Mobile Applications to Support Multiple Sclerosis Communities: The Post-COVID-19 Scenario.

Introduction: The increase in the use of mobile apps since the COVID-19 pandemic, even among people with multiple sclerosis (PwMS) and health care providers (HCPs), has enabled access to reliable information, symptoms monitoring and management, and social connections. The pandemic has undoubtedly contributed to the acceleration of the "digital revolution." But how far has it progressed for the MS communities? Methods: Italian Google Play and App Store were queried, selecting MS-specific apps in English or Italian language and usable by a wide public. Results: Fifty-four (n = 54) MS-specific apps were identified; most were PwMS-oriented (83%), free of charge (94%), and in English language (76%). The 45 PwMS-oriented apps focused on increasing MS knowledge (71%), tracking symptoms (33%), and promoting networking with peers or HCPs (38%). The 13 HCPs-oriented tools addressed education and updates on MS (62%), disease assessment and management (54%), and research (15%). Google Search tool was also queried to find non-MS-specific apps to fulfill some unmet domains (as sleep, pain, sexual or mental health). Twenty-four additional apps were listed to provide a valuable contribution. Conclusion: The "digital revolution" led to increasingly customized tools for PwMS, especially as m-health or social-networking apps. However, apps to support other specific MS-relevant domains, appealing HCPs-oriented apps, and specific mobile tools for MS caregivers are still lacking. The absence of data assessing the usability and quality of MS apps in ecologically contexts leads to not reliable conclusions about potential benefits. A strong dialogue between MS communities and the digital industry is encouraged to fill this gap.

Dietary interventions for multiple sclerosis-related outcomes.

