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American Journal of Psychiatry and Neuroscience
2015; 3(3): 40-49
Published online March 30, 2015 (http://www.sciencepublishinggroup.com/j/ajpn)
ISSN: 2330-4243 (Print); ISSN: 2330-426X (Online)
Brain atrophy in Multiple Sclerosis
, Seifer Gustavo
, Kuperman Gaston
, Villa Andrés María
Department of Neurology, British Hospital, Buenos Aires, Argentina
Department of Neurology, José María Ramos Mejía Hospital, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
Department of Medicine, Novartis Argentina
email@example.com (G. Seifer)
To cite this article:
Rugilo Carlos, Seifer Gustavo, Kuperman Gaston, Villa Andrés María. Brain atrophy in Multiple Sclerosis. American Journal of Psychiatry
and Neuroscience. Vol. 3, No. 3, 2015, pp. 40-49. doi: 10.11648/j.ajpn.20150303.11
Multiple sclerosis (MS) has traditionally been considered to be primarily an inflammatory demyelinating disorder
affecting the white matter. Nowadays it is recognized as both an inflammatory and a neurodegenerative condition involving the
white and grey matter. Grey matter atrophy occurs in the earliest stages of MS, progresses faster than in healthy individuals,
and shows significant correlations with cognitive function and physical disability; indeed, brain atrophy is the best predictor of
subsequent disability and can be measured using magnetic resonance imaging (MRI). There are a number of MRI methods for
measuring global or regional brain volume, including cross-sectional and longitudinal techniques. Preventing brain volume loss
may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating
an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be
important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article summarizes the
knowledge on brain volume in MS.
Multiple Sclerosis, Brain Atrophy, Brain Volume Loss
Multiple sclerosis (MS) is a chronic disorder of the central
nervous system (CNS), characterized pathologically by
multifocal areas of inflammation and demyelination in the
brain and spinal cord that evolve over time, and clinically by a
variable course. Most patients develop significant locomotor
disability in 15-20 years after onset [1-4]. In approximately
85% of patients who develop MS, clinical onset is
characterized by an acute episode of neurological deficit due
to a single lesion within the CNS, and is known as a clinically
isolated syndrome (CIS) [2, 3].
While long recognized as a feature of late stages and/or
particularly severe MS, brain volume loss (atrophy) was
recently recognized and understood as occurring early in the
majority of patients with MS even in CIS and radiological
isolated syndrome (RID) patients [5-8]. (Figure 1) It was
thought to reflect the underlying permanent neuronal damage,
and is associated with irreversible disease progression and
clinical disability [5, 7, 9]. Both, gray matter (GM) and white
matter (WM) appear to manifest neurodegeneration, as
reflected by tissue atrophy [10-12] and it may be, at least in
part, independent of the degree of active inflammation
associated demyelination. This has led to considerable interest
in the development of protective strategies aimed at
preventing degeneration of axons, and thereby slowing or
halting the progression of disability in MS.
Atrophy measures are already becoming standard in many
MS treatment trials . Atrophy measures are complementary
to conventional magnetic resonance imaging (MRI) measures
of gadolinium enhancement, T1 hypointense and T2
hyperintense lesion volume.
In contrast to MRI-visible lesions, CNS atrophy is believed
to reflect the net effect of severe and potentially irreversible
processes such as demyelination and axonal loss.
Measurement of the size of CNS structures may provide an
indication of the total amount of tissue damage that has
occurred up to a given point in time.
Figure 1. Evolution in time of the pathophysiology of MS.
41 Rugilo Carlos et al.: Brain atrophy in Multiple Sclerosis
2. Pathophysiology of Atrophy in MS
First of all it is important to understand that the pathology
underlying atrophy is the result of multiple mechanisms, and
these mechanisms may not be constant over time in
individuals and populations.  More and less aggressive
variations may be associated with disease phenotype and,
possibly, histopathology types [14-17]. Disease phenotypes
and lesions at various stages are responsible of composite of
(transient) volume-gaining (edema by inflammatory
demyelination) and volume-losing processes obtained by MRI
volumetry. Inflammation and its transiently increased volume
effects can confound the interpretation of atrophy measures
after successful treatment, when treatment reduces the
inflammatory CNS volume, causing a pseudoatrophy [18, 19].
