Clinical Applications of Imaging Disease Burden in Multiple Sclerosis

MRI and Advanced Imaging Techniques

Claire Riley; Christina Azevedo; Mary Bailey; Daniel Pelletier

Expert Rev Neurother. 2012;12(3):323-333.

Abstract and Introduction

Abstract

This review will address the critical role of radiographic techniques in monitoring multiple sclerosis disease course and response to therapeutic interventions using conventional imaging. We propose an algorithm of obtaining a contrast-enhanced brain MRI 6 months after starting a disease-modifying therapy, and considering a gadolinium-enhancing lesion on that scan to indicate suboptimal response to therapy. New or enlarging T2 lesions should be followed on scans at 6-month intervals to assess for change, and the presence of one or more enhancing lesions on a 6- or 12-month scan, or two or more new or enlarging T2 lesions on a 12-month scan should prompt consideration of therapy change. New techniques such as PET imaging, magnetic resonance spectroscopy, magnetic resonance relaxometry, iron-sensitive imaging and perfusion MRI will also be overviewed, with their potential roles in monitoring disease course and activity.

Introduction

Recent updates to the MRI diagnostic criteria for multiple sclerosis (MS) have simplified the guidelines and allowed for earlier diagnosis with preserved diagnostic sensitivity and specificity.^[1] CNS lesions disseminated in space and time remain the two key features of the diagnosis, and the latter can be established with a single scan in a patient with a clinically silent gadolinium (GAD)-enhancing lesion and another clinically silent T2 lesion. Alternatively, any new T2 lesion after an original scan can define dissemination in time. Dissemination in space may be satisfied by at least one T2 lesion in two of the following four characteristic areas for MS: periventricular, juxtacortical, infratentorial and spinal cord. These 2010 criteria make diagnosis of relapsing–remitting MS (RRMS) more straightforward compared with a prior version of the McDonald criteria, revised in 2005.^[2]

While MRI metrics as described above have been critically important in MS diagnostic criteria, in this review we will focus on the importance of white matter lesions in clinical decision-making, specifically in determining suboptimal response to therapy. Several advanced imaging techniques have potential importance in diagnosing MS and following progression and response to treatment. These include methods of imaging gray matter in MS patients, in addition to normal-appearing white matter and quantification of brain atrophy. We will discuss these methods, as well as potential applications of myelin and iron-sensitive imaging and other advanced imaging techniques that hold promise for furthering the understanding of MS. We recognize, however, that at this time the mainstay of imaging in MS is focused on lesions and conventional techniques.

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Next Section

Abstract and Introduction
Clinical Relevance of White Matter MS Lesions Detected on Clinical MRI Scans
Brain Atrophy in MS
Imaging Normal-appearing Tissue in MS
Expert Commentary
Five-year View
References
Sidebar

Table 1. Relationship between conventional MRI metrics and clinical outcomes.
Study (year)	MRI metric	Summary of findings	Ref.
Sormani et al. (2010)	New or enlarging T2 lesions, or GAD-enhancing lesions	Meta-analysis of 19 RRMS RCTs that showed a significant correlation between treatment effect on MRI lesions and EDSS worsening	[4]
Sormani et al. (2009)	New or enlarging T2 lesions, or GAD-enhancing lesions in studies with monthly scans	Meta-analysis of 23 RRMS RCTs that showed a strong correlation between treatment effect on MRI lesions and relapse rate	[3]
Fisniku et al. (2008)	T2 lesion volume	Change in lesion volume in the first 5 years of follow-up correlated with EDSS at 20 years	[9]
Li et al. (2006)	T2 lesion volume	T2 lesion volume correlated with EDSS and relapse rate, although the correlation was less robust in patients with EDSS above 4.5	[11]
Weiner et al. (2000)	T2 lesion volume and number of GAD-enhancing lesions	RRMS patients showed correlation between number of GAD-enhancing lesions and rising EDSS and relapse rate Chronic progressive patients demonstrated a correlation between increasing T2 lesion volume and EDSS and ambulation index	[10]

EDSS: Expanded Disability Status Scale; GAD: Gadolinium; RCT: Randomized controlled trial; RRMS: Relapsing–remitting multiple sclerosis.

Table 2. Relationships between brain atrophy and clinical outcomes.
Study (year)	MRI method (subjects, n)	Major finding(s)	Ref.
Calabrese et al. (2007)	BPF, GMF, WMF and CTh (115)	Global cortical thinning found in all patients with MS, including those with 'possible MS' by McDonald criteria	[16]
Amato et al. (2007)	SIENAX to obtain NCV (28)	NCV change was significantly higher in 12 MS patients with deteriorating cognitive function on neuropsychological testing compared with 16 MS patients with stable or improving cognitive function	[18]
Zivadinov et al. (2008)	NA	A comprehensive review of the effect of disease-modifying therapies and their effects on brain volume	[77]
Henry et al. (2008)	VBM (90)	Significant atrophy in thalamus, hypothalamus, putamen, caudate and brainstem at initial CIS presentation compared with controls	[17]
Fisher et al. (2008)	BPF, GMF and WMF (87)	GMF change was 3.4-fold greater in CIS converting to RRMS compared with controls, and 14-fold greater in RRMS converting to SPMS	[26]
Fisniku et al. (2008)	SIENAX (73)	Significantly more gray matter atrophy, but not white matter atrophy, in SPMS vs RRMS and RRMS vs CIS. GMF, but not WMF, correlated with EDSS and MSFC	[27]
Mowry et al. (2009)	SIENAX (507)	Higher lesion burden and lower gray matter volume were correlated with worse scores of Emotional Well-Being and Reduced Thinking/Fatigue subscales of the Functional Assessment in Multiple Sclerosis	[20]
Tao et al. (2009)	TBM (88)	Significant atrophy of thalamus, caudate and putamen, even at modest levels of EDSS	[29]
Roosendaal et al. (2011)	SIENAX (977)	Gray matter volume was a better predictor than white matter volume or lesion volume of disability and cognitive impairment, as measured by EDSS and PASAT, respectively	[28]

BPF: Brain parenchymal fraction; CIS: Clinically isolated syndrome; CTh: Cortical thickness; EDSS: Expanded Disability Status Scale; GMF: Gray matter fraction; MS: Multiple sclerosis; MSFC: Multiple sclerosis functional composite; NA: Not applicable; NCV: Normalized cortical volume; PASAT: Paced auditory serial addition test; RRMS: Relapsing–remitting multiple sclerosis; SIENAX: Structural image evaluation using normalization of atrophy for cross-sectional measurement; SPMS: Secondary-progressive multiple sclerosis; TBM: Tensor-based morphometry; VBM: Voxel-based morphometry, WMF: White matter fraction.

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