Natural history studies have identified factors that predict evolution to multiple sclerosis or risk of disability accumulation over time. Although these studies are based on large multicentre ...cohorts with long follow-ups, they have limitations such as lack of standardized protocols, a retrospective data collection or lack of a systematic magnetic resonance imaging acquisition and analysis protocol, often resulting in failure to take magnetic resonance and oligoclonal bands into account as joint covariates in the prediction models. To overcome some of these limitations, the aim of our study was to identify and stratify baseline demographic, clinical, radiological and biological characteristics that might predict multiple sclerosis development and disability accumulation using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndromes. From 1995 to 2013, 1058 patients with clinically isolated syndromes were included. We evaluated the influence of baseline prognostic factors on the risk for developing clinically definite multiple sclerosis, McDonald multiple sclerosis, and disability accumulation (Expanded Disability Status Scale score of 3.0) based on univariate (hazard ratio with 95% confidence intervals) and multivariate (adjusted hazard ratio with 95% confidence intervals) Cox regression models. We ultimately included 1015 patients followed for a mean of 81 (standard deviation = 57) months. Female/male ratio was 2.1. Females exhibited a similar risk of conversion to multiple sclerosis and of disability accumulation compared to males. Each younger decade at onset was associated with a greater risk of conversion to multiple sclerosis and with a protective effect on disability. Patients with optic neuritis had a lower risk of clinically definite multiple sclerosis hazard ratio 0.6 (0.5-0.8) and disability progression hazard ratio 0.5 (0.3-0.8); however, this protective effect remained marginal only for disability adjusted hazard ratio 0.6 (0.4-1.0) in adjusted models. The presence of oligoclonal bands increased the risk of clinically definite multiple sclerosis adjusted hazard ratio 1.3 (1.0-1.8) and of disability adjusted hazard ratio 2.0 (1.2-3.6) independently of other factors. The presence of 10 or more brain lesions on magnetic resonance increased the risk of clinically definite multiple sclerosis adjusted hazard ratio 11.3 (6.7-19.3) and disability adjusted hazard ratio 2.9 (1.4-6.0). Disease-modifying treatment before the second attack reduced the risk of McDonald multiple sclerosis adjusted hazard ratio 0.6 (0.4-0.9) and disability accumulation adjusted hazard ratio 0.5 (0.3-0.9). We conclude that the demographic and topographic characteristics are low-impact prognostic factors, the presence of oligoclonal bands is a medium-impact prognostic factor, and the number of lesions on brain magnetic resonance is a high-impact prognostic factor.
Background:
The usefulness of performing a spinal cord (SC) magnetic resonance imaging (MRI) in all clinically isolated syndromes (CIS) is controversial.
Objective:
To assess the value of SC lesions ...for predicting multiple sclerosis (MS) diagnosis and disability accrual in CIS.
Methods:
Concerning SC lesions and MS diagnosis (2010 McDonald), adjusted Cox regression analyses were performed in increasingly specific CIS groups: all cases (n = 207), non-SC CIS (n = 143), non-SC CIS with abnormal brain MRI (n = 90) and non-SC CIS with abnormal brain MRI not fulfilling 2010 MS (n = 67). For the outcome Expanded Disability Status Scale (EDSS) ≥3.0, similar analyses were performed in all cases (n = 207), non-SC CIS (n = 143) and SC CIS (n = 64). Performance at 2 years was assessed for all outcomes.
Results:
The presence of SC lesions increased MS risk 2.0–2.6 times independently of factors like brain lesions. If considering lesion number, the risk ranged from 1.6 to 2.1 for one lesion to 2.4–3.3 for ≥2. SC lesions increased the short-term disability risk around fivefold, better demonstrated in non-SC CIS. SC lesions were very specific for evolution to MS and showed very high sensitivity for EDSS ≥3.0.
