OBJECTIVETo characterize the distribution and regional evolution of cervical cord atrophy in patients with multiple sclerosis (MS) in a multicenter dataset.
METHODSMRI and clinical evaluations were ...acquired from 179 controls and 435 patients (35 clinically isolated syndromes CIS, 259 relapsing-remitting multiple sclerosis RRMS, 99 secondary progressive multiple sclerosis SPMS, and 42 primary progressive multiple sclerosis PPMS). Sixty-nine controls and 178 patients underwent a 1-year MRI and clinical follow-up. Patients were classified as clinically stable/worsened according to their disability change. Longitudinal changes of cord atrophy were investigated with linear mixed-effect models. Sample size calculations were performed using age-, sex- and site-adjusted annualized percentage normalized cord cross-sectional area (CSAn) changes.
RESULTSBaseline CSAn was lower in patients with MS vs controls (p < 0.001), but not different between controls and patients with CIS or between patients with early RRMS (disease duration ≤5 years) and patients with CIS. Patients with late RRMS (disease duration >5 years) showed significant cord atrophy vs patients with early RRMS (p = 0.02). Patients with progressive MS had decreased CSAn (p < 0.001) vs patients with RRMS. Atrophy was located between C1/C2 and C5 in patients with RRMS vs patients with CIS, and widespread along the cord in patients with progressive MS vs patients with RRMS, with an additional C5/C6 involvement in patients with SPMS vs patients with PPMS. At follow-up, CSAn decreased in all phenotypes (p < 0.001), except CIS. Cord atrophy rates were highest in patients with early RRMS and clinically worsened patients, who had a more widespread cord involvement than stable patients. The sample size per arm required to detect a 50% treatment effect was 118 for patients with early RRMS.
CONCLUSIONSCord atrophy increased in MS during 1 year, except for CIS. Faster atrophy contributed to explain clinical worsening.
Background:
Deep gray matter (DGM) atrophy is common in multiple sclerosis (MS), but no studies have investigated surface-based structure changes over time with respect to healthy controls (HCs). ...Moreover, the relationship between cognition and the spatio-temporal evolution of DGM atrophy is poorly understood.
Objectives:
To explore DGM structural differences between MS and HCs over time in relation to neuropsychological (NP) outcomes.
Methods:
The participants were 44 relapsing-remitting and 20 secondary progressive MS patients and 22 HCs. All were scanned using 3T magnetic resonance imaging (MRI) at baseline and 3-year follow-up. NP examination emphasized consensus standard tests of processing speed and memory. We performed both volumetric and shape analysis of DGM structures and assessed their relationships with cognition.
Results:
Compared to HCs, MS patients presented with significantly smaller DGM volumes. For the thalamus and caudate, differences in shape were mostly localized along the lateral ventricles. NP outcomes were related to both volume and shape of the DGM structures. Over 3 years, decreased cognitive processing speed was related to localized atrophy on the anterior and superior surface of the left thalamus.
Conclusions:
These findings highlight the role of atrophy in the anterior nucleus of the thalamus and its relation to cognitive decline in MS.
The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse ...suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis Disability Status Scale 6, 8, 10 by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing–remitting phase. Survival was compared among groups stratified by (i) early relapses—number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing–remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus ≥3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing–remitting phase attacks nor of relapses experienced during the relapsing–remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing–remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence—to a lesser degree—its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing–remitting patients.
Cognitive fatigue is a major symptom of Multiple Sclerosis (MS), from the early stages of the disease. This study aims to detect if brain microstructure is altered early in the disease course and is ...associated with cognitive fatigue in people with MS (pwMS) compared to matched healthy controls (HC). Recently diagnosed pwMS (N = 18, age < 45 years old) with either a Relapsing–Remitting or a Clinically Isolated Syndrome course of the disease, and HC (N = 19) matched for sex, age and education were analyzed. Quantitative multiparameter maps (MTsat, PD, R1 and R2*) of pwMS and HC were calculated. Parameters were extracted within the normal appearing white matter, cortical grey matter and deep grey matter (NAWM, NACGM and NADGM, respectively). Bayesian T-test for independent samples assessed between-group differences in brain microstructure while associations between score at a cognitive fatigue scale and each parameter in each tissue class were investigated with Generalized Linear Mixed Models. Patients exhibited lower MTsat and R1 values within NAWM and NACGM, and higher R1 values in NADGM compared to HC. Cognitive fatigue was associated with PD measured in every tissue class and to MTsat in NAWM, regardless of group. Disease-specific negative correlations were found in pwMS in NAWM (R1, R2*) and NACGM (R1). These findings suggest that brain microstructure within normal appearing tissues is already altered in the very early stages of the disease. Moreover, additional microstructure alterations (e.g. diffuse and widespread demyelination or axonal degeneration) in pwMS may lead to disease-specific complaint of cognitive fatigue.
