Views & Reviews

The contribution of magnetic resonance

imaging to the diagnosis of
multiple sclerosis
F. Fazekas, MD; F. Barkhof, MD; M. Filippi, MD; R.I. Grossman, MD; D.K.B. Li, MD; W.I. McDonald, MD;
H.F. McFarland, MD; D.W. Paty, MD; J.H. Simon, MD; J.S. Wolinsky, MD; and D.H. Miller, MD

Article abstractMRI is very sensitive in showing MS lesions throughout the CNS. Using MRI for diagnostic purposes,
however useful, is a complex issue because of limited specificity of findings and a variety of options as to when, how, and
which patients to examine. Comparability of data and a common view regarding the impact of MRI are needed. Following
a review of the typical appearance and pattern of MS lesions including differential diagnostic considerations, we suggest
economic MRI examination protocols for the brain and spine. Recommendations for referral to MRI consider the need to
avoid misdiagnosis and the probability of detecting findings of diagnostic relevance. We also suggest MRI classes of
evidence for MS to determine the diagnostic weight of findings and their incorporation into the clinical evaluation. These
proposals should help to optimize and standardize the use of MRI in the diagnosis of MS.
NEUROLOGY 1999;53:448456

MRI is by far the most sensitive technique for detect-
ing MS lesions in vivo throughout the CNS. As a
consequence, MRI has become an important tool for
diagnosing MS and providing surrogate markers in
therapeutic trials. Guidelines for the use of MRI in
monitoring treatment efficacy have been issued.1-3
However, less work has been done toward developing
consensus guidelines for diagnostic evaluation. This
is for a variety of reasons. First, whereas MRI shows
typical lesions in the majority of patients with clini-
cally definite MS, and at times, such a finding is
more robust than vague clinical symptoms, other dis-
orders can also produce changes typical for MS. MS-
like lesions may even be seen in asymptomatic
individuals. Secondly, there are a few patients with
clinically definite MS who do not show MRI abnor-
malities in either the brain or the spinal cord. Pro-
viding strict diagnostic criteria may therefore 1)
overestimate the importance of MRI, 2) suggest a
diagnosis of MS even in the absence of clinical find-
ings, or 3) underestimate the frequency of this disor-
der if MRI changes do not meet certain criteria.4-6
Third, it is difficult to condense adequately the
knowledge of experienced interpreters into simple di-
agnostic criteria. Finally, all MRI information should
be viewed in the context of the clinical situation and
complementary investigational results. Despite all
these concerns, however, there is a need to standard-
ize MRI as a diagnostic tool, especially with the
rapid technical developments of recent years includ-
ing hardware improvements and a wide choice of
new sequences. There is need for a consensus on
which MRI findings are of diagnostic support and to
what extent. Economic concerns will also influence
the diagnostic protocol.
A task force of the North Atlantic Collaboration in
MS has reviewed the use of MRI as diagnostic tool
for MS in clinical practice based on current litera-
ture and expert opinion. The review covered the
range of MRI findings in MS lesions and comparison
with other disorders. Based on this review, recom-
mendations have been developed for 1) indications
for referral for diagnostic MRI studies, 2) the exami-
nation protocol, and 3) interpretation of MRI find-
ings in the context of MS diagnosis. The review and
recommendations are presented here.

From the Karl-Franzens University (Dr. Fazekas), Graz, Austria; Vrije Universiteit Hospital (Dr. Barkhof), Amsterdam, the Netherlands; Scientific Institute
Ospedale San Raffaele (Dr. Filippi), Neuroimaging Research Unit, Department of Neuroscience, University of Milan, Italy; University of Pennsylvania
Medical Center (Dr. Grossman), Philadelphia, PA; University of British Columbia (Drs. Li and Paty), Vancouver, Canada; Institute of Neurology (Drs.
McDonald and Miller), London, UK; National Institutes of Health (Dr. McFarland), Bethesda, MD; University of Colorado Health Sciences Center (Dr.
Simon), Denver, CO; and University of Texas Medical School at Houston (Dr. Wolinsky), Houston, TX.
Based on a meeting of the North Atlantic Collaboration on Multiple Sclerosis (NATOMS); Cambridge, UK; November 2123, 1997. Coordinators were D.H.M.
and H.F.M. Participants were supported by the United States and Canadian MS Societies and the European Community (ERBCHRXCT 940684 European
Magnetic Resonance Network in Multiple Sclerosis). The authors constitute the NATOMS Task Force on the Diagnostic Use of MRI in MS.
Received November 18, 1998. Accepted in final form April 29, 1999.
