A novel classification of fatigue in multiple sclerosis based on longitudinal assessments

Background: Magnetic resonance imaging (MRI) studies of multiple sclerosis–related fatigue had limited reproducibility. Temporal fatigue fluctuations have not been considered. Objective: To investigate whether a novel group allocation that reflects temporal dynamics of fatigue improves our ability to detect fatigue-associated structural brain abnormalities. Methods: Patient stratification based on biennial fatigue assessments: sustained fatigue (SF, n = 29, fatigued at the latest ⩾2 assessments), one time-point fatigue (1F, n = 15, fatigued at the latest, but non-fatigued at the penultimate assessment), reversible fatigue (RF, n = 31, non-fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 54). Brain parenchymal fraction (BPF) and T2 lesion volume (T2LV) were compared between these groups and were derived using a conventional, single time-point fatigued versus non-fatigued stratification. Results: The SF versus NF stratification yielded improved power. SF ( p = 0.005) and RF ( p = 0.043) showed significantly higher T2LV than NF. T2LV showed no significant differences in SF versus 1F, SF versus RF, or 1F versus RF. Fatigued versus non-fatigued patients showed significantly higher T2LV ( p = 0.030). We found no significant differences in BPF between the groups. Conclusion: Taking into account temporal fatigue dynamics increases the statistical power with respect to T2LV and may improve characterization of brain pathological correlates of MS-related fatigue.

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Has your patient's multiple sclerosis lesion burden or brain atrophy actually changed?

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1061oa ◽

2004 ◽

Vol 10 (4) ◽

pp. 402-406 ◽

Cited By ~ 16

Author(s):

Xingchang Wei ◽

Charles RG Guttmann ◽

Simon K Warfield ◽

Michael Eliasziw ◽

J Ross Mitchell

Keyword(s):

Multiple Sclerosis ◽

Measurement Error ◽

Brain Tissue ◽

Brain Atrophy ◽

Multiple Sclerosis Lesion ◽

Lesion Volume ◽

Measurement Variability ◽

Brain Parenchymal Fraction ◽

Significant Change ◽

Brain Parenchymal

Changes in mean magnetic resonance imaging (MRI)-derived measurements between patient groups are often used to determine outcomes in therapeutic trials and other longitudinal studies of multiple sclerosis (MS). However, in day-to-day clinical practice the changes withinindividual patients may also be of interest. In this paper, we estimated the measurement error of an automated brain tissue quantification algorithm and determined the thresholds for statistically significant change of MRI-derived T2 lesion volume and brain atrophy in individual patients. Twenty patients with MS were scanned twice within 30 min. Brain tissue volumes were measured using the computer algorithm. Brain atrophy was estimated by calculation of brain parenchymal fraction. The threshold of change between repeated scans that represented statistically significant change beyond measurement error with 95% certainty was 0.65 mL for T2 lesion burden and 0.0056 for brain parenchymal fraction. Changes in lesion burden and brain atrophy below these thresholds can be safely (with 95% certainty) explained by measurement variability alone. These values provide clinical neurologists with a useful reference to interpret MRI-derived measures in individual patients.

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Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458518765666 ◽

2018 ◽

Vol 25 (5) ◽

pp. 678-686 ◽

Cited By ~ 62

Author(s):

Nelly Siller ◽

Jens Kuhle ◽

Muthuraman Muthuraman ◽

Christian Barro ◽

Timo Uphaus ◽

...

Keyword(s):

Multiple Sclerosis ◽

Single Molecule ◽

Light Chain ◽

Neuronal Damage ◽

Axonal Damage ◽

Lesion Volume ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Magnetic Resonance Imaging Mri ◽

Brain Parenchymal

Background: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament – a major component of the neuro-axonal cytoskeleton – is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. Objective: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. Methods: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1–3 consecutive follow-ups (42 patients; range: 6–37 months). Results: Baseline sNfL correlated significantly with T2 lesion volume ( r = 0.555, p < 0.0001). There was no correlation between baseline sNfL and age, Expanded Disability Status Scale (EDSS) score or other calculated MRI measures. However, T2 lesion volume increased ( r = 0.67, p < 0.0001) and brain parenchymal volume decreased more rapidly in patients with higher baseline sNfL ( r = −0.623, p = 0.0004). Gd-enhancing lesions correlated positively with sNfL levels. Initiation of disease-modifying treatment led to a significant decrease in sNfL levels. Conclusion: sNfL indicates acute inflammation as demonstrated by correlation with Gd+ lesions. It is a promising biomarker for neuro-axonal damage in early multiple sclerosis (MS) patients, since higher baseline sNfL levels predicted future brain atrophy within 2 years.

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Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging

Multiple Sclerosis Journal ◽

10.1177/13524585211023345 ◽

2021 ◽

pp. 135245852110233

Author(s):

Irene M Vavasour ◽

Peng Sun ◽

Carina Graf ◽

Jackie T Yik ◽

Shannon H Kolind ◽

...

