Publications by authors named "Valentina Tomassini"

52 Publications

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study.

J Neurol 2021 Feb 22. Epub 2021 Feb 22.

Clinica Neurologica, Centro Sclerosi Multipla, Azienda Ospedaliera di Padova, Padova, Italy.

Objective: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment.

Methods: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment.

Results: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007).

Conclusions: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.
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http://dx.doi.org/10.1007/s00415-021-10455-3DOI Listing
February 2021

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

Eur J Neurol 2021 Apr 12;28(4):1299-1307. Epub 2021 Jan 12.

Department of Clinical and Experimental Epilepsy, Queen Square, UCL Queen Square Institute of Neurology, London, UK.

Background And Purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS.

Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected.

Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline.

Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
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http://dx.doi.org/10.1111/ene.14672DOI Listing
April 2021

A frequency-domain machine learning method for dual-calibrated fMRI mapping of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO).

Front Artif Intell 2020 Mar;3

CUBRIC, Department of Psychology, Cardiff University, Cardiff, United Kingdom.

Magnetic resonance imaging (MRI) offers the possibility to non-invasively map the brain's metabolic oxygen consumption (CMRO), which is essential for understanding and monitoring neural function in both health and disease. However, in depth study of oxygen metabolism with MRI has so far been hindered by the lack of robust methods. One MRI method of mapping CMRO is based on the simultaneous acquisition of cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) weighted images during respiratory modulation of both oxygen and carbon dioxide. Although this dual-calibrated methodology has shown promise in the research setting, current analysis methods are unstable in the presence of noise and/or are computationally demanding. In this paper, we present a machine learning implementation for the multi-parametric assessment of dual-calibrated fMRI data. The proposed method aims to address the issues of stability, accuracy, and computational overhead, removing significant barriers to the investigation of oxygen metabolism with MRI. The method utilizes a time-frequency transformation of the acquired perfusion and BOLD-weighted data, from which appropriate feature vectors are selected for training of machine learning regressors. The implemented machine learning methods are chosen for their robustness to noise and their ability to map complex non-linear relationships (such as those that exist between BOLD signal weighting and blood oxygenation). An extremely randomized trees (ET) regressor is used to estimate resting blood flow and a multi-layer perceptron (MLP) is used to estimate CMRO and the oxygen extraction fraction (OEF). Synthetic data with additive noise are used to train the regressors, with data simulated to cover a wide range of physiologically plausible parameters. The performance of the implemented analysis method is compared to published methods both in simulation and with data (n=30). The proposed method is demonstrated to significantly reduce computation time, error, and proportional bias in both CMRO and OEF estimates. The introduction of the proposed analysis pipeline has the potential to not only increase the detectability of metabolic difference between groups of subjects, but may also allow for single subject examinations within a clinical context.
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http://dx.doi.org/10.3389/frai.2020.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116003PMC
March 2020

Predictors of training-related improvement in visuomotor performance in patients with multiple sclerosis: A behavioural and MRI study.

Mult Scler 2020 Aug 4:1352458520943788. Epub 2020 Aug 4.

Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK/Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK/Helen Durham Centre for Neuroinflammation, University Hospital of Wales, Cardiff, UK/Institute for Advanced Biomedical Technologies (ITAB), Department of Neurosciences, Imaging and Clinical Sciences, University 'G. d'Annunzio' of Chieti-Pescara, Chieti, Italy.

Background: The development of tailored recovery-oriented strategies in multiple sclerosis requires early identification of an individual's potential for functional recovery.

Objective: To identify predictors of visuomotor performance improvements, a proxy of functional recovery, using a predictive statistical model that combines demographic, clinical and magnetic resonance imaging (MRI) data.

Methods: Right-handed multiple sclerosis patients underwent baseline disability assessment and MRI of the brain structure, function and vascular health. They subsequently undertook 4 weeks of right upper limb visuomotor practice. Changes in performance with practice were our outcome measure. We identified predictors of improvement in a of patients using lasso regression; we calculated the best performing model in a and applied this model to a

Results: Patients improved their visuomotor performance with practice. Younger age, better visuomotor abilities, less severe disease burden and concurrent use of preventive treatments predicted improvements. Neuroimaging localised outcome-relevant sensory motor regions, the microstructure and activity of which correlated with performance improvements.

Conclusion: Initial characteristics, including age, disease duration, visuo-spatial abilities, hand dexterity, self-evaluated disease impact and the presence of disease-modifying treatments, can predict functional recovery in individual patients, potentially improving their clinical management and stratification in clinical trials. MRI is a correlate of outcome, potentially supporting individual prognosis.
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http://dx.doi.org/10.1177/1352458520943788DOI Listing
August 2020

Harmonization of real-world studies in multiple sclerosis: Retrospective analysis from the rirems group.

Mult Scler Relat Disord 2020 Oct 12;45:102394. Epub 2020 Jul 12.

Rehabilitation Department, Mons. L. Novarese, Moncrivello, Vercelli, Italy.