Address correspondence and reprint requests to Dr. Franz Fazekas, Department of Neurology and MRI Center, Karl-Franzens University, Auenbruggerplatz
22, A-8036 Graz, Austria; e-mail: franz.fazekas@kfunigraz.ac.at

448 Copyright 1999 by the American Academy of Neurology

MRI characteristics of MS lesions. Both acute
and chronic MS lesions appear bright on proton den-
sity (PD)- and T2-weighted scans, as do other brain
pathologies. Discrete MS lesions are relatively well
circumscribed but may show a halo of less striking
hyperintensity, probably consistent with edema in
the very acute stage of inflammation. MS lesions
tend to appear round or ovoid in shape and their size
commonly ranges from a few millimeters to more
than one centimeter in diameter.7 Differences in
shape are partly a consequence of the angle of the
imaging plane with the course of cerebral venules
that frequently constitute the center of an MS le-
sion.8 Irregular areas of signal hyperintensity result
from confluence of lesions. As a consequence,
periventricular signal changes may take on a scal-
loped appearance. Rarely, disease foci can be very
large, with a pseudotumor appearance. Slight signal
alteration between or surrounding discrete lesions
has also been observed on T2-weighted images of the
brain and appears to represent a more diffuse com-
ponent of the disease process.9 The term dirty white
matter has been coined for such ill-defined abnor-
malities, which occur mainly in the deep and
periventricular white matter and sometimes may be
difficult to differentiate from the normal range of
variability in white matter myelination. Whereas
relatively static in extent, these regions have also
been noted as a place for new, typical lesion forma-
tion at follow-up.10
Around 10 to 20% of T2 hyperintensities are also
seen on T1-weighted images as areas of low signal
intensity compared with normal white matter. In the
acute phase, T1 hypointensity probably is a conse-
quence of marked edema with or without matrix de-
struction, and can disappear as inflammation
abates.11 Chronic foci of hypointensity also known as
persisting black holes indicate areas with more se-
vere tissue damage.12 On corresponding PD-weighted
images, the center of these lesions, although more
difficult to define, is also lower in signal intensity
(because of a T1 saturation effect). This pattern be-
comes even more apparent using a sequence with T2
weighting but suppression of signal from CSF, such
as fluid-attenuated inversion recovery (FLAIR).13
Large plaques are more likely to develop T1 hypoin-
tensity, both acutely as well as in their chronic
stage.11 Infratentorially, MS-related signal abnor-
malities are often more diffuse and less bright, and
there is a lower probability for black holes to de-
velop in this region.11,14
A high propensity of MS lesions for certain brain
regions has been noted pathologically and in accor-
dance is seen on MRI. Characteristic areas of in-
volvement are the periventricular white matter
including the corpus callosum, the cortico-subcortical
regions, and the infratentorial brain regions. Dis-
crete hyperintensities adjacent to the body or tempo-
ral horn of the lateral ventricles are frequent in MS
and rarely seen with other disorders.15 Lesions
around the frontal or posterior horns are also often
seen but more difficult to separate from the phenom-
enon of hyperintense periventricular caps in normal
subjects, at least in the early stage of the disease.
Lesions of the corpus callosum are located preferen-
tially at its inferior border toward the lateral ventri-
cle or extend radiating toward the periphery.16-18
This appearance is the corollary to the pathologists
eponym of Dawsons fingers and can be best appreci-
ated on PD/T2-weighted sagittal views. Pathologic
examinations of MS brains report a high number of
cortical lesions, but apparently this finding cannot
yet be fully reproduced by MRI.19 Confounding fac-
tors are the small size of such abnormalities, less
optimal contrast of MS lesions against adjacent gray
compared to white matter, and partial volume effects
with adjacent CSF. More recently developed segmen-
tation algorithms promise a more comprehensive ap-
preciation of cortical involvement in MS.20 Areas of
signal hyperintensity adjacent to the cortex are more
easily detected on conventional MRI. They are seen
in around two thirds of patients with clinically defi-
nite MS21 and appear to be a rather characteristic
finding in early stages of the disease.22 Detection of
these lesions is facilitated by the use of FLAIR23,24
and the administration of contrast material.22,25 Pre-
ferred infratentorial locations of MS lesions are the
floor of the fourth ventricle, the cerebellar peduncles,
and the surface of the pons.15
MS lesions are further characterized by their dy-
namic evolution. In relapsing-remitting or secondary
progressive MS, disease activity shown by MRI is 5
to 10 times higher than can be recognized clinical-
ly.1,2 The presence of blood brain barrier disruption
as indicated by contrast enhancement in new lesions
serves best to delineate acute inflammation, and
when present tends to persist for 2 to 6 weeks.25-27
Contrast enhancement also indicates the recurrence
of inflammation within preexisting lesions. Steroid
treatment of acute attacks shortens the period of
enhancement.28 Acute lesions wax and wane in size
and intensity, but some T2 abnormality will persist
in most instances. Rarely, lesions disappear. Lesions
falsely missed at follow-up are most likely those with
a diameter below MRI slice thickness and infratento-
rial lesions because their signal intensity may barely
exceed that of normal brain tissue in the chronic
stage. Repair mechanisms, including remyelination,
may contribute to signal normalization. With ongo-
ing disease, new lesions or the enlargement of preex-
isting lesions can be seen to occur simultaneously
with the shrinkage of other previously active
plaques.
