10.1177/1051228405283362Journal of Neuroimaging Supplement to Vol 15 No 4Bakshi: MRI in MS

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Magnetic Resonance ImagingAdvances in Multiple Sclerosis

Rohit Bakshi, MD, FAAN

Guest Editor

A B S T R A C T

Magnetic resonance imaging (MRI) has become a core compo-nent of clinical management and scientific research in multiplesclerosis (MS), providing essential information about tissuestructure and function. MRI is now the most important labora-tory diagnostic and longitudinal monitoring technology. A num-ber of conventional MRI techniques, which include T2-weighted, T1-weighted, and gadolinium-enhanced imaging,are used to identify overt lesions and quantify tissue atrophy.MRI is highly sensitive in detecting brain and spinal cord involve-ment in MS and can visualize multifocal lesions, occult disease,and macroscopic atrophy. Advanced MRI techniques, such asmagnetization transfer imaging, spectroscopy, diffusion-weighted imaging, and functional MRI, have added to ourunderstanding of the pathogenesis of the disease. The preciserole of these newer imaging approaches continues to bedefined. In this supplement to the Journal of Neuroimaging, theauthors review the role of conventional and advanced MRI tech-niques in detecting tissue changes in MS, diagnosing and moni-toring patients, and charting the progression of disease in newand established patients.

Key words: Magnetic resonance imaging, multiple sclerosis,lesions, magnetic resonance spectroscopy, magnetizationtransfer, brain atrophy, diffusion imaging, functional MRI.

Bakshi R.Magnetic resonance imaging advances in

multiple sclerosis.J Neuroimaging 2005;15:5S-9S.

DOI: 10.1177/1051228405283362

Magnetic resonance imaging (MRI) is the most importantparaclinical technology used to detect tissue changes inpatients with multiple sclerosis (MS). It is now a criticalcomponent of the diagnosis and management of the dis-ease, providing information essential in monitoring dis-ease activity and disease severity in patients with estab-

lished MS.1-4 MRI findings also offer valuable prognosticinformation in the early stage of disease, such as inpatients with clinically isolated demyelinating syndromes(CIS).4,5 MRI metrics also provide primary outcome mea-sures for phase 1/2 trials and supportive outcome mea-sures for phase 3 trials of MS therapies.1 Recent advancesin imaging technology underscore the increasing utility ofMRI in disease management and scientific and clinicalresearch.

Clinical protocols for conventional MRI typicallyinclude a variety of image acquisitions and approaches.6

The most useful are axial and sagittal fluid-attenuatedinversion recovery, axial dual spin-echo or single late-echo T2-weighted imaging, and pre- and post-gadolinium(Gd)-enhanced axial spin-echo T1-weighted imaging.Conventional images also provide information on centralnervous system (CNS) atrophy that can be derived bothby qualitative and quantitative analysis.3 There are a num-ber of advanced MRI techniques that appear to be moresensitive than conventional imaging in the detection ofoccult tissue damage or metabolic changes. Theseapproaches include diffusion-weighted imaging, magneti-zation transfer, spectroscopy, and functional MRI.Although these advanced technologies have shed light onthe pathogenesis of MS and provide useful tools for scien-tific investigation, their precise role in clinical practiceremains to be established.

On conventional MRI scans, several manifestations ofMS lesions are notable, such as hyperintensities on T2-

Copyright © 2005 by the American Society of Neuroimaging 5S

Received September 30, 2005, and in revised form Octo-ber 5, 2005. Accepted for publication October 5, 2005.

From the Center for Neurological Imaging, Partners Mul-tiple Sclerosis Center, and the Departments of Neurologyand Radiology, Brigham and Women’s Hospital, Har-vard Medical School, Boston, Massachusetts.

Address correspondence to Rohit Bakshi, MD,FAAN, Brigham and Women’s Hospital, 77 Avenue LouisPasteur–HIM 730, Boston, MA 02115. E-mail: rbakshi@bwh.harvard.edu.

weighted images, hypointensities on T1-weightedimages, and Gd-enhancing foci on postcontrast images.There also has been increasing interest in the role of MRIin defining brain and spinal cord atrophy. CNS atrophy isbecoming an important biomarker of disease severity,particularly in view of its relationship to physical disabil-ity and cognitive impairment3,7,8 and ability to predict dis-ease progression over the long term.9 Despite the sensitiv-ity of MRI in detecting MS lesions, there may bediscordance between imaging findings and clinical assess-ments, such as the Expanded Disability Status Scale(EDSS).10,11 This disconnect is likely due in part to thedetection on MRI of clinically silent lesions that may notimmediately affect brain function.11 However, over thelong term, the accumulation of MRI lesions may gradu-ally exhaust brain reserve capacity. Consistent with thishypothesis, longitudinal studies show predictive value forearly MRI findings toward long-term accumulation ofdisability5,9 and cognitive impairment.12 Assessment ofdestructive aspects of the disease7,8,13 and the use ofadvanced MRI technologies3 have begun to resolve thisclinical-MRI paradox. Moreover, even though globalmeasures of MRI lesions may not correlate well with dis-ability, assessments that compare lesion location with spe-cific aspects of disability reveal much better correlations.14