Cortical inflammatory lesions have been correlated with disability and cortical atrophy in multiple sclerosis. The extent to which cortical lesion load is associated with longer-term physical and ...cognitive disability in different multiple sclerosis phenotypes has not yet been investigated. Thus, a 5-year prospective longitudinal study was carried on in a large group of patients with multiple sclerosis. Three hundred and twelve consecutive patients suffering from multiple sclerosis (157 relapsing remitting, 35 paediatric, 45 benign, 44 primary progressive and 31 secondary progressive) were enrolled in a 5-year prospective clinical and neuroimaging study. Several magnetic resonance parameters (including cortical lesion number and volume, contrast-enhancing cortical lesions and grey matter atrophy) were analysed to find associations with clinical and cognitive outcomes. Patients with high cortical lesion load had higher Expanded Disability Status Scale increase (median = 1.5; range = 0-3) during the study than both patients with low cortical lesion load (median = 1.0; range = 1-3, P < 0.001) and without cortical lesions (median = 0.5; range = -1 to 2, P < 0.001). Compared with clinically stable patients, 101 (32.4%) patients showing clinical progression at 5 years had the highest rate of cortical lesion accumulation (P < 0.001). Stepwise regression analysis revealed significant and independent contributions from age (β = 0.55), cortical lesion volume (β = 0.58), T(2) white matter lesion volume (β = 0.34) and grey matter fraction (β = 0.42) as predictors (final model with r(2 )= 0.657, P < 0.001) of Expanded Disability Status Scale change. Disease duration (β = 0.52, P < 0.001), cortical lesion volume (β = 0.67, P < 0.001), grey matter fraction (β = 0.56, P < 0.001) and T(2) white matter lesion volume (β = 0.31, P = 0.040) at baseline were found to be independent predictors of cognitive status at the end of the study. While confirming the relevance of cortical pathology in all multiple sclerosis phenotypes, but benign, our study suggests that grey matter and white matter changes in multiple sclerosis occur, at least, partly independently, and that grey matter, more than white matter, damage is associated with physical and cognitive disability progression. Thus, the combination of grey and white matter parameters gives a more comprehensive view of multiple sclerosis pathology and allows a better understanding of the progressive phase of the disease, which, however, seems more related to cortical damage than to subcortical white matter changes.
Background and purpose
Peripapillary hyper‐reflective ovoid masslike structures (PHOMS) are a novel finding during retinal optical coherence tomography in patients with multiple sclerosis (MS). To ...date, there are no data on the occurrence of PHOMS in early MS. The aim of this study was to investigate the frequency of PHOMS in patients with first diagnosed early relapsing–remitting MS (RRMS) and to search for associations of PHOMS with disease patterns in different MS subtypes.
Methods
This was a cross‐sectional analysis in two different cohorts: cohort 1, consisting of early RRMS patients (n = 349); cohort 2, consisting of patients with primary progressive MS (PPMS) (n = 66) and RRMS (n = 65).
Results
Peripapillary hyper‐reflective ovoid masslike structures were detected in 18.3% of patients with early RRMS. The occurrence of PHOMS was not associated with age, disease duration and disability. Investigating clinical patterns and the occurrence of PHOMS (cohort 2), an association of PHOMS with higher Expanded Disability Status Scale measures (PHOMS 4.9, 3.7–6.1; no PHOMS 3.5, 3.0–5.3; p = 0.03) and longer disease durations (PHOMS 6.5 years, 1.9–11.0; no PHOMS 1.0 years, 0.0–4.0, p = 0.0007) was found in patients with PPMS but not RRMS. After p value adjustment, the disease duration appeared to be more relevant (β = 0.16, p = 0.06).
