The Value of Brain Magnetic Resonance in Multiple Sclerosis of the ARCHIVES, Capra In thisal1 issue report the results of biweekly (MRI)
nonspecific, however, so that in diag¬ nosing MS, MRI must be used in the
in the brain stem or cerebellum, and 3% were in the cervical spinal cord. Seventy percent of the lesions occurred in T2-weighted hyperintense areas already found in previous examinations. Excluding each patient's
many MRI lesions in this disease? It is clear that most of the brain lesions are unaccompanied by evident clinical changes. For example, Jacobs et al5 reported that only 5% of MRI lesions in patients with MS could be clearly related to clinical symptoms and that 75% of lesions were "clinically silent." As in the report by Capra et al,1 the symptomatic lesions were observed more commonly in the brain stem or cerebellum. Kiel et al6 reported that the correlation between the number of brain lesions and the amount of functional disability defined by the Incapacity Status Scale was not sig¬ nificant, and Uhlenbrock et al7 were similarly unable to find a correlation between lesion number and Kurtzke Disability Status Scale. However, the apparent correlation between MRI lesion load and impairment severity is heavily dependent on the way im¬ pairment is measured and how it is correlated with the MRI images. Some investigators have found a cor¬ relation between the Expanded Dis¬ ability Status Scale (EDSS) score8 and the extent of MRI abnormalities.9,10 The EDSS may be even more closely related to the amount of brain-stem and cerebellar involvement seen with MRI,11 which is not surprising since the EDSS closely reflects motor func¬ tion. Forebrain lesion load, however, is more closely related to measures of cognitive and memory impairment12 than to motor impairment. Further
in context of a careful clinical evaluation magnetic resonance imaging 10 patients with relapsing-remitting by a physician skilled in the diagno¬ multiple sclerosis (MS). A total of sis of the disease. Injudicious use of 93 gadolinium-pentetic acid (Gd- MRI scanning or overinterpretation DTPA)-enhancing lesions were ob- of MRI scans constitutes the leading served in eight patients studied dur- cause of an inaccurate diagnosis of ing a 3-month period. Of the MS at the present time. Beyond its value as a diagnostic enhancing lesions, 88% were in the what is the significance of the 9% were white test, matter, supratentorial
first and last scan, 64 newly enhancing lesions were observed. In 50% of the newly enhancing lesions, Gd enhancement was no longer evident on the subsequent scan, suggesting that the duration of enhancement was 4 weeks or less. Seven clinical relapses occurred in six patients, all with concurrent Gd enhancement. Gadolinium-enhancing lesions were noted in 18 MRI examinations without clinical exacerbations. One can conclude from this report that Gd-enhancing lesions frequently occur without clin¬ ical symptoms, are common in areas of previously identified T2-weighted signal changes, and generally persist for only a few weeks. What is the po¬ tential clinical significance of this? The value of cranial MRI in docu¬ menting disseminated white matter lesions for the purpose of diagnosing MS is well established,2"4 since
periventricular high signal changes are observed in T2-weighted images in a high frequency of patients with
MS. The appearance of lesions is
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evidence for the biologic significance of MRI changes is provided by the observation that the extent of lesion load, like disability status, increases with disease duration,713 although this observation has not been con¬ firmed by all investigators.10 A number of prospective studies of serial brain MRI scans have suggested that new lesions appear with a much higher frequency than do clinical exacerbations. Isaac et al14 studied seven patients with rel¬ apsing-remitting MS with monthly MRI scans during a 6-month period. Eighteen new and 10 enlarging MRI lesions were observed in five pa¬ tients, while only five clinical relapses were observed in three patients. Willoughby et al15 performed brain MRI biweekly for 4 to 6 months in nine patients with relapsingremitting MS. Six of the nine pa¬ tients had development of 12 asymp¬ tomatic new lesions unaccompanied by clinical exacerbations. Serial imaging of patients with a progres¬ sive course16 showed a significantly higher rate of new lesion accrual than did patients classified clinically as having exacerbating remitting dis¬ ease, suggesting that the rate of ap¬ pearance of new lesions correlates with the clinical pattern and severity of disease. The presence of lesion enhance¬ ment following administration of gadolinium-pentetic acid / dimeglumine (gadolinium) is thought to rep¬ resent "active" MS plaques.13,17 Harris et al18 followed six patients with relapsing-remitting MS with month¬ ly Gd-enhanced MRI scans over a course of 8 to 11 months. While only two patients experienced clinical ex¬ acerbations during the study, numer¬ ous enhancing lesions were present in each case. The average number of Gd-enhancing lesions per scan
ranged from 0.7 to 6.2. Neither the frequency of clinical exacerbation nor the change in disability during the study correlated with the frequency of Gd-enhancing lesion accrual, al¬ though the duration of follow-up was short to observe clinical deterio¬ ration. What then are the critical questions to be addressed in future studies of the role of brain MRI in MS? (1) What is the predictive value of brain MRI when a patient first presents to the physician with neurologic symp¬ toms? Early studies19,20 suggest that disseminated lesions on brain MRI scans predict subsequent clinical dis¬ semination in patients with monotoo
symptomatic presentations such as optic neuritis or transverse myelitis.
A study sponsored by the National Institutes of Health is ongoing to de¬ termine the predictive value of MRI at the time of first MS symptoms (R.
