Review

Clinically isolated syndromes suggestive of multiple

sclerosis, part 2: non-conventional MRI, recovery processes,
and management
David Miller, Frederik Barkhof, Xavier Montalban, Alan Thompson, Massimo Filippi Lancet Neurol 2005; 4: 341–48
See Review Lancet Neurol 2005;
The onset of multiple sclerosis (MS) in 85% of young adults is with a subacute clinically isolated syndrome (CIS) of 4: 281–88

the optic nerves, brainstem, or spinal cord. Whereas multifocal brain lesions are present on MRI in many patients MS NMR Research Unit,
Institute of Neurology,
with a CIS, some patients have additional abnormalities on quantitative MRI in otherwise normal-appearing white
University College London,
and grey matter that suggest an extensive pathological process. Functional outcome for patients with symptomatic London, UK (D Miller FRCP,
CIS lesions is determined by the interplay of inflammation, demyelination, axonal damage, remyelination, and A Thompson FRCP);
cortical adaptation. Recovery of function may be accelerated by high dose corticosteroids, and although interferon Department of
Neuroradiology, VU Medical
beta delays the development of a second relapse, its long-term effect is unknown. A better understanding of Centre, Amsterdam,
pathological and pathogenetic processes in patients with a CIS will facilitate the development of disease-modifying Netherlands (F Barkhof MD);
treatments for patients with MS before they become disabled. Continued clinical and laboratory investigation of Department of
patients with a CIS should be encouraged. Neuroimmunology, Hospital
Vall d’Hebron, Barcelona, Spain
(X Montalban MD);
Introduction Conventional MRI shows T2-visible lesions but does Neuroimaging Research Unit,
In 85% of young adults who develop multiple sclerosis not show other abnormalities. However, several Scientific Institute and
(MS), onset is with an acute, clinically isolated syndrome quantitative MRI techniques can show abnormalities in University Ospedale San
Raffaele, Milan, Italy
(CIS) of the optic nerves, brainstem, or spinal cord. In otherwise normal-appearing brain tissue; these (M Filippi MD)
part 1 of this review, published in the May 2005 issue, techniques have the potential to increase knowledge of Correspondence to:
the clinical presentation, pathogenesis, diagnosis, and the pathobiology of MS. Conventional MRI lesion Prof D H Miller, NMR Research
prognosis of CISs were covered. In part 2 we review non- measures are of limited value for prognosis in the early Unit, Department of
conventional MRI findings, recovery processes, and stages of the disease, and quantitative MRI techniques Neuroinflammation, Institute of
Neurology, University College
management of patients. have potential to give a clearer prognosis. London, London WC1N 3BG, UK
Magnetisation-transfer MRI has been one of the most d.miller@ion.ucl.ac.uk
Abnormalities on non-conventional MRI widely used methods for the assessment of patients
Progressive brain atrophy is a well-known feature of with MS and can detect “occult” tissue damage in the
MS and is thought to be a marker of irreversible tissue brain and cervical cord.7 Low magnetisation-transfer
damage.1 However, the exact causes and timing of ratios have been detected in normal-appearing brain
atrophy in MS are unknown. The assessment of brain tissue of patients with CIS at presentation, and in one
and spinal-cord atrophy in patients with a CIS should study, the extent of these abnormalities was reported to
help to define how early irreversible tissue loss occurs be an independent predictor of subsequent disease
in MS. Dalton and co-workers2 prospectively followed- progression.8 However, other studies9,10 with region-
up 55 patients with CISs for 3 years. After 1 year, of-interest or whole-brain-histogram analysis of
patients with MS (according to the McDonald criteria3) magnetisation-transfer MRI data did not find that low
had substantially more ventricular enlargement than magnetisation-transfer ratios predict disease
those without such disease progression. After 3 years, progression. Another study11 showed magnetisation-
29 (53%) of the patients had progressed to MS and transfer-ratio abnormalities in a group of patients with
ventricular volume and grey-matter atrophy were a recent onset of CIS and in a group with a remote
greater in those with MS than in those who did not onset of CIS; the similar findings in both groups, and
