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Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions., Haider et al. followed a cohort of individuals for 30 years after their initial presentation with symptoms suggestive of multiple sclerosis. Cortical involvement was the main correlate of progressive disease and disability and therefore might provide a promising diagnostic and therapeutic target.

Previous cohort studies on paediatric multiple sclerosis (MS) have reported very low frequencies for a primary progressive MS (PPMS) course ranging from 0% to 7%. We identified six patients presenting prior to the age of 18 years and fulfilling the 2017 McDonald Criteria for PPMS. Presentation with progressive neurological symptoms and signs in young people should prompt evaluation for genetic causes such as leukodystrophies, hereditary spastic paraparesis and mitochondrial diseases given the rarity of primary progressive course in paediatric MS. In the absence of an alternative diagnosis, with new therapeutic options becoming available for PPMS, this diagnosis should then be considered.

ObjectivesTraumatic and non-traumatic spinal cord injury produce neurodegeneration across the entire neuraxis. However, the spatiotemporal dynamics of spinal cord grey and white matter neurodegeneration above and below the injury is understudied.MethodsWe acquired longitudinal data from 13 traumatic and 3 non-traumatic spinal cord injury patients (8–8 cervical and thoracic cord injuries) within 1.5 years after injury and 10 healthy controls over the same period. The protocol encompassed structural and diffusion-weighted MRI rostral (C2/C3) and caudal (lumbar enlargement) to the injury level to track tissue-specific neurodegeneration. Regression models assessed group differences in the temporal evolution of tissue-specific changes and associations with clinical outcomes.ResultsAt 2 months post-injury, white matter area was decreased by 8.5% and grey matter by 15.9% in the lumbar enlargement, while at C2/C3 only white matter was decreased (−9.7%). Patients had decreased cervical fractional anisotropy (FA: −11.3%) and increased radial diffusivity (+20.5%) in the dorsal column, while FA was lower in the lateral (−10.3%) and ventral columns (−9.7%) of the lumbar enlargement. White matter decreased by 0.34% and 0.35% per month at C2/C3 and lumbar enlargement, respectively, and grey matter decreased at C2/C3 by 0.70% per month.ConclusionsThis study describes the spatiotemporal dynamics of tissue-specific spinal cord neurodegeneration above and below a spinal cord injury. While above the injury, grey matter atrophy lagged initially behind white matter neurodegeneration, in the lumbar enlargement these processes progressed in parallel. Tracking trajectories of tissue-specific neurodegeneration provides valuable assessment tools for monitoring recovery and treatment effects.

Pathophysiological changes in the spinal cord white and grey matter resulting from injury can be observed with MRI techniques. These techniques provide sensitive markers of macrostructural and microstructural tissue integrity, which correlate with histological findings. Spinal cord MRI findings in traumatic spinal cord injury (tSCI) and nontraumatic spinal cord injury - the most common form of which is degenerative cervical myelopathy (DCM) - have provided important insights into the pathophysiological processes taking place not just at the focal injury site but also rostral and caudal to the spinal injury. Although tSCI and DCM have different aetiologies, they show similar degrees of spinal cord pathology remote from the injury site, suggesting the involvement of similar secondary degenerative mechanisms. Advanced quantitative MRI protocols that are sensitive to spinal cord pathology have the potential to improve diagnosis and, more importantly, predict outcomes in patients with tSCI or nontraumatic spinal cord injury. This Review describes the insights into tSCI and DCM that have been revealed by neuroimaging and outlines current activities and future directions for the field.

