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Are magnetic resonance findings predictive of clinical outcome in therapeutic trials in multiple sclerosis The dilemma of interferon-.

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BRIEF REVIEW
Are Magnetic Resonance Findings Predictive
of Clinical Outcome in Therapeutic Trials in
Multiple Sclerosis? The Dilemma of
Interferon+
~
W. I. McDonald, D. H. Miller, and A. J. Thompson
Considerable excitement has been generated among
patients and neurologists by the report that in a doubleblind placebo-controlled trial, a particular interferon-p
(interferon-@1-b, Betaseron) significantly reduces the
frequency of relapse, and of new pathological activity
as judged by standard T2-weighted brain magnetic resonance imaging (MRI) El, 2). No difference, however,
was observed in the rate of clinical deterioration between the actively and the placebo-treated groups, a
not unexpected result given the short duration of the
trial (2 years for all patients and 3 years for some), the
known variability in the course of multiple sclerosis
(MS) 131, the size and nature of the population studied
(the investigation was restricted to patients with relapsing/remitting disease), and the crude and poorly reproducible nature of clinical disability scales 14, 5). Indeed
it is becawe of the problems with quantifying disability
that MRI has been so welcome as an alternative measure of disease activity.
Encouraging though these results are, they raise
among others, two important practical questions. Is it
safe to predict on the basis of the MRI results (which
were more impressive than the clinical results) that the
rate of accumulation of disability will be diminished by
interferon-@?Will interferon+ be effective in progressive MS?
Magnetic Resonance Imaging and
Clinical Outcome
Most neurologists have been struck by the apparent
lack of correlation between standard T2-weighted
brain MRI and disability, and some have questioned
whether it is appropriate to use this modality as an end
point in therapeutic trials. In attempting to assess the
relationship between MRI appearances and clinical
deficit it is first necessary to enquire what the MRI
changes represent in pathological terms. Standard T2From the Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
Received Jan 20, 1994, and in revised form Mar 14. Accepted for
publication Apr 6, 1994.
weighted MRI simply reveals water protons and the
pathological changes reflect changes in the amount of
water and its association with macromolecules, i.e., it
has low specificity. Other MR techniques probably increase pathological specificity in the context of evaluating MS lesions. There is reasonable evidence to infer
that gadolinium enhancement is associated with active
inflammation (perivascular lymphocytes and dense
macrophage infiltration 16-S)), proton MR spectroscopy provides a measure of myelin breakdown and
axonal dysfunction or loss [9, lo), and that magnetization transfer imaging is sensitive to tissue disruption
resulting from demyelination or axonal loss [ 11).
Recent MR investigations have elucidated the sequence of pathological changes that occur as the new
lesion develops and evolves into a chronic residual scar
[12-19). They have also provided new insights into
how the changing clinical features of relapse and remission are produced 112). The earliest detectable event
is a breakdown of the blood-brain barrier in association with inflammation 113). There is good evidence
that the inflammation is immune mediated E14). Demyelination (inferred from the presence of large peaks
attributable to methyl and methylene groups on short
echo time proton spectroscopy) occurs early in the inflammatory phase, though the precise timing is unknown [ 157. Demyelination and probably inflammation contribute to conduction block and the production
of symptoms 1161. Edema develops and reaches a peak
after about a month 117, 181. The blood-brain barrier
leakage then ceases and the edema is absorbed 119).
During this phase conduction is restored [IC), probably as a result of the generation and extension of sodium channels along the persistently demyelinated
axons [20-24). When these events commence is uncertain, though in acute toxin-induced demyelination
they begin within a few days of the insult E20). RemyAddress correspondence to Prof McDonald, Institute of Neurology,
Queen Square, London W C l N 3BG, UK.
14 Copyright 0 1994 by the American Neurological Association
elination 1251, when it occurs, will contribute 1261,
though the usual persistence of delay in the visual
evoked potential after optic neuritis suggests that it
probably plays a relatively small part. A smaller residual scar remains after 2 to 3 months. Many chronic
lesions (more than >2 years old) show extensive axon
loss 1271.