BACKGROUND: Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system. Although the exact pathogenesis remains unknown, the leading theory is that it results from immune system dysregulation. Approved disease-modifying therapy appears to modulate the immune system to improve MS-related outcomes. There is substantial interest in the ability of dietary interventions to influence MS-related outcomes. This is an update of the Cochrane Review 'Dietary interventions for multiple sclerosis' (Farinotti 2003; Farinotti 2007; Farinotti 2012). OBJECTIVES: To assess the effects of dietary interventions (including dietary plans with recommendations for specific whole foods, macronutrients, and natural health products) compared to placebo or another intervention on health outcomes (including MS-related outcomes and serious adverse events) in people with MS. SEARCH METHODS: On 30 May 2019, we searched CENTRAL, MEDLINE, Embase, and Web of Science. We also searched ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (ICTRP), and Networked Digital Library of Theses and Dissertations (NDLTD). We checked reference lists in identified trials and requested information from trial authors to identify any additional published or unpublished data. SELECTION CRITERIA: We included any randomized controlled trial (RCT) or controlled clinical trial (CCT) examining the effect of a dietary intervention versus placebo or another intervention among participants with MS on MS-related outcomes, including relapses, disability progression, and magnetic resonance imaging (MRI) measures. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Planned primary outcomes were number of participants experiencing relapse and change in disability progression, according to a validated disability scale at the last reported follow-up. Secondary outcomes included MRI activity, safety, and patient-reported outcomes. We entered and analysed data in Review Manager 5. MAIN RESULTS: We found 41 full-text articles examining 30 trials following full-text review. Participants were adults with MS, defined by established criteria, presenting to MS clinics in Europe, North America, and the Middle East. Study design varied considerably, although all trials had at least one methodological issue leading to unknown or high risk of bias. Trials examined: supplementation to increase polyunsaturated fatty acids (PUFAs) (11 trials); a variety of antioxidant supplements (10 trials); dietary programmes (3 trials); and other dietary supplements (e.g. acetyl L-carnitine, biotin, creatine, palmitoylethanolamide, probiotic, riboflavin) (6 trials). In three trials comparing PUFAs with monounsaturated fatty acids (MUFAs), the evidence was very uncertain concerning difference in relapses (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.20; 3 studies, 217 participants; 75% in the PUFA group versus 74% in the MUFA group; very low-certainty evidence). Among four trials comparing PUFAs with MUFAs, there may be little to no difference in global impression of deterioration (RR 0.85, 95% CI 0.71 to 1.03; 4 studies, 542 participants; 40% in the PUFA group versus 47% in the MUFA group; low-certainty evidence). In two trials comparing PUFAs with MUFAs (102 participants), there was very low-certainty evidence for change in disability progression. None of the PUFA versus MUFA trials examined MRI outcomes. In one trial comparing PUFAs with MUFAs (40 participants), there were no serious adverse events; based on low-certainty evidence. In two trials comparing different PUFAs (omega-3 versus omega-6), there may be little to no difference in relapses (RR 1.02, 95% CI 0.62 to 1.66; 2 studies, 129 participants; 30% in the omega-3 versus 29% in the omega-6 group; low-certainty evidence). Among three trials comparing omega-3 with omega-6, there may be little to no difference in change in disability progression, measured as mean change in Expanded Disability Status Scale (EDSS) (mean difference (MD) 0.00, 95% CI -0.30 to 0.30; 3 studies, 166 participants; low-certainty evidence). In one trial comparing omega-3 with omega-6, there was likely no difference in global impression of deterioration (RR 0.99, 95% CI 0.51 to 1.91; 1 study, 86 participants; 29% in omega-3 versus 29% in omega-6 group; moderate-certainty evidence). In one trial comparing omega-3 with omega-6 (86 participants), there was likely no difference in number of new T1- weighted gadolinium-enhancing lesions, based on moderate-certainty evidence. In four trials comparing omega-3 with omega-6, there may be little to no difference in serious adverse events (RR 1.12, 95% CI 0.38 to 3.31; 4 studies, 230 participants; 6% in omega-3 versus 5% in omega-6 group; low-certainty evidence). In four trials examining antioxidant supplementation with placebo, there may be little to no difference in relapses (RR 0.98, 95% CI 0.59 to 1.64; 4 studies, 345 participants; 17% in the antioxidant group versus 17% in the placebo group; low-certainty evidence). In six trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning change in disability progression, measured as mean change of EDSS (MD -0.19, 95% CI -0.49 to 0.11; 6 studies, 490 participants; very low-certainty evidence). In two trials examining antioxidant supplementation with placebo, there may be little to no difference in global impression of deterioration (RR 0.99, 95% 0.50 to 1.93; 2 studies, 190 participants; 15% in the antioxidant group versus 15% in the placebo group; low-certainty evidence). In two trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning difference in gadolinium-enhancing lesions (RR 0.67, 95% CI 0.09 to 4.88; 2 studies, 131 participants; 11% in the antioxidant group versus 16% in the placebo group; very low-certainty evidence). In three trials examining antioxidant supplementation versus placebo, there may be little to no difference in serious adverse events (RR. 0.72, 95% CI 0.17 to 3.08; 3 studies, 222 participants; 3% in the antioxidant group versus 4% in the placebo group; low-certainty evidence). AUTHORS' CONCLUSIONS: There are a variety of controlled trials addressing the effects of dietary interventions for MS with substantial variation in active treatment, comparator, and outcomes of interest. PUFA administration may not differ when compared to alternatives with regards to relapse rate, disability worsening, or overall clinical status in people with MS, but evidence is uncertain. Similarly, at present, there is insufficient evidence to determine whether supplementation with antioxidants or other dietary interventions have any impact on MS-related outcomes.

Exercise Combined with Electrotherapy Enhances Motor Function in an Adolescent with Spinal Muscular Atrophy Type III.