Keyword(s):

Multiple Sclerosis ◽

Specific Information ◽

Axonal Loss ◽

Normal Appearing White Matter ◽

Relapsing Remitting ◽

Tissue Changes ◽

Spectrum Imaging ◽

Magnetic Resonance Imaging Mri ◽

And Diffusion

Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T1 and T2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS. Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes. Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T1, T2, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes. Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures. Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS.

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Heterogeneous pathological processes account for thalamic degeneration in multiple sclerosis: Insights from 7 T imaging

Multiple Sclerosis Journal ◽

10.1177/1352458517726382 ◽

2017 ◽

Vol 24 (11) ◽

pp. 1433-1444 ◽

Cited By ~ 17

Author(s):

Céline Louapre ◽

Sindhuja T Govindarajan ◽

Costanza Giannì ◽

Nancy Madigan ◽

Jacob A Sloane ◽

...

Keyword(s):

Multiple Sclerosis ◽

Progressive Multiple Sclerosis ◽

Lesion Volume ◽

Thalamic Lesion ◽

Cortical Lesions ◽

Focal Lesions ◽

Thalamic Degeneration ◽

Relapsing Remitting ◽

Thalamic Lesions ◽

Magnetic Resonance Imaging Mri

Background: Thalamic degeneration impacts multiple sclerosis (MS) prognosis. Objective: To investigate heterogeneous thalamic pathology, its correlation with white matter (WM), cortical lesions and thickness, and as function of distance from cerebrospinal fluid (CSF). Methods: In 41 MS subjects and 17 controls, using 3 and 7 T imaging, we tested for (1) differences in thalamic volume and quantitative T2* (q-T2*) (2) globally and (3) within concentric bands originating from the CSF/thalamus interface; (4) the relation between thalamic, cortical, and WM metrics; and (5) the contribution of magnetic resonance imaging (MRI) metrics to clinical scores. We also assessed MS thalamic lesion distribution as a function of distance from CSF. Results: Thalamic lesions were mainly located next to the ventricles. Thalamic volume was decreased in MS versus controls ( p < 10−2); global q-T2* was longer in secondary progressive multiple sclerosis (SPMS) only ( p < 10−2), indicating myelin and/or iron loss. Thalamic atrophy and longer q-T2* correlated with WM lesion volume ( p < 0.01). In relapsing-remitting MS, q-T2* thalamic abnormalities were located next to the WM ( p < 0.01 (uncorrected), p = 0.09 (corrected)), while they were homogeneously distributed in SPMS. Cortical MRI metrics were the strongest predictors of clinical outcome. Conclusion: Heterogeneous pathological processes affect the thalamus in MS. While focal lesions are likely mainly driven by CSF-mediated factors, overall thalamic degeneration develops in association with WM lesions.

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Discrepancies in the interpretation of clinical symptoms and signs in the diagnosis of multiple sclerosis. A proposal for standardization

Multiple Sclerosis Journal ◽

10.1191/1352458505ms1149oa ◽

2005 ◽

Vol 11 (2) ◽

pp. 227-231 ◽

Cited By ~ 23

Author(s):

Bernard MJ Uitdehaag ◽

Ludwig Kappos ◽

Lars Bauer ◽

Mark S Freedman ◽

David Miller ◽

...

Keyword(s):

Multiple Sclerosis ◽

Demyelinating Disease ◽

Clinical Symptoms ◽

Clinical Findings ◽

Large Trial ◽

Mri Findings ◽

Mcdonald Criteria ◽

Magnetic Resonance Imaging Mri ◽

Eligibility Assessment

The new McDonald diagnostic criteria for multiple sclerosis (MS) incorporate detailed criteria for the interpretation and classification of magnetic resonance imaging (MRI) findings, but, in contrast, provide no instructions for the interpretation of clinical findings. Because MS according to the McDonald criteria is one of the primary endpoints in a large trial enrolling patients after the first manifestation suggestive for a demyelinating disease (BENEFIT study), it was decided to organize a centralized eligibility assessment for this trial. During this eligibility assessment it was observed that there were marked inconsistencies in the decisions of participating neurologists with respect to the classification of clinical symptoms as being caused by one or more lesions provoking discussions in about one in every five patients. This paper describes these inconsistencies and their sources, and recommends a systematic approach that attempts to reduce the variability in interpreting clinical findings.

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A phase II trial of anti-CD4 antibodies in the treatment of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/135245859600100611 ◽

1996 ◽

Vol 1 (6) ◽

pp. 339-342 ◽

Cited By ~ 17

Author(s):

BW vanOosten ◽

M Lai ◽

F Barkhof ◽

DH Miller ◽

IF Moseley ◽

...

Keyword(s):

Multiple Sclerosis ◽

Statistical Power ◽

Primary Outcome Measure ◽

T Helper ◽

Effector Cells ◽

Natural History Studies ◽

Mri Scans ◽

Magnetic Resonance Imaging Mri ◽

The Brain ◽

Experimental Allergic

In multiple sclerosis (MS) myelin damage is the result of a chronic inflammatory process mediated by CD4 positive T helper/effector cells. In experimental allergic encephalomyelitis (EAE), the animal model of MS, treatment with anti-CD4 antibodies can prevent the onset of disease. Natural history studies have demonstrated that gadolinium enhanced magnetic resonance imaging (MRI) of the brain is more sensitive and objective in assessing inflammatory disease activity in MS than clinical monitoring, so that less patients and shorter studies suffice to reach the same statistical power as compared to trials using clinical outcome parameters. In this paper we describe the design of an exploratory trial of chimeric monoclonal anti-CD4 antibodies in the treatment of MS. For this study we chose the number of active MS lesions on monthly gadolinium enhanced MRI scans as the primary outcome measure.