It is important to realize that though the functional
loss produced by the lesions of MS depends on the
phase of their pathological evolution, the different
phases look alike on standard unenhanced MRI. It is
therefore not surprising that, in cross-sectional studies,
there is a poor correlation between such images and
neurological deficit, even when a clinically eloquent
structure such as the optic nerve is involved. For example, though there is a relationship between lesion
length and visual outcome in optic neuritis, full clinical
recovery is commonly seen with a persistent MRI abnormality of the optic nerve [28). Other factors such
as the location, size, and orientation of lesions are also
relevant 112, 131; even quite extensive lesions in the
periventricular white matter will not produce a motor
or sensory deficit, though there is a correlation with
cognitive impairment 129-3 11.
Fortunately a number of recent observations suggest
that there is a closer relationship between the changes
seen with other MR techniques and clinical deficit.
First, Thompson and colleagues 1321, using serial gadolinium diethylenetriaminepentaacetic acid (DTPA) enhancement to detect blood-brain barrier breakdown
(i.e., disease activity) found that the frequency of new
enhancing lesions over a 6-month period is much
higher in patients who have entered the secondary progressive phase of the disease { 191(when disability accumulates progressively after an initially relapsing and
remitting course) than in patients with “benign” MS
{ 3 2 ] , i.e., patients with a score of not greater than 3
on the Kurtzke Extended Disability Status Scale
(EDSS) after at least 10 years. This observation accords
with the clinical finding that frequent relapses are predictive of greater disability 133.
A second line of evidence comes from recent high
resolution MRI studies on the spinal cord. Atrophy
(presumably indicating demyelination and/or axonal
loss), as measured by a decrease in the transverse area
at C-5, correlates with the severity of pyramidal deficit
and disability as measured by the EDSS 1331.
Third, the technique of T2 magnetization decay analysis has been applied to chronic cerebral lesions in patients with benign and secondary progressive MS 1341.
A biexponential decay (which provides evidence for
axonal loss 127)) was significantly more frequent in the
more disabled patients.
Very recently, Gass and co-workers [351 have examined the magnetization transfer ratio [l 1) in the lesions
of groups of MS patients, This powerful technique pro-
vides an index of tissue disruption, to which both demyelination and axon loss probably contribute. Again,
they found a strong correlation between a low magnetization transfer ratio (indicating white matter tissue loss)
and disability in MS.
These investigations are either cross sectional or follow-up was for only 6 months. A longer term prospective study is therefore of particular interest, even using
standard T2-weighted MRI. It is well known that the
presence of additional silent abnormalities on T2weighted brain images at presentation with isolated
clinical syndromes of the kind seen in demyelinating
disease (e.g., optic neuritis) is associated with a high
risk of subsequent development of MS [36-421. In
a recent study, 65% of such patients had developed
clinically definite MS by 5 years {42]. The volume of
cerebral lesions at presentation showed a significant
correlation with the EDSS score 5 years later 1431.
Thus, several lines of evidence, using a variety of
MR techniques, suggest that the frequency of new disease activity, the total extent of abnormality, and the
pathological characteristics of the lesions (in particular
evidence for tissue disruption) are predictive of subsequent disability. Accordingly, it is probable that the
reduction in frequency of new MRI activity in patients
treated with interferon-p will result in the slowing of
the progression of disability. It must be emphasized
however that the relationship between MRI and disability is not yet fully defined and a trial of interferon-p
with rate of progress of disability as the primary end
point is required before it can be accepted as having a
useful clinical effect. It is likely that it does, but the
point remains to be established.
The Role of Magnetic Resonance Imaging in
Clinical Trials
What then is the place of MRI at present in clinical
trials? We see two roles: first, and potentially most
valuable, in screening new putative therapies to see
whether they favorably modify the pathological evolution of the disease; secmd, as a supplementary marker
of disease activity in phase 111 studies in which disability is the primary outcome measure.
The special advantage of MRI in monitoring treatment is its ability to detect new pathological activity
that is 5 to 10 times more frequent than clinical relapse
in patients with early relapsinglremitting or secondary
progressive MS [17-19, 32, 443.Active lesions are
best detected on gadolinium-DTPA-enhanced images
at approximately monthly intervals [45-47), though a
small number of additional new lesions are detected in
unenhanced images 1481; ideally both types of image
should be obtained. Calculations based on data from
the Institute of Neurology in London and the Free
University Hospital in Amsterdam show that it should
be possible with monthly MRI for 6 months to detect
Brief Review: McDonald
et
al: Predictive Value of MRI in MS
15
a 60% reduction in active lesions with a greater than
90% power in a sample size of 2 x 40 patients using
a parallel group, placebo-controlled design [49}. Such a
design is ideal for screening new agents and is currently
being used to monitor the efficacy of monoclonal antiCD4 antibodies, mitoxantrone, and 15 t deoxyspergualin in trials being conducted in Europe and Australia. Two limitations are that it may miss a therapeutic
effect if there is a long delay between starting treatment and a response occurring, and that it is not possible to determine whether an observed treatment effect
will be sustained in the long term. A further 6-month
period of monitoring after an interval would overcome
these difficulties.