Background: Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies. In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods: RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ).

Results: Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p = 0.02; τ=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p = 0.02; τ=1.00).

Discussion: We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.
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http://dx.doi.org/10.1016/j.msard.2020.102394DOI Listing
October 2020

Diagnosis and management of multiple sclerosis: MRI in clinical practice.

J Neurol 2020 Oct 29;267(10):2917-2925. Epub 2020 May 29.

Newcastle Hospitals, Newcastle, UK.

Background: Recent changes in the understanding and management of multiple sclerosis (MS) have increased the role of MRI in supporting diagnosis and disease monitoring. However, published guidelines on the use of MRI in MS do not translate easily into different clinical settings and considerable variation in practice remains. Here, informed by published guidelines for the use of MRI in MS, we identified a clinically informative MRI protocol applicable in a variety of clinical settings, from district general hospitals to tertiary centres.

Methods: MS specialists geographically representing the UK National Health Service and with expertise in MRI examined existing guidelines on the use of MRI in MS and identification of challenges in their applications in various clinical settings informed the formulation of a feasible MRI protocol.

Results: We identified a minimum set of MRI information, based on clinical relevance, as well as on applicability to various clinical settings. This informed the selection of MRI acquisitions for scanning protocols, differentiated on the basis of their purpose and stage of the disease, and indication of timing for scans. Advice on standardisation of MRI requests and reporting, and proposed timing and frequency of MRI scans were generated.

Conclusions: The proposed MRI protocol can adapt to a range of clinical settings, aiding the impetus towards standardisation of practice and offering an example of research-informed service improvement to support optimisation of resources. Other neurological conditions, where a gap still exists between published guidelines and their clinical implementation, may benefit from this same approach.
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http://dx.doi.org/10.1007/s00415-020-09930-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501096PMC
October 2020

Cerebral Metabolic Changes During Visuomotor Adaptation Assessed Using Quantitative fMRI.

Front Physiol 2020 8;11:428. Epub 2020 May 8.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, United Kingdom.

The brain retains a lifelong ability to adapt through learning and in response to injury or disease-related damage, a process known as functional neuroplasticity. The neural energetics underlying functional brain plasticity have not been thoroughly investigated experimentally in the healthy human brain. A better understanding of the blood flow and metabolic changes that accompany motor skill acquisition, and which facilitate plasticity, is needed before subsequent translation to treatment interventions for recovery of function in disease. The aim of the current study was to characterize cerebral blood flow (CBF) and oxygen consumption (relative CMRO) responses, using calibrated fMRI conducted in 20 healthy participants, during performance of a serial reaction time task which induces rapid motor adaptation. Regions of interest (ROIs) were defined from areas showing task-induced BOLD and CBF responses that decreased over time. BOLD, CBF and relative CMRO responses were calculated for each block of the task. Motor and somatosensory cortices and the cerebellum showed statistically significant positive responses to the task compared to baseline, but with decreasing amplitudes of BOLD, CBF, and CMRO response as the task progressed. In the cerebellum, there was a sustained positive BOLD response in the absence of a significant CMRO increase from baseline, for all but the first task blocks. This suggests that the brain may continue to elevate the supply energy even after CMRO has returned to near baseline levels. Relying on BOLD fMRI data alone in studies of plasticity may not reveal the nature of underlying metabolic responses and their changes over time. Calibrated fMRI approaches may offer a more complete picture of the energetic changes supporting plasticity and learning.
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http://dx.doi.org/10.3389/fphys.2020.00428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227432PMC
May 2020

Exergames for balance dysfunction in neurological disability: a meta-analysis with meta-regression.

J Neurol 2020 May 23. Epub 2020 May 23.

Rehabilitation Unit 'Mons. L. Novarese' Hospital, Loc. Trompone, 13040, Moncrivello, VC, Italy.

Objective: To evaluate systematically the efficacy of exergames for balance dysfunction in neurological conditions and to identify factors of exergaming protocols that may influence their effects.

Methods: We searched electronic databases for randomized clinical trials investigating the effect of commercial exergames versus alternative interventions on balance dysfunction as assessed by standard clinical scales in adults with acquired neurological disabilities. Standardized mean differences (Hedge's g) were calculated with random-effects models. Subgroup analyses and meta-regression were run to explore potential modifiers of effect size.

Results: Out of 106 screened articles, 41 fulfilled criteria for meta-analysis, with a total of 1223 patients included. Diseases under investigation were stroke, Parkinson's disease, multiple sclerosis, mild cognitive impairment or early Alzheimer's disease, traumatic brain injury, and myelopathy. The pooled effect size of exergames on balance was moderate (g = 0.43, p < 0.001), with higher frequency (number of sessions per week) associated with larger effect (β = 0.24, p = 0.01). There was no effect mediated by the overall duration of the intervention and intensity of a single session. The beneficial effect of exergames could be maintained for at least 4 weeks after discontinuation, but their retention effect was specifically explored in only 11 studies, thus requiring future investigation. Mild to moderate adverse events were reported in a minority of studies. We estimated a low risk of bias, mainly attributable to the lack of double-blindness and not reporting intention-to-treat analysis.

