Serial gadolinium-enhanced MRI of the brain and spinal cord in early relapsing-remitting multiple sclerosis
Citation Manager Formats
Make Comment
See Comments

Abstract
Although serial MRI studies of the brain in relapsing-remitting MS have demonstrated frequent asymptomatic disease activity, less is known about the spinal cord. We carried out monthly gadolinium-enhanced brain and spinal cord MRI scans over 1 year in 10 patients with relapsing-remitting MS. Six of the patients had a total of 11 clinical relapses, eight of which involved the spinal cord. A total of 167 active (enhancing or new nonenhancing) lesions in the brain and 19 in the spinal cord were present. Only one active brain lesion was symptomatic compared with six spinal cord lesions. Overall, one-third of new spinal cord lesions were symptomatic, and three-quarters of clinical spinal cord relapses were associated with a new MRI lesion in a location appropriate to the symptoms. Activity in both the spinal cord and brain was more common around the time of relapse. There was a strong association between the spinal cord and brain MRI activity. We did not detect progressive spinal cord atrophy from measurements of a spinal cord cross-sectional area. We conclude that, in relapsing-remitting MS, imaging of the brain alone will detect 90% of active lesions; spinal cord MRI using current technology will therefore provide only modest gains in treatment trials in which lesion activity is the primary outcome measure. The lack of progressive spinal cord atrophy in these patients, suggesting that significant axonal loss has not occurred, is in keeping with their good recovery after relapse. That brain and spinal cord lesions occur concurrently implies a systemic trigger for disease activity.
NEUROLOGY 1996;46: 373-378.
Serial MRI studies of the brain have greatly enhanced our understanding of the natural history and pathophysiology of MS. Studies using either serial T2-weighted [1-3] or T1-weighted images after the administration of gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) [4-10] have demonstrated that the disease is often active even in the absence of clinical change; in patients with relapsing-remitting and secondary progressive MS, disease activity is found on MRI up to 10 times as frequently as clinical relapse. [1,8-11] Brain MRI has gained acceptance as a useful marker of disease activity in the context of clinical trials. [12-16] However, much of the symptomatology of MS implicates the spinal cord, a site not studied by MRI in comparable detail. Although previous studies have shown that it is possible to detect MS lesions within the spinal cord using MRI, [17-22] especially using multiarray receiver coils and fast spin echo (FSE) pulse sequences, [23] there are few published serial data. Weibe et al [24] studied 29 patients over 6 months, but only scanned them three times a month or during a clinical relapse. Capra et al [9] imaged 10 patients every 2 weeks for 3 months.
We carried out monthly Gd-DTPA-enhanced brain and spinal cord MRI scans over 1 year in 10 patients with relapsing-remitting MS to establish how frequently new spinal cord lesions appear and how often they are symptomatic; the frequency and duration of Gd-DTPA enhancement; and the relationship between spinal cord disease and brain disease. From this natural history data, we hope to establish the role (if any) of serial spinal cord imaging in treatment trials. We previously reported a parallel study of progressive MS [25].
Methods.
We studied 10 women, aged 22 to 45 years, with clinically definite or laboratory-supported definite MS, according to Poser et al.'s criteria. [26] Ethical approval was obtained for the study and all patients gave their written informed consent to participate.
At the outset of the study, a detailed history was obtained and a full neurologic examination was carried out. Disability was rated according to Kurtzke's functional system and expanded disability status scale (EDSS). [27] MRI and clinical examination were then performed monthly over 1 year. At each visit any new symptoms or signs were elicited and the Kurtzke scores were reassessed by a single observer (J.T.), who was blinded to the MRI results. A relapse was defined as the occurrence of a symptom of neurologic dysfunction lasting more than 24 hours. [26] Remission was defined as an improvement in signs or symptoms, or both, lasting for at least 1 month.
All imaging was performed on a 1.5-tesla Signa system (IGE Medical Systems, Milwaukee, WI). Brain MRI was carried out using a standard quadrature head coil. Pilot scans were obtained in axial, coronal, and sagittal planes to ensure adequate repositioning. Axial dual echo (proton density and T2-weighted) fast spin echo (FSE3500/18,90, echo train length of 8), and, 5 minutes after the administration of Gd-DTPA (Magnevist 0.1 mmol/kg, Schering), T1-weighted spin echo (SE575/19) images were obtained For all cranial images, contiguous interleaved 4-mm slices, one excitation, and a 192 times 256 matrix with 24-cm field of view (FOV) were used. Spinal imaging using a spinal multiarray receiver coil, was carried out immediately after brain MRI Sagittal T1-weighted spin echo images (SE500/19, 4-mm contiguous interleaved slices, 256 times 512 matrix, 24 times 48-cm rectangular FOV, two excitations) were first obtained, approximately 10 to 15 minutes after Gd-DTPA injection. Then, two sets of sagittal FSE images with different degrees of T2 weighting were obtained, the parameters used were FSE2500/51 and FSE2500/102, echo train length of 16, 3-mm contiguous interleaved slices, 512 times 512 matrix, 48 times 48-cm FOV, two excitations. On the first and last visits only, axial proton density-weighted gradient echo images (GE300/15, flip angle of 15 degrees, 5-mm slice thickness, 256 times 256 matrix, 20-cm FOV, four excitations) at four vertebral levels (C5, T2, T7, T11) were obtained for measurement of spinal cord atrophy Total examination time was approximately 1 hour.