have MS. White-matter volume did not change over in those with normal and abnormal conventional
time in either subgroup.4 Measures of lesion load and scans, prompted the researchers to propose that
atrophy measures were moderately related, suggesting magnetisation-transfer MRI abnormalities in CIS
that T2-visible lesions account only partially for the suggest susceptibility to demyelination. Recent studies
observed changes in brain volume. Similar results were of patients with CISs has found no abnormality
also found when brain atrophy was measured in the in cervical-cord magnetisation-transfer-ratios12 but
Early Treatment of MS (ETOMS) trial.5 In 43 patients abnormal measures of diffusion in normal-appearing
with a CIS, atrophy of the spinal cord was also white matter;13 however these findings were not
assessed;6 although the area of the spinal cord in predictive of subsequent lesion dissemination (as
patients with a CIS and an abnormal brain MRI at defined by the McDonald criteria) at 3 months and
presentation was slightly smaller than that of healthy 12 months.13 Overall, the published findings on
controls, there was no measurable change in patients magnetisation-transfer ratio and diffusion suggest that
or controls over 1 year. subtle white-matter damage might occur at a very early

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 Review
stage in patients with a CIS but do not predict short-
term lesion development.
In patients with established MS, proton-magnetic-
resonance spectroscopy studies have found low
N-acetylaspartate14 and high myoinositol concen-
trations.15 By contrast, small and preliminary studies on
patients with CIS16,17 found no abnormalities in brain
metabolites. More recently, one of us with other
researchers18 used a new unlocalised proton-magnetic-
resonance spectroscopy technique to show a decrease in
the concentration of N-acetylaspartate in the whole brain
in a group of 31 patients with a CIS. Fernando and co-
workers19 studied 96 patients with CIS within 6 months
of the clinical episode and found high myoinositol and
creatine in white matter, suggesting that glial
proliferation is an early event in MS (figure 1).
As found in patients with established MS,20 in patients
with a CIS non-conventional MRI measures might be
better than lesion load in reflecting clinical status. Notably,
patients with a CIS and cognitive impairment had a lower
ratio of N-acetylaspartate to creatine and a lower brain
parenchymal fraction than patients with a CIS and
normal cognition, whereas there was no difference in T2-
lesion and T1-lesion volumes between the two groups.21
Patients with CIS in this study also had white-matter
volume loss but not grey-matter volume loss.
In about 20% of patients with MS, optic neuritis is
the initial symptom of the disease. Although the
assessment of optic-nerve pathology has been
hampered by several methodological factors (the small
size of the nerve, motion artifacts, and the effect of
surrounding CSF, lipids, and bony structures) it is
possible to obtain high quality T1-weighted and T2-
weighted images,22 as well as reliable quantitative
data.23,24 In patients with MS, the magnetisation-
transfer ratio is substantially lower in affected optic
nerves than in unaffected ones. Furthermore, low
magnetisation-transfer ratio is associated with delay in
the latency of visual evoked potentials.23,25 Inglese and
Choline
Total N-acetyl-aspartate
Myoinositol
Creatine
Glutamate
4·0 3·8 3·6 3·4 3·2 3·0 2·8 2·6 2·4 2·2 2·0 1·8 1·6 1·4 1·2 1·0 4·0 3·8 3·6 3·4 3·2 3·0 2·8 2·6 2·4 2·2 2·0 1·8 1·6 1·4 1·2 1·0
Chemical shift (parts per million)
Figure 1: T2-weighted MRI of a patient with a CIS
The square shows short echo-time proton spectra from a voxel of white-matter (left). Spectrum from the white-matter of a patient with a CIS (middle) and a healthy person (right). The peak in
myoinositol is larger in the patient than in the control. Reproduced with permission from Oxford University Press.19
342
co-workers24 found that magnetisation-transfer ratio
was lower in the optic nerves of patients with MS
without recovery than in those with clinical recovery,
and that magnetisation-transfer ratio was similarly low
in patients with Leber’s hereditary optic neuropathy,
suggesting that axonal loss is likely to be an important
contributor to low magnetisation-transfer ratio in MS.
