PC de InAs/GaAs

While there are now a number of MRI techniques available to monitor disease progression in MS, none has yet replaced clinical indices as the primary outcome measure in phase III trials. The major reason for this is the lack of strong relationship between clinical and MRI markers of progression. The most important requirement of a surrogate marker is that it should be predictive

of long term clinical outcome (Whitaker et al, 1995). The most established MR surrogate for

disease progression is serial brain T2 total lesion volume (TLV) measurement. In practice, it is

often a shorter TE, PD weighted sequence that is used in lesion volume measurement rather than

a strictly Tj weighted sequence, but by convention, terms such as Tj lesion volume and T2 lesion

Several natural history studies and clinical trials have demonstrated significant correlations between EDSS and Tj lesion volume both cross sectionally and longitudinally. However, the level of correlation is typically modest (Table 1.9). This may be in part due to the limitations of the EDSS, but several other factors are also likely to be important:

• Increased signal on a conventional Tj weighted image results from a change in the local

water environment and T2 relaxation time. Any stage of MS lesion development and

evolution, fi*om early inflammation and oedema, to chronic, destructive pathology with demyelination and axonal loss, can therefore be represented as an area of high signal that contributes to the measured brain lesion volume. Considering this lack of specificity for the more destructive elements of MS pathology, it is not surprising that stronger correlations have not been demonstrated.

• Standard measures of brain lesion volume give equal weighting to all brain lesions,

regardless of their anatomical location. Since the majority of MS lesions occur in regions that do not directly contribute to locomotor disability, it is not at all surprising that the association between the EDSS, with its emphasis on locomotor function, and total brain lesion volume is poor. When corticospinal tract lesion volume is considered in isolation, a slightly stronger correlation has been demonstrated (Riahi et ai, 1998). Furthermore,

measurement of brain lesion volume ignores the impact of spinal cord lesions that may substantially contribute to gait disturbance. However, little correlation between cord

lesion volume and EDSS has been observed (Kidd et al, 1993), suggesting that lesion

site per se is not decisive in determining disability.

correlation may be substantial. A number of potential sources of measurement error exist in both image acquisition and data analysis. The anticipated annual change in brain lesion volume is small, typically 5-10%, and if a measuring instrument is to be responsive to such a change, a high level of accuracy and reproducibility are prerequisites. Efforts are now being directed towards identifying and resolving the many possible sources of measurement error, and this may yet lead to the demonstration of stronger clinical/MRI correlations.

• There is growing evidence that the lesion volume visible on a conventional Tj weighted

sequence does not provide a full measure of the total disease burden. Postmortem work has revealed microscopic changes in the normal appearing white matter (NAWM) (Allen

et al, 1979). Furthermore, MR studies using magnetisation transfer imaging (Dousset et

al, 1992; Filippi et al, 1995b; Loevner et al, 1995a), MR spectroscopy (Arnold et al,

1992; Husted et al, 1994; Davie et al, 1997; Rooney et al, 1997), and Tj and Tj

measurement (Barbosa et al, 1994; Gasperini et al, 1996) have demonstrated that the

contribution of such MR occult pathology to the total burden of abnormality may be important. The presence of microscopic pathology in the NAWM may well contribute to the lack of clinical/MRI correlation using Tj lesion volume measurements alone.

• Cortical lesions, poorly seen on Tj weighted MRI, and cortical adaptation to subcortical

pathology (measurable using functional MRI) may both affect disability independent of Tj lesion volume.

Due to this uncertain relationship between MRI and long term clinical outcome, it is appropriate

may yet change if improvements in clinical and MR measuring instruments reveal stronger correlations. At present, however, the role of MRI is as a secondary outcome measure, providing important additional information on the long-term effect of treatment on the pathological process. Its utility in this regard was first demonstrated by the North American trial of interferon beta-lb in relapsing remitting MS, where the effect of treatment on stabilisation of brain Tj lesion volume and the development of new Tj lesions provided powerful support for treatment efficacy (Paty er a/., 1993).

Study Clinical/M RI parameter r-value for

correlation No. of patients Reference Cyclosporine (SP) Parallel group

Baseline EDSS vs baseline lesion volume

0.22 163 Zhao et al.,

1997

Cyclosporine (SP) Parallel group

Change in EDSS vs change in lesion volume

0.19 163 _{Zhao et al.,}

1997

Natural History (RR and SP)

Baseline EDSS vs baseline lesion volume

0.33 46 Truyen et al.,

1996

Natural History (RR, SP, benign and PP)

Baseline EDSS vs baseline lesion volume

0.33 43 Gass et al,

1994

Interferon beta la (RR) Parallel group

Baseline EDSS vs baseline lesion volume

0.22 237 _{Simon et al,}

1998

Natural History (RR, SP, benign and PP)

Baseline EDSS vs baseline lesion volume

0.46 41 _{Gasperini et}

al, 1996

Natural History (RR, SP, benign and PP)

Baseline EDSS vs baseline lesion volume

0.30 130 Mammi et al,

1996

Natural History (RR, SP, benign and PP)

Baseline EDSS vs baseline lesion volume

0.49 56 _{Gawne-Cain et}

al, 1998

Natural History (RR) Baseline EDSS vs baseline lesion volume

0.60 39 _{Riahi et al,}

1998