When axonal injury occurs, several potential mechanisms
could explain the amplifying functional and structural
consequences, the latter resulting in additional volume loss.
These include Wallerian degeneration (axonal distal segment)
and retrograde or anterograde transneuronal degeneration [20,
Na+ channels and axonal degeneration
The available evidence suggests that Na+ channels are
important participants in axonal degeneration in MS. Nav1.6
are the predominant Na+ channel isoform found in axonal
membranes in the CNS in mature nodes of Ranvier [22, 23].
When an axon is demyelinated acquires higher and diffuse
expression of Nav1.6 producing a persistent Na+ current that
can drive the Na+–Ca2+ exchanger to operate in a reverse
mode, importing Ca2+ and triggering secondary cascades and
axonal damage [23, 24]. In addition, NO-induced
mitochondrial damage, changes in mitochondrial gene
expression, and hypoxia/ischaemia due to perivascular
inflammation seem to contribute to axonal energy failure,
which in turn leads to loss of function of Na+/K+ ATPase and
impaired ability of the axon to maintain resting potential and
to export Na+ [25, 26]. Great Ca2+ influx into the axon
triggers calcium-induced calcium release from internal stores,
and the activation of NO synthase, proteases and lipases.
Nav1.6 channels are also involved in the activation of
microglia and macrophages, which contribute to the
production of NO, and in phagocytosis by these cells .
It is also possible that some axons degenerate in MS in the
absence of demyelination. Therefore, if the inadequacy of ATP
supply in MS occurs in neurons in which axons are not
demyelinated, the axons might be suffered Ca2+-mediated
injury [26, 27].
3. Methods for Measuring Brain Atrophy
The MRI methods available to measure brain volume fall
into two main categories: longitudinal or cross-sectional
segmentation-based (cross-sectional) and registration-based
(longitudinal) techniques. Longitudinal methods measure
change in brain volume over time by comparing two MRI
scans acquired at different time points . Cross-sectional
methods measure brain volume at a single time point using a
single MRI scan (Table 1).
Segmentation techniques can measure the whole brain
volume or any specific brain structure. Within the
segmentation-based method is the BPF, which measure the
ratio between brain parenchymal tissue with the total
intracranial volume (cerebrospinal fluid and brain tissue). BPF
is an automatic method that takes into account the variability
of head size . The quantitative two dimensional measures
of lateral or third ventricular volume/width can be used easily
in daily practice .
In the registration-based method, serial scans of the patients
are compared, the SIENA is an automatic method
registration-based with longitudinal purpose and limited
regional analysis. SIENAX is its cross sectional variant .
The other method is the voxel-based morphometry (VBM)
which allows the entire brain to be explored regional with
cross sectional or longitudinal purposes [32, 33].
BPF and SIENA are the most frequently used methods to
measure brain volume in clinical practice and in MS trials
Table 1. Most common MRI methods to measure brain volume loss in MS.
Ventricular volumes (VV)
Structural Image Evaluation, using Normalisation of Atrophy (SIENA)
Structural Image Evaluation, using Normalisation of Atrophy - cross
Brain Parenchymal Fraction (BPF)
Voxel-Based Morphometry (VBM)
4. Which is the Annual Rate of Atrophy
and is Stable Process over Time
As healthy people age, brain volume decreases as part of a
normal process. It has been estimated that this rate of annual
brain volume loss in healthy subjects ranges from 0.1% to
0.3% [34, 37]. Studies have shown that the rate of brain
volume loss in patients with MS is higher, ranging from 0.5%
to 1.3% annually [12, 38-42].
The rate of brain atrophy in an individual patient may be
affected by a number of factors, MS phenotype, toxic agents,
genetic factors and the presence of MS inflammatory lesions.
Patients with the apolipoprotein E-ε4 genotype showed an
annual increase in brain volume loss five times higher than in
patients without this genotype , although other studies
could not show this relation with brain atrophy .
The estimates of brain atrophy rates have varied between
studies when compared different MS subtypes. Many studies
have shown higher or similar [9, 38, 41, 45, 46] atrophy
progression in secondary progressive MS (SPMS) patients
when compared to those at earlier stages of MS. De Stefano et
al,  found heterogeneity in percent brain volume change
(PBVC) across MS subtypes and different stage disease.