BACKGROUND: Electrotherapy is widely used in physical therapy to increase muscle mass, improve motor function, and assist physical activity in several neurologic conditions. However, concerning Spinal Muscular Atrophy (SMA), limited evidence exists on the role of electrotherapy as an adjunct for improving muscle strength and function. CASE REPORT: An adolescent (13 y.o.) with SMA type III underwent an 18-week strengthening program divided into two stages. During Phase I (weeks: 1-8), a home-based program for quadriceps strengthening through neuromuscular electrical stimulation (NMES) was provided. In Phase II (weeks: 9-18), at-home NMES was combined with functional electrical stimulation (FES) assisting volitional cycling for a broader, systemic conditioning. The treatment improved patient's structural and functional motor outcomes (quadriceps circumference and strength, Tinetti scale, and Hammersmith scale) as well as independence in stair climbing. CLINICAL REHABILITATION IMPACT: The purpose of this report is to raise awareness of the potential role of electrotherapy to help improving motor performance in SMA patients and, secondly, to foster further research aimed at assessing the actual contribution this intervention may have as an add-on therapy to existing care.

Hand Passive Mobilization Performed with Robotic Assistance: Acute Effects on Upper Limb Perfusion and Spasticity in Stroke Survivors.

This single arm pre-post study aimed at evaluating the acute effects induced by a single session of robot-assisted passive hand mobilization on local perfusion and upper limb (UL) function in poststroke hemiparetic participants. Twenty-three patients with subacute or chronic stroke received 20 min passive mobilization of the paretic hand with robotic assistance. Near-infrared spectroscopy (NIRS) was used to detect changes in forearm tissue perfusion. Muscle tone of the paretic UL was assessed by the Modified Ashworth Scale (MAS). Symptoms concerning UL heaviness, joint stiffness, and pain were evaluated as secondary outcomes by self-reporting. Significant (p = 0.014) improvements were found in forearm perfusion when all fingers were mobilized simultaneously. After the intervention, MAS scores decreased globally, being the changes statistically significant for the wrist (from 1.6 ± 1.0 to 1.1 ± 1.0; p = 0.001) and fingers (from 1.2 ± 1.1 to 0.7 ± 0.9; p = 0.004). Subjects reported decreased UL heaviness and stiffness after treatment, especially for the hand, as well as diminished pain when present. This study supports novel evidence that hand robotic assistance promotes local UL circulation changes, may help in the management of spasticity, and acutely alleviates reported symptoms of heaviness, stiffness, and pain in subjects with poststroke hemiparesis. This opens new scenarios for the implications in everyday clinical practice. Clinical Trial Registration Number is NCT03243123.

Mapping face encoding using functional MRI in multiple sclerosis across disease phenotypes.

Using fMRI during a face encoding (FE) task, we investigated the behavioral and fMRI correlates of FE in patients with relapse-onset multiple sclerosis (MS) at different stages of the disease and their relation with attentive-executive performance and structural MRI measures of disease-related damage. A fMRI FE task was administered to 75 MS patients (11 clinically isolated syndromes - CIS, 40 relapsing-remitting - RRMS - and 24 secondary progressive - SPMS) and 22 healthy controls (HC). fMRI activity during the face encoding condition was correlated with behavioral, clinical, neuropsychological and structural MRI variables. All study subjects activated brain regions belonging to face perception and encoding network, and deactivated areas of the default-mode network. Compared to HC, MS patients had the concomitant presence of areas of increased and decreased activations as well as increased and decreased deactivations. Compared to HC or RRMS, CIS patients experienced an increased recruitment of posterior-visual areas. Thalami, para-hippocampal gyri and right anterior cingulum were more activated in RRMS vs CIS or SPMS patients, while an increased recruitment of frontal areas was observed in SPMS vs RRMS. Areas of abnormal activations were significantly correlated with clinical, cognitive-behavioral and structural MRI measures. Abnormalities of FE network occur in MS and vary across disease clinical phenotypes. Early in the disease, an increased recruitment of areas typically devoted to face perception and encoding occurs. In SPMS patients, abnormal functional recruitment of frontal lobe areas might contribute to the severity of clinical manifestations.

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.

Hippocampal-DMN disconnectivity in MS is related to WM lesions and depression.