Spinal cord lesions in MS share a similar signal
pattern as cerebral lesions except for the absence of
black holes.14 On sagittal scans, spinal cord plaques
characteristically have a cigar shape and may be
located centrally, anteriorly, or posteriorly. Axial
scans show their extension toward the periphery
with a propensity for the dorsal columns. Spinal MS
lesions rarely occupy more than half of the cross-
sectional area of the cord or exceed two vertebral
August (1 of 1) 1999 NEUROLOGY 53 449
segments in length. Lesions are seen more often in
the cervical than thoracic spinal cord and are most
common in the midcervical region.29-31 Acute lesions,
although infrequent, can produce mass effect with
swelling of the cord and may enhance after the appli-
cation of contrast material. Disease activity, includ-
ing contrast enhancement and the development of
new lesions, is much less frequent in the spine than
in the brain.32 Global signal changes of the spinal
cord have also been reported in MS.33 They consist of
diffuse mild hyperintensity on PD-weighted scans
and were seen most often in patients with a primary
progressive course of the disease.33 However, this
finding has yet to be replicated.
MRI also can detect MS lesions in the optic nerve.
The challenge to delineate lesions within the nerve,
despite its tortuosity and mobility and the surround-
ing orbital fat, can be solved with fat-suppression
sequences and phased array coils.34,35 In optic neuri-
tis, there is a moderately strong relation between
lesion length and the rapidity and degree of visual
recovery.36 When investigating cases of optic neurop-
athy, the diagnostic information provided by MRI
clearly supersedes that of CT. This finding is partly
due to the detection of coexisting demyelinating
brain lesions as well as a high sensitivity of MRI for
other intraorbital pathology.37 However, there is lit-
tle need to detect demyelinating optic nerve lesions
in routine diagnostic MRIvisual evoked potentials
are an equally sensitive tool for such purpose.
Prevalence of MRI findings according to stage
and course of MS. Patients who present with a
first symptom suggestive of MS may show a normal
scan or one or more signal hyperintensities on MRI
of the brain. The probability of developing clinically
definite MS is strongly influenced by the number of
lesions at first presentation.38-41 In a prospective
study, infratentorial, juxtacortical, and periventricu-
lar lesion location and gadolinium enhancement
were the four features which in a regression model
were able to predict conversion to clinically definite
MS with a sensitivity of 82% and a specificity of
78%.22 The long-term evolution of MRI changes has
not yet been analyzed in detail. Obviously, continu-
ing accumulation of new lesions should increase both
the total area of signal abnormality and the number
of brain regions involved and ultimately can lead to
confluent hyperintensity extending from the lateral
ventricles toward the periphery and down into the
brainstem as frequently seen in later stages of MS.
Except at the clinical onset, the correlation of lesion
load with clinical disability is generally limited but
statistically significant.42 With advancing disease,
atrophy of the brain and spinal cord may also be-
come apparent.43,44
Lesion patterns of patients with relapsing-
remitting or secondary progressive MS are rather
similar. In comparison, patients with a primary pro-
gressive course of the disease tend to have fewer and
smaller lesions.45 This holds true for periventricular
450 NEUROLOGY 53 August (1 of 1) 1999
and nonperiventricular regions.46 Disease activity as
shown by the number of new and enhancing lesions
is also much lower in patients with primary progres-
sive MS than in the two other groups.45,47
MS lesions within the spinal cord are more diffi-
cult to detect than in the brain because of a lower
conspicuity and greater technical challenges for their
delineation. Therefore, patients presenting with spi-
nal cord symptoms may well have a negative MRI of
the spine but can show cerebral lesions that are typ-
ical for MS.30,48 However, the inverse can also occur.
Patients with suspected MS may have a normal or
equivocal MRI examination of the brain but can
show characteristic lesions in the spinal cord.6 Such
findings are more common for patients with primary
progressive MS, but can be seen in classic relapsing-
remitting MS.
Differential diagnosis and diagnostic criteria
for MS. Disorders that can cause MRI signal hy-
perintensities of the white matter are numerous.
