Multiple sclerosis (MS) is an inflammatory disease of the central nervous. Magnetic Resonance Imaging in Multiple Sclerosis

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1 DIAGNOSIS AND MANAGEMENT UPDATE Magnetic Resonance Imaging in Multiple Sclerosis Salvatore Q. Napoli, MD, * Rohit Bakshi, MD * *Partners, Multiple Sclerosis Center, Boston, MA, Center for Neurological Imaging, Departments of Neurology and Radiology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA Magnetic resonance imaging (MRI) has played a central role in the clinical management and scientific investigation of multiple sclerosis (MS) and has become the most important ancillary tool for diagnosing and monitoring the disease. Conventional MRI techniques are used to assess overt lesions and atrophy in the central nervous system and include spin-echo T2-weighted, pre- and post-gadolinium-enhanced spin-echo T1-weighted, and fluid-attenuated inversion-recovery images. Advanced MRI techniques such as diffusion-weighted imaging, magnetization transfer imaging, magnetic resonance spectroscopy, and functional MRI have increased our understanding of the pathogenesis of MS. The role of these newer techniques in clinical practice remains under investigation. In this review, we will focus on the role of MRI in the diagnosis and management of MS. We will also review how advanced MRI techniques contribute to our understanding of MS. [Rev Neurol Dis. 2005;2(3): ] 2005 MedReviews, LLC Key words: Multiple sclerosis Magnetic resonance imaging Magnetic resonance spectroscopy Diffusion-weighted imaging Magnetization transfer Brain atrophy Spinal cord atrophy Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) of suspected autoimmune origin. It is characterized by multifocal and widespread demyelination and axonal loss affecting the brain, spinal cord, and optic nerve. Magnetic resonance imaging (MRI) has become the most important ancillary tool for diagnosing and monitoring the disease. 1-5 The central role of MRI in clinical management and scientific investigation continues to expand with advances in imaging technology. MRI is an essential tool in the initial evaluation of patients suspected of having the VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 109

2 MRI in MS continued disease, and provides valuable prognostic information for those presenting with a clinically isolated syndrome (CIS) of demyelination. 2 In addition, MRI findings serve as a primary outcome measure in phase I/II trials and as a secondary supportive outcome measure in phase III trials of MS therapies. 3 Recommended clinical protocols using conventional MRI typically consist of several image acquisitions. 4,5 These include axial and sagittal fluid-attenuated inversionrecovery (FLAIR), axial dual-echo or single-echo T2-weighted, and preand post-gadolinium (Gd)-enhanced axial spin-echo T1-weighted images. In addition to these conventional sequences, advanced MRI techniques, such as diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI), magnetic resonance spectroscopy (MRS), and functional MRI (fmri), have increased the sensitivity for detecting tissue injury and have increased our understanding of the pathogenesis of MS. However, the role of these newer techniques in clinical practice remains unclear. Multiple sclerosis lesions shown by conventional MRI fall into several categories, such as hyperintensities on T2-weighted images, hypointensities on T1-weighted images, and Gd-enhancing lesions. Another MRI measure of disease severity of growing interest is atrophy of the brain and spinal cord. CNS atrophy carries particular relevance in relation to physical disability and cognitive impairment. 6-8 Although MRI is a highly sensitive tool in detecting MS lesions, there may be a paradox between clinical and MRI findings. 9 This is partially the result of clinically silent lesions on MRI that do not affect brain function. 10 Longitudinal studies, 11 indices of tissue destruction, 6,7,12 and advanced MRI techniques 3 have partially resolved this discrepancy. In addition, although global MRI lesion measures can correlate poorly with overall disability, The central role of MRI in clinical management and scientific investigation of MS continues to expand with advances in imaging technology. improved correlations have been found by taking into account lesion location and disability subscales scores. 