Further support for the idea that axonal loss is one of
the pathological substrates of optic-nerve damage
comes from findings of nerve atrophy after an episode
of optic neuritis.26–28
Recovery processes
Structural repair mechanisms and insights from MRI in
optic neuritis
The optic nerve, when studied both experimentally and
clinically, serves as a window revealing general
mechanisms of symptom onset and recovery equally
applicable to isolated and recurrent demyelination
elsewhere in the CNS. Altered structure and function in
the complex oligodendrocyte–axon unit should be part of
any explanation of symptom onset and recovery.29 In
addition, given the capacity for CNS plasticity and
functional adaptation, clinical recovery might not result
from structural repair within the primary lesion alone.
Acute cytokine release induces transient conduction
block, probably caused by damage from nitric oxide.
With intact myelination and preserved axons, the
recovery mechanism involves removal of inflammatory
mediators and reversal of the functional deficit. More
prolonged exposure impairs both structure and
function, leading to persistent demyelination and axonal
damage. Recovery can occur through three mechanisms:
remyelination, development of continuous conduction
through sodium channels that develop along the
demyelinated segment, and cortical plasticity.
Substantial axonal loss could occur and result in
permanent loss of structure and function. Axon loss
might be acute, caused by the effects of inflammation, or
Choline
Total N-acetyl-aspartate
Myoinositol Creatine
Glutamate
Chemical shift (parts per million)
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chronic, caused by persistent inflammation or lack of
trophic support from myelin.
In patients with optic neuritis, recovery is related to
MRI findings for both the location and extent of
abnormality. Long lesions located in the optic canal have
been associated with poor visual recovery. In 101 of 107
patients with acute optic neuritis, assessment with
gadolinium enhanced fat-suppression MRI found that
the affected optic nerve was enhanced but none of the
unaffected nerves were enhanced.30 MRI with
gadolinium therefore seems to be sensitive in the
detection of acute optic neuritis. Although lesions in the
canal or over longer segments of the optic nerve were
predictive of poor vision at onset, they were not
predictive of recovery. Pain was common when optic
neuritis involved the orbital segment of the optic nerve.31
Changes in magnetisation-transfer ratio over 1 year
were assessed with magnetisation-transfer MRI in 29
patients with acute optic neuritis and in healthy people.25
Whereas magnetisation-transfer ratios of the unaffected
optic nerve and of the optic nerves of healthy controls
were stable during follow-up, the diseased optic nerve
magnetisation-transfer ratio decreased over time and
was lowest at about 240 days. The magnetisation-
transfer ratio of the diseased optic nerve seems to
increase after reaching the lowest point, although not
significantly. Time-averaged magnetisation-transfer
ratios and mean visual-evoked-potential latency were
related, suggesting that magnetisation-transfer ratio is a
measure of the structural integrity of the optic nerve
and, possibly, the extent of myelination. A decrease in
optic-nerve magnetisation-transfer ratio early in the
disease process is consistent with demyelination and
Wallerian degeneration, whereas occurrence of the
lowest magnetisation-transfer ratio late in the disease
process might be caused by slow clearance of myelin
debris; a subsequent rise in magnetisation-transfer ratio
could be due to remyelination.
Tissue volume of optic nerves changes for up to 1 year
after the onset of optic neuritis.28 At first, nerves swell;
the cross-sectional area of the nerve increases by a
median of 20%. Consistent with acute inflammation,
swelling resolves over several months. Atrophy then
starts, with a mean decrease of 12% in nerve area after
1 year. The mean loss of nerve tissue after a single attack
of optic neuritis is small, which suggests that only a few
optic nerve axons are lost. Thus, patients’ generally good
visual outcome is not surprising.
Cortical adaptation and insights from functional MRI
One of the factors that might contribute to visual
recovery after acute optic neuritis is cortical adaptation.32
Study of 12 patients with acute monosymptomatic optic
neuritis found a low functional MRI (fMRI) response,
reflecting low input during acute visual loss.33 However,
5 weeks after onset of optic neuritis, there was a
significant increase in the volume of activation and in
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Review
blood-oxygenation level dependent signal in response to
binocular stimulation. Monocular stimulation of the
affected eye resulted in cortical activated volumes and
BOLD signal increases that were consistent with the
results of visual testing. These findings suggest that
transient adaptive changes happen in the visual cortex
during recovery.
Comparison of 20 patients who had acute unilateral
optic neuritis with 46 healthy people over 1 year by use of
fMRI found differences over time in the patients’ visual
cortex and extraoccipital regions—including the lateral
temporal cortex, insula, corpus striatum, orbitofrontal
cortex, and inferior parietal region—when either the
affected or unaffected eyes were used.34 These differences
were most prominent soon after clinical onset and
subsided after a few months. Markers of optic-nerve
structure (cross-sectional area and gadolinium
enhancement), clinical function, and the fMRI response
for both the affected and the unaffected eyes were
associated, particularly at baseline. Visual function at
baseline was inversely related to optic-nerve damage and
directly related to the extent of response on fMRI. At
baseline and 1 month later, low fMRI responses (for both
affected and unaffected eyes) were associated with
substantial optic-nerve damage, whereas at 3 months,
baseline optic-nerve damage was associated with the
amount of fMRI activity outside the visual cortex. Two
studies33,34 suggest there are prominent dynamic
spatiotemporal functional cortical changes after acute
optic neuritis, which might have an adaptive function
during early recovery.
fMRI has also been used to assess functional cortical
changes associated with motor tasks in patients with a
CIS.35,36 When patients do a simple motor task with the
dominant hand, cortical activations in the “classic”
motor areas differ,35 suggesting that cortical
reorganisation might occur early in MS. The extent of
these cortical activations is strongly associated with the
concentration of N-acetylaspartate in brain tissue. In
patients with a CIS, there is pronounced use of the
contralateral primary sensorimotor cortex when the
same motor task was done with the non-dominant
hand.36 The findings are similar when these patients do
the task with the dominant foot and there is an anterior
shift of the centre of activation.36 During a complex
motor task involving the dominant hand and foot,
patients with a CIS have an increased recruitment of a
widespread network (including the frontal lobe, the
insula, and the thalamus), thought to commonly
function in motor, sensory, and multimodal integration
processing.36 The effect of isolated spinal-cord disease on
cortical adaptation has been assessed through study of a
group of patients with a previous episode of acute
myelitis.37 Increased activation of several cortical regions
of the “classic” motor network was found, and the
activity of some of these areas was related to the severity
of spinal-cord damage.
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 Review
In a 1 year follow-up study of patients with a CIS, those
who developed clinically definite MS had a different
fMRI response on motor tasks at first presentation than
those who did not (figure 2).38 By comparison with those
who did not develop MS, those who did had substantial
bilateral activations of the superior frontal sulcus, the
superior frontal gyrus, the infraparietal sulcus, and the
putamen; in addition, they had high activation of the
ipsilateral middle frontal gyrus, superior temporal gyrus,
cuneus, and contralateral fusiform gyrus. Those who did
not develop MS had more substantial activations than
those who did develop MS in the contralateral primary
somatomotor cortex and supplementary motor area, the
ipsilateral paracentral lobule, and the cerebellar
hemisphere. These results suggest that activation of the
regions normally involved in a task seems to be a
favourable prognostic factor, whereas a widespread
recruitment of additional areas seems to be associated
with short-term disease activity.
Overall, fMRI studies of patients with a CIS suggest
that cortical reorganisation occurs and has the potential
to improve long-term patient outcomes, even at this
early stage of the disease process.
Management
Acceleration of recovery from the CIS
Many patients with a mild CIS will recover
spontaneously without the need for specific treatment.
Corticosteroids are used when the symptoms are
A B
C D
25
20
15
10
5
0
Figure 2: Pattern of cortical activations during a simple motor task
The dominant, functionally unaffected right hand is used in patients with CISs suggestive of MS who developed
definite MS over a short period of follow-up (top) and those who did not (bottom). Activation of the sensorimotor
network is most extensive and widespread in those who developed definite MS.
344
functionally disabling or when the patient is not
improving spontaneously. The CIS that has been most
carefully studied in randomised-controlled trials is optic
neuritis. The Optic Neuritis Treatment Trial (ONTT)
showed that treatment with a 3 day course of
intravenous methylprednisolone and then 11 days of
oral prednisone was associated with a more rapid
recovery of vision compared with placebo.39 After 1 year,
vision was not different between the group given an
active treatment and that given a placebo.40 A 2 week
course of oral prednisone alone did not accelerate
recovery compared with placebo, but was associated with
an increased probability of having recurrent episodes of
optic neuritis.
The Quality Standards Subcommittee of the American
Academy of Neurology concluded: “Higher dose oral or
parenteral methylprednisolone or ACTH [adrenocortico-
trophic hormone] may hasten the speed and degree of
recovery of visual function in persons with acute
monosymptomatic optic neuritis. There is, however, no
evidence of long-term benefit for visual function. The
decision to use these medications to speed recovery but
not to improve ultimate visual outcome should therefore
be based on other non-evidence-based factors such as
quality of life, risk to the patient, visual function in the
unaffected eye, or other factors that the clinician deems
appropriate”.41
Plasma exchange has been assessed in a small trial
that included a “sham-exchange” control in patients with
a severe neurological deficit due to an episode of CNS
inflammation that did not improve after conventional
treatment with intravenous methylprednisolone.42 Eight
(42%) of 19 patients in the treatment arm improved
compared with one (6%) of 17 patients in the control
arm. Improvement was most likely if plasma exchange
was given within 2 weeks of presentation with a severe
neurological deficit. This finding was supported by the
results of subsequent use of plasma exchange in a non-
trial setting; about half of the patients substantially
improved in the days and weeks after treatment.43
Plasma exchange is likely to be beneficial only when the
patient acquires a severe neurological deficit from a
single acute inflammatory CNS lesion, not if many
lesions cause the deficit to accumulate in small steps.
Response to plasma exchange might reflect an antibody-
mediated pathogenesis of the underlying disease, and
this is supported by IgG and complement deposition in
the lesions of responsive patients.44
A recent double-blind, placebo-controlled trial of
intravenous immunoglobulin in 68 patients with acute
optic neuritis showed no effect of treatment on vision
during 6 months of follow-up.45
Treatments to delay the development of MS
Although the ONTT did not aim to assess whether
treatment delayed conversion to MS, patients treated
with intravenous methylprednisolone and oral
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prednisone had a lower risk of developing clinically
definite MS over the next 2 years than patients given a
placebo (9% vs 17%).46 However, after the third year of
follow-up the treatment and placebo groups’ risks of
conversion to clinically definite MS did not differ.47
Two randomised, double-blind, placebo-controlled
trials of interferon beta-1a in patients with a CIS and an
abnormal MRI brain scan found an association between
treatment with interferon beta-1a and a delay in the
development of clinically definite MS.48,49
Subgroup analysis in the ETOMS trial found that
conversion to clinically definite MS was more common
as the number of Barkhof MRI criteria met increased,
and treatment was more likely to delay conversion to MS
in those who fulfilled many of the MRI criteria. Thus, in
patients who met one or two Barkhof criteria at
presentation, clinically definite MS developed in five
(23%) of 22 who took placebo and in four (21%) of 19
who took interferon beta-1a; in those who met three or
four criteria, these figures were 64 (49%) of 132 for
placebo and 48 (35%) of 135 for interferon beta-1a.50 In
the Controlled High Risk Subjects Avonex MS
Prevention Study (CHAMPS), development of clinically
definite MS was more common in patients with
gadolinium enhancing lesions at presentation;51 the
treatment effect was also larger in this patient subgroup.
Follow-up in the ETOMS trial and CHAMPS was not
long enough to assess whether treatment delayed the
development of irreversible disability. Nevertheless, in
the ETOMS study, a low, weekly dose of interferon beta-
1a reduced the brain tissue lost in 2 years by about 30%.5
Findings from longer follow-up (over 5 years) of some of
the patients in the CHAMPS study suggest that the
disease course was improved in those who received
immediate treatment with interferon beta-1a.52 However,
about 30% of patients were lost to follow-up.
More frequent treatment with interferon beta-1b
(8 mU on alternate days) is now being trialled in patients
with a CIS; the primary endpoint of this study, like that
of earlier CIS trials, is clinically definite MS. In addition,
patients are being recruited for an extension study
designed to compare immediate and delayed interferon-
beta treatment and also to investigate the development
of disability.
A trial of glatiramer acetate is also in progress in
patients with CISs. Intravenous immunoglobulin has
been studied in a placebo-controlled trial in 91 patients
presenting with a first episode of suspected
demyelination; after 1 year of active treatment patients
were less likely to develop clinically definite MS;
however, the short follow-up and small size of this study
limit the interpretation.53
Diagnosis and treatment of individual patients
The questions coming from group studies of diagnosis,
natural history, and treatment trials are how, and when,
these studies’ findings should affect the management of
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Review
the individual patient. Three issues are generally relevant:
the existing chance of conversion to clinically definite MS
or development of disability, the usefulness of the
diagnostic test, and the effectiveness of treatment.
Evidence is accumulating that treatment may delay the
onset of clinically definite MS, although data about the
effect on disability are lacking. One study suggests early
treatment might decrease cerebral atrophy,5 which is
notable because cerebral atrophy could signify disability.54
Most clinicians who see patients with a CIS or suspected
early MS would now agree that it is important to diagnose
early, and having done so, to weigh-up the potential
benefits, risks, and uncertainties of disease modifying
treatment, while ensuring the patient is fully informed
and participates in the decision-making process.
When to diagnose MS
A single contrast-enhanced scan from a patient who
presents with a CIS could be sufficient to diagnose MS,
some have argued, because the presence of both
enhancing and non-enhancing lesions strongly suggests
simultaneous dissemination in space and time.55
However, MRI criteria from the scan at presentation
have been only modestly reliable in the prediction of
clinically definite MS,56,57 and monophasic acute
disseminated encephalomyelitis—an important,
although less common, clinical and radiological
differential diagnosis in this setting—can not be
excluded. An alternative strategy is to require follow-up
MRI scans to show dissemination in time by the
development of new, subclinical lesions at least
3 months after the CIS presents, as recommended by the
McDonald criteria,3 especially if a new T2 lesion is
included at any time after 3 months of follow-up.58 This
approach is not likely to delay diagnosis for long—with
these criteria about 50% of patients with a CIS are
diagnosed as having MS within 1 year. Use of MRI to
assess dissemination in space and time—which we
favour (panel 1)—will also reduce diagnostic and
treatment errors from undue hastiness, and this
approach is supported by prospective group studies that
show a high specificity for clinically definite MS.56,57
A more conservative approach to diagnosis would be to
require the traditional criteria for clinical dissemination in
space and time. Delaying the diagnosis might further
reduce the risk of false-positive diagnosis—eg, in patients
with recurrent cerebrovascular insults mistaken for
demyelination. However, there are disadvantages to a
conservative approach: patients who clearly have MS are
denied the diagnosis; and delayed diagnosis increases the
risk of cerebral atrophy and disability, particularly in high-
risk patients (eg, with a CIS that is severe clinically and has
many cerebral lesions on MRI) in whom the treatment
