CE: Tripti; WCO/310602; Total nos of Pages: 8;

WCO 310602

REVIEW

CURRENT
OPINION Multiple sclerosis: clinical aspects
Jiwon Oh a,, Angela Vidal-Jordana b,, and Xavier Montalban a,b

Purpose of review
Multiple sclerosis is a chronic, predominantly immune-mediated disease of the central nervous system, and
one of the most common causes of neurological disability in young adults globally. This review will discuss
the epidemiology, diagnosis, disease course, and prognosis of multiple sclerosis and will focus on recent
evidence and advances in these aspects of the disease.
Recent findings
Multiple sclerosis is increasing in incidence and prevalence globally, even in traditionally low-prevalence
regions of the world. Recent revisions have been proposed to the existing multiple sclerosis diagnostic
criteria, which will facilitate earlier diagnosis and treatment in appropriate patients. Classifying multiple
sclerosis into distinct disease phenotypes can be challenging, and recent refinements have been proposed
to clarify existing definitions. The prognosis of multiple sclerosis varies substantially across individual
patients, and a combination of clinical, imaging, and laboratory markers can be useful in predicting
clinical course and optimizing treatment in individual patients.
Summary
A number of recent advances have been made in the clinical diagnosis and prognostication of multiple
sclerosis patients. Future research will enable the development of more accurate biomarkers of disease
categorization and prognosis, which will enable timely personalized treatment in individual multiple
sclerosis patients.
Keywords
diagnosis, disease course, epidemiology, multiple sclerosis, phenotypes, prognosis, subtypes

INTRODUCTION median prevalence of multiple sclerosis is 33 per

Multiple sclerosis is a chronic autoimmune disease
of the central nervous system (CNS) in which
inflammation, demyelination, and axonal loss
occurs in even early stages of the disease. The
disease course can be extremely variable across
individual patients, and although significant treat-
ment advances have been made in recent years,
multiple sclerosis remains one of the most fre-
quent causes of neurological disability in young
people [1].
This review will summarize various clinical
aspects of multiple sclerosis, including epidemiol-
ogy, diagnosis, disease course, and prognosis, and
will focus on recent evidence and advances in our
understanding of these aspects of the disease.
EPIDEMIOLOGY
The onset of multiple sclerosis usually occurs in
young adulthood, between 20 and 40 years of age;
women are two to three times more frequently
affected than men, and this difference seems to be
increasing in some areas of the world [2]. The global
100 000 people, with significant variance between
different countries. North America and Europe have
the highest prevalence (with 140 and 108 per
100 000 people, respectively), and Asia and sub-
Saharan Africa countries have the lowest prevalence
(2.2 and 2.1 per 100 000 people, respectively) [3],
although there is substantial regional variation in
different parts of Asia (0.77 per 100 000 in Hong
Kong; 85.80 per 100 000 in Iran) [4]. Recent studies
have demonstrated an increasing prevalence dem-
onstrated in a number of regions, including north-
ern Japan (18.6 per 100 000) [5]. Regardless of
a
Division of Neurology, Department of Medicine, St. Michael’s Hospital,
University of Toronto, Toronto, Ontario, Canada and bCentre d’Esclerosi
Múltiple de Catalunya (Cemcat), Servei de Neurologia-Neuroinmunolo-
gia, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barce-
lona, Spain
Correspondence to Xavier Montalban, MD, PhD, 30 Bond Street, Shuter
3-046, Toronto, ON M5B1W8, Canada. E-mail: montalbanx@smh.ca

Jiwon Oh and Angela Vidal-Jordana contributed equally to this work.
Curr Opin Neurol 2018, 31:000–000
DOI:10.1097/WCO.0000000000000622