13 We will review the role of MRI in the diagnosis and management of MS. We will review lesion detection by conventional MRI and also discuss how advanced MRI techniques contribute to our understanding of the disease. Figure 1. (A,B): Axial T2-weighted (A) and FLAIR (B) images of a 30-year-old woman with relapsing-remitting MS. The patient s first symptom was optic neuritis. The hyperintense lesions are typical for MS: periventricular, oval/ovoid, and generally greater than 5 mm in diameter. Note how FLAIR shows the lesions more conspicuously than the T2-weighted image. (C,D): Axial T2- weighted (C) and sagittal FLAIR (D) images of a 35-year-old man with relapsingremitting MS. The lesion is in the middle cerebellar peduncle, a characteristic location for MS; the pons also contains lesions. Sagittal FLAIR shows lesions that are oriented perpendicular to the long axis of the ventricles. This is secondary to the perivenular propensity for inflammatory demyelination and is also known as Dawson s fingers. Hyperintense Lesions on T2-Weighted Images Hyperintense lesions on T2-weighted MRI scans reflect general increases in water content and thus are nonspecific for the underlying pathology. Accordingly, factors such as inflammation, gliosis, edema, demyelination, remyelination, wallerian degeneration, and axonal loss cannot be easily distinguished on T2- weighted images. Lesions may be seen throughout the brain, including the white matter and, less commonly, the gray matter. In the white matter, MS lesions may affect the periventricular regions, corpus callosum, juxtacortical gray-white matter junction, and infratentorial brain regions (Figures 1 and 2). 5 In the posterior fossa, involvement typically includes lesions in the brain stem, middle cerebellar peduncles, and cerebellar white matter (Figure 1). Direct involvement of the cerebral cortex may also occur (Figure 2). 14 Lesions are commonly oval or ovoid and usually 5 mm or greater in 110 VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

3 MRI in MS diameter (Figures 1 and 2). 5 Periventricular white matter lesions typically make contact with the ependymal surface of the ventricles and are perpendicular to the long axis of the lateral ventricles due to perivenular demyelination ( Dawson s fingers ) (Figure 1). Lesions in the corpus callosum most commonly affect the inner surface adjacent to the lateral ventricles. Spinal cord hyperintense lesions on T2-weighted images can be found in 50% to 90% of patients with MS (Figure 3). One factor contributing to the lack of strong correlation between clinical disability and brain MRI is the presence of spinal cord disease. Spinal cord lesions typically involve no more than 1 to 2 contiguous spinal levels and less than half of the cord cross-sectional area (Figure 3). 15 Lesions involving multiple contiguous levels and more than half of the cord diameter are characteristic of non-ms myelitis such as Devic disease and post-infectious myelitis. 15 FLAIR imaging uses heavy T2 weighting with an inversion recovery Figure 2. (A, B): Axial T2-weighted (A) and FLAIR (B) images of a 35-year-old woman with relapsing-remitting MS. (C, D): Axial T2-weighted (C) and FLAIR (D) images of a 33-year-old woman with relapsing-remitting MS. These images show the superiority of FLAIR in detecting both periventricular and cortical/juxtacortical supratentorial lesions. pulse, thus maximizing contrast between lesions and normal tissue or cerebrospinal fluid (CSF) (Figures 1 and 2). These images are most helpful in identifying lesions adjacent to the CSF, such as in periventricular or cortical/juxtacortical areas (Figures 1 and 2). 14 FLAIR has less utility for posterior fossa or spinal involvement. The extent of T2 hyperintense lesion load is of prognostic value early in the disease course. In a 5-year longitudinal study, 38 of 84 patients who initially presented with CIS developed probable or definite MS. 16 A higher T2 lesion volume at presentation was an independent risk factor for conversion to MS. The rate of progression of T2 lesion volume from baseline predicted the evolution of disability at 5 years. In a 10-year follow-up study of patients with CIS, the risk of progression to clinically definite MS was low (11%) among those with a negative brain MRI at baseline. 17 However, if there were 2 or more brain lesions at presentation, the risk of conversion at 10 years was increased to 90%. 17 The increase in T2 lesion volume in the Figure 3. Sagittal T2-weighted (left), T1-weighted post-gadolinium contrast (middle), and axial T2-weighted (right) images show an MS lesion in the lower cervical spinal cord (arrows). This patient is a 26-year-old man with relapsing-remitting MS whose first symptom consisted of bilateral foot numbness extending up to the abdomen. MS lesions in the spinal cord typically occupy no more than 1-2 levels and less than half of the cord cross-sectional area. VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 111

4 MRI in MS continued Figure 4. Axial T1-weighted (left), T2-weighted (middle), and FLAIR (right) images of a 40-year-old woman with relapsing-remitting MS. Note the T1 hypointense lesion or black hole (arrow) in the periventricular white matter. This lesion had persisted since the previous year and thus most likely represents severe demyelination and axonal loss. first 5 years predicted the level of disability (using the Expanded Disability Status Scale) at 14 years. 11 Therefore, early T2 hyperintense lesion load and its evolution have prognostic value in patients with CIS in terms of conversion to definite MS and development of long-term disability. Hypointense Lesions on T1-Weighted Images T2-hyperintense lesions in the brain are sometimes seen on corresponding T1-weighted images as areas of hypointensity ( black holes ) relative to normal white matter (Figure 4). Approximately half of acute, newly formed T1 hypointense lesions will revert to isointensity. Such transient T1 hypointense lesions most likely represent reversible edema, inflammation, demyelination, and remyelination. 18,19 However, some hypointense lesions that become isointense do so with associated atrophy. 20 Acute T1 hypointense lesions that show a small amount and shorter duration of tissue enhancement have a high probability of returning to isointensity. The acute hypointense lesions that disappear will usually do so within 6 months. 21 Chronic T1 hypointense lesions persisting over several months are likely to represent irreversible changes such as profound demyelination and axon loss. 18 Brain T1 hypointense lesions show a better correlation with clinical disability than T2 hyperintense lesions. This is seen particularly in secondary progressive MS patients. 12 Patients carrying the apolipoprotein E-epsilon 4 allele are more likely to increase their proportionate T1 lesion load. 22 Gadolinium-Enhancing Lesions Gadolinium-enhancing lesions in MS are correlated histopathologically with T cell migration across the blood-brain barrier. 23 Enhancement persists for an average of 3 weeks and then resolves. 24 The number of Gdenhancing lesions often correlates with and predicts clinical relapses. 10,25,26 The lesions are a more sensitive measure of disease activity than the presence of clinical relapses. 27 Gadolinium-enhancing lesions are thus useful as a sample size sparing primary outcome measure in phase I/II clinical trials. 3 However they are not strong predictors of the development of cumulative disability over time. 10 Gadoliniumenhancing lesions are more commonly seen in relapsing-remitting MS than in primary progressive and secondary progressive MS. There are various morphologies that can be seen in Gd-enhancing lesions in MS The number of gadolinium-enhancing lesions often correlates with and predicts clinical relapses. (Figure 5). The most common pattern is homogeneous. Heterogeneous, tumor-like, and ringenhanced patterns may also occur. An incomplete or open ring pattern is particularly characteristic of MS as compared to the ring enhancement seen in other diseases. 28 Figure 5. Axial T1-weighted post-gadolinium contrast images of 3 patients with relapsing-remitting MS show multiple enhancing lesions. The homogeneous pattern of enhancement is the most common pattern seen in MS. There are also open-ring (arrow) and closed-ring patterns (right image). The open ring typically faces the ventricle. Tumor-like and heterogeneous patterns may also be seen (not shown). 112 VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

5 MRI in MS atrophy also occurs early in the disease process 39 and shows a moderate to strong relationship with physical disability, particularly in patients with primary progressive and secondary progressive MS (Figure 6). 6,35 Various methods are available to measure global or regional brain atrophy 40,41 or spinal cord atrophy. 42 These techniques continue to improve with technological advances in MRI hardware and software. Figure 6. Axial T1-weighted images (A,B) showing brain atrophy in a 30-year-old man with secondary progressive MS (A) with moderate to severe cerebral atrophy compared to normal age-matched healthy control (B). The T1- weighted sagittal images of the same patient (C) and age-matched control (D) show corpus callosum atrophy, a common finding in MS. T2-weighted sagittal images of a 50-year-old woman with benign relapsing-remitting MS (E) and a 57-year-old woman with secondary progressive MS (F) show spinal cord atrophy in the latter. MRI Diagnostic Criteria for MS There have been several criteria proposed to integrate MRI as a sensitive and specific ancillary tool for the diagnosis of MS The criteria proposed by the International Panel on the Diagnosis of Multiple Sclerosis 2 were based on previously proposed MRI criteria. 29,30 The International Panel criteria show a high sensitivity (83%), specificity (83%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years in patients initially presenting with CIS. 33 In addition, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology recently published recommendations on the role of MRI in diagnosing MS in patients with CIS. 34 Brain Atrophy and Spinal Cord Atrophy MRI measurements of brain and spinal atrophy provide a method for assessing the neurodegenerative aspects of disease progression in MS. CNS atrophy is emerging as a clinically relevant biomarker for longitudinal monitoring of patients that provides information complementary to lesion assessments. 6-8,35 In comparison to conventional MRI lesion measurements, atrophy is more closely associated with a variety of clinical manifestations of MS such as cognitive dysfunction, physical disability, mood disturbances, and decreased quality of life. 6-8,35 CNS atrophy seems to begin in the early stages of MS, such as in the first 1 to 2 years in patients with CIS and in early relapsing-remitting MS. 6,36,37 Longitudinal studies have shown a link between brain atrophy and subsequent long-term progressive neurological impairment. 6,8,35 In addition, brain atrophy predicts cognitive dysfunction. 7,38 Spinal cord Figure 7. Axial T2-weighted images of a 55- year-old woman with secondary progressive MS (left) compared to age-matched healthy control (right). Note the T2 hypointensity in the basal ganglia of the patient with MS, most likely representing iron deposition. The patient also has brain atrophy. T1 and T2 Shortening Lesions in MS may cause T1 shortening, thus appearing hyperintense on non-contrast T1-weighted images. These areas may reflect lipid-laden macrophages, non-heme iron, or other paramagnetic substances. The lesions are more common in secondary progressive than relapsingremitting MS. 43 T2 shortening, seen as hypointensity on T2-weighted images (Figure 7), may occur in the cortical and subcortical gray matter in patients with MS Crosssectional studies have found an association between T2 hypointensity and physical disability, 44,45 and T2 hypointensities show a stronger correlation with disability and clinical course than do conventional MRI lesions. 45 T2 hypointensity shows a particularly close relationship to brain atrophy 45,46 and predicts the rate of whole brain atrophy over VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 113

6 MRI in MS continued Figure 8. A 36-year-old woman with active relapsing-remitting MS. Multiple gadolinium-enhancing lesions are seen on the axial T1-weighted post-contrast image (left). The lesions are hyperintense on the diffusion-weighted image (middle); however, the hyperintensity on the diffusion-weighted image does not generally represent restricted diffusion as the lesions are hyperintense on the apparent diffusion coefficient (ADC) map (right). Thus, many of the lesions are associated with increased diffusivity and T2 shine-through effects. However, the periphery of one of the lesions is hypointense on the ADC map, consistent with restricted diffusion (arrow). 2 years in patients with early relapsingremitting MS. 46 T2 hypointensity in MS gray matter most likely represents pathologic iron deposition. Iron accumulation may occur as a secondary effect of neurodegeneration, or play a direct role in the pathophysiology of MS through the generation of free radicals, oxidative stress, and neurotoxicity. Advanced MRI Techniques Advanced MRI techniques with potential applications to MS include DWI, MTI, MRS, and fmri. One of the major uses of these methods is to identify disease involvement in areas free of overt lesions on conventional MRI scans, the so-called normal appearing brain tissue. 47 Some of these methods may also show sensitivity to tissue changes that precede the development of an overt lesion by a few months. 3 MTI is based on interactions between protons in free or bound water pools. MS-related tissue damage is manifested by a decrease in magnetization transfer ratio (MTR). 48 This decrease in MTR is not specific for the underlying pathology; however, profound decreases are suggestive of severe injury. Proton MRS provides quantitative measures of neurometabolites that reflect a wide range of tissue changes such as active gliosis, inflammatory demyelination/remyelination, and loss of axonal/neuronal integrity. 