Interestingly, however, this heterogeneity disappeared when
PBVC values were corrected for the baseline normalized brain
volume (NBV). This suggests that the rate of atrophy
progression is very similar in the different MS subtypes and, at
late disease stages, does not seem to show nonlinear
American Journal of Psychiatry and Neuroscience 2015; 3(3): 40-49 42
progression  or a true acceleration . For the patients
with CIS, brain atrophy rates are greater in patients who are
worsening clinically. This indicate that measures of brain
atrophy should have relevance on clinical progression.
Perhaps measures of gray matter atrophy could show
correlation with measures of cognitive impairment [47, 48].
5. How Early Begins the Atrophy and
which is the Gray Matter Damage
MS was traditionally considered to be primarily a white
matter disorder, it has become apparent during the last decade
that brain atrophy and specially grey matter atrophy, occurs
from the earliest stages. Many studies support the idea of an
early onset of whole brain atrophy, specially grey matter
atrophy, in the first year after CIS and predicts conversion in
Filippi et al  found that in early MS, mean whole brain
NAA was reduced by 22% compared with healthy controls (p
< 0.0001) and this change did not correlate with T2-lesion
volume (diffuse damage). This finding suggests that
widespread irreversible axonal pathology is independent of
MRI-detectable inflammation and is present at early stages of
disease, perhaps even before diagnosis [40, 52, 53].
Brain atrophy rates are higher in those CIS patients who
subsequently develop MS compared with those who remain
CIS [50, 53-55]. In the ETOMS (Early Treatment of Multiple
Sclerosis) trial, a difference in median annual PBVC was
found between patients who developed clinical definitive MS
(CDMS) versus patients who did not (0.92% and 0.56%,
respectively) . Pérez-Miralles et al  also found similar
results, those patients with a second attack had larger PBVC
change (-0.65% versus +0.059%; p < 0.001) concluding that
global brain and grey matter volume loss occurred within the
first year after a CIS and predicts conversion to MS.
Several studies show that gray matter volume loss in MS
occurs early in the disease, both deep gray (eg. thalamus) as
well as the cortical gray matter [58-60]. Dalton et al 
showed that progressive gray matter, and not white matter
atrophy, was seen in the population progressing to a diagnosis
of MS after a CIS and is related to physical disability and
It was reported that neocortical atrophy was a prominent
feature of relapsing remitting MS (RRMS), and suggested that
neocortical atrophy occurs in the earliest stages of MS and is
even seen when white matter lesion accumulation is minimal
[12, 39, 57, 59]. Many studies have shown that in MS patients
there is diffuse cortical atrophy and thinning of the cerebral
cortex. Sailer et al.  showed that the mean overall
thickness of the cortical ribbon in MS patients was 2.30 mm,
compared with 2.48 mm in healthy controls. In addition,
patients with severe disability and/or long-standing course
showed marked focal thinning of the motor cortex (mean 2.35
mm vs 2.74 mm) . Other studies of early MS showed
greater atrophy of gray matter than of white matter [51, 59,
It has been shown that the normalised thalamic volume in
MS patients was decreased by an average of 17%, compared
with healthy controls, and the mean width of the third
ventricle was increased by two-fold .
It is unknown whether these losses are due to focal or more
diffuse gray matter pathology, nor the relative contribution of
direct axonal injury nor retrograde degeneration [61, 63, 64].
The pattern of cortical atrophy in patients with RRMS were
found in the anterior cingulate cortex, the insula and the
transverse temporal gyrus . This pattern differs from that
seen in normal ageing, in which, the atrophy occurs mainly in
the primary motor and premotor cortices, the prefrontal cortex
and the calcarine cortex .
6. Clinical Signification
One of the MRI measures that have been proposed to assess
MS progression (physical and cognitive disability) is the
estimation of brain and spinal atrophy [5, 41, 48, 67-71]. Due
to a relative short follow-up periods of 6 months to 3 years,
previous longitudinal studies in MS have not shown consistent
or strong relation between brain atrophy and disability [30, 72,
Gray matter atrophy correlates and predicts both physical
and cognitive disability in MS patients [74-78].