Conclusion:
SC lesions are independent predictors of MS in all CIS and contribute to short-term disability accrual. SC MRIs in CIS could be useful to estimate their prognosis.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
In early multiple sclerosis, a clearer understanding of normal-brain tissue microstructural and metabolic abnormalities will provide valuable insights into its pathophysiology. We used ...multi-parametric quantitative MRI to detect alterations in brain tissues of patients with their first demyelinating episode. We acquired neurite orientation dispersion and density imaging to investigate morphology of neurites (dendrites and axons) and 23Na MRI (to estimate total sodium concentration, a reflection of underlying changes in metabolic function). In this cross-sectional study, we enrolled 42 patients diagnosed with clinically isolated syndrome or multiple sclerosis within 3 months of their first demyelinating event and 16 healthy controls. Physical and cognitive scales were assessed. At 3 T, we acquired brain and spinal cord structural scans, and neurite orientation dispersion and density imaging. Thirty-two patients and 13 healthy controls also underwent brain 23Na MRI. We measured neurite density and orientation dispersion indices and total sodium concentration in brain normal-appearing white matter, white matter lesions, and grey matter. We used linear regression models (adjusting for brain parenchymal fraction and lesion load) and Spearman correlation tests (significance level P ≤ 0.01). Patients showed higher orientation dispersion index in normal-appearing white matter, including the corpus callosum, where they also showed lower neurite density index and higher total sodium concentration, compared with healthy controls. In grey matter, compared with healthy controls, patients demonstrated: lower orientation dispersion index in frontal, parietal and temporal cortices; lower neurite density index in parietal, temporal and occipital cortices; and higher total sodium concentration in limbic and frontal cortices. Brain volumes did not differ between patients and controls. In patients, higher orientation dispersion index in corpus callosum was associated with worse performance on timed walk test (P = 0.009, B = 0.01, 99% confidence interval = 0.0001 to 0.02), independent of brain and lesion volumes. Higher total sodium concentration in left frontal middle gyrus was associated with higher disability on Expanded Disability Status Scale (rs = 0.5, P = 0.005). Increased axonal dispersion was found in normal-appearing white matter, particularly corpus callosum, where there was also axonal degeneration and total sodium accumulation. The association between increased axonal dispersion in the corpus callosum and worse walking performance implies that morphological and metabolic alterations in this structure could mechanistically contribute to disability in multiple sclerosis. As brain volumes were neither altered nor related to disability in patients, our findings suggest that these two advanced MRI techniques are more sensitive at detecting clinically relevant pathology in early multiple sclerosis.
Opinion statement
Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system that may entail severe levels of disability in the long term. However, independently ...of the level of disability, MS patients frequently experience severe fatigue that can be as disabling as objective neurological deficits. For that reason, it is mandatory to perform an early diagnosis of MS-related fatigue and start a suitable treatment as soon as possible. In clinical practice, MS-related fatigue should be assessed and managed by a multidisciplinary team involving neurologists, MS nurses, occupational therapists, and physiotherapists. When assessing a person with MS-related fatigue, the first step is to rule out potential triggers or causes of fatigue, which may be related to MS, such as urinary dysfunction, pain, or muscular spasms leading to a sleep disorder, or unrelated to it. Once these causes have been ruled out and appropriately tackled, a careful therapeutic intervention needs to be decided. Therapeutic interventions for MS-related fatigue can be pharmacological or non-pharmacological. Regarding the pharmacological treatments, although many drugs have been tested in clinical trials, only amantadine is currently recommended for this indication. Regarding the non-pharmacological approaches, they can be broadly divided into physical, psychological, and mixed physical/psychological interventions. Several studies, many of them randomised clinical trials, support the use of all these types of non-pharmacological interventions to treat MS-related fatigue. Recent publications suggest that the implementation of mixed approaches, which have a naturally comprehensive nature, may have excellent results in clinical practice, in relation not only to fatigue levels but also to more general aspects of MS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Time‐dependence is a key feature of the diffusion‐weighted (DW) signal, knowledge of which informs biophysical modelling. Here, we study time‐dependence in the human spinal cord, as its ...axonal structure is specific and different from the brain.
Methods
We run Monte Carlo simulations using a synthetic model of spinal cord white matter (WM) (large axons), and of brain WM (smaller axons). Furthermore, we study clinically feasible multi‐shell DW scans of the cervical spinal cord (b = 0; b = 711 s mm−2; b = 2855 s mm−2), obtained using three diffusion times (Δ of 29, 52 and 76 ms) from three volunteers.