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A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab

Multiple Sclerosis Journal ◽

10.1177/1352458518770085 ◽

2018 ◽

Vol 25 (6) ◽

pp. 811-818 ◽

Cited By ~ 8

Author(s):

Irene M Vavasour ◽

Roger Tam ◽

David KB Li ◽

Cornelia Laule ◽

Carolyn Taylor ◽

...

Keyword(s):

Multiple Sclerosis ◽

Magnetic Resonance ◽

Cortical Thickness ◽

Diffusion Tensor ◽

Imaging Study ◽

Water Fraction ◽

Normal Appearing White Matter ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal ◽

Multiple Sclerosis Patients

Background: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment. Objective: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab. Methods: A total of 42 relapsing–remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2 relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated. Results: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year. Conclusion: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

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Relevance of hypointense brain MRI lesions for long-term worsening of clinical disability in relapsing multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458513494490 ◽

2013 ◽

Vol 20 (2) ◽

pp. 214-219 ◽

Cited By ~ 25

Author(s):

Antonio Giorgio ◽

Maria Laura Stromillo ◽

Maria Letizia Bartolozzi ◽

Francesca Rossi ◽

Marco Battaglini ◽

...

Keyword(s):

Multiple Sclerosis ◽

Brain Mri ◽

Univariate Analysis ◽

Brain Lesion ◽

Brain Magnetic Resonance Imaging ◽

Stepwise Multiple Regression ◽

Lesion Volume ◽

Magnetic Resonance Imaging Mri ◽

Relapsing Remitting Multiple Sclerosis

Background: The accrual of brain focal pathology is considered a good substrate of disability in relapsing–remitting multiple sclerosis (RRMS). However, knowledge on long-term lesion evolution and its relationship with disability progression is poor. Objective: The objective of this paper is to evaluate in RRMS the long-term clinical relevance of brain lesion evolution. Methods: In 58 RRMS patients we acquired, using the same scanner and protocol, brain magnetic resonance imaging (MRI) at baseline and 10±0.5 years later. MRI data were correlated with disability changes as measured by the Expanded Disability Status Scale (EDSS). Results: The annualized 10-year lesion volume (LV) growth was +0.25±0.5 cm3 (+6.7±8.7%) for T2-weighted (T2-W) lesions and +0.20±0.31 cm3 (+11.5±12.3%) for T1-weighted (T1-W) lesions. The univariate analysis showed moderate correlations between baseline MRI measures and EDSS at 10 years ( p < 0.001). Also, 10-year EDSS worsening correlated with LV growth and the number of new/enlarging lesions measured over the same period ( p < 0.005). In the stepwise multiple regression analysis, EDSS worsening over 10 years was best correlated with the combination of baseline T1-W lesion count and increasing T1-W LV ( R = 0.61, p < 0.001). Conclusion: In RRMS patients, long-term brain lesion accrual is associated with worsening in clinical disability. This is particularly true for hypointense, destructive lesions.

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Correlation Between Disability Measure and Black Hole (T1 Hypointense Lesion) Lesion Load in Brain Magnetic Resonance Imaging (MRI) of Patients With Multiple Sclerosis (MS): Protocol for a Systematic Review and Meta-analysis

10.21203/rs.3.rs-194103/v3 ◽

2021 ◽

Author(s):

Amir Valizadeh ◽

Elham Barati ◽

Mohammad Ali Sahraian ◽

Mohammad Reza Fattahi ◽

Mana Moassefi

Keyword(s):

Multiple Sclerosis ◽

Meta Analysis ◽

Rank Correlation ◽

Brain Magnetic Resonance Imaging ◽

Lesion Volume ◽

Spearman’S Rank Correlation ◽

Spearman’S Rank Correlation Coefficient ◽

Disability Status ◽

Formation And Evolution ◽

Magnetic Resonance Imaging Mri

Abstract Introduction: As the role of neurodegeneration in the pathophysiology of multiple sclerosis (MS) has become more prominent, the formation and evolution of chronic or persistent T1-hypointense lesions (Black Holes) have been used as markers of axonal loss and neuronal destruction to measure disease activity. However, findings regarding this subject are controversial. In this study we aim to clarify the level of importance of T1 hypointense lesions for estimating the prognosis of patients.Methods: We will search MEDLINE (through PubMed), Embase and Web of Science for relevant studies. We will extract the Spearman's rank correlation coefficient (SRCC) between the T1 hypointense lesion volume and Extended Disability Status Scale (EDSS) in participants. All included studies will be evaluated for the risk of bias. We will also perform a meta-analysis on the data. The risk of publication bias will be evaluated using Funnel plots. Finally, we will assess the confidence in cumulative evidence using an adapted version of GRADE.

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