Conclusions: The pooled evidence suggests that exergames improve balance dysfunction and are safe in several neurological conditions. The findings of high-frequency interventions associated with larger effect size, together with a possible sustained effect of exergaming, may guide treatment decisions and inform future research.
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http://dx.doi.org/10.1007/s00415-020-09918-wDOI Listing
May 2020

Assessment of the Effects of Aerobic Fitness on Cerebrovascular Function in Young Adults Using Multiple Inversion Time Arterial Spin Labeling MRI.

Front Physiol 2020 21;11:360. Epub 2020 Apr 21.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, United Kingdom.

This cross-sectional study investigated the effects of aerobic fitness on cerebrovascular function in the healthy brain. Gray matter cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) were quantified in a sample of young adults within a normal fitness range. Based on existing Transcranial Doppler ultrasound and fMRI evidence, we predicted a positive relationship between fitness and resting gray matter CBF and CVR. Exploratory hypotheses that higher Opeak would be associated with higher GM volume and cognitive performance were also investigated. 20 adults underwent a Opeak test and a battery of cognitive tests. All subjects also underwent an MRI scan where multiple inversion time (MTI) pulsed arterial spin labeling (PASL) was used to quantify resting CBF and CVR to 5% CO. Region of interest analysis showed a non-significant inverse correlation between whole-brain gray matter CBF and Opeak; = -0.4, = 0.08, corrected (') = 0.16 and a significant positive correlation between Opeak and whole-brain averaged gray matter CVR; = 0.62, = 0.003, ' = 0.006. Voxel-wise analysis revealed a significant inverse association between Opeak and resting CBF in the left and right thalamus, brainstem, right lateral occipital cortex, left intra-calcarine cortex and cerebellum. The results of this study suggest that aerobic fitness is associated with lower baseline CBF and greater CVR in young adults.
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http://dx.doi.org/10.3389/fphys.2020.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187806PMC
April 2020

Tractography in the presence of multiple sclerosis lesions.

Neuroimage 2020 04 24;209:116471. Epub 2019 Dec 24.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff, UK; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.

Accurate anatomical localisation of specific white matter tracts and the quantification of their tract-specific microstructural damage in conditions such as multiple sclerosis (MS) can contribute to a better understanding of symptomatology, disease evolution and intervention effects. Diffusion MRI-based tractography is being used increasingly to segment white matter tracts as regions-of-interest for subsequent quantitative analysis. Since MS lesions can interrupt the tractography algorithm's tract reconstruction, clinical studies frequently resort to atlas-based approaches, which are convenient but ignorant to individual variability in tract size and shape. Here, we revisit the problem of individual tractography in MS, comparing tractography algorithms using: (i) The diffusion tensor framework; (ii) constrained spherical deconvolution (CSD); and (iii) damped Richardson-Lucy (dRL) deconvolution. Firstly, using simulated and in vivo data from 29 MS patients and 19 healthy controls, we show that the three tracking algorithms respond differentially to MS pathology. While the tensor-based approach is unable to deal with crossing fibres, CSD produces spurious streamlines, in particular in tissue with high fibre loss and low diffusion anisotropy. With dRL, streamlines are increasingly interrupted in pathological tissue. Secondly, we demonstrate that despite the effects of lesions on the fibre orientation reconstruction algorithms, fibre tracking algorithms are still able to segment tracts that pass through areas with a high prevalence of lesions. Combining dRL-based tractography with an automated tract segmentation tool on data from 131 MS patients, the cortico-spinal tracts and arcuate fasciculi could be reconstructed in more than 90% of individuals. Comparing tract-specific microstructural parameters (fractional anisotropy, radial diffusivity and magnetisation transfer ratio) in individually segmented tracts to those from a tract probability map, we show that there is no systematic disease-related bias in the individually reconstructed tracts, suggesting that lesions and otherwise damaged parts are not systematically omitted during tractography. Thirdly, we demonstrate modest anatomical correspondence between the individual and tract probability-based approach, with a spatial overlap between 35 and 55%. Correlations between tract-averaged microstructural parameters in individually segmented tracts and the probability-map approach ranged between r=.53 (p<.001) for radial diffusivity in the right cortico-spinal tract and r=.97 (p<.001) for magnetisation transfer ratio in the arcuate fasciculi. Our results show that MS white matter lesions impact fibre orientation reconstructions but this does not appear to hinder the ability to anatomically reconstruct white matter tracts in MS. Individual tract segmentation in MS is feasible on a large scale and could prove a powerful tool for investigating diagnostic and prognostic markers.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116471DOI Listing
April 2020

Characteristics and treatment of Multiple Sclerosis-related trigeminal neuralgia: An Italian multi-centre study.

Mult Scler Relat Disord 2020 Jan 19;37:101461. Epub 2019 Oct 19.