benefit may be greater in the short term. 50
An early MRI-assisted diagnosis might confront
patients with the implications of a serious, chronic
disease, and although these patients might not have been
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Panel 1: Merits of MRI assessment of dissemination in
space and time for diagnosis of MS in patients with a CIS
Facilitates open discussion of potential for MS and appropriate
assessment with MRI to clarify prognosis (abnormal MRI=high
risk; normal MRI=low risk) or to make the diagnosis
Early MRI-assisted diagnosis with existing criteria3 is highly
specific for clinically definite MS56,57
Making the diagnosis of MS can reduce the patient’s anxiety
about the unknown diagnosis and facilitate support from MS
nurses
Opportunity to introduce an education programme at an
early stage so that patients can think about the implications
of diagnosis and participate in establishing a management
plan that incorporates decisions on lifestyle, work, and family
Opportunity for patient and physician to discuss use of MS
disease-modifying treatment before more CNS tissue
damage occurs
diagnosed until some years later with the old diagnostic
criteria, surveys consistently report a reduction in anxiety
when the diagnosis is made.59–61 In the present era of
openness in clinical practice, it seems inappropriate to
withold information on the likelihood of developing MS
from patients with a CIS, even when formal criteria for
diagnosis are not fulfilled. The potential diagnosis has
important practical implications for patients, including
lifestyle decisions and access to life insurance.
When to start disease-modifying treatments
Although there is strong evidence that patients with a CIS
and an abnormal MRI are likely to develop clinically
definite MS, and that interferon beta delays the
development of clinically definite disease, the long-term
effect of the treatment is unknown. Many patients with a
CIS and MRI lesions develop MS but have a benign
course, with little or no disability for the next
10–14 years.62,63 Moreover, not all of these patients will
relapse further. In the ONTT, 44% had not developed
clinically definite MS after 10 years.64 Interferon-beta
treatment of all patients with a CIS who have an abnormal
scan would include many patients who would have had a
good prognosis without treatment. Old65,66 and more
recent67 natural history studies have shown that many
patients experience a benign, long-term course of MS,
especially if they are free of disability 5 years after onset of
CIS. Together these findings suggest that an initial
approach of wait-and-see for the use of disease-modifying
treatment will serve the best interests of patients with CIS
in whom the clinical episode was mild and reversible,
even if accompanied by an abnormal scan. However, the
best follow-up of such patients is unknown. For example,
should these patients have repeat MRI studies, and if
these show new lesions, should disease-modifying
346
treatment be offered? Prospective follow-up studies are
needed to address these issues.
Whether treatment after a first attack has any greater
effect than delaying treatment until a second episode has
occurred is unknown. The traditional criterion for
treatment in many countries is a second episode. MRI
lesion load at presentation62,68 and the increase in lesion
load over the next 5 years62 is associated with future
disability. Because interferon beta reduces the
accumulation of new MRI lesions, the potential for
benefit may be greater if the drug is given earlier.
A balance between treating all patients with a CIS and
an abnormal MRI or none of these patients seems
sensible. Treatment could be offered to those patients
who have had a clinical episode of moderate or substantial
severity—particularly if multifocal or associated with poor
recovery—and are diagnosed with MS on the basis of
early MRI dissemination in space and time, noting that
such patients have a high risk of relapse.56–58 We find this
approach to be satisfactory (panel 2); it seems acceptable
to begin treatment after MS is diagnosed.
Summary and future research
Important progress has been made in the study of CISs.
The relation between CIS and MS has been elucidated
and diagnostic advances now provide a reliable
prediction, soon after presentation, of the risk of MS.
