MR finds widespread clinical use in MS diagnosis, management

August 1, 2005
George Hutton, MD

,
James R. Miller, MD

,
Ernst-wilhelm Radue, MD

MR imaging has provided important insights into the pathophysiology of multiple sclerosis.1 Conventional MR scans afford only gross estimates of the extent and nature of tissue damage associated with MS,2 however, and the data correlate poorly with measures of concurrent disability in patients. Advances in MRI technology have improved the correlation of its findings with clinical status and increased the utility of MRI data as surrogate markers in monitoring disease progression and response to therapy.3 Newer techniques, such as magnetization transfer (MT), diffusion-weighted, and functional MRI, as well as proton MR spectroscopy and measures of brain and spinal cord atrophy, may help further elucidate MS pathology2 and provide opportunities for new treatment approaches.4

MR imaging has provided important insights into the pathophysiology of multiple sclerosis.1 Conventional MR scans afford only gross estimates of the extent and nature of tissue damage associated with MS,2 however, and the data correlate poorly with measures of concurrent disability in patients. Advances in MRI technology have improved the correlation of its findings with clinical status and increased the utility of MRI data as surrogate markers in monitoring disease progression and response to therapy.3 Newer techniques, such as magnetization transfer (MT), diffusion-weighted, and functional MRI, as well as proton MR spectroscopy and measures of brain and spinal cord atrophy, may help further elucidate MS pathology2 and provide opportunities for new treatment approaches.4

MRI in the diagnosis of MS usually is recommended to confirm clinical findings and evaluate patients for other pathologies. Abnormalities seen with conventional MRI that are most often used to determine disease activity in patients with MS are hyperintense lesions visualized on T2-weighted images, hypointense lesions visualized on T1-weighted images, and gadolinium-enhanced hyperintense lesions visualized on postcontrast images (Table 1).2

T2-weighted images are used to assess edema and tissue destruction early in the inflammatory stage of MS. Later, when demyelination and gliosis occur,4 T2-weighted images are used most often to measure burden of disease, but they have limited sensitivity and specificity. There is generally a weak correlation between T2-weighted lesion load and concurrent clinical disability in patients with MS.9

Proton density-weighted scans are used to distinguish periventricular lesions from the cerebrospinal fluid.4,5 The fluid-attenuated inversion recovery sequence suppresses the T2 hyperintensity of fluid and starkly contrasts the ventricles from periventricular white matter lesions. FLAIR imaging also appears to make parenchymal hemisphere lesions stand out more prominently, and the ability to detect juxtacortical lesions is improved. Because of concerns regarding the presence of artifacts, FLAIR imaging is not as useful for evaluation of the spinal cord or posterior fossa. In these anatomic areas, proton density or spin-echo sequences are preferred.

On T1-weighted scans, hypointense lesions that do not persist may indicate a reversible change such as edema, whereas persistent lesions signify focal central nervous system damage such as axonal loss and demyelination. Persistent hypointense T1-weighted images correlate more closely with disability than do T2-weighted images and are known as "black holes." These persistent T1 lesions may be useful markers of disease progression, but their usefulness requires validation through further study.

Gadolinium enhancement is used to estimate inflammation-induced permeability changes of the blood-brain barrier. The ability to distinguish between active and inactive lesions makes gadolinium-enhanced lesions the most clinically relevant MRI measure for ongoing inflammatory activity in patients with MS.10-12

Table 2 summarizes the newer MRI techniques, and several studies detail the potential of magnetization transfer,15-19 diffusion-weighted and diffusion-tensor imaging,20-24 proton MR spectroscopy,25-30 functional MRI,31,32 and spinal cord imaging.33-35 Detailed discussion of these techniques is beyond the scope of this article.