Grossman, MD, oral communication, October 1991). (2) Does the rate of new or enhancing lesion accrual pre¬ dict the subsequent rate of clinical deterioration? The studies by Harris et al18 and Capra et al1 could poten¬ tially answer this question by careful follow-up of the patients to determine the extent of clinical disease progres¬ sion. (3) What are the optimal tech¬ niques for quantifying lesion burden in MS? Should we be counting le¬ sions? Should we be counting Gdenhancing lesions? Should we be measuring plaque volume? (4) What is the optimal frequency for serial MRI scans in patients with MS? Should the practicing clinician re¬ quest a follow-up MRI study to fol¬ low disease progression and guide therapy? Currently, a study spon¬ sored by the National Institute of Neurological Disorders and Stroke is investigating these questions by fol¬ lowing up 45 patients with frequent Gd-enhanced MRI studies as well as clinical and immunologie assessment (H. Weiner, MD, oral communica¬ tion, October 1991). (5) Can we test putative therapies in MS by directing
reduction in the rate of newly enhancing lesion ac¬ crual? Three studies are funded by the National Multiple Sclerosis Society looking at this question (D. E. Good¬ kin, MD, A. Rostami, MD, and J. Co¬ hen, MD, oral communications, De¬ cember 1991). (6) Can we discern the histopathologic features from proton MRI or with spectroscopy? Can we tell active from inactive lesions? Can we define the imaging features of remyelination? Studies to date suggest that similar appearances derived from T2weighted spin echo sequences are ob¬ served in tissue with different patho¬ treatment at
logic features.21 However, newer techniques may allow pathologic clas¬
sification of lesions in vivo. The article by Capra et al1 lends additional support to the view that pathologic events in MS are more fre¬ quent and widespread than is evident by clinical symptoms and signs. One has the feeling that we are just getting an inkling of the potential value of MRI in diagnosis and treatment of patients with MS. Richard A. Rudick, MD Cleveland, Ohio
to Dr Ru¬
dick, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH 44195-5244.
6. Kiel MK, Greenspun B, Grossman RI. Magnetic resonance imaging and degree of disability in multiple sclerosis. Arch Phys Med Rehabil.
1988;69:11-13. 7. Uhlenbrock D, Seidel D, Gehlen W, et al. imaging in multiple sclerosis: comparison with clinical, CSF, and visual evoked potential findings. Am J Neuroradiol. 1988;9:59-67. 8. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452. 9. Stevens JC, Farlow MR, Edwards MK, Yu P. Magnetic resonance imaging: clinical correlation in 64 patients with multiple sclerosis. Arch Neurol. 1986;43:1145-1148. 10. Huber SJ, Paulson GW, Chakeres D, et al. Magnetic resonance imaging and clinical correlations in multiple sclerosis. J Neurol Sci. 1988;86: MR
1-12. 11. Baumhefner
RW, Tourtellotte WW, Synal. Quantitative multiple sclerosis plaque assessment with magnetic resonance imaging: its correlation with clinical parameters, evoked potentials, and intra-blood-brain barrier IgG synthesis. Arch Neurol. 1990;47:19-26. 12. Rao SM, Leo GJ, Haughton VM, St. Aubin\x=req-\ Faubert P, Bernardin L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis. Neurology. 1989;39:161-166. 13. Steward JM, Houser OW, Baker HC, O'Brien PC, Rodriquez M. Magnetic resonance imaging and clinical relationships in multiple sclerosis. Mayo Clin Proc. 1987;62:174-184. 14. Isaac C, Li DKB, Genton M, et al. Multiple sclerosis: a serial study using MRI in relapsing patients. Neurology. 1988;38:1511-1515. 15. Willoughby EW, Grochowski E, Li DKB, Oger J, Kastrukoff LF, Paty DW. Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol. 1989;25:43-49. dulko K,
Li DKB, Oger JTF, et al. multiple sclerosis: serial brain imaging over six
Capra R, Marciano N, Vignolo LA, Chiesa A, Gasparotti R. Gadolinium-DTPA MRI in relapsing remitting multiple sclerosis patients. Arch Neurol.
months. Ann Neurol. 1989;26:248-256. 17. Gonzalez-Scarano F, Grossman RI, Galetta S, Atlas SW, Silberberg DH. Multiple sclerosis disease activity correlates with gadoliniumenhanced magnetic resonance imaging. Ann Neurol. 1987;21:300-306. 18. Harris JO, Frank JA, Patronas N, McFarlin DE, McFarland HF. Serial gadolinium-enhanced
1992;49:686-687. 2. Paty DW, Asbury AK, Herndon RM, et al. Use of magnetic resonance imaging in the diag-
multiple sclerosis: policy statement. Neurology. 1986;36:1575. 3. Lee KH, Hashimoto SA, Hooge JP, et al.
imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology. 1991;41:657-660. 4. Paty DW, Oger JJF, Kastrukoff LF, et al. MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology. Magnetic
5. Jacobs L, Kinkel WR, Polachini I, Kinkel RP. Correlations of nuclear magnetic resonance imaging, computerized tomography, and clinical profiles in multiple sclerosis. Neurology. 1986; 36:27-34.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/14/2015
resonance imaging scans in patients early, relapsing-remitting multiple sclerosis: implications for clinical trials and natural history.
Ann Neurol. 1991;29:548-555. 19. Kappos L, Gold R, Stadt D, Heun R, Keil W, Radu EW. MS: definite diagnosis at first presentation? the role of Gd-enhanced MRI. Neurology.
KH, Hashimoto SA, Hooge JP, et al. imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology. 1991;41:657-660. 21. NewsombeJ, Hawkins CP, Henderson CL, 20. Lee
al. Histopathology of multiple sclerosis lesions detected by magnetic resonance imaging in unfixed postmortem central nervous system tissue. et