Objective: To compare the performance of the 2017 McDonald criteria with that of the 2010 criteria for the diagnosis of multiple sclerosis (MS) in children in the clinical setting. Methods: In this retrospective, multi-centre study, we identified children who presented with symptoms suggestive of a clinically isolated syndrome (CIS) and were followed up for at least 2 years or until their second attack. Results: Of 156 children with CIS followed up for a median of 4.17 years, 94 (60.3%) were diagnosed with MS. In all, 83 (88.3%) of these fulfilled the 2010 dissemination in space (DIS) criteria at onset. Three additional children fulfilled the 2017 DIS criteria because of the inclusion of symptomatic lesions. Of the 59 children with MS who underwent post-gadolinium magnetic resonance imaging (MRI), 44 (74.6%) fulfilled the 2010 dissemination in time (DIT) criteria at baseline. When the presence of oligoclonal bands (OCBs) was used to substitute DIT, an additional 35 children (79/94, 84.0%) were diagnosed with MS according to the 2017 criteria. The 2017 criteria had higher accuracy (87.2% vs 66.7%), higher sensitivity (84.0% vs 46.8%), but reduced specificity (91.9% vs 96.8%) when compared to the 2010 criteria. Conclusion: The improved performance of the 2017 criteria when compared to the 2010 criteria was predominantly due to the inclusion of intrathecal OCBs.

Significance Traditional analysis of clinical trials precludes a mechanistic understanding of drug actions. This is further compounded by the use of outcome measures in clinical trials not directly related to the mechanism of action of the medication under study. Here, we applied structural equation models to the double-blind randomized controlled trial of simvastatin in secondary progressive multiple sclerosis to investigate causal associations that underlie treatment effects. Our results suggest that beneficial effects of simvastatin on reducing the rate of brain atrophy and slowing the deterioration of disability are independent of serum cholesterol reduction. Our work demonstrates that structural models can elucidate the statistical pathways underlying treatment effects in clinical trials of poorly understood neurodegenerative disorders, such as progressive multiple sclerosis., Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [β = −0.037; 95% credible interval (CI) = −0.075, −0.010]. This suggests that simvastatin’s beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.

The original version of this Article contained an error in Fig. 2, in which the plot shown in panel c was inadvertently duplicated in panel d. The correct version of Fig. 2 is: (Figure presented.) which replaces the previous incorrect version: (Figure presented.).

Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies. We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation. Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate. People with the lesion-led MS subtype show positive treatment response in selected clinical trials. Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials., Multiple sclerosis is a heterogeneous progressive disease. Here, the authors use an unsupervised machine learning algorithm to determine multiple sclerosis subtypes, progression, and response to potential therapeutic treatments based on neuroimaging data.

ObjectiveSporadic Creutzfeldt-Jakob disease (sCJD) causes rapidly-progressive dementia and complex abnormalities of motor systems with striking phenotypic heterogeneity, but no tools are available for the clinician to determine disease severity from bedside cognitive and neurological assessments. We used a robust statistical methodology and routinely-collected examination data to develop and validate short clinical rating scales quantifying longitudinal motor and cognitive dysfunction in sCJD.MethodsWe undertook a retrospective analysis of clinical examination data from the prospective National Prion Monitoring Cohort study, October 2008 – December 2016. Rasch analysis was used to iteratively construct interval scales measuring composite cognitive and motor dysfunction from pooled bedside neurological and cognitive examination tests.A longitudinal clinical examination dataset was constructed from a total of 528 patients with sCJD, comprising 1030 Motor Scale and 757 Cognitive Scale scores, over 130 patient-years of study, and used to demonstrate scale utility.ResultsThe Rasch-derived Motor Scale consists of 8 items, including examination items reliant on pyramidal, extrapyramidal and cerebellar systems. The Cognitive Scale comprises 6 items, and includes measures of executive function, language, visual perception and memory. Both scales are unidimensional, perform consistently regardless of age or gender and have excellent inter-rater reliability. Each scale can be completed in a few minutes at the bedside, as part of a normal neurocognitive examination. Several uses of the scales, in measuring longitudinal change, prognosis, and phenotypic heterogeneity are illustrated.InterpretationThese two novel scales measuring motor and cognitive dysfunction in sCJD should prove useful to objectively measure phenotypic and clinical change in future clinical trials and for patient stratification. This statistical approach can help to overcome obstacles to assessing clinical change in rapidly-progressive, multisystem conditions with limited longitudinal follow-up.

