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104 60 11.94 p<0.001

Table 9.1. Relationship between relapse and new brain and cord lesions on follow up studies in the six patients who relapsed. "Relapse" = imaging studies performed within a month before or after a clinical relapse, "Remission" = two months or more from a relapse. FET = Fisher's exact test.

Spinal cord cross sectional area

Intraobserver limits of agreement (Bland and Altman, 1986) were from -6.7 mm^ to 7.6 mm^ (-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 9.2. 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 of the order of

1 0%, 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.

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.

Level Area at start Area at end % difference

C5 8 8 .8 ±8.3 (78.7 - 106.5) 86.4 ±7.3 (68.4 - 93.4) -2.5 ± 6 .8 (-13.2-7.3) T2 56.2 ±7.6 (45.2 - 67.2) 53.9 ± 6.3 (43.6 - 62.3) -3.7 ± 6.2 (-9.4 - 9.9) T7 47.1 ±5.3 (39.4-53.1) 46.6 ± 5.0 (37.3 - 53.4) -0.6 ± 9.0 (-13.5-11.7) T il 61.9±7.1 (51.0-75.4) 61.4 ±7.8 (50.4-75.1) -0.4 ±11.0 (-13.7-24.4)

Table 9.2. Changes in spinal cord area by vertebral level. Values are given as mean (in mm^) ± standard deviation, with ranges in brackets.

DISCUSSION

In this study the dynamics of relapsing remitting MS in the spinal cord were characterised 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, 186 active lesions were seen during the study period, of which 19 (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: there seems no obvious pathophysiological mechanism by which a treatment would have a different effect in the brain and cord. Furthermore, as 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 (see chapter 1), there were many more active lesions in the brain than clinical relapses: overall there were 167 active brain lesions and only 11 relapses, a proportion of 15 to one. Furthermore, only one active brain lesion was probably symptomatic. Conversely, at least six (31%) of the active spinal cord lesions produced symptoms, not surprisingly given the tight packing of critical ascending and descending white matter tracts within the spinal cord. Wiebe et al (1992), who studied 29 patients (with relapsing remitting and progressive MS) with three three-monthly MRI studies and additional imaging during clinical relapses, made similar observations. Of the 25 changes they detected on spinal cord imaging, ten (40%) were symptomatic: compared to the current study, however, they found relatively little asymptomatic brain disease. This is to be expected, as small lesions, which had ceased enhancing within three months, may have been overlooked on the unenhanced images (Miller et al, 1993b). In the study by Capra

et al (1992), two of three contrast-enhancing spinal cord lesions (detected by fortnightly imaging for three months in ten patients) were symptomatic, compared to 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 due to the greater technical difficulty in producing high quality, artefact-free T^-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 (Grossman et al, 1986; Thompson et al, 1992; Smith et al,

1993). Of greater significance was the finding that bndn activity was more common in the presence of spinal cord activity. That new lesions should tend to develop simultaneously at widely spaced anatomical sites argues strongly in favour of a generalised, systemic stimulus, rather than a local trigger to lesion formation, providing a further rationale for systemic treatment strategies to combat MS.

As in chapter 6, measurements of spinal cord cross-sectional area were reasonably reproducible, although there were in some cases apparent increases in area of up to 10% over the course of the study, which are most unlikely to be genuine. Furthermore, it is noticeable that the values obtained in the current study were approximately 10% smaller that in the earlier study (performed more than a year earlier). Although it is possible that the patients in the current study genuinely did have smaller spinal cords, it seems highly likely that this difference represents a change in the strategy used by the measurer. This is a problem identified in a previous study involving manual tracing (Paty et a l, 1993) and highlights the need for a more fully automated method of measurement. One has subsequently been developed (Losseff et al, 1996a). No patient developed significant further fixed disability over the study period, apart from one patient probably just entering the progressive phase. Within the limitations of the measuring technique, there was no discernable progressive atrophy of the spinal cord over the study period. This would be

compatible with a lack of significant axonal loss 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 lesions developing (Kidd et ai, 1996). 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 thought to be sensitive to axonal loss or tissue disruption, such as proton spectroscopy (Matthews et al, 1991; Davie et al, 1994) and magnetisation transfer imaging (Dousset