This article will briefly review the role of MRI in thediagnosis and management of MS and preview the arti-cles in this supplement to the Journal of Neuroimaging serv-ing as an overview of established and emerging MRItechniques.

Conventional MRI Measures

Hyperintense Lesions on T2-Weighted Images

Hyperintense lesions on T2-weighted MRI scans are in-dicative of an increase in water content. As a result, T2-weighted lesions are nonspecific for the underlying pa-thology and cannot distinguish among inflammation,gliosis, edema, demyelination, remyelination, Walleriandegeneration, and axonal loss.1 MS lesions have beenidentified primarily in white matter but also in gray matterand may affect the periventricular and infratentorial brainregions, corpus callosum, juxtacortical gray-white matterjunction in the white matter, and the brain stem, middlecerebellar peduncles, and cerebellar white matter in theposterior fossa.1,6 In some cases, direct involvement of thecerebral cortex also may be apparent.15

Between 50% and 90% of all MS patients showhyperintense T2 lesions in the spinal cord.16 The presenceof spinal cord disease is an important confounding factor,which may contribute to the poor correlation between

clinical disability and brain MRI findings. MS lesions typ-ically involve no more than 1 or 2 contiguous spinal levelsand less than one half of the cord cross-sectional area,whereas non-MS myelitis usually affects multiple contigu-ous levels and more than one half of the cord diameter.17

The presence of characteristic cord lesions on MRI addsboth sensitivity and specificity to confirm the diagnosis ofMS.4,16,17

Brain T2 hyperintense lesion load early in the clinicalcourse is a predictor of long-term disability from MS.5,16

Longitudinal studies of patients with CIS show that a nor-mal brain MRI at baseline indicates a low risk (11%) ofprogression to clinically definite MS, but the presence of 2or more lesions markedly increases the risk of conversionto clinically definite MS to >85%.18 Early progression ofT2 burden of disease is an independent risk factor for thedevelopment of long-term disability.5

Hypointense Lesions on T1-Weighted Images

A subset of T2 hyperintense lesions in the brain may alsoshow hypointensity on corresponding T1-weighted scans.At the time of the acute appearance of new T1hypointense lesions, almost half of these represent areasof reversible edema, inflammation, and demyelinationand will return to isointensity over the next severalmonths.19,20 However, chronic lesions that persist overseveral months likely represent irreversible and profoundtissue damage due to demyelination and axonal loss.20

Brain hypointense T1-weighted lesions have correlatedbetter with disability than have lesions on T2-weightedimages in some13 but not all studies.21

Gd-Enhancing Lesions

Gd-enhancing lesions are correlated histopathologicallywith T cell migration across the blood-brain barrier andare indicative of active inflammation.22 These lesions aremore sensitive to disease activity than clinical relapses.Moreover, the appearance of Gd-enhancing lesions pre-dicts future relapses but not long-term disability.23 Gd-enhancing lesions, which may appear as homogeneous,heterogeneous, tumor-like, and ring enhanced, are morecommonly seen in patients with relapsing-remitting MS(RRMS) than in patients with progressive forms of the dis-ease. The open-ring pattern is particularly characteristicof MS lesions.24

Brain and Spinal Cord Atrophy

MRI measurement of brain and spinal cord atrophy isemerging as a clinically relevant biomarker of neuro-degeneration in MS.3 Atrophy is particularly useful in lon-gitudinal monitoring of patients, as it is a powerfulpredictor of long-term progressive neurological impair-

6S Journal of Neuroimaging Supplement to Vol 15 No 4

ment and cognitive dysfunction.3,7-9,12 Brain atrophy,which appears to begin early in the disease process, suchas in patients with CIS or early RRMS, is more closely as-sociated with clinical manifestations of the disease, in-cluding cognitive dysfunction, physical disability, mooddisturbances, and diminished quality of life, than are con-ventional T1 hypointense and T2 hyperintense lesion as-sessments.3,7-9,12 Spinal cord atrophy also is apparent in thefirst few years of MS25 and is well correlated with physicaldisability, especially in patients with progressive dis-ease.3,7,25 There are various methods of measuring globalor regional brain atrophy and spinal cord atrophy, andthese techniques continue to be refined as MRI technol-ogy continues to improve.3,25,26

