Continuous evolution of magnetic resonance imaging in multiple sclerosis
J Neurol
Continuous evolution of magnetic resonance imaging in multiple sclerosis
E. C. Tallantyre 0 1
N. P. Robertson 0 1
0 Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University , Cardiff , UK
1 & N. P. Robertson
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Since the introduction of MR imaging into routine clinical
practice in the 1990s, it has become firmly embedded into
the diagnostic criteria of multiple sclerosis (MS).
Furthermore, serial MR brain imaging is increasingly being used
to complement contemporary clinical assessment of MS
disease activity. Clinical imaging in MS largely relies upon
the detection of T2-hyperintense and T1-gadolinium
enhancing lesions, as surrogate markers of foci of
inflammatory demyelination in the white matter. Beyond the
scope of conventional clinical imaging, advanced MR
technology is now capable of detecting and quantifying
pathology in tissue compartments previously thought to be
unaffected in MS. The appreciation of microscopic damage
within the ‘‘normal-appearing white matter’’ and grey
matter of the brain and spinal cord has considerably
advanced our knowledge of the pathophysiology of MS.
In this month’s journal club we describe three papers
that relate to MR imaging in MS. This first paper describes
the latest MR criteria for MS diagnosis. The second paper
describes the imaging characteristics of the radiologically
isolated syndrome and how they, along with clinical
factors, relate to the subsequent onset of symptomatic
demyelinating disease. The third paper uses advanced MR
technology to uncover the regional pattern of cortical
atrophy in MS and its relationship to white matter
pathology and clinical disability.
MRI criteria for the diagnosis of multiple sclerosis:
MAGNIMS consensus guidelines
Many patients who present with clinical syndromes typical
of inflammatory-demyelination in the CNS are found to
have subclinical lesions on MRI scans. The detection of
subclinical brain or cord lesions with typical morphology
predicts a higher risk of subsequent conversion to MS.
Indeed, since 2001 the diagnostic criteria of MS have
permitted MR imaging to confirm the diagnosis of MS,
either at baseline or after an interval in an individual with a
typical clinical syndrome. The MR imaging criteria
stipulate the conditions in which the requirements for
dissemination of demyelination in space and time can be made in
those who have experienced a single clinical attack or a
progressive course from onset.
This paper describes the most recent refinement of the
MR criteria used to define MS, based on the most
contemporary imaging data and techniques. The guidelines are
based on the findings of an international workshop, held in
March 2015 under the auspices of MAGNIMS (a European
collaborative research network that studies the use of MRI
in MS). Recommendations are based on both expert
opinion and literature review.
The main changes to existing MRI criteria relate to the
definition of dissemination in space. The new criteria
propose that the optic nerve is incorporated as one of five
lesion locations (along with periventricular, infratentorial,
cortical/juxtacortical and spinal cord) that can be used to
define dissemination in space. The presence of lesions in
two out of these five areas is deemed sufficient evidence to
define dissemination in space. In all except the
periventricular region, only one lesion is required to be present.
These most recent guidelines suggest that at least three
periventricular lesions should be required to establish
dissemination in space at this location, in view of the low
specificity of a solitary periventricular lesion. No
distinction is required between lesions considered to be
symptomatic or asymptomatic.
The criteria for dissemination in time remain
unchanged: the detection of either one new T2 lesion or one new
gadolinium-enhancing lesion after any interval, or the
coexistence of enhancing and non-enhancing lesions at any
time. In these new recommendations, interval spinal cord
imaging is not recommended in asymptomatic individuals
for clarification about dissemination in time as clinically
silent cord lesions are recognised to be rare.
Comment
These new criteria incorporate the most recent evidence
and opinion in the field and in some ways they reflect a
simplification of the older criteria (for example avoiding
the clinical dilemma of whether a lesion is symptomatic,
which can be challenging outside of the optic nerve and
spinal cord). However, these new criteria may also be an
unwelcome change for our reporting radiologists and for
the minority of individuals whose diagnosis becomes
altered, given that prospective validation of sensitivity and
specificity in a longitudinal clinical cohort has not yet been
demonstrated.
It is important to stress that these criteria only apply to
those individuals who have a clinical presentation that is
typical of MS. The MR criteria for dissemination in space
and time could readily be met in individuals with certain
other neurological conditions. So it is crucial to remember
that the diagnosis of MS lies additionally in the exclusion of
any better explanation for the symptoms. The new proposal
to apply these MR criteria to individuals with a
radiologically isolated syndrome (uncovered inadvertently when
imaging for another reason) is aimed at facilitating a prompt
diagnosis whenever symptoms typical of CNS
demyelination occur, but it may also enhance our understanding of the
pre-clinical phase of MS (see Kantarci et al. below).
Filippi et al. (2016) Lancet Neurol 15:292–303.
Primary progressive multiple sclerosis evolving from radiologically isolated syndrome
Increasing use of MR scanning and improvements in MR
technology have led to the relatively frequent identification
of individuals who have incidental lesions in the brain or
spinal cord. However, the concept of a ‘‘radiologically
isolated syndrome’’ (RIS) of MS is a relatively recent
phenomenon. First described in the literature in 2009, RIS
describes the incidental finding of CNS lesions that have a
morphology and location typical for
inflammatory-demyelination (the latter is established using the Barkhof
criteria), and which cannot be explained by another
process, including cerebral small vessel disease. RIS has since
been shown to convert to symptomatic MS in around a
third of individuals over a 5-year period, with higher risk
conferred by young age, male sex and spinal cord lesions at
baseline.
In this paper, the authors have used a comparison of the
imaging features of RIS according to whether individuals
go on to develop a relapsing or primary progressive (PP)
phenotype of MS, to provide insights into whether these
disease subtypes should be regarded as separate entities.
