontinued treatment due to side effects, 71.7 % were responders with a mean 32 % reduction in sNRS (p < 0.001). In responders sNRS further decreased between 4 and 14 weeks (p = 0.03). Similarly, pNRS improvement was seen during the first month and between 4 and 14 weeks (p < 0.001 and p = 0.004, respectively). Moreover, at 4 weeks responders showed a significant (p < 0.05) improvement in cMAS, AI and 10MWT, which was maintained at 14 weeks. At 1-year follow-up, a benefit was still evident on spasticity and painful symptoms with a low drop-out rate. Confusion/ideomotor slowing, fatigue and dizziness were the most frequent side effects; no major adverse events were reported. Shorter disease duration at treatment start was associated with better response. This real-world study confirms nabiximols efficacy and safety in the treatment of MS-related spasticity and pain, which is maintained up to 48 weeks.

In vivo evidence of hippocampal dentate gyrus expansion in multiple sclerosis.

Using MR-based radial mapping, we assessed morphological alterations of the hippocampal dentate gyrus (DG) in patients with relapse-onset multiple sclerosis (MS). We analyzed different stages of the disease and the association of DG alterations with hippocampal-related cognitive functions. Using high-resolution morphological imaging, hippocampal radial mapping analysis was performed in 28 relapsing-remitting (RR), 34 secondary progressive, and 26 benign MS patients and 28 healthy controls (HC). Between-groups differences of DG radial distance (from surface points to the central core of the hippocampus) and correlations with clinical, neuropsychological, and radiological measures were evaluated using surface-based mesh modeling. Compared with HC, all MS clinical phenotypes revealed a larger radial distance of the DG, which was more marked on the left side. Radial distance enlargement was more pronounced in RRMS patients compared with the other disease clinical phenotypes and was inversely correlated to disease duration. Radial distance enlargement was correlated with higher T2 lesion volume and a better cognitive performance in RRMS and with a poor cognitive performance in secondary progressive and benign MS patients. Surface expansion of the DG might represent an inflammation-induced neurogenic (reactive) process of the subgranular zone of the hippocampus primarily aimed at rescuing the functional competence of hippocampal circuitry.