The hippocampus is part of the default-mode network (DMN) and is functionally hit early in multiple sclerosis (MS). Hippocampal and DMN dysfunctions have been associated with depression, both in patients with MS and in major depressive disorders. We hypothesized that white matter lesions may contribute, through a disconnection mechanism, to hippocampal dysfunction. To test this, we assessed the relationship between hippocampal resting-state (RS) functional connectivity (FC) abnormalities with brain T2 lesion volumes and the presence and severity of depression. Structural and RS fMRI images were acquired from 69 patients with cognitively intact MS and 42 matched healthy controls (HC). Depression was quantified using the Montgomery-Asberg Depression Rating Scale. Seed-voxel hippocampal RS FC was assessed. SPM8 was used for between-group comparisons and correlation analysis between RS FC abnormalities with clinical and structural MRI variables. Compared to HC, patients with MS showed a significant atrophy of the whole brain and left hippocampus (P < 0.001), and a distributed pattern of decreased RS FC between the hippocampi and several cortical-subcortical regions, which were mostly located within the DMN. Reduced hippocampal RS FC with regions of the DMN was strongly correlated with higher T2 lesion volume, longer disease duration, and the severity of depression and disability. In patients with cognitively preserved MS, brain focal WM lesions are related to the functional integration of the hippocampus to other brain regions of the DMN, suggesting a disconnection syndrome. Such a disruption of hippocampal RS FC is likely to contribute to the occurrence of depression and to clinical disability.

Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis.

BACKGROUND: Different therapeutic strategies are available for treatment of multiple sclerosis (MS) including immunosuppressants, immunomodulators, and monoclonal antibodies. Their relative effectiveness in the prevention of relapse or disability progression is unclear due to the limited number of direct comparison trials. A summary of the results, including both direct and indirect comparisons of treatment effects, may help to clarify the above uncertainty. OBJECTIVES: To estimate the relative efficacy and acceptability of interferon ß-1b (IFNß-1b) (Betaseron), interferon ß-1a (IFNß-1a) (Rebif and Avonex), glatiramer acetate, natalizumab, mitoxantrone, methotrexate, cyclophosphamide, azathioprine, intravenous immunoglobulins, and long-term corticosteroids versus placebo or another active agent in participants with MS and to provide a ranking of the treatments according to their effectiveness and risk-benefit balance. SEARCH METHODS: We searched the Cochrane Database of Systematic Reviews, the Cochrane MS Group Trials Register, and the Food and Drug Administration (FDA) reports. The most recent search was run in February 2012. SELECTION CRITERIA: Randomized controlled trials (RCTs) that studied one of the 11 treatments for use in adults with MS and that reported our pre-specified efficacy outcomes were considered for inclusion. DATA COLLECTION AND ANALYSIS: Identifying search results and data extraction were performed independently by two authors. Data synthesis was performed by pairwise meta-analysis and network meta-analysis that was performed within a Bayesian framework. The body of evidence for outcomes within the pairwise meta-analysis was assessed according to GRADE, as very low, low, moderate, or high quality. MAIN RESULTS: Forty-four trials were included in this review, in which 17,401 participants had been randomised. Twenty-three trials included relapsing-remitting MS (RRMS) (9096 participants, 52%), 18 trials included progressive MS (7726, 44%), and three trials included both RRMS and progressive MS (579, 3%). The majority of the included trials were short-term studies, with the median duration being 24 months. The results originated mostly from 33 trials on IFNß, glatiramer acetate, and natalizumab that overall contributed outcome data for 9881 participants (66%).From the pairwise meta-analysis, there was high quality evidence that natalizumab and IFNß-1a (Rebif) were effective against recurrence of relapses in RRMS during the first 24 months of treatment compared to placebo (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.24 to 0.43; OR 0.45, 95% CI 0.28 to 0.71, respectively); they were more effective than IFNß-1a (Avonex) (OR 0.28, 95% CI 0.22 to 0.36; OR 0.19, 95% CI 0.06 to 0.60, respectively). IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having clinical relapses compared to placebo (OR 0.55, 95% CI 0.31 to 0.99; OR 0.15, 95% CI 0.04 to 0.54, respectively) but the quality of evidence for these treatments was graded as moderate. From the network meta-analysis, the most effective drug appeared to be natalizumab (median OR versus placebo 0.29, 95% credible intervals (CrI) 0.17 to 0.51), followed by IFNß-1a (Rebif) (median OR versus placebo 0.44, 95% CrI 0.24 to 0.70), mitoxantrone (median OR versus placebo 0.43, 95% CrI 0.20 to 0.87), glatiramer acetate (median OR versus placebo 0.48, 95% CrI 0.38 to 0.75), IFNß-1b (Betaseron) (median OR versus placebo 0.48, 95% CrI 0.29 to 0.78). However, our confidence was moderate for direct comparison of mitoxantrone and IFNB-1b vs placebo and very low for direct comparison of glatiramer vs placebo. The relapse outcome for RRMS at three years' follow-up was not reported by any of the included trials.Disability progression was based on surrogate markers in the majority of included studies and was unavailable for RRMS beyond two to three years. The pairwise meta-analysis suggested, with moderate quality evidence, that natalizumab and IFNß-1a (Rebif) probably decreased the odds of the participants with RRMS having disability progression at two years' follow-up, with an absolute reduction of 14% and 10%, respectively, compared to placebo. Natalizumab and IFNß-1b (Betaseron) were significantly more effective (OR 0.62, 95% CI 0.49 to 0.78; OR 0.35, 95% CI 0.17 to 0.70, respectively) than IFNß-1a (Avonex) in reducing the number of the participants with RRMS who had progression at two years' follow-up, and confidence in this result was graded as moderate. From the network meta-analyses, mitoxantrone appeared to be the most effective agent in decreasing the odds of the participants with RRMS having progression at two years' follow-up, but our confidence was very low for direct comparison of mitoxantrone vs placebo. Both pairwise and network meta-analysis revealed that none of the individual agents included in this review were effective in preventing disability progression over two or three years in patients with progressive MS.There was not a dose-effect relationship for any of the included treatments with the exception of mitoxantrone. AUTHORS' CONCLUSIONS: Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNß-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNß-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNß-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNß-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNß-1a (Rebif) or between azathioprine and IFNß-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.