If such screening studies show a major impact of
therapy on MRI activity, is this sufficient evidence to
recommend general use of the therapy, thereby
avoiding the expense and delay of proceeding with a
full scale phase 111 clinical trial? To answer this question, we need to know the predictive value of shortterm frequent MRI activity for long-term disability.
Such data are not yet available. Until a clear relationship is established, we would recommend proceeding
with a phase 111 study, particularly if the treatment
under consideration is expensive or has appreciable
side effects.
In large scale phase 111 trials, the total pathological
extent of the disease detectable on yearly T2-weighted
brain MRI has been used as a supplementary measure
of disease activitylprogression. Brain lesion load can
be measured in a crude, semiquantitative fashion by
grading the size of lesions by the largest diameter [so}.
However, such a crude technique is of dubious value
in monitoring treatment. Lesion area can be measured
more precisely by manual outlining on a computerized
image. This technique has been used extensively by
the MS MRI group at the University of British Columbia in Vancouver, who have demonstrated an intrarater
variability of 6% in experienced hands, and an average
increase in lesion area of about 10% per annum in
untreated patients [2, 5 1, 521, suggesting a very useful
role in measuring the pathological extent of disease
during large scale clinical trials.
The utility of this approach was demonstrated in the
recent interferon-p study, where there was a significantly smaller rate of increase in lesion load in patients
treated with high-dose interferon-p [2]. However, this
study also revealed a significant discrepancy, in that
there was a 10% reduction in lesion loads measured
after 3 years in all patients (treated and untreated) compared with the 2-year lesion loads. This has been attributed to a systematic change in the manual technique
applied by the single observer who performed the measurements. I t is thus desirable to develop more fully
automated techniques to outline lesions. Some have
already been developed [53, 541 and shown to im-
16 Annals of Neurology Vol 36 No 1 July 1004
prove reproducibility C541. The accuracy of lesion load
measurement will be further increased by careful repositioning and acquiring thinner slices (e.g., 3 mm),
which reduces partial volume errors [ 5 5 ] .
In the future, it would be valuable to develop techniques that improve resolution and pathological specificity in the spinal cord, the site of many disabling lesions. Such developments would offer the prospect of
improved correlations between MR parameters and
clinical disability.
Interferon-p and Progressive
Multiple Sclerosis
A pressing question is whether interferon-p will be
effective in secondary progressive MS, ie., progressive
after an initially relapsing/remitting course. Because
the distribution of lesions and the frequency and duration of enhancement are the same in the two forms
[19, 321, it is reasonable to suppose that interferon-p
might have a similar effect in both. However, the nature of the change leading to insidious progression is
unknown, and it is clear that a double-blind, placebocontrolled trial in secondary progressive MS is required using both MRI and clinical end points. The
need for such a trial is urgent because entry into the
secondary progressive phase is the main clinical determinant of disability [56].
Primary progressive MS (i.e., disease that is progressive from onset without relapses or remissions) presents a greater problem. New cerebral lesions are less
frequent than in the other forms of MS and they enhance less frequently, i.e., 5 % compared with 80%
[ 191. These observations suggest that primary progressive MS might be less inflammatory than the other
forms of the disease, a suggestion supported by a recent comparative postmortem study of the two progressive forms of MS [571. The mode of action of
interferon-p in MS in unknown but probably involves
modulation of the inflammatory process [l}. It is thus
impossible to predict whether interferon-p will modify
the course of primary progressive MS, but because the
process is at least in part inflammatory it might, and a
trial is warranted. Serial gadolinium-enhanced MRI is
unlikely to be helpful, and a trial with a primary clinical
end point is needed. The use of MR techniques for
monitoring tissue disruption in the brain and especially
the spinal cord may prove to be helpful, but further
development work is required before they can be confidently applied.
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