MEASURE OF ATROPHY

A variety of MRI techniques can be used to measure whole-brain atrophy in MS patients.2,36 The brain parenchymal fraction (BPF) is defined as the ratio of brain parenchymal volume to the sum of brain and ventricular CSF volumes.37 Use of BPF has two inherent advantages: Normalization of the brain parenchymal volume to brain size reduces interindividual variation in brain size, and BPF has high test-retest reproducibility.37 A potential disadvantage is that BPF does not account for CSF volume external to the outer surface of the brain, which can increase with progressive brain atrophy or loss of gray matter volume.38

Structural image evaluation using normalization of atrophy (SIENA) has been used to analyze longitudinal (temporal) brain changes.39 It is fully automated and reliable and can be applied to data acquired with different pulse sequences.39 SIENA is a 3D method that should not be applied to 2D images, however.

Although it is not used frequently in routine assessment of MS patients, MR measurement of spinal cord atrophy is an emerging area of interest.40 Evidence suggests that brain and spinal cord atrophy observed in these patients may begin at disease onset (see figure).37 This possibility is supported by a longitudinal study showing increased brain ventricle size and decreased brain width in patients with MS.41 In a postmortem study of 70 randomly selected cases of MS, spinal cord involvement was evident in 99%.42 Atrophy suggests that the CNS responds to tissue destruction by shrinkage and reorganization, which is visible at the edges of the brain and spinal cord.43

A considerable loss of axonal density and volume, as well as of myelin, occurs in lesions associated with MS.43-45 Small atrophic changes in various brain structures can be quantified, and such regional atrophy can be correlated with disability,46 dementia,47 and lower-than-average scores on neuropsychological tests.48,49 As demonstrated in a controlled study of 60 patients with MS,50,51 a strong correlation appears to exist between the level of the Expanded Disability Status Scale (EDSS) score and brain stem and upper spinal cord atrophy (r = -0.7, p< 0.001).

Brain atrophy reflects ongoing pathology that begins early in MS52 and correlates with disability53 and cognitive dysfunction.54 MR technology has high sensitivity to visualize MS lesions, making it possible to determine that atrophy exists. MRI estimates of brain atrophy, however, can vary depending on the type of pulse sequence and segmentation algorithm used. Standardization of these techniques is warranted.55

CLINICAL ROLE

MR can play a role in MS care from diagnosis through treatment monitoring.

- Diagnosis of MS. Other disorders can cause white matter lesions with MR imaging characteristics similar to those of MS.1 Other cerebral abnormalities that cause hyperintense T2-weighted lesions, however, may be present at locations or have appearances that are not typical of MS. In vascular disease, for example, white matter lesions tend to be located more peripherally than MS lesions. Multifocal hyperintensities on T2-weighted images that are associated with aging tend to be smaller and more randomly located throughout deep and subcortical supratentorial white matter, while T2-hyperintense lesions found in MS are typically localized in the periventricular areas.4

Migraine and systemic lupus erythematosus also typically affect deep white matter more peripherally than does MS. Usually, infectious diseases such as human immunodeficiency virus and Lyme disease have associated clinical sequelae that distinguish them from MS.4 Interestingly, spinal cord lesions, though more difficult to detect than brain lesions, add a degree of specificity to MS diagnosis because T2-hyperintense spinal cord lesions do not occur with normal aging.56 The cranial MRI pattern of MS is relatively specific and corroborates clinical judgment when age is taken into consideration along with imaging abnormalities: lesion numbers, distribution, size, shape, associated volume changes, and contrast enhancement.4

- Evaluation of suspected MS. Obtaining an early MR scan for patients with suspected MS is now an accepted practice. In a longitudinal study of patients with an initial clinically isolated syndrome, early lesion development was found to have a significant influence on long-term disability. EDSS scores at the 14-year follow-up examination were found to correlate with T2 lesion volume at five years as well as with the increase in lesion volume over the first five years.57 This study and others that have investigated the prognostic value of MRI in patients with clinically isolated syndrome suggestive of MS58 are leading to a consensus that prompt diagnostic MR scans should be obtained to estimate the risk of future attacks in these patients.59

In patients with clinically isolated syndrome, several MRI markers are highly predictive of the future development of clinically definite MS.60 The appearance of three or more white matter lesions on a T2-weighted MR scan is a sensitive predictor ( > 80%) of the development of clinically definite MS within seven to 10 years. Also highly predictive of subsequent development of clinically definite MS are the appearance of two or more gadolinium-enhanced lesions at baseline and the presence of either new T2 lesions or new gadolinium-enhanced lesions three months or more after a clinically isolated demyelinating event. Conversely, patients with clinically isolated syndrome are less likely to develop clinically definite MS when their baseline MRI findings are normal.