The clinical courses of multiple sclerosis were defined in 1996 and refined in 2013 to provide a time-based assessment of the current status of the individual. These definitions have been successfully used by clinicians, clinical trialists, and regulatory authorities. Recent regulatory decisions produced variations and discrepancies in the use of the clinical course descriptions. We provide here a clarification of the concepts underlying these descriptions and restate the principles used in their development. Importantly, we highlight the critical importance of time framing the disease course modifiers activity and progression and clarify the difference between the terms worsening and progressing.

Structural network-based approaches can assess white matter connections revealing topological alterations in multiple sclerosis (MS). However, principal network (PN) organisation and its clinical relevance in MS has not been explored yet. Here, structural networks were reconstructed from diffusion data in 58 relapsing-remitting MS (RRMS), 28 primary progressive MS (PPMS), 36 secondary progressive (SPMS) and 51 healthy controls (HCs). Network hubs’ strengths were compared with HCs. Then, PN analysis was performed in each clinical subtype. Regression analysis was applied to investigate the associations between nodal strength derived from the first and second PNs (PN1 and PN2) in MS, with clinical disability. Compared with HCs, MS patients had preserved hub number, but some hubs exhibited reduced strength. PN1 comprised 10 hubs in HCs, RRMS and PPMS but did not include the right thalamus in SPMS. PN2 comprised 10 hub regions with intra-hemispheric connections in HCs. In MS, this subnetwork did not include the right putamen whilst in SPMS the right thalamus was also not included. Decreased nodal strength of the right thalamus and putamen from the PNs correlated strongly with higher clinical disability. These PN analyses suggest distinct patterns of disruptions in MS subtypes which are clinically relevant

Graphical abstract, Highlights • We present SPACE-MS, a tool to assess the spatial distribution of brain lesions. • SPACE-MS metrics mainly reflect caudality and spatial spreading of brain lesions. • More caudal and more widespread brain lesions correlate with worse disability. • SPACE-MS metrics can be automatically obtained using routine anatomical scans. • The usefulness of the SPACE-MS approach should be explored in other conditions., Predicting disability in progressive multiple sclerosis (MS) is extremely challenging. Although there is some evidence that the spatial distribution of white matter (WM) lesions may play a role in disability accumulation, the lack of well-established quantitative metrics that characterise these aspects of MS pathology makes it difficult to assess their relevance for clinical progression. This study introduces a novel approach, called SPACE-MS, to quantitatively characterise spatial distributional features of brain MS lesions, so that these can be assessed as predictors of disability accumulation. In SPACE-MS, the covariance matrix of the spatial positions of each patient’s lesional voxels is computed and its eigenvalues extracted. These are combined to derive rotationally-invariant metrics known to be common and robust descriptors of ellipsoid shape such as anisotropy, planarity and sphericity. Additionally, SPACE-MS metrics include a neuraxis caudality index, which we defined for the whole-brain lesion mask as well as for the most caudal brain lesion. These indicate how distant from the supplementary motor cortex (along the neuraxis) the whole-brain mask or the most caudal brain lesions are. We applied SPACE-MS to data from 515 patients involved in three studies: the MS-SMART (NCT01910259) and MS-STAT1 (NCT00647348) secondary progressive MS trials, and an observational study of primary and secondary progressive MS. Patients were assessed on motor and cognitive disability scales and underwent structural brain MRI (1.5/3.0 T), at baseline and after 2 years. The MRI protocol included 3DT1-weighted (1x1x1mm3) and 2DT2-weighted (1x1x3mm3) anatomical imaging. WM lesions were semiautomatically segmented on the T2-weighted scans, deriving whole-brain lesion masks. After co-registering the masks to the T1 images, SPACE-MS metrics were calculated and analysed through a series of multiple linear regression models, which were built to assess the ability of spatial distributional metrics to explain concurrent and future disability after adjusting for confounders. Patients whose WM lesions laid more caudally along the neuraxis or were more isotropically distributed in the brain (i.e. with whole-brain lesion masks displaying a high sphericity index) at baseline had greater motor and/or cognitive disability at baseline and over time, independently of brain lesion load and atrophy measures. In conclusion, here we introduced the SPACE-MS approach, which we showed is able to capture clinically relevant spatial distributional features of MS lesions independently of the sheer amount of lesions and brain tissue loss. Location of lesions in lower parts of the brain, where neurite density is particularly high, such as in the cerebellum and brainstem, and greater spatial spreading of lesions (i.e. more isotropic whole-brain lesion masks), possibly reflecting a higher number of WM tracts involved, are associated with clinical deterioration in progressive MS. The usefulness of the SPACE-MS approach, here demonstrated in MS, may be explored in other conditions also characterised by the presence of brain WM lesions.