Fortunately, the pattern of signal abnormalities as-
sociated with these diseases is rather different from
MS in most disorders. Moreover, the possibility of a
false positive interpretation of non-MS hyperintensi-
ties strongly depends on their prevalence within the
suspected MS population. Therefore, the following
categories of disorders that need to be considered in
the differential diagnosis include more frequent or
representative examples of diseases only. Overall,
they are much less common than MS, except for inci-
dental or microangiopathy-related hyperintensities.
Brain. Incidental hyperintensities/hypoxic-ische-
mic disorders. Punctate or patchy white matter sig-
nal hyperintensities are frequently seen with normal
aging. They are noted in about half of the normal
population around the age of 50 years.7 Occurrence
of incidental MRI lesions is not restricted to the el-
derly brain, however, and can also be seen in
younger individuals and even in children. Cerebro-
vascular risk factors such as hypertension and mi-
graine are associated with a higher frequency of such
lesions. Incidental hyperintensities are randomly
distributed throughout the deep and subcortical
white matter. Infratentorial regions are usually
spared. Small symmetric periventricular caps pre-
dominantly around the frontal horns are a normal
morphologic variation and smooth lining or bands of
periventricular hyperintensity in the absence of ob-
structed CSF pathways are a nonspecific finding.49
Irregular and sometimes extensive periventricular
hyperintensity is seen in patients with subcortical
arteriosclerotic encephalopathy. Confluent signal
changes typically spare the subcortical U-fibers.
Clearly demarcated lacunar lesions within the areas
of white matter signal abnormality and in the basal
ganglia are frequent and characteristic50 and may
even be seen within the corpus callosum. In contrast
to MS lesions, the center of a lacune tends to appear
isointense to CSF on all sequences because of com-
plete tissue destruction. Ill-defined hyperintensity
may also be seen in the pons but is usually confined
to its central parts. As subcortical arteriosclerotic
encephalopathy usually does not develop before the
fifth decade, this problem of differential diagnosis is
encountered primarily when MS is suspected later
in life.
Immune-mediated vasculopathies. Vasculitis and
immune-mediated vasculopathies are important to
consider in the differential diagnosis of MS and need
not be associated with a typical pattern of infarction.
Systemic lupus erythematosus and the antiphospho-
lipid syndrome can cause nonspecific focal white
matter hyperintensities.51,52 These lesions are located
primarily in the deep and subcortical white matter.
Behcets disease involves primarily the brainstem
and the diencephalon.53
Infectious and inflammatory diseases. A few pa-
tients with Lyme disease have shown a lesion pat-
tern similar to MS but such finding is uncommon.
Neurosarcoidosis can be associated with multiple
lesions throughout the CNS. Almost exclusively
cortico-subcortical location of lesions and frequently
associated granulomatous leptomeningitis as evi-
denced using gadolinium are different from MS in
most cases. Progressive multifocal leukoencephalop-
athy, HIV encephalitis, subacute sclerosing panen-
cephalitis, and other inflammatory disorders of the
brain may cause nonspecific white matter changes
but will usually not mimic a lesion pattern that is
typical for MS.
Early on, acute disseminated encephalomyelitis
(ADEM) may not be separable from MS. Areas of
inflammation in ADEM may share all the features of
acute MS lesions. At the beginning of the disease,
extensive perifocal edema and contrast enhancement
of most lesions suggest a rather aggressive process
and lesion uniformity attests to a monophasic event,
even though a mix of enhancing and nonenhancing
lesions can sometimes be found. Some patients with
ADEM exhibit symmetric lesions in cerebellar pe-
duncles or cerebral white mattera pattern unlike
MS. Chronic lesions characterized by tissue destruc-
tion with atrophy should be absent. Lesions tend
to resolve at follow-up and new lesions should not
occur.54,55
Leukodystrophies and toxic metabolic diseases. These
disorders are very rare and include various types of
dysmyelination or demyelination caused by inborn
metabolic errors and damage to the white matter
from toxins including radiation therapy. Most of
these diseases are associated with a rather symmet-
ric and confluent pattern of white matter signal ab-
normality that lacks the discrete multifocality of
lesions common to MS. It must be noted, however,
that MS-like lesions have been reported for individu-
als with Lebers hereditary optic neuropathy, a mito-
chondrial disease,56 and patients with vitamin B12
deficiency.57
Malignancies. Brain tumors such as a glioma
can cause an area of signal hyperintensity that may
be indistinguishable from demyelination presenting
Table 1 Composite features of brain lesions characteristic for MS
Authors Features
Paty et al.58 Three or more T2 hyperintensities with one
bordering the lateral ventricle
Fazekas et al.7 Three or more T2 hyperintensities and at least
two of the following lesion characteristics:
size . 5 mm, abutting the ventricular body,
infratentorial location
Barkhof et al.22 Cumulative chance model for conversion to MS
(80% with all four features fulfilled):
gadolinium-enhancing lesion (at least 1);
juxtacortical location (at least 1);
periventricular location (at least 3);
infratentorial location (at least 1)
as a solitary or mass lesion. Lymphoma or even met-
astatic disease may have to be considered with mul-
tiple lesions. Short-term lesion evolution usually
suffices to make a clear diagnosis if morphologic fea-
tures are not sufficiently specific at first, but some-
times biopsy is required for a definitive diagnosis.
The differences in lesion distribution, shape, and
size between the above disorders and MS have stim-
ulated the development of criteria for MRI differen-
tial diagnosis.7,58 More recently, the pattern of
features typical for MS lesions was expanded in a
search for predictors of conversion to clinically defi-
nite MS following a first symptom22 (table 1). All
three sets of criteria appear valid but the different
purposes for which they were developed should be
recognized. The criteria of Paty et al.58 were defined
to determine MRIs capability of predicting the de-
velopment of clinically definite MS in patients with
suspected MS, whereas the criteria of Fazekas et al.7
were developed in an attempt to separate MRI signal
abnormalities of MS patients from incidental signal
hyperintensities of the normal population. Both rely
on features readily apparent on PD/T2-weighted
scans. Retrospective comparison in a series of 1,500
consecutive MRI scans showed a somewhat higher
specificity of the Fazekas criteria (96% versus 92%)
at the cost of a lower sensitivity (81% versus 87%).15
The criteria of Barkhof et al. include findings on
contrast enhanced T1-weighted MRI and are clearly
of value in predicting those patients who will go on
to develop clinically definite MS following an isolated
first clinical symptom.22 How these criteria would
perform in the distinction from other white matter
diseases has not been tested.
Caution is advised not to use any of these criteria
too rigidly. They all attempt to expand rather than to
replace experienced image interpretation and must
be viewed in the context of clinical and other investi-
gative findings; e.g., on the one hand, just one single
lesion of typical shape and location can serve to sup-
port the clinical suspicion of MS, whereas, on the
other hand, it would be possible to have a patient
with vascular lesions or even cerebral metastases
fulfill all MRI criteria for MS but clearly not have
the disease.
August (1 of 1) 1999 NEUROLOGY 53 451
 Spinal cord. In contrast to the brain, there is no
evidence for the occurrence of incidental intramedul-
lary hyperintensities related to aging or cerebrovas-
cular risk factors.59 Otherwise, the differential
diagnosis of single or multiple spinal cord signal ab-
normalities has to consider similar etiologies as in
the brain; i.e., vasculitis and immune-mediated vas-
culopathies, infectious and inflammatory diseases
such as viral myelitis, neurosarcoidosis60 or ADEM,
and glioma. Dural arteriovenous fistulas may also
present with waxing and waning of focal intramedul-
lary hyperintensity and can usually be detected on
good quality MR images; in the case of suboptimal
MRI studies or remaining clinical uncertainty they
may have to be excluded by spinal angiography.
Technical considerations and imaging proto-
col. The sensitivity of an MRI examination for de-
tecting MS lesions will depend on the choice of the
imaging protocol and the quality of its performance.
Despite numerous comparisons of pulse sequences,
protocol recommendations need to be rather general
because of variations in the feasibility, quality, and
utility of pulse sequences on different scanners.
Overall, there is a trend toward using faster pulse
sequences to shorten the examination times, but this
may be at the cost of sensitivity. A detailed descrip-
tion and evaluation of the various pulse sequences is
obtained from recent reviews.3,42,61 Development of a
standardized imaging protocol including uniform
slice thickness and imaging planes for patients with
suspected MS should help to optimize the examina-
tion procedure at multiple sites and aid the compar-
ison of serial examinations that may be needed in
difficult diagnostic settings. Imaging at high field
strengths ($1 tesla) is preferable because high signal
can be used to facilitate the detection of even small
lesions. This is especially true for imaging of the
spine.
Brain imaging. Maximal slice thickness should
be 5 mm with an interslice gap of #10%. Axial scans
should be obtained perpendicular to the interhemi-
spheric fissure and parallel to either the bicommis-
ural line or a line connecting the lower borders of the
genu and splenium of the corpus callosum. To follow
these landmarks, axial scanning must be planned
from both coronal (position of interhemispheric fis-
sure) and sagittal (delineation of corpus callosum)
scout views using appropriate angulations. Imple-
mentation of this procedure in clinical practice en-
sures comparable scanning planes and thus
facilitates the interpretation of follow-up studies.
However, the use of MRI in follow-up of patients to
make treatment decisions cannot be recommended at
this time.
T2-weighted sequences (long echo time [TE] and
long repetition time [TR]) are most sensitive for the
parenchymal changes of MS because of the longer T2
of lesions versus normal white matter. However, it
may be difficult to separate bright lesions in a
periventricular or cortico-subcortical location from
452 NEUROLOGY 53 August (1 of 1) 1999
the high signal intensity of CSF on purely T2-
weighted scans. If the signal of CSF is darker, a
much better lesionCSF contrast is obtained. This is
achieved by so-called PD-weighted images (short TE
and long TR). Both PD and T2 weighting can be
achieved with a conventional dual spin-echo se-
quence or a rapid acquisition relaxation enhanced
(RARE) dual spin-echo sequence. RARE sequences
have been also designated as turbo or fast spin-echo
techniques.
Another approach to facilitate lesion discrimina-
tion in the proximity of CSF spaces can be taken
with a T2-weighted sequence that includes suppres-
sion of signal from water, such as FLAIR. Some
FLAIR sequences appear less sensitive for infraten-
torial lesions, which is a drawback in view of the
diagnostic importance of infratentorial lesions. On
the other hand, FLAIR provides an apparent better
delineation of signal hyperintensities in cortico-
subcortical locations.23,24 Therefore, combination of a
RARE T2-weighted sequence with a FLAIR sequence
is another option.
To obtain scans in a second plane takes advantage
of MRIs multiplanar imaging capability and conveys
further diagnostic information. T1-weighted scans
are frequently used in this context as they show the
anatomy of important midline structures such as the
corpus callosum, optic chiasm, pituitary gland,
brainstem including the aqueduct, and the cranio-
vertebral junction. PD/T2-weighted sagittal scans
add to the detection of lesions in the corpus callosum
that are rather characteristic for MS16,17 but at the
cost of anatomic detail. Sagittal FLAIR has the ad-
vantage of better visualization of lesions at the infe-
rior borders of the corpus callosum but at this time
may be prone to pulsation artifacts.18,61
Contrast enhancement is a means to increase di-
agnostic certainty. First, it may provide additional
proof for the dissemination of lesions in time; i.e.,
the combined presence of acute contrast-enhancing
and old nonenhancing lesions.22,62 In this context,
it is important to note that incidental or micro-
angiopathy-related white matter hyperintensities
typically do not enhance. Secondly, contrast enhance-
ment may help to clarify atypical T2 abnormalities
and to visualize structural abnormalities that are
not seen or may go undetected on noncontrast scans,
such as leptomeningeal/cortical disease including
sarcoidosis and neoplastic infiltration; vascular
malformations, particularly capillary telangiectasia;
dural arteriovenous malformations or venous angio-
mas; and meningiomas. In addition, contrast en-
hancement may indicate a level of disease activity
that has prognostic implications.63-65 Contrast-
enhanced scans may be of less additional diagnostic
value if 1) clinical uncertainty is low and 2) PD/T2
scans are characteristic.
Gadolinium chelates in a dosage of 0.1 mmol/kg
body weight suffice for diagnostic MRI. A minimum
time interval of 5 minutes between the injection of
contrast material and the postcontrast T1-weighted
Table 2 MRI protocol suggestions for diagnostic workup of
clinically suspected MS
Region Suggestions
Brain*
Axial PD/T2-weighted (CSE or RARE)
Sagittal T1 or PD/T2 or FLAIR
Axial Postcontrast T1-weighted (0.1 mmol/kg Gd)
(CSE or RARE)
Spine, entire cord
Sagittal T2-weighted (CSE or RARE)
T1-weighted (SE)
Sagittal/axial Postcontrast T1-weighted (0.1 mmol/kg Gd)
(CSE or RARE)
Axial T2-weighted (GE or RARE)
* Always use the same acquisition parameters, slice angle, and
position (internal landmarks).
Strongly recommended.
Always use the same acquisition parameters.
Complementary.
PD 5 proton density; CSE 5 conventional spin-echo; RARE 5
rapid acquisition relaxation enhanced; FLAIR 5 fluid-attenuated
inversion recovery; Gd 5 gadolinium; SE 5 spin echo; GE 5
gradient echo.
series should be employed. To use this interval, a
T2-weighted sequence such as in the sagittal plane
can be performed during this waiting period. Injec-
tion via a long IV line may also help to save time and
to avoid patient movement. For the sake of compari-
son it is advisable to obtain contrast-enhanced T1-
weighted scans in the axial plane and with an
identical image geometry to the PD/T2 series. Mag-
netization transfer (MT) weighting should not be
used to increase conspicuity of contrast-enhancing
lesions unless a precontrast T1-weighted scan with
the same technique has been obtained beforehand;
otherwise, there is a high risk of falsely labeling
lesions as contrast enhancing, especially when using
MT saturation pulses.66 Table 2 summarizes sugges-
tions for a routine examination protocol of the brain.