Although a prognosis cannot be offered with certainty, the information provided by MRI in addition to clinical assessment permits a reasonably reliable early prognosis for some patients. The availability of disease-modifying therapies such as interferon-beta (IFNb) provides an opportunity to slow disease progression with early treatment. Data from the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS), for example, have shown that in patients with a first demyelinating event, initiation of treatment with IFNb-1a reduced the probability of developing clinically definite MS by as much as 44% (p = 0.002).61

- Established MS. To assess the degree of pathology associated with active MS, measurements of disease activity usually are obtained using conventional MRI methods such as gadolinium enhancement and T2-weighted lesion volume.7,62 The typical clinical measurements are relapse rate and disability, according to EDSS measurements. MRI and clinical assessment indirectly measure underlying MS pathology and provide fundamentally different information that can be divergent.4 For example, the frequency of gadolinium-enhanced lesions on MRI is much greater than the frequency of clinical relapse,63 which implies that the pathologic activity of MS is greater than what can be measured using clinical end points.2 The number and volume of T2-weighted lesions can be substantial, even in the absence of overt MS symptoms. In addition, there appears to be little difference in the number and dynamics of T2-weighted lesions in patients with clinically isolated syndrome compared with those who have early relapsing-remitting MS (RRMS).4 It is known that atrophy increases temporally during MS progression, but the rates of brain and spinal cord atrophy at different disease stages are not necessarily consistent with one another.45 Ultimately, further longitudinal study of representative patient populations is needed to clarify the evolution of brain and spinal cord atrophy.2

- MS treatment monitoring. Available data demonstrate that disease-modifying therapies such as corticosteroids, IFNb, and glatiramer acetate reduce the frequency of gadolinium-enhanced lesions and the rate of T2-lesion volume accumulation, both surrogate markers for CNS inflammatory activity in MS.4 Intravenous methylprednisolone (IVMP) produces the temporary effect of reducing gadolinium-enhanced lesions and slowing atrophy and lesion volume accumulation.64 The efficacy of IVMP was assessed in a retrospective analysis of an open-label crossover trial of IFNb-1b involving 26 patients with RRMS who were selected based on review of an MRI database. They received IVMP 1 g/day for three to five days (without taper to oral corticosteroids) following an acute exacerbation.65 Serial monthly MRIs were performed in the 26 patients during treatment with IFNb-1b (study period: six to 36 months); 12 also were evaluated at the baseline stage (duration: seven to 48 months) of the open-label trial (i.e., the natural history group). At three months after IVMP treatment, the number of gadolinium-enhanced lesions observed was significantly reduced in both the IFNb-1b and natural history groups.65

MR studies are used to assess the efficacy of other disease-modifying therapies in MS as well. In a randomized, placebo-controlled trial involving 341 patients with RRMS, MR data from proton density or T2-weighted images were collected annually for up to five years.66 Patients received either IFNb-1b, 1.6 million IU; IFNb-1b, 8 million IU; or placebo subcutaneously every other day for three to five years. At five-year follow-up, both IFNb-1b dosages resulted in a reduction in the annual lesion accumulation activity index relative to placebo (p = 0.001). In a large phase III randomized trial, intramuscular IFNb-1a, 30 microg once weekly, significantly decreased the number of new and enlarging gadolinium-enhanced brain lesions shown on annual MR examinations conducted over two years (pPound Sterling 0.024).67 A randomized double-blind placebo-controlled MR study indicated that patients with RRMS treated with glatiramer acetate had 29% fewer total gadolinium-enhanced lesions over nine months.68 The number and volume of T2-weighted lesions decreased significantly, and the relapse rate was reduced in the glatiramer acetate-treated group (p = 0.012), which paralleled the decrease in gadolinium-enhancement frequency.

