Brain atrophy and lesion load predict long term disability in multiple sclerosis
VU University Medical Center1, University of Genoa2, University of Graz3, Autonomous University of Barcelona4, Hebron University5, University College London6, National Institute for Health Research7, University of Oxford8, University of Siena9, Heidelberg University10, University Hospital of Basel11
01 Oct 2013-Journal of Neurology, Neurosurgery, and Psychiatry (BMJ Publishing Group)-Vol. 84, Iss: 10, pp 1082-1091
TL;DR: This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.
Abstract: Objective To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS). Design From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1–2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing–remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0–3.5, n=111) or moderately impaired (EDSS=4–6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores. Results In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R 2 =0.74 in the whole group and R 2 =0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R 2 =0.68), lesion volumes in moderately impaired relapse onset patients (R 2 =0.21) and whole brain atrophy in primary progressive MS (R 2 =0.34). Conclusions This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.
Citations
More filters
TL;DR: The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein–Barr virus are likely to play a role in disease development, and potentially preventive strategies could be studied.
Abstract: Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene-environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.
798 citations
Cites background from "Brain atrophy and lesion load predi..."
...The importance of brain atrophy seen on volumetric MRI is increasingly realized, as when taken alongside lesion load there is good correlation with long-term clinical outcomes [57]....
[...]
TL;DR: Recommendations on how and when to use MRI for disease monitoring are presented, and some promising MRI approaches that may be introduced into clinical practice in the near future are discussed.
Abstract: The role of MRI in the assessment of multiple sclerosis (MS) goes far beyond the diagnostic process. MRI techniques can be used as regular monitoring to help stage patients with MS and measure disease progression. MRI can also be used to measure lesion burden, thus providing useful information for the prediction of long-term disability. With the introduction of a new generation of immunomodulatory and/or immunosuppressive drugs for the treatment of MS, MRI also makes an important contribution to the monitoring of treatment, and can be used to determine baseline tissue damage and detect subsequent repair. This use of MRI can help predict treatment response and assess the efficacy and safety of new therapies. In the second part of the MAGNIMS (Magnetic Resonance Imaging in MS) network's guidelines on the use of MRI in MS, we focus on the implementation of this technique in prognostic and monitoring tasks. We present recommendations on how and when to use MRI for disease monitoring, and discuss some promising MRI approaches that may be introduced into clinical practice in the near future.
411 citations
TL;DR: The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS, to maximize neurological reserve, cognitive function and physical function by reducing disease activity.
Abstract: Introduction We present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used widely among those committed to creating a better future for people with MS and their families. Methods Structured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs). Results Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services. We recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and disability progression should be included in the definition of disease activity and monitored regularly when practical. On suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A shared decision-making process that embodies dialogue and considers all appropriate DMTs should be implemented. Monitoring data should be recorded formally in registries to generate real-world evidence. In many jurisdictions, access to DMTs is limited. To improve treatment access the relevant bodies should consider all costs to all parties when conducting economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models. Conclusions The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.
279 citations
Cites background from "Brain atrophy and lesion load predi..."
...There is strong evidence for using MRI lesions as a predictor of relapses and disability progression from analyses and meta-analyses of data from clinical trials and real-world sources involving tens of thousands of people with MS (Table 7) (Sormani et al., 2009, 2010; Kalincik et al., 2012; Fahrbach et al., 2013; Popescu et al., 2013; Sormani and Bruzzi, 2013; Dobson et al., 2014; Uher et al., 2014)....
[...]
...Changes in total lesion load (total volume of lesions visible on MRI) during the first 1–2 years of treatment predict long-term (10 years) disability progression (Popescu et al., 2013)...
[...]
...Active lesions New lesions Retrospective analysis Disability progression (after 10 years) Changes in brain atrophy and lesion load both predict EDSS disability progression 10 years after the initial MRI scan in a ‘relapse onset’ subgroup containing people with CIS, RRMS and SPMS MRI scans conducted in people with MS who also had 10-year follow-up disability data (N1⁄4166) (Popescu et al., 2013) Total volume of lesions (change over 1– 2 years) Brain atrophy...
[...]
..., 2015) Brain atrophy Retrospective analysis Disability progression (after 10 years) Brain atrophy and lesion volume both predict EDSS disability progression 10 years after the initial MRI scan in a ‘relapse onset’ subgroup containing people with CIS, RRMS and SPMS MRI scans conducted in people with MS who also had 10-year follow-up disability data (N1⁄4166) (Popescu et al., 2013) Total volume of lesions visible on MRI (change over first 1–2 years) Brain atrophy (change over...
[...]
...Preserving brain volume (Kalincik et al., 2012; Popescu et al., 2013; Sormani et al., 2014; Uher et al., 2014; Radue et al., 2015) and cognitive reserve (Schwartz et al....
[...]