Mitoxantrone for multiple sclerosis.

BACKGROUND: This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. OBJECTIVES: The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. DATA COLLECTION AND ANALYSIS: The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used. MAIN RESULTS: Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX. AUTHORS' CONCLUSIONS: MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (˜12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.

Interferon ß for secondary progressive multiple sclerosis: a systematic review.

BACKGROUND: It is unclear whether recombinant ß interferons (IFNß) can be effective in secondary progressive multiple sclerosis (SPMS). The aim was to determine whether IFNß can reduce the risk of disability and cognitive impairment progression in SPMS. METHODS: Using Cochrane methodology, we reviewed all randomised placebo controlled trials of IFNß in SPMS patients (1995-March 2012). RESULTS: 5 trials (3082 patients) were included. After 3 years, interferons did not reduce disability progression, confirmed at 6 months (RR 0.98, 95% CI 0.82 to 1.16). A small reduction in the number of patients who had relapses during the first 3 years of treatment (RR 0.91, 0.84 to 0.97) was found. No analysis of cognitive data was possible. More treated than placebo patients dropped out for adverse events. CONCLUSION: 3 year treatment with IFNß does not delay permanent disability in SPMS but reduces relapse risk, indicating that the anti-inflammatory effect of IFNß is unable to prevent MS progression once it has become established.

Neural intersections of the phonological, visual magnocellular and motor/cerebellar systems in normal readers: implications for imaging studies on dyslexia.