The increasing use of MRI, both as a diagnostic tool in patients with clinically isolated syndrome and in evaluation of treatment outcome in clinical trials, warrants standardization of MR measures used in MS. The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology has published a report on the utility of MRI in suspected MS. In addition to recommendations on the use of MRI in the diagnosis of clinically definite MS, the report proposes that MR techniques and scans be standardized.60

FUTURE ROLE

The increasing availability of MR technology and the pharmacoeconomics of MS therapies may support the routine use of MRI to determine therapeutic efficacy or establish treatment failure. Best practices for currently available MRI technology will necessitate a high-quality, consistent scanning protocol.

MRI techniques such as measures of atrophy and MRS imaging to assess axonal integrity may provide supplementary data for future treatment decisions. Available data indicate that patients receiving disease-modifying agents who do not demonstrate a reduction in gadolinium enhancement on frequent, serially acquired MR scans may not be responding to therapy.69 Newer MRI measurements may better reflect focal inflammatory activity and pathologic MS evolution than does clinical relapse rate or EDSS. MRI is more sensitive, more objective, and more precise than clinical assessment in determining MS disease activity. The availability of MRI outcome measurements may allow for clinical trials that are shorter and require enrollment of fewer patients than trials based on clinical outcome measurements.4

Dr. Hutton is an assistant professor of neurology at Baylor College of Medicine and assistant medical director at Maxine Mesinger MS Clinic of Baylor and the Methodist Hospital in Houston. Dr. Miller, now retired, was an associate professor of neurology at Columbia University. Dr. Radue is a professor of neuroradiology at the Universitatsinstitut fur Diagnostische Radiologie in Basel, Switzerland. Dr. Hutton has received grants/research support from Ilex Medical, Teva, Genentech, Biogen Idec, Elan, and Berlex. He is a consultant to Teva, Biogen Idec, and Serono, and has received honoraria from Biogen Idec, Berlex, Serono and Pfizer. He is a member of the speakers' bureau for Biogen Idec and Pfizer. Dr. Miller has received honoraria from Biogen and is a member of the speakers' bureau for Biogen and Berlex.

References

1. Zivadinov R, Bakshi R. Role of MRI in multiple sclerosis I: inflammation and lesions. Front Biosci 2004;9:665-683.

2. Filippi M, Rocca MA, Comi G. The use of quantitative magnetic-resonance-based techniques to monitor the evolution of multiple sclerosis. Lancet Neurol 2003;2:1-27.

3. Zivadinov R, Bakshi R. Role of MRI in multiple sclerosis II: brain and spinal cord atrophy. Front Biosci 2004;9:647-664.

4. Arnold DL, Matthews PM. MRI in the diagnosis and management of multiple sclerosis. Neurology 2002;58:1-24.

5. Barkhof F, van Walderveen M. Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance. Philos Trans R Soc Lond B Biol Sci 1999;354:1675-1686.

6. McDonald WI, Miller DH, Barnes D. The pathological evolution of multiple sclerosis. Neuropathol Appl Neurobiol 1992;18:319-334.

7. Stevenson VL, Miller DH. Magnetic resonance imaging in the monitoring of disease progression in multiple sclerosis. Mult Scler 1999;5:268-272.

8. Miller DH, Barkhof F, Nauta JJ. Gadolinium enhancement increases the sensitivity of MRI in detecting disease activity in multiple sclerosis. Brain 1993;116:1077-1094.

9. Barkhof F. MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS). Mult Scler 1999;5:283-286.

10. Smith SM, Stone LA, Albert PS, et al. Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentetate dimeglumine-enhancing magnetic resonance imaging lesions. Ann Neurol 1993;33:480-489.

11. Khoury SJ, Guttmann CRG, Orav EJ, et al. Longitudinal MRI in multiple sclerosis: correlation between disability and lesion burden. Neurology 1994;44:2120-2124.

12. Kappos L, Moeri D, Radue EW, et al. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta analysis. Lancet 1999;353:964-969.

13. Simon JH. Brain and spinal cord atrophy in multiple sclerosis. Role as a surrogate measure of disease progression. CNS Drugs 2001;15:427-436.