49 most MS lesions are isointense or hyperintense (Figure 8). 50 Functional MRI assesses brain activation in response to applied motor or visual stimuli by alterations in signal intensity that result from changes in blood deoxyhemoglobin. There is a growing interest in the use of fmri in MS Abnormal patterns of increased activation during task performance in the early stages of MS have been shown with fmri, suggesting an adaptive response to brain injury. This increased activation can involve both ipsilateral and contralateral hemispheres, indicating recruitment of secondary pathways and reorganization of distant sites. The degree of fmri abnormalities is related to MRI lesion burden, suggesting that the disease process progressively consumes cerebral reserve capacity. One of the major uses of advanced MRI methods is to identify disease involvement in areas free of overt lesions on conventional MRI scans, the so-called normal appearing brain tissue. Increases in choline, lactate, and lipids are thought to represent inflammation and demyelination/ remyelination. Increases in myoinositol may reflect gliosis. Decreases in N-acetylaspartate most likely reflect axonal and/or neuronal injury. DWI is a quantitative measure of diffusional properties of water molecules. The diffusion is influenced by CNS tissue cellular environment, including cell membranes, cell organelles, and axons. Lesions in MS are commonly hyperintense on DWI scans due to T2 shine-through effects that belie the increased diffusivity seen in the majority of lesions (Figure 8). 50 This hyperintensity can be differentiated from true restriction of diffusion using apparent diffusion coefficient maps, on which [Dr. Napoli is supported by the Sylvia Lawry Fellowship from the National Multiple Sclerosis Society and is a consultant to Serono, Biogen Idec, and Teva Neuroscience. Dr. Bakshi acknowledges support of research grants from the National Institutes of Health (NIH-NINDS 1 K23 NS42379) and the National Multiple Sclerosis Society (RG 3574A1) and is a consultant to Biogen Idec, Berlex, Serono, and Teva Neuroscience.] References 1. Zivadinov R, Bakshi R. Role of MRI in multiple sclerosis I: inflammation and lesions. Front Biosci. 2004;9: McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50: Bakshi R, Minagar A, Jaisani Z, Wolinsky JS. Imaging of multiple sclerosis: role in neurotherapeutics. NeuroRx. 2005;2: VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

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Longitudinal MRI in multiple sclerosis: correlation between disability and lesion burden. Neurology. 1994; 44: Mcfarland HF, Stone LA, Calabresi PA, et al. MRI studies of multiple sclerosis: implications for the natural history of the disease and for monitoring effectiveness of experimental therapies. Mult Scler.1996;2: Masdeu JC, Quinto C, Olivera C, et al. Open ring imaging sign: highly specific for atypical brain demyelination. Neurology. 2000;54: Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to Main Points Magnetic resonance imaging (MRI) plays a central role in both the clinical management and scientific investigation of multiple sclerosis (MS) and has become the most important ancillary tool for diagnosing and monitoring the disease. Conventional MRI techniques include fluid-attenuated inversion-recovery, spin-echo T2-weighted, and pre- and postgadolinium-enhanced T1-weighted images. Hyperintense lesions on T2-weighted images are non-specific for the underlying pathology of MS lesions such as inflammation, gliosis, edema, demyelination, remyelination, wallerian degeneration, and axonal loss. The extent of T2 hyperintense lesion load and its evolution early in the disease course has prognostic value for clinical progression. Hypointense lesions on T1-weighted images may be transient or persistent. Those persisting for several months represent irreversible changes such as profound demyelination and axon loss. Gadolinium-enhancing lesions represent T cell migration across the blood-brain barrier and are a more sensitive measure of disease activity than the presence of clinical relapses. MRI measurement of brain and spinal cord atrophy is of growing interest for providing a measure of the neurodegenerative aspects of the disease. Central nervous system atrophy is more closely related to physical disability and cognitive impairment than are conventional lesion assessments. Advanced MRI techniques can identify disease involvement in areas free of overt lesions on conventional MRI scans in the gray and white matter. VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 115

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