We used fMRI to explore the extent of the anatomical overlap of three neural systems that the literature on developmental dyslexia associates with reading: the auditory phonological, the visual magnocellular, and the motor/cerebellar systems. Twenty-eight normal subjects performed four tasks during fMRI scans: word and pseudoword reading, auditory rhyming for letter names, visual motion perception, and a motor sequence learning task. We found that the left occipitotemporal cortex (OTC), which previous studies reported to be dysfunctional in dyslexia, can be fractionated into different functional areas: an anterior and lateral area that was activated by both reading and auditory rhyming tasks; a posterior area that was commonly activated by both the reading and the motion perception task and a medial/intermediate area, including the so-called Visual Word Form Area, which was specifically activated by the reading task. These results show that the left OTC is an area of segregated convergence of different functional systems. We compared our results with the hypoactivation pattern reported for reading in a previous cross-cultural PET study on 36 dyslexic subjects from three countries. The region of decreased activation in dyslexia overlapped with regions that are specific for reading and those activated during both the auditory rhyming task and the single word and pseudoword reading task described in the present fMRI study. No overlap was found with the activation patterns for the visual motion perception task or for the motor sequence learning task. These observations challenge current theories of dyslexia.

Network meta-analysis models to account for variability in treatment definitions: application to dose effects.

For a network meta-analysis, an interlinked network of nodes representing competing treatments is needed. It is often challenging to define the nodes as these typically refer to similar but rarely identical interventions. The objectives of this paper are as follows: (i) to present a series of network meta-analysis models that account for variation in the definition of the nodes and (ii) to exemplify the models where variation in the treatment definitions relates to the dose. Starting from the model that assumes each node has a 'fixed' definition, we gradually introduce terms to explain variability by assuming that each node has several subnodes that relate to different doses. The effects of subnodes are considered monotonic, linked with a 'random walk', random but exchangeable, or have a linear pattern around the treatment mean effect. Each model can be combined with different assumptions for the consistency of effects and might impact on the ranking of the treatments. Goodness of fit, heterogeneity and inconsistency were assessed. The models are illustrated in a star network for the effectiveness of fluoride toothpaste and in a full network comparing agents for multiple sclerosis. The fit and parsimony measures indicate that in the fluoride network the impact of the dose subnodes is important whereas in the multiple sclerosis network the model without subnodes is the most appropriate. The proposed approach can be a useful exploratory tool to explain sources of heterogeneity and inconsistency when there is doubt whether similar interventions should be grouped under the same node.

Dietary interventions for multiple sclerosis.

BACKGROUND: Clinical and experimental data suggest that certain dietary regimens, particularly those including polyunsaturated fatty acids (PUFAs) and vitamins, might improve outcomes in people with multiple sclerosis (MS). Diets and dietary supplements are much used by people with MS in the belief that they might improve disease outcomes and overcome the effectiveness limits of conventional treatments.This is an update of the Cochrane review "Dietary intervention for multiple sclerosis" (first published on The Cochrane Library 2007, Issue 1). OBJECTIVES: To answer MS patients' questions regarding the efficacy and safety of dietary regimens for MS. Can changes in dietary habits be an effective intervention for MS patients? Are the potential side effects of these interventions known, and have they been measured? Are potential interactions between dietary interventions and other curative or symptomatic treatments known and have they been studied? SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (November 2011), CENTRAL (The Cochrane Library 2011, Issue 4), MEDLINE (PubMed) (1966 to November 2011), EMBASE (embase.com) (1974 to November 2011) and reference lists of papers found. SELECTION CRITERIA: All controlled trials (randomised controlled trials (RCTs) and controlled clinical trials (CCTs)) on a specific dietary intervention, diet plan or dietary supplementation, except for vitamin D supplementation, compared to no dietary modification or placebo were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently selected articles, assessed trial quality and extracted data. Data were entered and analysed in RevMan.Dichotomous data were summarised as relative risks (RR) with 95% confidence intervals (95% CI) using a random-effects model in the presence of heterogeneity (I² > 60%). Continuous data were analysed using weighted mean differences, determined by the difference between the pre- and post-intervention changes in the treatment and control groups. MAIN RESULTS: Six RCTs that investigated PUFAs emerged from the search strategy, accounting for 794 randomised patients.PUFAs did not have a significant effect on disease progression at 24 months. Omega-6 fatty acids (11 to 23 g/day linoleic acid) didn't show any benefit in 144 MS patients (RR 1.04, 95% CI 0.66 to 1.63). Linoleic acid (2.9 to 3.4 g/day) had no benefit in 65 chronic progressive MS patients (RR 0.78, 95% CI 0.43 to 1.42). Omega-3 fatty acids had no benefit in 292 relapsing remitting MS patients (RR 0.82, 95% CI 0.65 to 1.03, P = 0.08).Slight potential benefits in relapse outcomes were associated with omega-6 fatty acids in some studies, however these findings were limited by the reduced validity of the endpoints. No judgements about safety or patient-reported outcomes were possible. In general, trial quality was poor.No studies on vitamin supplementation and allergen-free diets were analysed as none met the eligibility criteria, mainly due to lack of clinical outcomes. AUTHORS' CONCLUSIONS: PUFAs seem to have no major effect on the main clinical outcome in MS (disease progression), but they may tend to reduce the frequency of relapses over two years. However, the data that are available are insufficient to assess a real benefit or harm from PUFA supplementation because of their uncertain quality.Evidence on the possible benefits and risks of vitamin supplementation and antioxidant supplements in MS is lacking. More research is required to assess the effectiveness of dietary interventions in MS.