14. Miller DH, Barkhof F, Frank JA, et al. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002;125:1676-1695.

15. Lai HM, Davie CA, Gass A, et al. Serial magnetisation transfer ratios in gadolinium-enhancing lesions in multiple sclerosis. J Neurol 1997;244:308-311.

16. Filippi M, Rocca MA, Comi G. Magnetization transfer ratios of multiple sclerosis lesions with variable durations of enhancement. J Neurol Sci 1998;159:162-165.

17. Filippi M, Rocca MA, Martino G, et al. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 1998;43:809-814.

18. Van Waesberghe JHTM, Kamphorst W, De Groot CJA, et al. Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 1999;46:747-754.

19. Pike GB, De Stefano N, Narayanan S, et al. Multiple sclerosis: Magnetization transfer MR imaging of white matter before lesion appearance on T2-weighted images. Radiology 2000;215:824-830.

20. Filippi M, Inglese M. Overview of diffusion-weighted magnetic resonance studies of multiple sclerosis. J Neurol Sci 2001;186:S37-S43.

21. Chenevert TL, Brunberg, Pipe JG. Anisotropic diffusion in human white matter: demonstration with MR techniques in vivo. Radiology 1990;177:401-405.

22. Nusbaum AO, Tang CY, Wei T-C, et al. Whole-brain diffusion MR histograms differ between MS subtypes. Neurology 2000;54:1421-1426.

23. Rovaris M, Bozzali M, Iannucci G, et al. Assessment of normal-appearing white and gray matter in patients with primary progressive multiple sclerosis. A diffusion-tensor magnetic resonance imaging study. Arch Neurol 2002;59:1406-1412.

24. Bruck W, Bitsch A, Kolenda H, et al. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 1997;42:783-793.

25. De Stefano N, Narayanan S, Mortilla M, et al. Imaging axonal damage in multiple sclerosis by means of MR spectroscopy. Neurol Sci 2000;21:S883-S887.

26. Wolinsky JS, Narayana PA, Fenstermacher MJ. Proton magnetic resonance spectroscopy in multiple sclerosis. Neurology 1990;40:1764-1769.

27. De Stefano N, Mathews PM, Antel JP, et al. Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol 1995;38:901-909.

28. De Stefano N, Mathews PM, Fu L, et al. Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 1998;121:1469-1477.

29. Narayana PA, Doyle TJ, Lai D, Wolinsky JS. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998;43:56-71.

30. Suhy J, Rooney WD, Goodkin DE, et al. 1H MRSI comparison of white matter and lesions in primary progressive and relapsing-remitting MS. Mult Scler 2000;6:148-155.

31. Ogawa S, Menon RS, Tank DW, et al. Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model. Biophys J 1993;64:803-812.

32. Mainero C, Caramia F, Pozzilli C, et al. fMRI evidence of brain reorganization during attention and memory tasks in multiple sclerosis. Neuroimage 2004;21:858-867.

33. Taber KH, Herrick RC, Weathers SW, Kumar AJ, Schomer DF, Hayman LA. Pitfalls and artifacts encountered in clinical MR imaging of the spine. Radiographics 1998;18:1499-1521.

34. Grossman RI, Barkhof F, Filippi M. Assessment of spinal cord damage in MS using MRI. J Neurol Sci 2000;172(Suppl 1):S36-S39.

35. Thorpe JW, Kidd D, Moseley IF, et al. Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI. Brain 1996;119:709-714.

36. Pelletier D, Garrison K, Henry R. Measurement of whole-brain atrophy in multiple sclerosis. J Neuroimaging 2004;14(3 suppl):11-19.

37. Rudick RA, Fisher E, Lee J-C, et al. Use of brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 1999;53:1698-1704.

38. De Stefano N, Matthews PM, Filippi M, et al. Evidence of early cortical atrophy in MS. Relevance to white matter changes and disability. Neurology 2003;60:1157-1162.

39. Smith SM, De Stefano N, Jenkinson M, Matthews PM. Normalized accurate measurement of longitudinal brain change. JCAT 2001;25:466-475.

40. Lin X, Tench CR, Evangelou N, et al. Measurement of spinal cord atrophy in multiple sclerosis. J Neuroimaging 2004;14(3 suppl):20-26.

41. Simon JH, Jacobs LD, Campion MK, et al. A longitudinal study of brain atrophy in relapsing multiple sclerosis. Neurology 1999;53:139-148.

42. Ikuta F, Zimmerman HM. Distribution of plaques in seventy autopsy cases of multiple sclerosis in the United States. Neurology 1976;26:26-28.

43. Losseff NA, Miller DH. Measures of brain and spinal cord atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 1998;64 (suppl 1):S102-S105.

44. Evangelou N, Esiri MM, Smith S, et al. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 2000;47:391-395.

45. Liu C, Edwards S, Gong Q, et al. Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 1999;66:323-330.

46. Dietemann JL, Beigelman C, Rumbach L, et al. Multiple sclerosis and corpus callosum atrophy: relationship of MRI findings to clinical data. Neuroradiology 1988;30:478-480.

47. Huber SJ, Paulson GW, Shuttleworth EC, et al. Magnetic resonance imaging correlates of dementia in multiple sclerosis. Arch Neurol 1987;44:732-736.

48. Clark CM, James G, Li D, et al. Ventricular size, cognitive function and depression in patients with multiple sclerosis. Can J Neurol Sci 1992;19:352-356.

49. Comi G, Filippi M, Martinelli V, et al. Brain magnetic resonance imaging correlates of cognitive impairment in multiple sclerosis. J Neurol Sci 1993;115(suppl):S66-S73.

50. Losseff NA, Webb SL, O'Riordan JI, et al. Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 1996;119:701-708.

51. Stevenson VL, Leary SM, Losseff NA, et al. Spinal cord atrophy and disability in MS: a longitudinal study. Neurology 1998;51:234-238.

52. Brex PA, Jenkins R, Fox NC, et al. Detection of ventricular enlargement in patients at the earliest clinical stage of MS. Neurology 2000;54:1689-1691.

53. Collins DL, Narayanan S, Caramanos Z, et al. Relation of cerebral atrophy in multiple sclerosis to severity of disease and axonal injury [abstract]. Neurology 2000;54(suppl 3):A17. Abstract SO8.003.

54. Zivadinov R, De Masi R, Nasuelli D, et al. MRI techniques and cognitive impairment in the early phase of relapsing-remitting multiple sclerosis. Neuroradiology 2001;43:272-278.

55. Leigh R, Ostuni J, Pham D, et al. Estimating cerebral atrophy in multiple sclerosis patients from various MR pulse sequences. Mult Scler 2002;8:420-429.

56. Hickman SJ, Miller DH. Imaging of the spine in multiple sclerosis. Neuroimag Clin North Am 2000;10:689-704.

57. Brex PA, Ciccarelli O, O'Riordan JI, Sailer M, Thompson AJ, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. NEJM 2002;346:158-164.

58. Morrissey SP, Miller DH, Kendall BE, et al. The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Brain 1993;116:135-146.

59. 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;50:121-127.

60. Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in suspected MS. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003;61:602-611.

62. O'Riordan JI, Thompson AJ, Kingsley DPE, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain 1998;121:495-503.

63. Kalkers NF, Bergers L, de Groot V, et al. Concurrent validity of the MS Functional Composite using MRI as a biological disease marker. Neurology 2001;56:215-219.

64. Barkhof F, Hommes OR, Scheltens P, Valk J. Quantitative MRI changes in gadolinium-DTPA enhancement after high-dose intravenous methylprednisolone in multiple sclerosis. Neurology 1991;41:1219-1222.

65. Rao AB, Richert N, Howard T, et al. Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFNb-1b. Neurology 2002;59:688-694.

66. Zhao GJ, Koopmans RA, Li DKB, et al. Effect of interferon b-1b in MS. Neurology 2000;54:200-206.

67. Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of intramuscular interferon b-1a for relapsing multiple sclerosis. Ann Neurol 1998;43:79-87.

68. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001;49:290-297.

69. Frank JA, Stone LA, Smith ME, et al. Serial contrast-enhanced magnetic resonance imaging in patients with early relapsing-remitting multiple sclerosis: implications for treatment trials. Ann Neurol 1994;36(suppl):S86-S90.