Multiple sclerosis (MS) is subdivided into four phenotypes on the basis of medical history and clinical symptoms. These phenotypes are defined retrospectively and lack clear pathobiological underpinning. Since Magnetic Resonance Imaging (MRI) better reflects disease pathology than clinical symptoms, we aimed to explore MRI-driven subtypes of MS based on pathological changes visible on MRI using unsupervised machine learning. In separate train and external validation sets we looked at a total of 21,170 patient-years of data from 15 randomised controlled trials and three observational cohorts to explore MRI-driven subtypes and test whether these subtypes had differential clinical outcomes. We processed MRI data to obtain measures of brain volumes, lesion volumes, and normal appearing white matter T1/T2. We identified three MRI-driven subtypes who were similar in how they accumulated MRI abnormality. Based on the earliest abnormalities suggested by our model they were called: cortex-led, normal appearing white matter-led, and lesion-led subtypes. In the external validation datasets, the lesion-led subtype showed a faster disability progression and higher disease activity than the cortex-led subtype. In all datasets, MRI-driven subtypes were associated with disability progression (βSubtype=0.04, p=0.02; βStage=-0.06, p

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Summary Exercise can be a beneficial rehabilitation strategy for people with multiple sclerosis to manage symptoms, restore function, optimise quality of life, promote wellness, and boost participation in activities of daily living. However, this population typically engages in low levels of health-promoting physical activity compared with adults from the general population, a fact which has not changed in the past 25 years despite growing evidence of the benefits of exercise. To overcome this challenge, the main limitations to promoting exercise through the patient–clinician interaction must be addressed. These limitations are the inadequate quality and scope of existing evidence, incomplete understanding of the mechanisms underlying the beneficial effects of exercise in people with multiple sclerosis, and the absence of a conceptual framework and toolkit for translating the evidence into practice. Future research to address those limitations will be essential to inform decisions about the inclusion of exercise in the clinical care of people with multiple sclerosis.

Introduction: In order to estimate the value of interventions in multiple sclerosis (MS) – where lifetime costs and outcomes cannot be observed – outcome data have to be combined with costs. This requires that cost data be regularly updated. Objectives and methods: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of disability, from the societal perspective, in EUR (2015). Results: A total of 779 patients (mean age = 57 years) participated; 72% were below retirement age and of these, 36% were employed. Employment was related to disease severity, and MS affected productivity at work for 84% of patients. Overall, 96% and 72% of the patients experienced fatigue and cognition as a problem. Mean utility and annual costs were 0.735 and 11,400GBP at Expanded Disability Status Scale (EDSS) = 0–3, 0.534 and 22,700GBP at EDSS = 4–6.5, and 0.135 and 36,500GBP at EDSS = 7–9. The mean cost of a relapse was estimated at 790GBP. Conclusion: This study illustrates the burden of MS on UK patients and provides current data on MS that are important for development of health policies.

Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future.

Background: There is a growing number of cohorts and registries collecting phenotypic and genotypic data from groups of multiple sclerosis patients. Improved awareness and better coordination of these efforts is needed. Objective: The purpose of this report is to provide a global landscape of the major longitudinal MS patient data collection efforts and share recommendations for increasing their impact. Methods: A workshop that included over 50 MS research and clinical experts from both academia and industry was convened to evaluate how current and future MS cohorts could be better used to provide answers to urgent questions about progressive MS. Results: The landscape analysis revealed a significant number of largely uncoordinated parallel studies. Strategic oversight and direction is needed to streamline and leverage existing and future efforts. A number of recommendations for enhancing these efforts were developed. Conclusions: Better coordination, increased leverage of evolving technology, cohort designs that focus on the most important unanswered questions, improved access, and more sustained funding will be needed to close the gaps in our understanding of progressive MS and accelerate the development of effective therapies.