Interferon beta for secondary progressive multiple sclerosis.

BACKGROUND: Therapy with either recombinant beta-1a or beta-1b interferons (IFNs) is worldwide approved for Relapsing Remitting Multiple Sclerosis (RRMS). A major unanswered question is whether this treatment is able to safely reverse or retard the progressive phase of the disease. OBJECTIVES: The main objective was to verify whether IFNs treatment in Secondary Progressive Multiple Sclerosis (SPMS) is more effective than placebo in reducing the number of patients who experience disability progression. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis Group's Trials Register (1995 to 15 February 2011), the reference lists of relevant articles and conference proceedings. Regulatory agencies were used as additional sources of information. SELECTION CRITERIA: We included all randomised, double or single blind, placebo-controlled trials (RCTs) evaluating the efficacy of IFNs versus placebo in SPMS patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all reports retrieved from the search. They independently extracted clinical, safety and MRI data, using a predefined data extraction form, resolving disagreements after discussion with a third reviewer. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using Risk Ratio (RR) with 95% confidence intervals (CI) for the binary outcomes and Standard Mean Difference with 95% CI for the continuous outcomes. MAIN RESULTS: Five RCTs met the inclusion criteria, from which 3122 (1829 IFN and 1293 placebo) treated patients contributed to the analysis. Included population was heterogeneous in terms of baseline clinical characteristics of the disease, in particular the percentage of patients affected by secondary progression with superimposed relapse ranging from 72% to 44%. IFN beta 1a and 1b did not decrease the risk of progression sustained at 6 months (RR, 95% CI: 0.98, [0.82-1.16]) after three years of treatment. A significant decrease of the risk of progression sustained at 3 months (RR, 95% CI: 0.88 [0.80, 0.97]) and of the risk of developing new relapses at three years (RR 0.91, [0.84-0.97]) were found. The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging (MRI), performed in subgroups of patients; in spite of no effect on progression, the radiological data supported an effect on MRI parameters. The safety profile reflects what is commonly reported in MS IFN-treated patients. AUTHORS' CONCLUSIONS: Well designed RCTs, evaluating a high number of patients were included in the review. Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS. We were unable to verify the effect on cognitive function for the lack of comparable data. This treatment significantly reduces the risk of relapse and of short -term relapse-related disability.Overall, these results show that IFNs' anti-inflammatory effect is unable to retard progression, when established. In the future, no new RCTs for IFNs versus placebo in SPMS will probably be undertaken, because research is now focusing on innovative drugs. We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS.