Brain, Vol. 123, No. 11, 2187-2188,
November 2000
© 2000 Oxford University Press
Editorial |
MRI: measure of efficacy
Action Research professor of Clinical Neurology, Radcliffe Infirmary, University of Oxford, UK
Even the briefest account of progress in the difficult field of adult human demylinating disease would highlight the prominent role played by MRI scanning. The methodology has been prominent in studying disease dynamics and has been applied widely to the evaluation of therapeutic efficacy as epitomized by studies with the type 1 interferons. It has allowed non-invasive identification of objectively measured activity in multiple sclerosis, a disorder notoriously difficult to evaluate. The rationale has been compelling. Enter MRI, and not only could the disease burden of demyelination be computed and the accumulation of new lesions be quantified, but also ongoing activity could be dated by use of contrast enhancing agents.
Near arrest of accumulating disease burden on T2-weighted scans was achieved in the original pivotal study of type 1 interferons (Paty et al., 1993
), and this has been re-confirmed. Initially, few doubted that if new lesions were prevented to this degree, translation into prevention of disability in the longer-term would follow. This was a key factor in the approval of interferon-ß by the FDA under the rules of US orphan drug legislation. However, there were indications from the outset that there might be problems in confirming this. Cross-sectional studies showed surprisingly weak correlations between MRI measures and disability and it was not easy to show that relapse suppression resulted in disability reduction. However, these somewhat unexpected findings were originally dismissed as misleading artefacts of short-term follow-up. In a context where motivation to demonstrate long-term efficacy should be extremely high, the dearth of long-term results has been puzzling. The correlation of long-term change in MRI with even longer-term change in disability has been particularly elusive. Appropriately, there has been considerable vigour expended in identifying other MRI measures which might prove to be more powerful predictors in the short- and longer-term.
Even though it goes without saying that MRI measures as surrogates need to be better than clinical ones, it has not always been found necessary by investigators to compare MRI parameters to even the most banal of these such as duration of disease. Now, more than a decade after the initiation of the original pivotal trial of interferon (INFB MS Study Group, 1993), key questions about the relevance of MRI measures to long-term outcome remain unanswered. As newer measures are introduced, but have not yet been validated themselves, the role of MRI as a surrogate marker warrants re-evaluation.
The targets are reasonably clear, since several criteria have been laid out for the validation of surrogate markers in disease. Notably, the near complete suppression of T2 burden accumulation and of gadolinium enhancement have not associated with clear delay of progression in the three large secondary progressive multiple sclerosis trials. The fact that half of placebo patients worsen in these short-term studies makes light of the argument that it is the insensitivity of clinical scales which are somehow to blame for not finding what must be the case. With the recognition that changes in brain/parenchymal volume could be identified, even within the relatively short-term follow-up of a clinical trial, and the recognition that axonal loss is an important accompaniment of long-term disability, this methodology was reasonably applied to the evaluation of efficacy in clinical studies. Again it was widely believed that influencing the rate of atrophy would surely be a good indicator of therapeutic efficacy.
The paper by Molyneux and colleagues in this issue demonstrates in a 95-patient subgroup of the European secondary progressive multiple sclerosis trial that this is not necessarily so (Molyneux et al., 2000). The results are unlike those for gadolinium enhancement and T2 burden. For these measures, suppression by type 1 interferons was striking, yet correlations with subsequent disability were weak. Now Molyneux and colleagues show that effects on `atrophy' do not seem to correlate with the clinical findings reported in the same study where therapeutic effects judged by suppression of relapses and disability were identified. To be sure, there may be some uncertainty about the clinical effect since two other large studies were unable to confirm the initial results of Polman and colleagues (European Study Group on Interferon beta-1b in Secondary Progressive MS, 1998). It is clear that clinical outcome measures of progression need redefinition (Rice and Ebers, 1998; Liu and Blumhardt, 2000). Nevertheless, the fact that no correlation was seen between disability and change in cerebral volume begs the question as to what atrophy really means.
However tempting it is to analogize with grey matter degenerations and ascribe atrophy to neuronal/axonal loss and its consequences, atrophy can surely have many causes. It is known that considerable recoverable atrophy probably occurs without axonal loss, such as in the protein catabolic states of malnutrition, Cushing's disease and chronic steroid administration. In the case of slowly growing tumours, the spinal cord may be reduced to a ribbon-like appearance, presumably by extraordinary thinning of myelin sheaths. The time-course of complete recovery which may follow removal implies that the compressed axons remained intact (Bucy, 1963). Thinning of myelin also seen in secondary remyelination and gliosis with contraction of the neuropil, and demyelination itself may all result in tissue shrinkage. Nor can it be confidently assumed that atrophy early in disease will be accounted for by the same factors seen in the longer-term. This study confirms the potential usefulness of atrophy since measurable changes occurred in the context of a clinical trial, and it may be that suppression of atrophy will be a taller order than suppression of enhancement, T2 burden or new lesion appearance.
The authors do not give direct data on whether or not the almost complete suppression of T2 lesion burden change had any effect on atrophy. However, a negative result might be expected given the large effect on T2 volume in these same patients and the inability to show atrophy suppression. The use of mean changes in volume in this analysis derived from the total group assumes a normal distribution of such changes, something which has yet to be shown. However, these findings are consistent with a recent study (Saidane et al., 2000) showing no correlation of brain parenchymal volume with age and gadolinium lesion load.
The role of MRI in therapeutic monitoring must be considered in flux and Molyneux and colleagues are to be commended for publishing their results in timely fashion. The statement that MRI `shows the pathology' should probably be amended for the time being to `some of the pathology' and the search for better measures should be intensified. In the meantime, the implications for any therapy used because of short-term clinical or MRI efficacy highlight the need for long-term validation of both clinical and MRI surrogates as predictors of outcome.
References
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Liu C, Blumhardt LD. Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts. J Neurol Neurosurg Psychiatry 2000; 68: 450–7.
Molyneux PD, Kappos L, Polman C, Pozzilli C, Barkhof F, Filippi M, et al. and the European Study Group on Interferon beta-1b in Secondary Progressive MS. The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. Brain 2000; 123: 2256–63.
Paty DW, Li DKB, UBC MS/MRI Study Group, INFB Multiple Sclerosis Study Group. Interferon beta 1b is effective in relapsing-remitting multiple sclerosis. 11. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 662–7.
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