Following extensive progress in the treatment of relapsing multiple sclerosis, the major challenge in the field is now to develop effective therapies for progressive forms of multiple sclerosis. As the first signs of success emerge, now is the time to consider the research needed to move the field forward.

OBJECTIVE: Clinical outcomes in multiple sclerosis (MS) are highly variable. We aim to determine the long-term clinical outcomes in MS, and to identify early prognostic features of these outcomes. METHODS: One hundred thirty-two people presenting with a clinically isolated syndrome were prospectively recruited between 1984 and 1987, and followed up clinically and radiologically 1, 5, 10, 14, 20, and now 30 years later. All available notes and magnetic resonance imaging scans were reviewed, and MS was defined according to the 2010 McDonald criteria. RESULTS: Clinical outcome data were obtained in 120 participants at 30 years. Eighty were known to have developed MS by 30 years. Expanded Disability Status Scale (EDSS) scores were available in 107 participants, of whom 77 had MS; 32 (42%) remained fully ambulatory (EDSS scores ≤3.5), all of whom had relapsing-remitting MS (RRMS), 3 (4%) had RRMS and EDSS scores >3.5, 26 (34%) had secondary progressive MS (all had EDSS scores >3.5), and MS contributed to death in 16 (20%). Of those with MS, 11 received disease-modifying therapy. The strongest early predictors (within 5 years of presentation) of secondary progressive MS at 30 years were presence of baseline infratentorial lesions and deep white matter lesions at 1 year. INTERPRETATION: Thirty years after onset, in a largely untreated cohort, there was a divergence of MS outcomes; some people accrued substantial disability early on, whereas others ran a more favorable long-term course. These outcomes could, in part, be predicted by radiological findings from within 1 year of first presentation. ANN NEUROL 2020;87:63-74. ispartof: ANNALS OF NEUROLOGY vol:87 issue:1 pages:63-74 ispartof: location:United States status: published

Spinal cord involvement is an important cause of disability in patients with multiple sclerosis or neuromyelitis optica spectrum disorders (NMOSDs). Multiple sclerosis and NMOSDs can be distinguished from other disorders that cause myelopathy by results from laboratory and radiological investigations. However, limitations in the sensitivity and specificity of spinal cord imaging and poor correlation with disability megasures have impeded the understanding of the relationship between spinal cord involvement and clinical manifestations. Nevertheless, studies of the pathological features of multiple sclerosis and NMOSDs have shown that quantitatively different mechanisms lead to differences in clinical course and pattern of accrual of permanent disability in the two disorders. Better understanding of these mechanisms is necessary to develop more informative clinical measures, electrophysiological methods, fluid biomarkers, and imaging techniques to detect and monitor spinal cord involvement in the diagnosis and management of patients with multiple sclerosis or NMOSDs, and as outcome measures in clinical trials.

Irish legislation on Advance Healthcare Directives (Assisted Decision Making Capacity Act 2015, ADMC) proposes to change the basis of decision making from acting in the patient’s best interests to following the expressed will and intentions of the patient. Refusal of life-saving care can occur, without sound reasons. The implications for care in life-threatening emergencies have not been explored among clinicians. An anonymous questionnaire survey of Advanced Paramedics (AP) covering awareness of the legislation, attitudes to and experience of refusal of care and potential actions in emergency scenarios now and if the legislation were in force. The scenarios covered end-of-life and deliberate self-harm situations potentially requiring resuscitation. All 482 graduates of the Advanced Paramedic Training Programme were invited to take part. Overall, 85/389 (21.9%) valid contacts responded, with demographic characteristics similar to the overall population. Attitudes ranged from highly positive to highly negative in relation to the potential impact of the legislation on professional and operational responsibilities. Respondents described marked changes in whether they would offer resuscitation if the ADMC were in place. Irish legislation which changes the traditional basis of medical practice away from the best interests of the patient may affect the resuscitation practices of Advanced Paramedics in life-threatening situations. It has significant implications for medical education, professional practice and clinician-patient interactions. This legislation and similar planned legislation may have implications for other EU jurisdictions.