Increasingly, it is recognised that individuals entering a
progressive phase of MS share many common
characteristics, irrespective of whether they progress from the time
of symptom-onset (PPMS) or following a relapsing-onset
of symptoms (secondary progressive MS). This raises the
possibility of a shared, common biology of focal
inflammatory-demyelinating CNS lesions, and suggests that any
distinction between these subtypes may be on arbitrary
clinical grounds of whether any demyelinating lesion was
symptomatic before the detection of progressive disability.
The authors describe the outcomes of a multi-centre RIS
cohort of 453 patients. These individuals have been
retrospectively identified but prospectively followed-up for
clinical evidence of symptomatic CNS demyelination for
durations ranging between 0.2 and 20 years. Baseline MRI
features were analysed, in combination with clinical and
demographic variables, to determine their value in
predicting a relapsing versus primary progressive
symptomonset. Of the 453 patients, 128 developed symptoms in
keeping with CNS inflammatory-demyelination. Of these,
113 (88 %) had a relapsing phenotype while 15 (12 %) had
a primary progressive phenotype. Median time to
conversion was 3.5 years in those who developed PPMS. The
presence of at least one enhancing lesion and the presence
of at least one spinal cord lesion were both more common
in individuals who developed any form of symptomatic
CNS demyelination. Subjects who evolved to PPMS were
more likely to be male sex, older and to have at least one
spinal cord lesion compared with those who had a
relapsing-onset of symptoms. Perhaps surprisingly, there was no
significant difference in the proportion of enhancing
lesions between the relapsing- and progressive-onset
groups. Neither was there any significant difference in
time-to-conversion or CSF findings between those who
developed relapsing versus progressive symptoms.
Comment
The similarities presented here in the subclinical
disease activity of individuals with a relapsing-onset and
progressive-onset MS, supports the notion that the
mechanisms of progression are likely to be similar in these two
subgroups. The radiological predilection towards the spinal
cord in PPMS is in keeping with the prevailing clinical
phenotype in this subgroup. But it remains unexplained
why radiological disease activity is less likely to manifest
clinically as relapses in those with PPMS.
Studying the natural history of RIS prospectively at a
population-level would pose a huge challenge of resources.
Naturally, the randomness of case identification and
absence of systematic follow-up in this study introduces
potential for bias. But overall this study demonstrates the
value of international collaborative endeavour in the study
of rare diseases, or in this case, preclinical syndrome.
Kantarci et al. (2016) Ann Neurol 79:288–294
Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant
The presence of grey matter pathology was documented in
the earliest histopathological descriptions of MS. But grey
matter pathology has received renewed interest in the last
decade since demyelination of the grey matter was
demonstrated to be widespread and to be a focus of
neuroaxonal injury. Advanced MRI such as volumetry,
diffusion-weighted imaging and magnetization-transfer imaging
have all provided useful information on the extent and
clinical relevance of grey matter pathology in MS. Grey
matter atrophy has been shown to occur during the earliest
stages of MS, but is most prominent in the later,
progressive phase of the illness. Grey matter atrophy has been
demonstrated to represent neuro-axonal loss and correlates
more closely with physical and cognitive disability than
any white matter imaging marker. But uncertainty remains
over the cause of grey matter atrophy in MS and whether it
is a diffuse process or adheres to a more regional pattern.
In this paper, the authors studied the pattern of cortical
thickness in 208 patients with MS and 60 healthy controls.
Using a novel technique called source based morphometry
they sought to detect covariance in regional cortical
thickness that was disseminated in space but related as part
a functional network. Patients underwent detailed
neuropsychological testing and physical examination to allow
correlation of the clinical and imaging findings.
Results revealed ten discrete co-varying patterns of
cortical thickness, of which six were more prominent in
MS. Most of the patterns were non-random, symmetric and
localized to known networks such as sensorimotor, limbic
or default mode networks. As expected, global cortical
thickness was lower in individuals with MS versus healthy
controls. However, the presence of certain patterns of
cortical atrophy showed more clinical relevance than
global cortical atrophy. Higher EDSS was associated with
cortical atrophy patterns including the bilateral
sensorimotor and insular cortices. Combined with age and global
cortical thickness, regional patterns explained 29 % of the
variance in EDSS. Reduced cognitive ability was
particularly associated discrete cortical atrophy patterns involving
the limbic system and default mode network in a model
explaining 43 % of the clinical variance. The addition of
white matter imaging metrics into these models only
marginally improved the explanation of clinical measures.
Those cortical atrophy patterns that differed most
between MS and control participants were strongly
associated with T2 lesion load but not with measures of
normalappearing white matter integrity. The relationships between
white matter lesions and cortical atrophy differed
according to clinical MS subgroups suggesting that some cortical
regions remain more sensitive to white matter pathology
throughout the entire course of MS.
Comments
While imaging lacks the sensitivity or specificity of
histopathology, it offers the enormous advantage of
longitudinal study and insights into disease at all time-points.
This paper illustrates how these strengths offer the
potential to unravel some of the mysteries underlying CNS
disease pathophysiology. The findings of this study led the
authors to hypothesise that white matter demyelination
initially drives cortical atrophy in anatomically connected
regions. They suggest that neuronal loss within ‘‘cortical
hubs’’ then leads to secondary (trans-synaptic)
degeneration in other anatomically connected cortical regions across
a network. One of the limitations of the paper,
acknowledged by the authors, is that white matter demyelination
was not defined on a network-level, only globally in the
whole brain. It may be that future studies can further refine
this hypothesis by relating pathological changes in all
anatomical domains of a network, longitudinally within
individuals.
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