Advanced MRI Techniques

Among the most important of the new MRI methods cur-rently under investigation in MS are magnetization trans-fer, spectroscopy, and diffusion-weighted imaging. Thesetechniques are especially helpful in identifying micro-scopic disease activity in areas that are free from overt le-sions on conventional MRI scans in gray or white matter,the so-called normal-appearing brain tissue,27 includingtissue changes that precede the development of overt le-sions by several months.3,27

More specifically, magnetization transfer imaging,which is based on interactions between protons in freeand bound water pools, is sensitive to demyelination.28

Proton magnetic resonance spectroscopy quantifiesneurometabolites (eg, choline, lactate, lipids, myo-inositol, and N-acetylaspartate) that are indicative of arange of tissues changes, such as gliosis, inflammation,demyelination, and loss of axonal or neuronal integrity.29

Diffusion-weighted MRI is a quantitative measure of theeffect of the cellular environment of CNS tissue on the dif-fusion properties of water molecules.30 The metricsderived from these scans reflect changes in the architec-ture of tissue, such as size, shape, geometry, and orienta-tion. Diffusion-weighted imaging is particularly sensitiveto fiber tract damage in MS, likely reflecting demyelina-tion or inflammation.30 Finally, functional MRI is a meansto assess brain activation during the performance of a cog-nitive, motor, or sensory task. In task performance stud-ies of patients in the early stages of MS, functional MRIscans have shown abnormal patterns of increased activa-tion.31-33 These changes may be evidence of an adaptiveresponse to brain injury in the ipsilateral and contralateralhemispheres, involving recruitment of secondary path-ways and reorganization of distant sites. All of theseadvanced MRI techniques offer the potential to markedly

improve disease management even as they expand ourunderstanding of the pathophysiology of MS.

“MRI Advances in MS”

The articles that comprise this supplement to the Journal ofNeuroimaging are devoted to the burgeoning use of MRI inMS. The first review sets the stage for those that follow. Init, Drs Zivadinov and Leist examine the relationship be-tween clinical and MRI measures of neurologic impair-ment and disability.34 They show how conventional MRImetrics have helped clarify and extend such clinical as-sessments as the EDSS and MS Functional Compositeand point out the limitations of the various MRI tech-niques. It is followed by a discussion of the dynamics ofMS lesion formation and evolution by Dr Filippi and col-leagues.35 They highlight the use of both conventionaland quantitative MRI approaches to monitor the courseof lesion progression and explore the important contribu-tion of serial imaging assessments to disease monitoring.This opening section concludes with an article from mygroup analyzing the role of MRI in measuring brain andspinal cord atrophy and the relationship between atrophyand clinical manifestations of the disease.36

The second section delves more deeply into advancedMRI approaches. Dr Narayana reviews the developmentof MR spectroscopy, demonstrating why this techniquemay offer a more robust correlation between diseaseactivity and clinical status than conventional MRI mea-sures do.37 Next, Dr Horsfield addresses the physical pro-cesses and methodologies involved in magnetizationtransfer imaging and the clinical significance of these find-ings.38 A presentation on recent advances in diffusionimaging follows in which Dr Warfield and colleaguesdescribe how this approach can be used to assess lesionsand detect diffuse occult disease in normal-appearingbrain tissue.39 The final review in this section, byDr Buckle, examines the emerging role of functional MRIin determining the response to neuronal injury and brainplasticity in MS.40

The supplement concludes with 2 reviews. The first, byDr Constantinescu and colleagues, highlights spinal cordimaging in MS, reviewing, in particular, lesion evolution,the detection of diffuse occult disease, and the correlationbetween measures of cord atrophy and the developmentof physical disability.41 The second, by Dr Guttmann andcolleagues, considers medical image processing and anal-ysis in MS research and shows how his group implementsadvanced processing and analysis techniques.42

In summary, the articles contained in this supplementoffer a concise state-of-the-art review of conventional andadvanced MRI techniques by recognized experts in the

Bakshi: MRI in MS 7S

field. The articles provide a wealth of information on therole of MRI technologies in detecting tissue changes inMS, diagnosing and monitoring patients, and charting theprogression of disease in new and established patients. Ihope the supplement will serve as a valuable reference forboth clinicians and scientists actively engaged in MSresearch and patient care.

Rohit Bakshi, MD, FAANGuest EditorBoston, MA, USA

This supplement was supported by an educational grant from TevaNeuroscience. BioScience Communications contributed to the editorialrefinement of this article and to the production of this supplement.Authors may have accepted honoraria for their supplementcontributions.

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