UCL Institute of Neurology1, University College London2, University of London3, University of Siena4, Sapienza University of Rome5, Vita-Salute San Raffaele University6, Autonomous University of Barcelona7, VU University Amsterdam8, VU University Medical Center9, Medical University of Graz10, National Institute for Health Research11, University of Pavia12
TL;DR: This work investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.
Abstract: OBJECTIVE: Gray 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. METHODS: We analyzed 3,604 brain high-resolution T1-weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], and 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 seven European centers. 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. RESULTS: SPMS 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% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001). INTERPRETATION: This large, multicenter 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. Ann Neurol 2018;83:210-222.
271 citations
TL;DR: The measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brainVolume loss in MS are reviewed.
Abstract: Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.
237 citations
Cites background from "Brain atrophy and lesion load predi..."
...It has recently been reported that, although the impact of brain volume on disability progression may vary with different disease courses, the rate of brain volume loss as well as T2 lesion volume at 1 year may predict disability progression over both 10 [58] and 13 years [80]....
[...]
References
More filters
VU University Amsterdam1, University of Rennes2, Vita-Salute San Raffaele University3, University of Düsseldorf4, University of Basel5, Icahn School of Medicine at Mount Sinai6, Foothills Medical Centre7, National Institutes of Health8, University of Toronto9, Lund University10, Mayo Clinic11, University of Texas Health Science Center at Houston12
TL;DR: New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease.
Abstract: New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.
4,862 citations
TL;DR: Improvements to this method are described, and an extension of SIENA is extended to a new method for cross-sectional (single time point) analysis, which provides easy manual review of their output by the automatic production of summary images.
1,932 citations
TL;DR: Lesion volume increases for at least 20 years in relapse-onset multiple sclerosis and the rate of lesion growth is three times higher in those who develop secondary progressive than inThose who remain relapsing remitting multiple sclerosis.
Abstract: Clinically isolated syndromes (CIS), such as optic neuritis, brainstem or spinal cord syndromes are frequently the first clinical presentations of multiple sclerosis However, not all CIS patients develop multiple sclerosis and in those who do, disability is highly variable In previous follow-up studies, brain lesions on T2-weighted MRI are associated with increased risk of multiple sclerosis and to an extent disability We evaluated the longitudinal relationships between the MRI lesions and clinical course over a period of 20 years CIS patients were recruited between 1984 and 1987 and previously followed up after 1, 5, 10 and 14 years Of the 140 subjects who were initially recruited with a CIS for a baseline MRI study, we followed up 107 patients after a mean of 202 years (range 18-277) Multiple sclerosis was diagnosed as clinically definite on clinical grounds only and disability determined using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) score Clinically definite multiple sclerosis developed in 67 out of 107 (63%) overall: 60 out of 73 (82%) with abnormal and 7 out of 34 (21%) with normal baseline MRI Multiple sclerosis was still relapsing-remitting in 39 (58%)--including 26 (39%) with a 'benign' course (EDSS < or = 3)--whilst 28 (42%) had developed secondary progression T2 lesion volume at all time-points correlated moderately with 20-year EDSS (r(s) values 048 to 067; P < 0001) and MSFC z-score [r(s) values (-050) to (-061); P < 0001] In those developing multiple sclerosis, a concurrent correlation of change in T2 lesion volume with change in EDSS was most evident in years 0-5 (r(s) = 069, P < 0001) The estimated rate of lesion growth over 20 years was 080 cm3/year in those who retained a relapsing remitting multiple sclerosis course, and 289 cm3/year in those who developed secondary progressive multiple sclerosis, a difference of 209 cm3/year (95% CI: 077, 296; P < 0001) This study extends previous follow-up of CIS patients and sheds new light on how the lesions evolve according to the natural history Baseline MRI findings are predictive for development of clinically definite multiple sclerosis Lesion volume and its change at earlier time points are correlated with disability after 20 years Lesion volume increases for at least 20 years in relapse-onset multiple sclerosis and the rate of lesion growth is three times higher in those who develop secondary progressive than in those who remain relapsing remitting multiple sclerosis
829 citations
TL;DR: In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis.
Abstract: Background In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability. Methods Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke's Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability). Results Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis ...
815 citations
University of Cambridge1, Max Planck Society2, Boston Children's Hospital3, University of Bari4, University of Cagliari5, University of Eastern Piedmont6, Charité7, Ruhr University Bochum8, Copenhagen University Hospital9, Oslo University Hospital10, Katholieke Universiteit Leuven11, Walter and Eliza Hall Institute of Medical Research12, Medical University of Łódź13
TL;DR: The Multiple Sclerosis Severity Score (MSSS) as mentioned in this paper measures the severity of a patient with multiple sclerosis using the Expanded Disability Status Scale (EDSS) score.
Abstract: Background: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. Methods: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. Results: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. Conclusion: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.
807 citations