Results
Both intra‐/extra‐axonal perpendicular diffusivities and kurtosis excess show time‐dependence in our synthetic spinal cord model. This time‐dependence is reflected mostly in the intra‐axonal perpendicular DW signal, which also exhibits strong decay, unlike our brain model. Time‐dependence of the total DW signal appears detectable in the presence of noise in our synthetic spinal cord model, but not in the brain. In WM in vivo, we observe time‐dependent macroscopic and microscopic diffusivities and diffusion kurtosis, NODDI and two‐compartment SMT metrics. Accounting for large axon calibers improves fitting of multi‐compartment models to a minor extent.
Conclusions
Time‐dependence of clinically viable DW MRI metrics can be detected in vivo in spinal cord WM, thus providing new opportunities for the non‐invasive estimation of microstructural properties. The time‐dependence of the perpendicular DW signal may feature strong intra‐axonal contributions due to large spinal axon caliber. Hence, a popular model known as “stick” (zero‐radius cylinder) may be sub‐optimal to describe signals from the largest spinal axons.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•Slowly expanding lesions (SELs) and persisting black holes (PBHs) are common in relapse-onset MS.•SELs and PBHs are positively associated.•SELs are consistent with neuroaxonal damage as assessed ...through low T1 and MTR values.•MS disability worsening on EDSS is predicted by higher SEL volumes from early disease onset.•Greater SEL volumes are related to higher risk of confirmed disability progression.
Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion’s metrics and clinical outcomes in relapse-onset MS has not been widely investigated.
To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients.
135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP).
Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI −0.005 to −0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed-effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95%CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006).
SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity and MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVE:To study the contribution of the symptomatic lesion in establishing multiple sclerosis (MS) diagnosis and prognosis.
METHODS:We performed an observational study based on a prospective ...clinically isolated syndrome (CIS) cohort of 1,107 patients recruited for clinical and brain MRI follow-up from 1995 to 2014. Eligible patients (n = 954) were divided into 4 groups according to baseline MRIpatients with a normal MRI (n = 290); patients with a single asymptomatic lesion (n = 18); patients with a single cord/brainstem symptomatic lesion (n = 35); and patients with more than 1 lesion (n = 611). For each group, we studied the risk of second attack, with 2005 McDonald MS and Expanded Disability Status Scale 3.0, using univariable and multivariable regression models adjusted by age, sex, oligoclonal bands, and disease-modifying treatments. We tested the diagnostic performance of a modified dissemination in space (DIS) criterion that includes symptomatic lesions in the total count and compared it to the DIS criteria (at least 1 asymptomatic lesion in at least 2 of the 4 MS characteristic MS locations) for all patients and for the subgroup of patients with brainstem or spinal cord topography.
RESULTS:Patients with a cord/brainstem single symptomatic lesion have a higher risk of second attack and disability accumulation than patients with 0 lesions but have a similar risk compared to patients with 1 asymptomatic lesion. Diagnostic properties are reasonably maintained when the symptomatic lesion qualifies for DIS.
CONCLUSIONS:Despite the recommendations of the 2010 McDonald criteria, symptomatic lesions should be taken into account when considering the diagnosis and prognosis of patients with CIS.
Background:
Pathology in the spinal cord of patients with primary progressive multiple sclerosis (PPMS) contributes to disability progression. We previously reported abnormal Q-space imaging ...(QSI)-derived indices in the spinal cord at baseline in patients with early PPMS, suggesting early neurodegeneration.
Objective:
The aim was to investigate whether changes in spinal cord QSI over 3 years in the same cohort are associated with disability progression and if baseline QSI metrics predict clinical outcome.
Methods:
Twenty-three PPMS patients and 23 healthy controls recruited at baseline were invited for follow-up cervical cord 3T magnetic resonance imaging (MRI) and clinical assessment after 1 year and 3 years. Cord cross-sectional area (CSA) and QSI measures were obtained, together with standard brain MRI measures. Mixed-effect models assessed MRI changes over time and their association with clinical changes. Linear regression identified baseline MRI indices associated with disability at 3 years.
Results:
Over time, patients deteriorated clinically and showed an increase in cord QSI indices of perpendicular diffusivity that was associated with disability worsening, independently of the decrease in CSA. Higher perpendicular diffusivity and lower CSA at baseline predicted worse disability at 3 years.
Conclusion:
Increasing spinal cord perpendicular diffusivity may indicate ongoing neurodegeneration, which underpins disability progression in PPMS, independently of the development of spinal cord atrophy.
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