Background: While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind. Objective: The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients. Methods: Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS). Results: A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance ( R2 = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. Conclusion: Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients.

Background and objectives: Treatment of spasticity poses a major challenge given the complex clinical presentation and variable efficacy and safety profiles of available drugs. We present a systematic review of the pharmacological treatment of spasticity in multiple sclerosis (MS) patients. Methods: Controlled trials and observational studies were identified. Scientific evidence was evaluated according to pre-specified levels of certainty. Results: The evidence supports the use of baclofen, tizanidine and gabapentin as first-line options. Diazepam or dantrolene could be considered if no clinical improvement is seen with the previous drugs. Nabiximols has a positive effect when used as add-on therapy in patients with poor response and/or tolerance to first-line oral treatments. Despite limited evidence, intrathecal baclofen and intrathecal phenol show a positive effect in severe spasticity and suboptimal response to oral drugs. Conclusion: The available studies on spasticity treatment offer some insight to guide clinical practice but are of variable methodological quality. Large, well-designed trials are needed to confirm the effectiveness of antispasticity agents and to produce evidence-based treatment algorithms.

We agree with Dr. Domingue's observation that the trajectory of recovery after spinal cord injury (SCI) is complex and difficult to predict. We should clarify that in the present study, we investigated the effects of traumatic SCI on neurodegeneration across the neuroaxis.1 However, we and others have shown that in cervical spondolytic myelopathy (i.e., nontraumatic SCI) remote tissue specific cord pathology is also evident.2,3 Surprisingly, the extent of neurodegeneration is similar to traumatic SCI, although these patients with nontraumatic SCI had only mild clinical symptoms.2 This suggests that, in a slow progressive disease (e.g., cervical spondolytic myelopathy), the CNS can compensate for neurodegenerative processes for much longer; however, with time, the competition between processes of reorganization and neurodegeneration is lost in favor of the latter. Nevertheless, the clinical viability of MRI-based structural measures for monitoring and predicting recovery after nontraumatic and traumatic SCI is feasible and will provide a tool to improve our understanding of the disease mechanism, which affects not only the spinal cord but also the brain after SCI.3–5 These new insights will enable us to better predict individual recovery trajectories and identify patients who could profit from further interventions to delay, or even prevent, further clinical deterioration.

[Excerpt] Introduction The management of multiple sclerosis (MS) has been a neurology success story for the past 25 years. Advances in understanding of the disease mechanisms and the dynamic nature of the disease have brought around 12 disease-modifying therapies (DMTs) to market in many countries.[...], This study was funded by F Hoffmann-La Roche., info:eu-repo/semantics/publishedVersion

The analysis of clinical trials is limited to pre-specified outcomes, thereby precluding a mechanistic understanding of the treatment response. Multivariate mechanistic models can elucidate the causal chain of events by simultaneous analysis of multi-modal data that link intermediate variables to outcomes of interest. A double-blind, randomised, controlled, phase 2 clinical trial in secondary progressive multiple sclerosis (MS-STAT, NCT00647348) demonstrated that simvastatin (80mg/day) over two years reduced the brain atrophy rate and was associated with beneficial effects on cognitive and disability outcomes. Therefore, this trial offers an opportunity to apply mechanistic models to investigate the hypothesised pathways that link simvastatin to clinical outcome measures, either directly or indirectly via changes in serum total cholesterol levels and to determine which is the more likely. We re-analysed the MS-STAT trial in which 140 patients with secondary progressive multiple sclerosis were randomised (1:1) to receive placebo or simvastatin (80 mg/day). At baseline and after one and two years patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS). Serum total cholesterol levels were measured at each visit. We calculated the annual percentage change of brain volume loss using mixed-effects models. With multivariate mechanistic models and Bayesian mediation analyses, a cholesterol-dependent model was compared to a cholesterol-independent model. As described previously, the simvastatin group showed a slower rate of brain atrophy and clinical deterioration (as reflected by both the EDSS and the block design test) and a faster decline in serum cholesterol levels (all p

Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.

We consider the problem of reconstructing brain networks in a longitudinal study, where diffusion-weighted and T1-weighted magnetic resonance images have been acquired at multiple time-points for the same subject. We introduce a method for registering diffusion-weighted and structural scans in a subject-specific half-way space and we demonstrate that half-way network metrics are strongly correlated with native network metrics. We also report sufficient agreement between the two techniques in a cohort comprising of healthy controls (n = 12) and multiple sclerosis patients (n = 12). The results remained unaffected when the analyses were evaluated in controls and patients separately. These study findings might be of particular interest in longitudinal structural network studies assessing network changes over time in normal and disease conditions.

Objectives: To measure the development of spinal cord (SC) atrophy over 1 year in patients with progressive multiple sclerosis (PMS) and determine the sample sizes required to demonstrate a reduction in spinal cord cross-sectional area (SC-CSA) as an outcome measure in clinical trials. Methods: In total, 44 PMS patients (26 primary progressive multiple sclerosis (PPMS), 18 secondary progressive multiple sclerosis (SPMS)) and 29 healthy controls (HCs) were studied at baseline and 12 months. SC-CSA was measured using the three-dimensional (3D) fast field echo sequences acquired at 3T and the active surface model. Multiple linear regressions were used to investigate changes in imaging measurements. Results: PPMS patients had shorter disease duration, lower Expanded Disability Status Scale (EDSS) and larger SC-CSA than SPMS patients. All patients together showed a significantly greater decrease in percentage SC-CSA change than HCs, which was driven by the PPMS. All patients deteriorated over 1 year, but no association was found between percentage SC-CSA change and clinical changes. The sample size per arm required to detect a 50% treatment effect over 1 year, at 80% power, was 57 for PPMS and 546 for SPMS. Conclusion: SC-CSA may become an outcome measure in trials of PPMS patients, when they are at an early stage of the disease, have moderate disability and modest SC atrophy.

Progressive multiple sclerosis (MS) will be a major area of research interest for years to come. No treatments exist and success in the field will generalise to other neurological conditions where neurodegeneration coexists with neuroinflammation. The issue is complex, and interdisciplinary approaches – uniting scientists with different competences (neurobiology, immunogenetics, etc.) and ‘mindsets’ (academia and industry) – will be decisive. The International Progressive MS Alliance is catalysing this process through various initiatives, the most recent of which was a meeting where scientists from academia (also outside the MS field) and from industry reviewed data and strategies to determine the next steps towards the translation of current knowledge into effective therapies. Key findings are: (i). Concerted efforts are essential to prioritise pathogenetic mechanisms according to impact on the disease and druggability. (ii). Combination therapies will probably be needed, possibly early in the disease, along with new trial designs and treatment schedules. (iii). Drug screenings are a pragmatic approach hopefully enriched by the use of neural and oligodendrocyte progenitors differentiated from induced pluripotent stem cells (iPSCs). (iv). The field of network biology will increase our ability to predict therapeutic targets. (v). Genome-wide association studies (GWAS) must try to identify variants associated with disease progression.

The application of imaging biomarkers has provided new insights into the mechanisms of damage in multiple sclerosis (MS) and the risk of MS development and progression. The goal of eliminating all disease activity requires a timely escalation of treatment. This increasing complexity is compounded by the need to treat comorbidities.

Background and purpose: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. Methods: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories – very high, high, low and very low − according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. Results: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

ObjectiveGrey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.MethodsWe analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome[CIS], 708 relapsingremitting[RRMS], 128 secondary-progressive[SPMS], 125 primary-progressive[PPMS]), over an average follow-up of 2.41 years (standard deviation[SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression.ResultsSPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; pppInterpretationThis large multi-centre and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.

Understanding the mechanisms underlying progression in multiple sclerosis (MS) and identifying appropriate therapeutic targets is a key challenge facing the MS community. This challenge has been championed internationally by organizations such as the Progressive MS Alliance, which has raised the profile of progressive MS and identified the key obstacles to treatment. This review will outline the considerable progress against these challenges.New insights into mechanisms underlying progression have opened up potential therapeutic opportunities. This has been complemented by ongoing validation of clinical and imaging outcomes for Phase II trials of progression, coupled with the development of innovative trial designs. The field has been greatly encouraged by recent positive Phase III trials in both primary and secondary progressive MS, albeit with modest benefit. Early trials of neuroprotection and repair have provided important new data with which to drive the field. Improving symptom management and advancing rehabilitation approaches, critical for this patient population which, taken together with identifying and managing comorbidities and risk factors, has an appreciable impact on health-related quality of life.Raising the profile of progressive MS has resulted in the first effective treatments with the promise of more to come.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small crosssectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research. © 2013 Elsevier Inc.

Presently, the only commercially available power generating thermoelectric (TE) modules are based on bismuth telluride (Bi2Te3) alloys and are limited to a hot side temperature of 250 °C due to the melting point of the solder interconnects and/or generally poor power generation performance above this point. For the purposes of demonstrating a TE generator or TEG with higher temperature capability, we selected skutterudite based materials to carry forward with module fabrication because these materials have adequate TE performance and are mechanically robust. We have previously reported the electrical power output for a 32 couple skutterudite TE module, a module that is type identical to ones used in a high temperature capable TEG prototype. The purpose of this previous work was to establish the expected power output of the modules as a function of varying hot and cold side temperatures. Recent upgrades to the TE module measurement system built at the Fraunhofer Institute for Physical Measurement Techniques allow for the assessment of not only the power output, as previously described, but also the thermal to electrical energy conversion efficiency. Here we report the power output and conversion efficiency of a 32 couple, high temperature skutterudite module at varying applied loading pressures and with different interface materials between the module and the heat source and sink of the test system. We demonstrate a 7% conversion efficiency at the module level when a temperature difference of 460 °C is established. Extrapolated values indicate that 7.5% is achievable when proper thermal interfaces and loading pressures are used.

The treatment of multiple sclerosis (MS) has evolved remarkably over the past 25 years. This progress has been enabled by advances in research, drug development and active engagement of the scientific community with regulatory authorities. However, an inconsistent approach to MS disease courses could have a negative impact on the drug development process.

We combined tract-based spatial statistics (TBSS) and magnetization transfer (MT) imaging to assess white matter (WM) tract-specific short-term changes in early primary-progressive multiple sclerosis (PPMS) and their relationships with clinical progression. Twenty-one PPMS patients within 5 years from onset underwent MT and diffusion tensor imaging (DTI) at baseline and after 12 months. Patients' disability was assessed. DTI data were processed to compute fractional anisotropy (FA) and to generate a common WM "skeleton," which represents the tracts that are "common" to all subjects using TBSS. The MT ratio (MTR) was computed from MT data and co-registered with the DTI. The skeletonization procedure derived for FA was applied to each subject's MTR image to obtain a "skeletonised" MTR map for every subject. Permutation tests were used to assess (i) changes in FA, principal diffusivities, and MTR over the follow-up, and (ii) associations between changes in imaging parameters and changes in disability. Patients showed significant decreases in MTR over one year in the corpus callosum (CC), bilateral corticospinal tract (CST), thalamic radiations, and superior and inferior longitudinal fasciculi. These changes were located both within lesions and the normal-appearing WM. No significant longitudinal change in skeletonised FA was found, but radial diffusivity (RD) significantly increased in several regions, including the CST bilaterally and the right inferior longitudinal fasciculus. MTR decreases, RD increases, and axial diffusivity decreases in the CC and CST correlated with a deterioration in the upper limb function. We detected tract-specific multimodal imaging changes that reflect the accrual of microstructural damage and possibly contribute to clinical impairment in PPMS. We propose a novel methodology that can be extended to other diseases to map cross-subject and tract-specific changes in MTR. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.