Rehabilitation Department, Mons. L. Novarese, Moncrivello, Vercelli, Italy.

Background: The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study.

Methods: Neurologists members of the RIREMS group (Rising Researchers in MS) enrolled MS patients with a TN diagnosis and filled out a spreadsheet comprising their clinical data.

Results: Population consisted of 298 patients. First-choice preventive treatments were carbamazepine and oxcarbazepine. A surgical procedure was performed in 81 (30%) patients, most commonly gamma knife stereotactic radiosurgery (37%), followed by microvascular decompression (22%) and radiofrequency thermocoagulation (21%); one third of patients underwent at least two procedures. Surgery was associated with higher disability, male sex and longer interval between MS and TN onset. Patients (77%) who stayed on at least one preventive medication at most recent follow-up, after a mean period of 8 years, had a higher disability compared to the untreated group. Furthermore, patients with higher disability at TN onset were less likely to discontinue their first preventive medication due to pain remission, had bilateral TN more frequently and underwent surgical interventions earlier.

Conclusion: MS patients with a higher disability at TN onset and with a longer interval between MS and TN onset had differing clinical features and outcomes: pain was more frequently bilateral, surgery was more frequent and anticipated, and preventive medication discontinuation due to pain remission was less common.
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http://dx.doi.org/10.1016/j.msard.2019.101461DOI Listing
January 2020

"Better explanations" in multiple sclerosis diagnostic workup: A 3-year longitudinal study.

Neurology 2019 05 1;92(22):e2527-e2537. Epub 2019 May 1.

From the Departments of Neuroscience, Biomedicine and Movement (M.C., A. Gajofatto) and Neurological and Movement Sciences (G.S.), University of Verona; Department of Neurosciences (C.G., C.T.), Azienda Ospedaliera San Camillo Forlanini, Roma; Department of Basic Medical Sciences, Neurosciences and Sense Organs (C.T., D.P.), University of Bari; Policlinico Gemelli (G.F.), Rome; Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC) (P.R.), Università di Palermo; Istituto Neurologico Mediterraneo (R.F.), Pozzilli; Department of Neurology and Psychiatry (L.P.), Sapienza University of Rome; Multiple Sclerosis Center (P.A.), ASST Valle Olona, PO di Gallarate; Multiple Sclerosis Center (C.C.), Ospedale di Montichiari, Spedali Civili di Brescia; Clinica Neurologica (M.D.), Dipartimento di Medicina, Università di Perugia; Department of Biomedical, Metabolic and Neurosciences (D.F.), University of Modena and Reggio Emilia, Modena; Neurologia 2-CRESM (S.M.), AOU San Luigi Gonzaga, Orbassano; Multiple Sclerosis Centre (S.L.), A.O.U. Policlinico-Vittorio Emanuele, Catania; Neurology Clinic (G.D.), Multiple Sclerosis Center, SS. Annunziata Hospital, Chieti; Department of Medicine, Surgery and Neuroscience (M.L.S.), University of Siena; Department of Medical Science and Public Health (E.C.), University of Cagliari; Department of Medical, Surgical, Neurological, Metabolic and Aging Science (A. Gallo), University of Campania; Department of Neuroscience, Reproductive Sciences (R.L.), University Federico II, Naples, Italy; Institute of Psychological Medicine and Clinical Neurosciences (V.T.), Cardiff University School of Medicine, UK; Ospedale di Vaio (I.P.), Centro SM, Fidenza, Parma; Ospedale San Raffaele (M.E.R.), Milan; and Department of Rehabilitation (C.S.), Mons L Novarese Hospital, Moncrivello, Italy.

Background: The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete.

Methods: A total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up.

Findings: A total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio [OR] 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis.

Interpretation: This observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS.
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http://dx.doi.org/10.1212/WNL.0000000000007573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659006PMC
May 2019

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis.

Hum Brain Mapp 2019 07 19;40(10):2917-2932. Epub 2019 Mar 19.

Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI-based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel-wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue-states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2-weighted hyperintense lesional tissue without T1-weighted hypointensity (T2L), and T1-weighted hypointense lesional tissue with corresponding T2-weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue-states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions.
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http://dx.doi.org/10.1002/hbm.24568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563497PMC
July 2019

Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis.

JAMA Neurol 2019 05;76(5):536-541

Institute of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.

Importance: Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline.

Objective: To analyze long-term outcomes in a population-based cohort according to initial treatment strategy.

Design, Setting And Participants: In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45).

Exposures: Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).

Main Outcomes And Measures: Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group.

Results: Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = -0.85; 95% CI, -1.38 to -0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

Conclusions And Relevance: In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.
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http://dx.doi.org/10.1001/jamaneurol.2018.4905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515582PMC
May 2019

Neurological update: MOG antibody disease.

J Neurol 2019 May 19;266(5):1280-1286. Epub 2018 Dec 19.

Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK.

Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOG-AD) is now recognised as a nosological entity with specific clinical and paraclinical features to aid early diagnosis. Although no age group is exempt, median age of onset is within the fourth decade of life, with optic neuritis being the most frequent presenting phenotype. Disease course can be either monophasic or relapsing, with subsequent relapses most commonly involving the optic nerve. Residual disability develops in 50-80% of patients, with transverse myelitis at onset being the most significant predictor of long-term outcome. Recent advances in MOG antibody testing offer improved sensitivity and specificity. To avoid misdiagnosis, MOG antibody testing should be undertaken in selected cases presenting clinical and paraclinical features that are felt to be in keeping with MOG-AD, using a validated cell-based assay. MRI characteristics can help in differentiating MOG-AD from other neuroinflammatory disorders, including multiple sclerosis and neuromyelitis optica. Cerebrospinal fluid oligoclonal bands are uncommon. Randomised control trials are limited, but observational open-label experience suggests a role for high-dose steroids and plasma exchange in the treatment of acute attacks, and for immunosuppressive therapies, such as steroids, oral immunosuppressants and rituximab as maintenance treatment.
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http://dx.doi.org/10.1007/s00415-018-9122-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469662PMC
May 2019

How common is truly benign MS in a UK population?

J Neurol Neurosurg Psychiatry 2019 05 3;90(5):522-528. Epub 2018 Sep 3.

Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.

Objectives: The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations.

Methods: We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions.

Results: Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1).

Conclusions: Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term 'benign' in clinical settings.
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http://dx.doi.org/10.1136/jnnp-2018-318802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581074PMC
May 2019

Predicting the profile of increasing disability in multiple sclerosis.

Mult Scler 2019 08 2;25(9):1306-1315. Epub 2018 Aug 2.

Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

Background: Effective therapeutic strategies to preserve function and delay progression in multiple sclerosis (MS) require early recognition of individual disease trajectories.

Objectives: To determine the profiles of disability evolution, identify their early predictors and develop a risk score of increasing disability.

Methods: We analysed demographic, clinical and magnetic resonance imaging (MRI) data from patients with relapsing MS, Expanded Disability Status Scale (EDSS) score of 3.0-4.0 and follow-up ≥ 2 years. Attaining EDSS = 6.0 defined ; relapses and/or MRI defined disease .

Results: In total, 344 out of 542 (63.5%) patients reached EDSS ≥ 6.0; of these, 220 (64.0%) showed disease activity. In patients with activity, the number of relapses before reaching EDSS 3.0-4.0 predicted increasing disability; age > 45 at baseline predicted increasing disability without activity. Combining age and number of relapses increased the risk of and shortened the time to EDSS = 6.0.

Conclusion: Increasing disability is frequently associated with persistent activity. The high number of relapses identifies early those patients worsening in the presence of activity. Age predicts increasing disability in the absence of activity. The presence of both factors increases the risk of developing severe disability. As this study likely describes the transition to progression, our findings contribute to improving patient management and stratification in trials on progressive MS.
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http://dx.doi.org/10.1177/1352458518790397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681428PMC
August 2019

Impact of the 2017 revisions to McDonald criteria on the diagnosis of multiple sclerosis.

Mult Scler 2018 11 15;24(13):1786-1787. Epub 2018 May 15.

2 Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK/ Helen Durham Centre for Neuroinflammation, University Hospital of Wales, Cardiff, UK.

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http://dx.doi.org/10.1177/1352458518778007DOI Listing
November 2018

Neurovascular Coupling During Visual Stimulation in Multiple Sclerosis: A MEG-fMRI Study.

Neuroscience 2019 04 23;403:54-69. Epub 2018 Mar 23.

Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University School of Psychology, Maindy Road, Cardiff CF24 4HQ, UK; Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, University Hospital Wales, Heath Park, CF14 4XN, UK. Electronic address:

The process of neurovascular coupling ensures that increases in neuronal activity are fed by increases in cerebral blood flow. Evidence suggests that neurovascular coupling may be impaired in Multiple Sclerosis (MS) due to a combination of brain hypoperfusion, altered cerebrovascular reactivity and oxygen metabolism, and altered levels of vasoactive compounds. Here, we tested the hypothesis that neurovascular coupling is impaired in MS. We characterized neurovascular coupling as the relationship between changes in neuronal oscillatory power within the gamma frequency band (30-80 Hz), as measured by magnetoencephalography (MEG), and associated hemodynamic changes (blood oxygenation level dependent, BOLD, and cerebral blood flow, CBF) as measured by functional MRI. We characterized these responses in the visual cortex in 13 MS patients and in 10 matched healthy controls using a reversing checkerboard stimulus at five visual contrasts. There were no significant group differences in visual acuity, P100 latencies, occipital gray matter (GM) volumes and baseline CBF. However, in the MS patients we found a significant reduction in peak gamma power, BOLD and CBF responses. There were no significant differences in neurovascular coupling between groups, in the visual cortex. Our results suggest that neuronal and vascular responses are altered in MS. Gamma power reduction could be an indicator of GM dysfunction, possibly mediated by GABAergic changes. Altered hemodynamic responses confirm previous reports of a vascular dysfunction in MS. Despite altered neuronal and vascular responses, neurovascular coupling appears to be preserved in MS, at least within the range of damage and disability studied here.
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http://dx.doi.org/10.1016/j.neuroscience.2018.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458991PMC
April 2019

A multicentRE observational analysiS of PErsistenCe to Treatment in the new multiple sclerosis era: the RESPECT study.

