To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS.
Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM).
During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00-2.77) as an independent predictor of evolution to definite MS.
Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients.
"More specifically, we have found significantly increased GM, and cortical atrophy in patients with SDP compared to to patients who remained stable or improved in their disability status over 48 months. This confirms the results of previous crosssectional (Calabrese et al., 2007, Henry et al., 2008, Audoin et al., 2010, Jure et al., 2010) and longitudinal CIS studies, (Dalton et al., 2004, Rocca et al., 2008, Raz et al., 2010) as well as longitudinal studies performed in early relapsing-remitting MS cohorts. (Horakova et al., 2008, Calabrese et al., 2012, Zivadinov et al., 2013a, Jacobsen et al., 2014) Our results were confirmed by an additional analysis that excluded MRI measures over the first 6 months of the study to minimize the potential effect of pseudo-atrophy. "
[Show abstract][Hide abstract] ABSTRACT: Background
Gray matter (GM) and white matter (WM) pathology has an important role in disease progression of multiple sclerosis (MS).
To investigate the association between the development of GM and WM pathology and clinical disease progression in patients with clinically isolated syndrome (CIS).
This prospective, observational, 48-month follow-up study examined 210 CIS patients treated with 30 µg of intramuscular interferon beta-1a once a week. MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Associations between clinical worsening [24-weeks sustained disability progression (SDP) and occurrence of a second clinical attack] and longitudinal changes in lesion accumulation and brain atrophy progression were investigated by a mixed-effect model analysis after correction for multiple comparisons.
SDP was observed in 32 (15.2%) CIS patients, while 146 (69.5%) were stable and 32 (15.2%) showed sustained disability improvement. 112 CIS patients (53.3%) developed clinically definite MS (CDMS). CIS patients who developed SDP showed increased lateral ventricle volume (p < .001), decreased GM (p = .011) and cortical (p = .001) volumes compared to patients who remained stable or improved in disability. Converters to CDMS showed an increased rate of accumulation of number of new/enlarging T2 lesions (p < .001), decreased whole brain (p = .007) and increased lateral ventricle (p = .025) volumes.
Development of GM pathology and LVV enlargement are associated with SDP. Conversion to CDMS in patients with CIS over 48 months is dependent on the accumulation of new lesions, LVV enlargement and whole brain atrophy progression.
"Abnormalities of GM are present early in CIS [90-95] and evolve with its progression to definite MS [11,96-98]. Numerous works have shown that the changes in GM are closely associated with both physical disability and cognitive impairment (see Table 1) [31,33,37,68,99-101]. "
[Show abstract][Hide abstract] ABSTRACT: Traditionally, multiple sclerosis has been viewed as a disease predominantly affecting white matter. However, this view has lately been subject to numerous changes, as new evidence of anatomical and histological changes as well as of molecular targets within the grey matter has arisen. This advance was driven mainly by novel imaging techniques, however, these have not yet been implemented in routine clinical practice. The changes in the grey matter are related to physical and cognitive disability seen in individuals with multiple sclerosis. Furthermore, damage to several grey matter structures can be associated with impairment of specific functions. Therefore, we conclude that grey matter damage - global and regional - has the potential to become a marker of disease activity, complementary to the currently used magnetic resonance markers (global brain atrophy and T2 hyperintense lesions). Furthermore, it may improve the prediction of the future disease course and response to therapy in individual patients and may also become a reliable additional surrogate marker of treatment effect.
"In NAWM, abnormalities have been demonstrated using a number of imaging techniques including MTR, MRS, DTI, and T2 relaxation.[30–35] In MS, evidence supports significant changes in NAWM beginning at an early stage of disease; patients with CIS tend to have identifiable changes in MTR in NAWM as compared to control individuals. Of note, when correlations were sought between MRI measures and conversion from CIS to MS, abnormities in NAWM did not contribute, whereas the number of lesions seen on T2-weighted images did. "
[Show abstract][Hide abstract] ABSTRACT: Magnetic Resonance Imaging (MRI) has brought in several benefits to the study of Multiple Sclerosis (MS). It provides accurate measurement of disease activity, facilitates precise diagnosis, and aid in the assessment of newer therapies. The imaging guidelines for MS are broadly divided in to approaches for imaging patients with suspected MS or clinically isolated syndromes (CIS) or for monitoring patients with established MS. In this review, the technical aspects of MR imaging for MS are briefly discussed. The imaging process need to capture the twin aspects of acute MS viz. the autoimmune acute inflammatory process and the neurodegenerative process. Gadolinium enhanced MRI can identify acute inflammatory lesions precisely. The commonly applied MRI marker of disease progression is brain atrophy. Whole brain magnetization Transfer Ratio (MTR) and Magnetic Resonance Spectroscopy (MRS) are two other techniques use to monitor disease progression. A variety of imaging techniques such as Double Inversion Recovery (DIR), Spoiled Gradient Recalled (SPGR) acquisition, and Fluid Attenuated Inversion Recovery (FLAIR) have been utilized to study the cortical changes in MS. MRI is now extensively used in the Phase I, II and III clinical trials of new therapies. As the technical aspects of MRI advance rapidly, and higher field strengths become available, it is hoped that the impact of MRI on our understanding of MS will be even more profound in the next decade.
Annals of Indian Academy of Neurology 03/2009; 12(4). DOI:10.4103/0972-2327.58284 · 0.60 Impact Factor
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