Fisher et al  showed the relation between atrophy
progression and later neurologic disability, suggesting that
atrophy progression during RRMS is clinically relevant and
may be used as useful marker for disease progression. Amato
et al. have shown that in patients with radiological isolated
syndrome, 27.6% of patients have signs of cognitive
impairment similar to those of RRMS . Fisniku et al 
showed that GM, but not WM, fraction correlated with
expanded disability status scale (p < 0.001) and MS
Functional Composite scores (p < 0.001). Corpus Callosum
(CC) atrophy was associated with cognitive impairment
measured with the verbal fluency test (VFT), Symbol Digit
Modalities Test (SDMT) and Paced Auditory Serial Addition
Test (PASAT). The atrophy of the anterior CC segment was
significantly associated with fatigue severity and poor
outcome in the long-term memory test . Using various
cognitive tests, localized cortical atrophy in the prefrontal,
parietal, temporal and insular regions has been associated with
deficits in verbal memory, information processing speed and
attention [82, 83]. Sailer et al.  showed significant
negative correlations between Expanded Disability Status
Scale (EDSS) scores and global cortical thickness (p= 0.011)
and the mean thickness of the motor cortex (p= 0.001).
Similary, in a case-control study there were significant
negative correlations between EDSS scores and the thickness
of the right parahippocampal (p ≤0.01), left lateral occipital (p
≤0.01) and left postcentral cortex (p≤0.001), and between
EDSS scores and the volumes of the right caudate (p ≤0.01)
and right nucleus accumbens (p ≤0.01) . Rudick et al. 
found a correlation between progression of grey matter
atrophy and Multiple Sclerosis Functional Composite (MSFC)
scores, but not between atrophy and EDSS scores.
43 Rugilo Carlos et al.: Brain atrophy in Multiple Sclerosis
Cognitive impairment, affecting attention, memory and
information processing speed, may be present in up to 70% of
MS patients [86, 87], and within first years in the disease .
In a study of patients with RRMS, the cognitive impairment
was correlated with significantly smaller normalised brain
volumes and normalised neocortical grey matter volumes than
those with normal cognition . Cortical atrophy appears to
be a good predictor of cognitive impairment, because even
mild impairment has been shown to be associated with
significant cortical thinning . Significant correlations have
also been reported between cognitive impairment and
thalamic atrophy .
The deep gray matter volumes (basal ganglia and especially
the thalamus) are correlated with disability and cognitive
impairment, with information processing speed [91, 92],
fatigue [81, 93] and EDSS scores [94, 95].
In general, prospective studies with interferon- (IFN) β and
glatiramer acetate (GA) have shown limited and inconsistent
evidence for a beneficial effect on brain atrophy (Table 2).
Table 2. Brain volume outcomes
Treatment Phase Duration Clinical type n Results
Placebo controlled trials
IFN-ß 1b SC Phase III 5 years CIS 468 NS
IFN-ß 1b SC Phase III 3 years SPMS 718 NS
IFN-ß 1a IM Phase III 2 years RRMS 172 NS
IFN-ß 1a SC Phase III 2 years CIS 309 NS
GA Phase III 1.5 years RRMS 207 SIG
GA Phase III 5 years CIS 409 SIG (early vs delayed tx)
Natalizumab Observational 2 years RRMS 39 SIG (WM)
Natalizumab Phase III 2 years RRMS 942 NS
Fingolimod Phase III 2 years RRMS 1272 SIG
Laquinimod Phase III 2 years RRMS 1331 SIG
Laquinimod Phase III 2 years RRMS 1106 SIG
Teriflunomide Phase III 2 years RRMS 1088 NS
DMF Phase III 2 years RRMS 540 SIG (bid), NS (tid)
DMF Phase III 2 years RRMS 681 NS
Active comparator controlled trials
IFN-ß 1b SC (vs GA) Phase III 3.5 years RRMS 2244 NS
IFN-ß 1a IM (dose comparison) Phase III 3 years RRMS 189 SIG
GA (vs INF ß) Post hoc 2 years RRMS 86 SIG (GM)
GA (vs IFN ß) Retrospective 5 years RRMS 275 SIG
Daclizumab (vs IFN, GA) Post hoc 11 years RRMS 70 SIG
Natalizumab (vs IFN ß) Pilot study 1.5 years RRMS 26 SIG
Alemtuzumab (vs IFN-ß 1a SC) Phase II 3 years RRMS 334 SIG
Alemtuzumab Phase III 2 years RRMS 840 SIG
Alemtuzumab Phase III 2 years RRMS 581 SIG
Fingolimod Phase III 1 year RRMS 1292 SIG
bid: twice daily, CIS: clinically isolated syndrome, DMF: dimethyl fumarate, GA: glatiramer acetate, GM: grey matter, IFN: interferon, IM: intramuscular, NS:
not significant, SIG: significant, RRMS: relapsing remitting MS, SPMS: secondary progressive MS, tid: three times daily, WM: white matter
Today we know that the pathophysiology of MS involves
inflammation, neurodegeneration and the failure of the repair
mechanisms. Classically the disease modifying treatments
have controlled the inflammatory component of the disease.