J Neurol 2018 May 16;265(5):1174-1183. Epub 2018 Mar 16.

Neurology Unit, Centro di Recupero e Rieducazione Funzionale, Moncrivello, VC, Italy.

In this independent, multicenter, retrospective study, we investigated the short-term persistence to treatment with first-line self-injectable or oral disease-modifying treatments (DMTs) in patients with relapsing-remitting multiple sclerosis. Data of patients regularly attending 21 Italian MS Centres who started a self-injectable or an oral DMT in 2015 were collected to: (1) estimate the proportion of patients discontinuing the treatment; (3) explore reasons for discontinuation; (3) identify baseline predictors of treatment discontinuation over a follow-up period of 12 months. We analyzed data of 1832 consecutive patients (1289 women, 543 men); 374 (20.4%) of them discontinued the prescribed DMT after a median time of 6 months (range 3 days to 11.5 months) due to poor tolerability (n = 163; 43.6%), disease activity (n = 95; 25.4%), adverse events (n = 64; 17.1%), convenience (i.e. availability of new drug formulations) and pregnancy planning (n = 21; 1.1%). Although the proportion of discontinuers was higher with self-injectable (n = 107; 22.9%) than with oral DMT (n = 215; 16.4%), the Cox regression model revealed no significant between-group difference (p = 0.12). Female sex [hazard ratio (HR) = 1.39, p = 0.01] and previous exposure to ≥ 3 DMTs (HR = 1.71, p = 0.009) were two independent risk factors for treatment discontinuation, regardless of prescribed DMTs. Our study confirms that persistence to treatment represents a clinical challenge, irrespective of the route of administration.
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http://dx.doi.org/10.1007/s00415-018-8831-xDOI Listing
May 2018

Effect on Cognition of Estroprogestins Combined with Interferon Beta in Multiple Sclerosis: Analysis of Secondary Outcomes from a Randomised Controlled Trial.

CNS Drugs 2017 Feb;31(2):161-168

MS Centre Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

Introduction: Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-β) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy.

Objectives: We investigated whether a combination of estroprogestins and IFN-β can improve cognition in women with MS.

Methods: Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-β-1a (Rebif, Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao's Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined 'cognitive impairment'.

Results: At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03).

Conclusions: This study suggests that the combination of high-dose estroprogestins and IFN-β may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised. Protocol Number NCT00151801, registered in ClinicalTrials.gov.
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http://dx.doi.org/10.1007/s40263-016-0401-0DOI Listing
February 2017

The effect of inflammation and its reduction on brain plasticity in multiple sclerosis: MRI evidence.

Hum Brain Mapp 2016 07 18;37(7):2431-45. Epub 2016 Mar 18.

Department of Neurology and Psychiatry, Sapienza University of Rome, Italy.

Brain plasticity is the basis for systems-level functional reorganization that promotes recovery in multiple sclerosis (MS). As inflammation interferes with plasticity, its pharmacological modulation may restore plasticity by promoting desired patterns of functional reorganization. Here, we tested the hypothesis that brain plasticity probed by a visuomotor adaptation task is impaired with MS inflammation and that pharmacological reduction of inflammation facilitates its restoration. MS patients were assessed twice before (sessions 1 and 2) and once after (session 3) the beginning of Interferon beta (IFN beta), using behavioural and structural MRI measures. During each session, 2 functional MRI runs of a visuomotor task, separated by 25-minutes of task practice, were performed. Within-session between-run change in task-related functional signal was our imaging marker of plasticity. During session 1, patients were compared with healthy controls. Comparison of patients' sessions 2 and 3 tested the effect of reduced inflammation on our imaging marker of plasticity. The proportion of patients with gadolinium-enhancing lesions reduced significantly during IFN beta. In session 1, patients demonstrated a greater between-run difference in functional MRI activity of secondary visual areas and cerebellum than controls. This abnormally large practice-induced signal change in visual areas, and in functionally connected posterior parietal and motor cortices, was reduced in patients in session 3 compared with 2. Our results suggest that MS inflammation alters short-term plasticity underlying motor practice. Reduction of inflammation with IFN beta is associated with a restoration of this plasticity, suggesting that modulation of inflammation may enhance recovery-oriented strategies that rely on patients' brain plasticity. Hum Brain Mapp 37:2431-2445, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069650PMC
July 2016

Oral contraceptives combined with interferon β in multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2015 Aug 18;2(4):e120. Epub 2015 Jun 18.