Spinal cord imaging. Spinal cord imaging is
even more quality-dependent than that of the brain.
Slice thickness should not exceed 3 mm with a max-
imum interslice gap of 10%. The entire spinal cord
should be imaged in patients with spinal cord syn-
dromes and especially when intending to rule out
compression of the spinal cord. MS lesions can be
found at all levels in the cord, but more often in the
cervical region.6,29 Surface coils help to increase sig-
nal to noise ratio and phased array coils are particu-
larly useful in providing images of the whole spinal
cord without moving the patient.59
Sagittal images should be performed with a T2-
weighted sequence (RARE, cardiac or peripheral
gated conventional spin-echo). The sensitivity of fast
FLAIR has been disappointing.67,68 Complementary
T1-weighted sagittal images are recommended. Axial
T2-weighted images help to define lesions suspected
from sagittal scans and to outline anatomic lesion
location clearly. Gadolinium-enhanced scans are less
likely to show contrast material uptake in MS le-
sions of the spinal cord69 but may be useful in the
differential diagnosis, e.g., by demonstrating lepto-
meningeal enhancement in sarcoidosis or extramed-
ullary disorders, such as arteriovenous malforma-
tions or neoplasms. Addition of fat suppression tech-
niques has no direct diagnostic impact in MS but can
serve to reduce artifacts from fat with more complex
imaging sequences.
Imaging the uncooperative patient. With the in-
troduction of very fast imaging techniques such as
turbo gradient spin-echo, echoplanar imaging
FLAIR, or half-fourier acquisition single-shot turbo
spin-echoFLAIR, scanning time can be reduced to a
few seconds.70 These sequences minimize motion ar-
tifacts in uncooperative patients. Although limita-
tions in signal to noise, contrast, and spatial
resolution are drawbacks of these techniques, large
lesions will be seen. Differences in lesion contrast
compared to conventional sequences and between
scanners due to different technologic implementation
must also be considered. More detailed evaluation of
the advantages and disadvantages of these ultrafast
methods is underway.71
Follow-up studies. Difficulties in diagnosis will
sometimes necessitate repeat MRI examinations.
Wherever possible, field strength and the imaging
protocol should be kept identical to the preceding
study if the same region of the CNS is examined.
This concerns not only the pulse sequence but also
image geometry such as slice position, thickness and
interslice gap, field of view, and matrix.
Suggestions for referral to MRI examination. The
clinical symptoms and signs in a given patient will
guide the clinicians decisions as to when to order an
MRI and what region of the CNS to have examined
(table 3).
Clinically isolated symptom suggestive of MS. MRI
of the brain is suggested in any patient presenting
with a clinically isolated symptom possibly attribut-
able to MS to collect supportive evidence and to rule
out other structural disorders. Whereas the use of
gadolinium may be superfluous in typical cases, its
overall use is strongly recommended. A complemen-
tary MRI examination of the spine is not necessary
in the absence of spinal cord symptoms although
cord lesions have been seen even in patients with
isolated optic neuritis72 or in those with normal brain
imaging.6 Unlike the incidental occurrence of cere-
bral hyperintensities with aging, they are a patho-
logic finding at all ages,59 and thus increase the
specificity of MRI especially in older patients.
MRI along the entire length of the spinal cord is
suggested in patients presenting with cord symp-
toms. This is both to exclude compression or other
treatable conditions and to search for support of MS.
Whereas demonstration of the symptomatic lesion
alone is not evidence for lesion dissemination in
August (1 of 1) 1999 NEUROLOGY 53 453
Table 3 Proposals for MRI examination regarding the clinical
setting of suspected or definitive MS
Disorder Proposed examination
Clinically isolated symptom
Presumed cerebral location MRI of the brain
Presumed spinal location MRI of the spine; MRI of the
brain recommended
Optic neuritis MRI of the brain recommended
Clinically definite MS
At initial evaluation MRI of the brain recommended;
MRI of the spine recom-
mended if brain findings
equivocal or in cases with
predominant spinal symptom-
atology, especially when
progressive
During course of the disease Consider repeat MRI of the
brain or repeat/first MRI of
the spine only if atypical
symptoms develop
space, it may nevertheless intuitively contribute to
diagnostic confidence. In this situation and in the
absence of any cord lesion, imaging of the brain to
detect additional lesions is worthwhile.30,48 Demon-
stration of more widespread affection of the CNS,
i.e., supportive evidence for MS, may become even
more important if the results of early treatment tri-
als are in favor of initiating immunomodulatory
treatment as soon as possible after the first clinical
event. These results will also affect the clinical need
for application of contrast material in patients with
isolated symptoms. Number and extent of cerebral
lesions have been repeatedly shown to parallel the
risk of conversion to clinically definite MS in pa-
tients with clinically isolated symptoms whether
they occur in the brain, spinal cord, or optic
nerves.38-41 Presence of a contrast-enhancing lesion
adds further predictive power22 and helps to satisfy
the MS criterion of lesion dissemination in time.