Recently, various trials have begun to evaluate the rate of
brain volume loss have yielded mixed results for the reasons
The need of drugs not only against the inflammatory
process is obvious, but also we need drugs that prevent or
reduce the progression of brain atrophy and/or facilitate the
Currently, there is no disease modifying therapy available
that completely stop the evolution from RRMS to the
progressive phase of the disease.
Zivadinov et al,  investigated the effects of intravenous
methylprednisolone on brain atrophy and disability
progression of 88 patients with RRMS. Patients received
either pulsed intravenous methylprednisolone (IVMP) (1
American Journal of Psychiatry and Neuroscience 2015; 3(3): 40-49 44
g/day for five days with oral prednisone taper) every four
months for three years and then every six months for two
subsequent years, or IVMP (1 g/day for five days with oral
prednisone taper) only for relapses, without other disease
modifying drugs. At the end of the five-year period, treatment
with pulsed IVMP significantly slowed development of T1
black holes (p < 0.0001), slowed brain atrophy and disability
progression (p = 0.003) .
For subcutaneous interferon β 1a,  , a study of 519
patients over two years with relapsing MS, found no treatment
effect. For IFN β 1b (8 MIU subcutaneous) in relapsing MS,
no large trial data are available.
In study of 227 patients with relapsing MS no atrophy was
detected with GA, over the nine-month double-blind phase of
the study .
In TEMSO trial changes of brain volume did not differ
significantly among the three study groups (teriflunomide 7
mg vs placebo, p=0.19; teriflunomide 14 mg vs placebo
Dimethyl fumarate (BG-12) presents inconsistent data
relating to the decrease in brain volume loss in the two
published trials against placebo. In the CONFIRM study the
difference fail to reach statistical power . In the DEFINE
study the difference was significant in the 240 mg twice daily
arm, but not in 240 mg three times daily arm .
Decreases in brain atrophy in RRMS patients have also
been reported with laquinimod .
Fingolimod have shown consistent data about decrease
brain volume loss in its three pivotal trials and their extensions
(Figure 2). In FREEDOMS trial,  fingolimod
significantly reduced the brain volume loss over 2 years,
compared with placebo (relative reduction, 35%; p<0.001), in
the FREEDOMS II  trial patients given placebo had
increased brain volume loss compared with those given
fingolimod at months 6, 12, and 24 (relative reduction, 33%;
p<0.001), and in the TRANSFORMS trial,  fingolimod
treatment resulted in a significantly lower rate of brain atrophy
than intramuscular IFNβ-1a (relative reduction, 32%;
Figure 2. Brain volume loss in phase III trials of Fingolimod (*p=0.05, **p=0.01, ***p=0.001).
MS was historically considered as an inflammatory disease
of the white matter (focal damage). Today there is much
evidence that supports, in addition, the affection of the gray
matter and neurodegenerative mechanisms, which are at least
partially independent of the inflammation.
The atrophy of the GM develops faster than WM atrophy
and predominates in early disease stages. The
neurodegenerative mechanism, produces permanent damage
and appears to correlate with physical and cognitive disability
of the patient.
Given this, it is vital the early treatment of MS with drugs
that control the inflammatory component and reduce the rate
of brain volume loss.
Conflict of Interests
Dr. Gustavo Seifer is Medical Scientific Liaison (MSL) for
Dr. Gaston Kuperman is Medical Manager for Novartis
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