Department of Neurology and Psychiatry (C.P., L.D.G., F.D.A., M.C.P., V.T., P.P.), Sapienza University of Rome, Italy; MS Center (C.P., L.D.G., V.T.B., F.M.), S. Andrea Hospital, Sapienza University of Rome, Italy; Centre for Primary Care and Public Health (V.G.), Queen Mary University of London, UK; TFS Trial Form Support S.L. (V.A.P., S.M.), Rome, Italy; Institute of Psychological Medicine and Clinical Neurosciences (V.T.), Cardiff University School of Medicine University Hospital of Wales (V.T.), Cardiff, UK; Santa Lucia Foundation (V.T.), Rome, Italy; and IRCCS Neuromed (P.P.), Pozzilli (IS), Italy.

Objective: To test the effect of oral contraceptives (OCs) in combination with interferon β (IFN-β) on disease activity in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: One hundred fifty women with RRMS were randomized in a 1:1:1 ratio to receive IFN-β-1a subcutaneously (SC) only (group 1), IFN-β-1a SC plus ethinylstradiol 20 μg and desogestrel 150 μg (group 2), or IFN-β-1a SC plus ethinylestradiol 40 μg and desogestrel 125 μg (group 3). The primary endpoint was the cumulative number of combined unique active (CUA) lesions on brain MRI at week 96. Secondary endpoints included MRI and clinical and safety measures.

Results: The estimated number of cumulative CUA lesions at week 96 was 0.98 (95% confidence interval [CI] 0.81-1.14) in group 1, 0.84 (95% CI 0.66-1.02) in group 2, and 0.72 (95% CI 0.53-0.91) in group 3, with a decrease of 14.1% (p = 0.24) and 26.5% (p = 0.04) when comparing group 1 with groups 2 and 3, respectively. The number of patients with no gadolinium-enhancing lesions was greater in group 3 than in group 1 (p = 0.03). No significant differences were detected in other secondary endpoints. IFN-β or OC discontinuations were equally distributed across groups.

Conclusions: Our results translate the observations derived from experimental models to patients, supporting the anti-inflammatory effects of OCs with high-dose estrogens, and suggest possible directions for future research.

Classification Of Evidence: This study provides Class II evidence that in women with RRMS, IFN-β plus ethinylstradiol and desogestrel decreases the cumulative number of active brain MRI lesions compared with IFN-β alone.
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http://dx.doi.org/10.1212/NXI.0000000000000120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476053PMC
August 2015

Neuroplasticity and motor rehabilitation in multiple sclerosis.

Front Neurol 2015 18;6:59. Epub 2015 Mar 18.

Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine , Cardiff , UK ; Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University , Cardiff , UK ; IRCCS Fondazione Santa Lucia , Rome , Italy.

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http://dx.doi.org/10.3389/fneur.2015.00059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364082PMC
April 2015

Impaired Functional Connectivity Unmasked by Simple Repetitive Motor Task in Early Relapsing-Remitting Multiple Sclerosis.

Neurorehabil Neural Repair 2015 Jul 21;29(6):557-65. Epub 2014 Nov 21.

Sapienza University, Rome, Italy IRCCS Neuromed, Pozzilli (IS), Italy.

Background: Resting brain activity can be modulated by motor tasks to adapt to function. In multiple sclerosis (MS) patients, altered resting-state functional connectivity (RS-FC) has been reported and associated with impaired function and disability; little is known on how RS-FC is modulated by a simple repetitive motor task.

Objective: To assess changes in RS-FC in early relapsing-remitting MS (RRMS) patients associated with repetitive thumb flexions (RTFs).

Methods: A total of 20 right-handed patients with early RRMS and 14 healthy controls underwent a resting functional magnetic resonance imaging (fMRI) scan, before and after 25 minutes of alternate 30-s blocks of right RTF and rest. Dual-regression analysis of resting fMRI data followed the independent component analysis. Individual spatial maps of coherence between brain areas for 2 networks of interest, sensorimotor and cerebellar, were compared at the group level and correlated with measures of both clinical impairment and brain damage.

Results: Significant RTF-induced differences in RS-FC were observed between groups in the cerebellar network because of increased RS-FC in patients but not in controls. In the sensorimotor network, the RS-FC after RTF increased in both groups, with no significant between-group differences. The sensorimotor and the cerebellar RS-FC were intercorrelated only in patients and only after the RTF. The sensorimotor RS-FC increase in patients correlated with structural MRI alterations.

Conclusions: Our study unmasked RS-FC changes of motor-related networks occurring after a simple repetitive motor task in early RRMS patients only. Evaluation of altered RSN dynamics might prove useful for anticipating neuroplasticity and for MRI-informed neurorehabilitation.
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http://dx.doi.org/10.1177/1545968314558600DOI Listing
July 2015

Modelling the natural history of primary progressive multiple sclerosis.

J Neurol Neurosurg Psychiatry 2015 Jan 14;86(1):13-9. Epub 2014 May 14.

Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Cardiff, UK Department of Neurology, Helen Durham Centre for Neuroinflammatory Disease, University Hospital of Wales, Cardiff, UK.

Background: A minority of patients with multiple sclerosis (MS) have primary progressive disease (PPMS). Treatment options are currently limited, but as prospects for interventional studies become more realistic, understanding contemporary outcome data will be key to successful trial design.

Methods: 234 PPMS patients were identified from a population-based cohort of 2131 (11.0%) and mean follow-up of 13.1 years. Time to established disability endpoints was compared with patients with relapsing-onset MS (ROMS) using survival analysis, and Cox regression employed to explore factors contributing to disability accumulation. Results were used to create predictive power models for clinical trials in PPMS.

Results: Time to fixed disability milestones was shorter than in ROMS (Expanded Disability Status Scale (EDSS) 4.0:8.1 vs. 17.1 years, p<0.001; EDSS 6.0: 9.6 vs. 22.1 years, p<0.001; EDSS 8.0: 20.7 vs. 39.7 years, p<0.001), but there were no differences in age-related disability. Age and cerebellar symptoms at onset affected rate of progression. Modelling of these data indicated that trials employing EDSS change of 1.0 as the primary outcome measure would be powered to detect a 20% difference in progression using 600 patients with initial EDSS of 4.0 per trial arm, or 400 patients with initial EDSS of 5.0 per arm. However, trials including patients with fixed EDSS of ≥6.0 will be underpowered even with large numbers or prolonged duration.

Conclusions: Disability progression in PPMS is variable and influenced by age at onset. Although progression is more rapid, age-related disability milestones are identical to relapsing-onset disease. These data offer a contemporary paradigm for clinical trial design in progressive MS.
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http://dx.doi.org/10.1136/jnnp-2014-307791DOI Listing
January 2015

Thyroid autoimmunity and dysfunction in multiple sclerosis patients during long-term treatment with interferon beta or glatiramer acetate: an Italian multicenter study.

Mult Scler 2014 08 10;20(9):1265-8. Epub 2014 Feb 10.

San Camillo Forlanini Hospital, Rome, Italy.

Few long-term follow-up data are available on thyroid dysfunction (TD) in multiple sclerosis (MS) patients treated with glatiramer acetate (GA) or with interferon-beta (IFNb). In a cohort of 787 relapsing-remitting MS (RRMS) patients whom were followed up for 8 years, we observed an increased prevalence of TD and thyroid autoimmunity (TA) within the first year of IFNb treatment, regardless of the dose or frequency of administration, while no change was observed with GA treatment. The increased prevalence of TD and TA within the first year of IFNb treatment suggested the need for close monitoring of thyroid function and autoimmunity, though only during the first year of IFNb treatment.
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http://dx.doi.org/10.1177/1352458514521311DOI Listing
August 2014

Evidence of impaired brain activity balance after passive sensorimotor stimulation in multiple sclerosis.

PLoS One 2013 14;8(6):e65315. Epub 2013 Jun 14.

Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.

Objectives: Examination of sensorimotor activation alone in multiple sclerosis (MS) patients may not yield a comprehensive view of cerebral response to task stimulation. Additional information may be obtained by examining the negative BOLD response (deactivation). Aim of this work was to characterize activation and deactivation patterns during passive hand movements in MS patients.

Methods: 13 relapsing remitting-MS patients (RRMS), 18 secondary progressive-MS patients (SPMS) and 15 healthy controls (HC) underwent an fMRI study during passive right-hand movements. Activation and deactivation contrasts in the three groups were entered into ANOVA, age and gender corrected. Post-hoc analysis was performed with one-sample and two-sample t-tests. For each patient we obtained lesion volume (LV) from both T1- and T2-weighted images.

Results: Activations showed a progressive extension to the ipsilateral brain hemisphere according to the group and the clinical form (HC
Conclusion: In RRMS patients, increased cortical activation was associated with increased deactivation of the posterior cortex suggesting a greater resting-state activity in the DMN, probably aimed at facilitating sensorimotor circuit engagement during task performance. In SPMS the coupling between increased sensorimotor activation/increased DMN deactivation was not observed suggesting disorganization between anticorrelated functional networks as a consequence of a higher level of disconnection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065315PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682993PMC
January 2014

Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride.

Brain 2013 Jan;136(Pt 1):106-15

Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.

Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1)-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, we showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis.
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http://dx.doi.org/10.1093/brain/aws325DOI Listing
January 2013

Neuroplasticity and functional recovery in multiple sclerosis.

Nat Rev Neurol 2012 11;8(11):635-46

School of Medicine, Cardiff University, UK.

The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain's recovery from damage, generating novel hypotheses about potential targets and modes of intervention, and laying the foundation for development of scientifically informed recovery-promoting strategies in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms that can be modulated by interventions and the development of robust measurements of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use to obtain reliable markers of the effects of interventions.
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http://dx.doi.org/10.1038/nrneurol.2012.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770511PMC
November 2012