Conclusion
Peripapillary hyper‐reflective ovoid masslike structures were found in 18% of patients with early MS. The presence of PHOMS might be associated with disease progression only in PPMS but not RRMS, suggesting that PHOMS might be embedded in neurodegenerative processes.
Peripapillary hyper‐reflective ovoid masslike structures (PHOMS) were detected in 18.3% of patients with early relapsing–remitting multiple sclerosis (MS). The occurrence of PHOMS was not associated with age, disease duration and disability in these patients. From further investigations of the clinical patterns and the occurrence of PHOMS in different suptypes of MS, an association of PHOMS with longer disease durations in patients with primary progressive MS was found.
Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of ...inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.
There has been growing interest in the use of retinal imaging for tracking disease progression in multiple sclerosis. However, systematic and detailed pathological descriptions of retinal tissue in ...multiple sclerosis are lacking. Graded, histological evaluations on eyes from 82 patients with multiple sclerosis and 10 subjects with other neurological diseases, with immunohistochemistry on a subset, were performed and correlated with clinical and pathological findings. Multiple sclerosis cases demonstrated evidence of retinal atrophy and inflammation even in late-stage disease. Retinal ganglion cell loss was significant and remaining neurons appeared shrunken and were partially engulfed by human leukocyte antigen-DR positive cells with the phenotype of microglia in samples subjected to immunohistochemistry. Neurofilament staining revealed variable but prominent degrees of axonal loss and injury. Neuronal loss was noted in the inner nuclear layer with focal reduction in cell density. Foamy-appearing human leukocyte antigen-DR positive cells were evident near vessels and periphlebitis was found in a small but significant number of multiple sclerosis cases. Glial fibrillary acidic protein staining showed extensive astrocyte hypertrophy and proliferation with prominent gliosis in multiple sclerosis cases. Frequent but previously unreported abnormalities in the iris were documented in the majority of chronic multiple sclerosis cases. The injury to both iris and retina could be seen at all stages of disease. Severity of retinal atrophy was correlated with overall brain weight at time of autopsy (P = 0.04) and a trend for increased atrophy was seen with longer disease duration (P = 0.13). This study provides the first large-scale pathological description of retinas in multiple sclerosis, including patients with different subtypes of disease at all stages, and with variable clinical severity. Changes were seen not only in the retinal nerve fibre layer and ganglion cell layer, but also in the inner nuclear layer, suggesting that retinal injury is more widespread than previously appreciated. Furthermore, the human retina is devoid of myelin, but inflammation was demonstrated to be prominent in multiple sclerosis and to persist in the retina at late stages of disease. The prominent gliosis and inflammation surrounding vessels of the inner retina could potentially impact optical coherence tomography evaluations in multiple sclerosis—as standard techniques exploit presumed differences in tissue reflectivity and utilize automated edge detection algorithms to judge axon loss in the nerve fibre layer. Deciphering the relationships between the different types of retinal pathology may aid us in understanding the factors that drive both inflammation and tissue atrophy in multiple sclerosis.
Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in ...multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.
Background:
Exercise training is beneficial, but most persons with multiple sclerosis (MS) are sedentary and physically inactive. This has prompted a new focus on the promotion of lifestyle physical ...activity in MS. We previously designed, tested, and refined a behavioral intervention delivered through the Internet that successfully increased lifestyle physical activity in MS, but have not evaluated the effects on secondary symptomatic and health-related quality of life (HRQOL) outcomes.
Objective:
We conducted a 6-month randomized controlled trial (RCT) that examined the efficacy of an Internet-delivered, behavioral intervention for improving outcomes of fatigue, depression, anxiety, pain, sleep quality, and HRQOL in 82 ambulatory persons with MS. The secondary aim was to replicate previous results regarding change in free-living physical activity.
Results:
There was a significant and positive effect of the intervention on fatigue severity (p=.001, ηρ2=.15) and its physical impact (p=.008, ηρ2=.09), depression (p=.006, ηρ2=.10), and anxiety (p=.006, ηρ2=.10). There were non-significant improvements in pain (p=.08, ηρ2=.04), sleep quality (p=.06, ηρ2=.05), and physical HRQOL (p=.06, ηρ2=.05). We replicated our previous results by demonstrating an increase in self-reported physical activity (p=.001, ηρ2=.13).
Conclusions:
Our results support behavioral interventions targeting lifestyle physical activity as an alternative approach for managing symptoms in MS.
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