The mechanisms of acute dysfunction, subsequent
recovery, and persistent deficit from the CIS are better
understood. In addition to multifocal white-matter
lesions, abnormalities are present in the normal-
appearing white and grey matter, and progressive brain
atrophy—suggesting neuroaxonal loss—develops early
in those who develop MS. Tools for treatment
monitoring—both clinical and paraclinical—provide a
more efficient and comprehensive assessment of
therapies that target inflammation, axonal protection,
and remyelination than was possible 10 years ago.
The potential for a better understanding of pathogenetic
mechanisms and effective disease-modifying treatments
Panel 2: Reasons for and against the use of disease-
modifying treatments in patients with a CIS
For Against
Clinically severe CIS with Clinically mild CIS with recovery
persistent disability
MRI criteria for MS fulfilled Normal MRI or few lesions
(dissemination in space
and time)
Delay time to next relapse Not known if disability is
prevented in the long term
Early treatment offers Early treatment will include
better chance of long- patients who would otherwise
term benefit have had a benign long-term course
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Search strategy and selection criteria
References for this review were identified by searches of the
authors’ files; from presentations at the MAGNIMS Workshop
(London, January 2004; see acknowledgments); access to
PubMed citations between 1985 and December 2004; and
references from relevant articles. A few abstracts and reports
from the MAGNIMS meeting were also included. The final
reference list was generated from papers that were original
and relevant to the topics covered in the review.
are compelling reasons for continuing to assess patients
with a CIS. Diagnostic criteria will likely evolve as new
data emerges from imaging and CSF research studies;
other plausible biomarkers should also be assessed for
their diagnostic use. Prediction of disability and the long-
term course of MS are limited: combinations of
conventional and non-conventional imaging and other
biomarker measures may be informative and long-term
prospective studies will be needed to establish convincing
association between laboratory and clinical findings. A
better understanding of early pathogenetic mechanisms
would come with access to pathological tissue from
patients with a CIS, but because this is rarely available,
greater reliance will inevitably be placed on in vivo
surrogate measures. New measures should be sought and
verified as a high priority for their cellular, pathological,
and immunological specificity.
Acknowledgments
Content for this review partly comes from presentations made at an
International Workshop on Clinically Isolated Syndromes held in London,
UK, in January 2004. The workshop was coordinated by MAGNIMS, a
European network of investigators who are interested in the application of
magnetic resonance methods to MS. Sponsorship support was received
from the MS Society of Great Britain and Northern Ireland, the Italian MS
Society, and the National MS Society (US). Workshop participants were:
O Andersen (Gothenburg), D Arnold (Montreal), F Barkhof (Amsterdam),
T Berger (Innsbruck), L Bo (Amsterdam), P Brex (London), A Compston
(Cambridge), C Confavreux (Lyons), C Dalton (London), M Daumer
(Munich), F Fazekas (Graz), K Fernando (London), M Filippi (Milan),
J Frederiksen (Copenhagen), S Hickman (London), R Hohlfeld (Munich),
M Inglese (New York), M Johnson (Leeds), L Kappos (Basel),
M Kupersmith (New York), C Lucchinetti (Rochester, Minnesota),
G Lycklama (Amsterdam), H McFarland (Washington DC), P Matthews
(Oxford), D Miller (London), X Montalban (Barcelona), G Plant (London,
England), C Polman (Amsterdam), S Reingold (New York), H Roed
(Copenhagen), M Rocca (Milan), M Ron (London), A Rovira (Barcelona),
M Rovaris (Milan), M Sandberg-Wollheim (Lund), J Simon (Denver),
F Sellebjerg (Copenhagen), A Thompson (London), M Tintoré (Barcelona),
A Toosy (London), B Weinshenker (Rochester, Minnesota), and J
Wolinsky (Houston). All authors are members of the MAGNIMS Steering
Committee.
Authors’ contributions
All authors contributed equally to the writing of this review.
Conflicts of interest
We have no conflicts of interest.
Role of the funding source
No funding source was involved in the preparation of this review or in
the decision to submit it for publication.
http://neurology.thelancet.com Vol 4 June 2005
Review
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