At the end of the study one neuroradiologist (I.M.) reviewed all the brain images sequentially and another (B.K.) reviewed the spinal cord studies. Both were blinded to the clinical history. Lesions were counted on the initial T2-weighted FSE images and a weighted lesion load was calculated by scoring lesions according to size: Table 3 Enhancement of lesions was recorded on all the T1-weighted images; on the follow-up images it was noted whether enhancement was new or persisting from a preceding imaging study. The T2-weighted images were scrutinized for any lesions that had appeared without showing enhancement on the T1-weighted images, as well as for any lesions that had changed in size or disappeared. For the purpose of analysis, an active lesion was defined as one showing gadolinium enhancement on a T1-weighted image or one that had newly appeared or enlarged on a T2-weighted image in the absence of gadolinium enhancement. A set of images was considered active if it contained active lesions.
Table 3.
Measurements of spinal cord area from the gradient echo images were made manually, as previously described [23] on a Sun Workstation using image analysis soft-ware (D L Plummer, Department of Medical Physics, University College, London) Each set of images was measured twice by a single observer (J.T.) who could not tell to which patient they belonged nor whether they were from the beginning or end of the study.
Statistical comparisons were carried out using the chisquare test (chi (2)) with Yates' correction or, for small numbers (expected values less than 5), Fisher's exact test. Comparisons of medians were performed using the Mann-Whitney U test. Spearman's rank correlation was used to assess correlation between nonparamentric data.
Results.
Clinical.
Disease duration (measured from the time of the first clinical episode) ranged from 15 months to 5 years (mean, 3 yr); the age at presentation was between 16 and 43 years (mean, 26 yr). Six patients initially presented with optic neuritis, two with partial myelitis, and two with episodes suggestive of brainstem pathology. During the study there were 11 clinical relapses in six patients. Eight of these implicated the spinal cord (sensory and/or motor disturbance in the limbs in six, new Lhermitte's sign and urinary disturbance in one each), one the brainstem (vertigo and vomiting), and two the optic nerves (optic neuritis). One patient received intravenous methylprednisolone (500 mg for 3 days) during a disabling sensory relapse. Three patients showed no clinical change during the study period. One patient, although showing no unequivocal change on neurologic examination, complained of increasing limitation of walking distance over the latter months of the study, suggesting that she might have been entering the progressive phase. Her EDSS changed from 4 to 5 over the course of the year. Overall, there was no difference between EDSS at the beginning of the study (median, 2.5; range, 1 to 4) and at the end (median, 2.25; range, 0 to 5).
Baseline MRI.
On the baseline T2-weighted images, 443 lesions were identified within the brain and 42 within the spinal cord (19 cervical and 23 thoracic). Baseline brain and spinal cord lesion load varied from 3 to 246 (median, 43) and 4 to 25 (median, 9), respectively. There was a tendency for those with the higher brain lesion load also to have higher spinal cord lesion load, but this did not reach statistical significance (r equals .535, p more than .1, Spearman's rank correlation). Three patients showed a total of 14 enhancing lesions in the brain, one of whom also had a single enhancing lesion in the thoracic cord.
Follow-up MRI.
One hundred eighteen follow-up examinations were carried out. Two patients showed no change in either brain or spinal cord MRI over the 1-year period. In the remaining eight patients, there were 144 new contrast-enhancing brain lesions (81 small, 28 medium, and 9 large) and nine new nonenhancing (5 small, 3 medium, and 1 large). Eleven new enhancing spinal cord lesions (7 small, 2 medium, and 2 large) were found (8 cervical and 3 thoracic), including two within a preexisting T2 lesion, as well as seven new nonenhancing lesions (5 small and 2 medium), all within the thoracic spinal cord. None of the spinal cord lesions showed contrast enhancement on more than one monthly scan, whereas 23 brain lesions (9 small, 11 medium, and 2 large) showed enhancement on two consecutive examinations and four lesions (2 medium and 2 large) on three examinations. Although lesions that had enhanced were often smaller on subsequent T2-weighted scans, no brain lesions completely disappeared. Four spinal cord lesions (1 small enhancing, 2 small, and 1 medium nonenhancing) became invisible on follow-up. No lesions became enlarged in the absence of contrast enhancement.
Overall, activity (new or persisting gadolinium enhancement or new or enlarging nonenhancing lesions) was more common on brain than spinal cord imaging: 57 of 128 of brain studies were active, compared with 15 of 128 spinal studies (chi (2) equals 32.48, p less than .001), contrast enhancement was found on 56 of 128 brain scans and 10 of 128 spinal cord scans. There was a clear relationship between the presence of activity in the brain and the spinal cord Figure 1. On the 113 occasions where there was no spinal cord activity, there was no brain activity on 69. Conversely, of the 15 occasions upon which there was spinal cord activity, brain activity was found on all but two scans. The difference was highly significant (chi (2) equals 10.36, p less than .002), and remained significant even when the data from the two patients who showed no activity were excluded (chi2 equals 5.57, p less than.02).
Figure 1. Concordance of brain and spinal cord activity in a 27-year-old woman with a recent sensory relapse with deafferentation of the left hand. (A) T2-weighted fast spin echo (FSE2500/102) of the spinal cord. There is a large lesion between C2 and C4. (B) Gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA)-enhanced T1-weighted spin echo (SE500/19) of the spinal cord. The lesion in the upper cervical cord shows patchy enhancement. (C) Gd-DTPA-enhanced T1-weighted spin echo (SE575/19) of the brain. There are several enhancing lesions.
Clinical versus MRI.
Of the 167 contrast-enhancing or new nonenhancing lesions in the brain identified during the course of the study, we were able to tentatively associate only one with detected symptoms--a contrast-enhancing lesion in the cerebellar peduncle 2 weeks after the patient had experienced 10 days of vertigo and vomiting. Conversely, of the 19 contrast-enhancing or new nonenhancing spinal cord lesions, at least six (4 cervical and 2 thoracic), five of which were contrast-enhancing, were probably symptomatic. This difference was highly significant (p less than .0001, Fisher's exact test).
New lesions in both spinal cord and brain was more common around the time of a relapse. In the six patients who relapsed, 27 follow-up imaging studies were carried out within 1 month before or after a relapse and 44 studies were carried out 2 months or more after a relapse. Significantly more new enhancing and nonenhancing lesions in the brain or the spinal cord, or in both, were found around the time of relapse Table 1. Including baseline examinations, 23 of 28 brain studies done around a relapse were active compared to 28 of 49 in remission; 11 of 28 spinal cord scans during relapse were active compared to 4 of 49 during remission. These differences were significant for both brain (chi2 equals 3.92, p less than .05) and spinal cord imaging (chi2 equals 9.11, p less than. 005). In the remaining four patients who did not relapse, only 6 of 51 brain and 0 of 51 spinal cord scans were active.
Table 1. Relationship between relapse and new brain and spinal cord lesions on follow-up studies in the six patients who relapsed
Spinal cord cross-sectional area.
Intraobserver limits of agreement [28] were from minus 6.7 mm2 to 7.6 mm2 (minus 11.6 to 12.9%); the mean intraobserver error was 4.8%. No data were available for one patient at presentation. Cross-sectional areas of the remaining nine patients are given in Table 2. There was no significant fall in cross-sectional area over the period of the study (Mann-Whitney U test). Several patients (including the one who appeared to be entering the progressive phase of the disease) seemed to show decreases on the order of 10%, but these were matched by apparent increases of the same magnitude in other patients, suggesting that they were likely to be within the inherent errors of the technique.
Table 2. Changes in spinal cord area by vertebral level
There was no significant correlation between spinal cord lesion load or increase in lesion load and either cross-sectional area or change in cross-sectional area.
Discussion.
In this study we attempted to characterize the dynamics of relapsing-remitting MS in the spinal cord using monthly Gd-DTPA-enhanced MRI. Of a total of 485 lesions detected on the baseline images, 42 (9%) were within the spinal cord. Overall, we saw 186 active lesions during the study period, 19 of which (10%) were within the spinal cord. Thus, if lesion count on brain MRI alone is used as a marker of disease activity in the context of a treatment trial in relapsing-remitting MS, approximately 10% of disease activity will be overlooked. Given the significant time penalty involved in spinal imaging, this is probably acceptable, especially since there seems to be no obvious pathophysiologic mechanism by which a treatment would have a different effect in the brain than in spinal cord. Furthermore, because there was spinal cord activity alone on only two of the 59 occasions on which MRI indicated any activity, the percentage of imaging studies revealing activity would fall very little (from 46 to 45%) if spinal MRI were omitted.
As found in many other studies, [1-11] there were many more active lesions in the brain than clinical relapses: Overall, there were 167 active brain lesions and only 11 relapses, a ratio of 15 to 1. Furthermore, only one active brain lesion was probably symptomatic. Conversely, at least six (31%) of the active spinal cord lesions produced symptoms, which is not surprising given the tight packing of critical ascending and descending white matter tracts within the spinal cord. Wiebe et al., [24] who studied 29 patients with relapsing-remitting and progressive MS with three MRI studies at three-month intervals, and additional imaging during clinical relapses, made similar observations. Of the 25 changes they detected on spinal cord imaging, 10 (40%) were symptomatic. Compared to the current study, however, they found relatively little asymptomatic brain disease. This is to be expected, because small lesions, which had ceased enhancing within 3 months, may have been overlooked on the unenhanced images. [29] In the study by Capra et al., [9] two of three contrast-enhancing spinal cord lesions (detected on biweekly imaging for 3 months in 10 patients) were symptomatic, compared with only one of 93 enhancing brain lesions.
New spinal cord lesions were less likely to enhance (61%), particularly in the thoracic region (30%), than new brain lesions (94%) and, unlike brain lesions, never demonstrated enhancement on more than one study. This is likely a result of the greater technical difficulty in producing high-quality, artifact-free T1-weighted images of the spinal cord and the small size of most of the spinal cord lesions, rather than to biological differences in the permeability of the blood-brain and blood-spinal cord barriers in new lesions.
Brain MRI activity was much higher around the time of clinical relapse. This confirms the findings of other authors. [30-32] Of greater significance was the finding that brain activity was more common in the presence of spinal cord activity. The fact that new lesions tend to develop simultaneously at widely spaced anatomic sites can be used to argue strongly in favor of a generalized, systemic stimulus, rather than a local trigger to lesion formation, providing a further rationale for systemic treatment strategies to combat MS.
No patient developed further significant, fixed disability over the study period, apart from one patient probably just entering the progressive phase. There was no discernible progressive atrophy of the spinal cord over the study period, as measured from axial gradient echo images. This is compatible with a lack of significant axonal loss [23] and contrasts with the findings in progressive (both primary and secondary) MS where there was a significant decrease in the spinal cord area over time, in association with an increase in locomotor disability, despite few new developing lesions. [25] This lends credence to the notion that, following an initial relapsing-remitting phase in which there are recurrent episodes of acute perivascular inflammation associated with blood-brain (and blood-spinal cord) barrier breakdown and demyelination but relatively little axonal loss, there can follow a phase of increasing axonal loss (with resultant atrophy) in the absence of acute inflammatory episodes. Further longitudinal studies incorporating newer MR techniques that are sensitive to axonal loss or tissue disruption, such as proton spectroscopy [33,34] and magnetization transfer imaging, [35,36] are needed to clarify this important issue. Furthermore, future advances in imaging, for example, with improved design of multiarray coils, higher matrices, and implementation of three-dimensional FSE allowing for the acquisition of thin (1 mm) axial slices, are likely to improve the MRI resolution of the spinal cord. Further serial studies using such techniques will be needed to evaluate their sensitivity to pathologic changes and the correlation of disease activity with clinical events.
- Copyright 1996 by Advanstar Communications Inc.
REFERENCES
- 1.↵
- 2.
Willoughby EW, Grochowski E, Li DKB, Oger J, Kastrukoff LF, Paty DW. Serial magnetic resonance scanning in patients with multiple sclerosis: a second prospective study in relapsing patients. Ann Neurol 1989;25:43-49.
- 3.
Truyen L, Gheuhens J, Parizel PM, Van den Vyver FL, Martin JJ. Long term follow-up of MS by standardized, non-contrast-enhanced MRI. J Neurol Sci 1991;106:35-40.
- 4.↵
- 5.
- 6.
Miller DH, Rudge P, Johnson G, et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 1988;111:927-939.
- 7.
- 8.
- 9.↵
Capra R, Marciano N, Vignolo LA, Chiesa A, Gasparotti R. Gadolinium-pentetic acid magnetic resonance imaging in patients with relapsing remitting multiple sclerosis. Arch Neurol 1992;49:687-689.
- 10.
McFarland HF, Frank JA, Albert PS, et al. Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis. Ann Neurol 1992;32:758-766.
- 11.
Stone LA, Smith ME, Albert PS, et al. Blood brain barrier disruption as measured by contrast enhanced MRI in patients with mild relapsing remitting multiple sclerosis: relationship to course, gender and age. Neurology 1995;45:1122-1126.
- 12.↵
Kappos L, Stadt D, Ratzka M, et al. Magnetic resonance imaging in the evaluation of treatment in multiple sclerosis. Neuroradiology 1988;30:299-302.
- 13.
Miller DH, Barkhof F, Berry I, Kappos L, Scotti G, Thompson AJ. Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines. J Neurol Neurosurg Psychiatry 1991;54:683-688.
- 14.
- 15.
Koopmans RA, Li DKB, Zhoa GJ, Redekop WK, Paty DW. MRI assessment of cyclosporine therapy of MS in a multicenter trial [abstract]. Neurology 1992;42(suppl 3):210.
- 16.
Paty DW, Li DKB, the UBC MS/MRI Study Group, the IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:662-667.
- 17.↵
- 18.
Maravilla KR, Weintreb JC, Suss R, Nunally RL. Magnetic resonance demonstration of multiple sclerosis plaques in the cervical cord. AJR 1985;144:381-385.
- 19.
Miller DH, McDonald WI, Blumhardt LD, et al. Magnetic resonance imaging in isolated noncompressive spinal cord syndromes. Ann Neurol 1987;22:714-723.
- 20.
Honig LS, Sheremata WA. Magnetic resonance imaging of spinal cord lesions in multiple sclerosis. J Neurol Neurosurg Psychiatry 1989;52:459-466.
- 21.
Turano G, Jones SJ, Miller DH, Du Boulay GH, Kakigi R, McDonald WI. Correlation of SEP abnormalities with brain and cervical cord MRI in multiple sclerosis. Brain 1991;114:663-681.
- 22.
- 23.↵
Kidd D, Thorpe JW, Thompson AJ, et al. Spinal cord MRI using multi-array coils and fast spin echo. II. Findings in multiple sclerosis. Neurology 1993;43:2632-2637.
- 24.↵
Wiebe S, Lee DH, Karlik SJ, et al. Serial cranial and spinal cord magnetic resonance imaging in multiple sclerosis. Ann Neurol 1992;32:643-650.
- 25.↵
Kidd D, Thompson AJ, Kendall BE, Miller DH, McDonald WI. A serial MRI study of the brain and spinal cord in progressive multiple sclerosis [abstract]. J Neurol 1994;241(suppl 1):S151.
- 26.↵
- 27.↵
Kurtzke JF. Rating neurological impairment in multiple sclerosis an expanded disability scale. Neurology 1983;33:1444-1452.
- 28.↵
- 29.↵
Miller DH, Barkhof F, Nauta JJP. Gadolinium enhancement increased the sensitivity of MRI in detecting disease activity in multiple sclerosis. Brain 1993;116:1077-1094.
- 30.↵
Grossman RI, Gonzales-Scarano F, Atlas SW, Galetta S, Silberberg DH. Multiple sclerosis: gadolinium enhancement in MR imaging. Radiology 1986;161:721-725.
- 31.
- 32.
- 33.↵
Matthews PM, Francis G, Antel J, Arnold DL. Proton magnetic resonance spectroscopy for metabolic characterization of plaques in multiple sclerosis. Neurology 1991;41:1251-1226.
- 34.
Davie CA, Hawkins CP, Barker GJ, et al. Serial proton magnetic resonance spectroscopy in acute multiple sclerosis. Brain 1994;117:49-58.
- 35.↵
Dousset V, Grossman RI, Ramer KN, et al. Experimental allergic encephalomyelitis and multiple sclerosis: lesion characterization with magnetization transfer imaging. Radiology 1992;182:483-491.
- 36.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Babak Hooshmand and Dr. David Smith
► Watch
Related Articles
- No related articles found.
Alert Me
Recommended articles
-
Articles
Multisequence MRI in clinically isolated syndromes and the early development of MSP.A. Brex, J.I. O’Riordan, K.A. Miszkiel et al.Neurology, October 01, 1999 -
Article
MS, MRI, and the 2010 McDonald criteriaA Canadian expert commentaryDaniel Selchen, Virender Bhan, Gregg Blevins et al.Neurology, December 03, 2012 -
Article
MRI in the evaluation of pediatric multiple sclerosisBrenda Banwell, Douglas L. Arnold, Jan-Mendelt Tillema et al.Neurology, August 29, 2016 -
Review
Secondary Progressive Multiple SclerosisNew InsightsBruce A.C. Cree, Douglas L. Arnold, Jeremy Chataway et al.Neurology, June 04, 2021