Clinically definite MS. Brain MRI is suggested
at least once in every patient with MS. A scan will
help to avoid admittedly rare but possible and poten-
tially treatable misdiagnosis. In addition, consider-
ing the costs of modern MS therapies, it is also
socioeconomically justified to avoid treatment of
non-MS patients by ensuring maximal diagnostic
certainty. If and how extent or pattern of lesions
could influence treatment decisions or serve to ex-
tract prognostic information is a matter of debate.3,42
Complementary MRI of the spine may be considered
for patients with equivocal brain findings and if spi-
nal cord symptomatology is predominant, such as is
often the case in primary progressive MS.
MRI follow-up examinations during the course of
MS will be needed rarely but can be important if
diagnostic issues arise. Again, they may be used to
clarify equivocal findings both in the brain and
454 NEUROLOGY 53 August (1 of 1) 1999
spine. Spinal MRI is also recommended in patients
with clinically definite MS who develop first or pro-
gressive spinal cord symptoms possibly attributable
to a different etiology.
Proposals for diagnostic interpretation. MRI
of the CNS is a very sensitive instrument for depict-
ing MS-related lesions. However, because of the vari-
ety of other etiologies of MRI signal changes, the
mere presence of lesions cannot suffice this purpose.
Limitations of previously suggested criteria for the
interpretation of MRI have been discussed above and
elsewhere.42,61 To circumvent these problems without
abstaining from a more MS-directed image interpre-
tation, we suggest indicating classes of evidence for
MS from MRI of the brain, spine, or both.
Class A: Supportive findings. This class com-
prises MRI lesions typical for MS based on their
location, shape, size, and contrast enhancement in-
cluding previously suggested sets of criteria (see ta-
ble 1).7,22,58 The respective criteria that have served
to label an MRI examination as consistent with
Class A findings should always be indicated.
Class B: Equivocal findings. This class com-
prises MRI changes that cannot be clearly attributed
to any one CNS disorder.
Class C: Normal findings. This class comprises
scans without any structural abnormality including
the absence of focal and diffuse signal changes.
Class D: Clinically significant non-MS findings.
This class comprises MRI abnormalities typical for
another CNS disorder that can also explain the pa-
tients symptoms, e.g. infarct, tumor, etc.
These classes can be used for relating MRI abnor-
malities of the brain or the spine to a referral diag-
nosis of suspected or definite MS with following
diagnostic implications:
Class A is in support of MS (in the setting of clini-
cal suspicion).
Class B and C neither refute nor support a diagno-
sis of MS. A normal MRI of the brain, however,
is clearly uncommon for MS.6
Class D rules against a diagnosis of MS.
This categorization does not obviate the need for
relating image interpretation to the clinical situa-
tion. A review of the MRI by the neurologist is al-
ways recommended for this purpose. Patients also
tend to appreciate and understand their situation
better if they have been shown the films. Judging the
probability of an MRI class in a given situation and
hence the plausibility of certain findings is impossi-
ble without knowledge of duration, stage, and course
of the disease. As an example, normal findings will
be expected more often in a patient with a first clin-
ical symptom suggestive of MS than in a patient
with an established course of relapsing-remitting
disease of several years duration. Categorization of
findings especially between Classes A and B will also
tend to vary somewhat with patient characteristics
such as age. In addition, equivocal findings of the
brain and spine can supplement each other to be-
come supportive.
By intention, proposed categories provide rather
loose rules on how to handle MRI findings. This is in
order not to endanger the needed interaction be-
tween clinician and interpreter by first steps to for-
mally integrate MRI into the entire process of MS
diagnosis. For research purposes, more strictly de-
fined and detailed MRI criteria can be formulated,
which will be the subject of a future review.
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The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis
F. Fazekas, F. Barkhof, M. Filippi, et al.
Neurology 1999;53;448
DOI 10.1212/WNL.53.3.448

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