1350-7540 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-neurology.com

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: Tripti; WCO/310602; Total nos of Pages: 8;
WCO 310602
Special commentary
KEY POINTS
 Multiple sclerosis is increasing in incidence and
prevalence globally, even in traditionally low-
prevalence regions of the world.
 Recent revisions have been proposed to the existing
multiple sclerosis diagnostic criteria, which will facilitate
earlier diagnosis and treatment in appropriate patients.
 Classifying multiple sclerosis into distinct disease
phenotypes can be challenging, and recent refinements
have been proposed to clarify existing definitions.
 The prognosis of multiple sclerosis varies substantially
across individual patients, and a combination of
clinical, imaging, and laboratory markers can be useful
in predicting clinical course and optimizing treatment in
individual patients.
 Future research will enable the development of more
accurate biomarkers of disease categorization and
prognosis in multiple sclerosis, which will facilitate
clinical care.
prevalence, the incidence of multiple sclerosis seems
to be increasing globally [6].
The ultimate cause of multiple sclerosis is
unknown, and generally, a multifactorial cause is
accepted where both genetic and environmental
factors determine an individual’s disease risk in a
complex interplay that is not fully understood [2].
Thus, in genetically susceptible individuals, which
are mainly determined by the major histocompati-
bility complex, a number of modifiable environ-
mental factors likely play a role in determining
whether the individual will develop multiple sclero-
sis. Amongst environmental factors that have been
assessed, strong evidence supports an association
between Epstein–Barr virus infection, cigarette
smoking, low levels of vitamin D, and an increased
BMI during adolescence with a higher risk of devel-
oping multiple sclerosis. Some of these factors, such
as vitamin D levels and cigarette smoking, may also
influence the subsequent multiple sclerosis disease
course [2].
Compared with the general population, multi-
ple sclerosis patients have a higher mortality rate
and shorter lifetime expectancy of approximately
10 years, especially in multiple sclerosis patients
with comorbidities such as psychiatric disorders,
cerebrovascular and cardiovascular disease, diabetes
&
or cancer [7 ]. However, two recent studies using the
Danish and
Norwegian nationwide samples have described
an increased survival rate among patients with mul-
& &
tiple sclerosis over the past six decades [8 ,9 ].
2 www.co-neurology.com
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
DIAGNOSIS
The diagnosis of multiple sclerosis can only be
established with clinical and/or radiological demon-
stration of lesions in the CNS that are disseminated
in space (DIS) and time (DIT). Prior to the availabil-
ity of MRI, the presence of DIS and DIT was entirely
based on clinical findings (i.e. presence of two relap-
ses in two different CNS areas). Fortunately, with the
availability of MRI, the most recent criteria incorpo-
rate MRI findings to establish the presence of DIS
and DIT, which often allows for an earlier diagnosis,
which can facilitate earlier treatment, whenever
appropriate. In fact, after the occurrence of a clini-
cally isolated syndrome (CIS), with the 2010 McDo-
nald criteria, the diagnosis of multiple sclerosis can
be established with a single MRI if it fulfils DIS and
DIT criteria [10,11]. Although the McDonald criteria
can greatly facilitate the diagnosis of multiple scle-
rosis, it is essential to note that these criteria are only
of utility when applied in the appropriate clinical
context. Specifically, the diagnostic criteria should
only be applied to patients presenting with typical
CIS symptoms and the diagnosis of multiple sclero-
sis is still considered a diagnosis of exclusion and all
alternative diagnoses should be considered and
excluded. Table 1 summarizes common presenting
symptoms of multiple sclerosis.
MRI
MRI is the most sensitive tool to detect the presence
of brain and spinal cord lesions in multiple sclerosis,
and is also helpful to exclude other diseases [12].
Specific guidelines for the clinical implementation
of brain and spinal cord MRI in the multiple sclerosis
diagnostic process have recently been published [13]
Table 1. Common presenting symptoms of multiple
sclerosis
Topography Symptoms
Optic nerve Mononuclear painful vision loss
Spinal cord Hemiparesis, mono/paraparesis
Hypoesthesia, dysesthesia, paraesthesia
Urinary and/or faecal sphincter dysfunction
Brainstem and Diplopia, oscillopsy
cerebellum
Vertigo
Gait ataxia, dismetria
Intentional/postural tremor
Facial paresis and/or hypoesthesia
Cerebral Faciobrachial–crural hemiparesis
hemisphere
Faciobrachial–crural hemihypoesthesia
Volume 31  Number 00  Month 2018
CE: Tripti; WCO/310602; Total nos of Pages: 8;
WCO 310602
and are beyond the scope of this chapter. MRI has
become one of the most important paraclinical
tools to establish the diagnosis of multiple sclerosis.
Since the MRI was first taken into consideration for
the 2001 McDonald criteria [14], these criteria have
been revised and modified in order to simplify their
use without losing sensitivity and specificity
[11,15].
The 2010 McDonald diagnostic criteria speci-
fied, for the first time, that spinal cord and brain-
stem lesions should be asymptomatic in order to
include them to fulfil criteria to demonstrate DIS
[11]. Since then, two publications have analysed the
impact of including symptomatic lesions in the
diagnostic criteria [16,17]. Tintore et al. demon-
strated that in patients presenting with a CIS, and
compared with patients with a baseline normal
brain MRI, the presence of a single symptomatic
lesion conferred a higher risk of developing multiple
sclerosis during the follow-up period of 72–98
months. This increased risk in patients with a single
symptomatic lesion was similar to the increased risk
in patients with a single asymptomatic lesion [17].
Moreover, if the lesion in the symptomatic region
was included in the DIS criteria, the diagnostic
performance of the MRI criteria improved by
increasing the sensitivity without compromising
specificity [16,17].
In 2016, the Magnetic Resonance Imaging in
multiple sclerosis (MAGNIMS) network proposed a
number of modifications to the MRI diagnostic
criteria [18] for multiple sclerosis. One of the pro-
posals was to increase the number of periventricular
lesions needed to fulfil DIS from at least 1 to at least
3 [18]. Two subsequent studies evaluated the per-
formance of this modification to the diagnostic
criteria and concluded that using at least one peri-
ventricular lesion had a higher sensitivity with a
slightly lower specificity. However, when the DIS
and DIT diagnostic criteria were used simulta-
neously, the modification to the DIS criteria did
not affect performance with regards to ability to
diagnose multiple sclerosis at first presentation
[19,20].
Intracortical lesions are a common feature in
multiple sclerosis. Since publication of the 2010
criteria, three studies have evaluated the utility of
including intracortical lesions as a new region to
fulfil DIS criteria. These studies collectively found
that the inclusion of intracortical lesions increased
the criteria’s accuracy by improving specificity with-
out compromising sensitivity [19,21,22]. However,
as imaging and detection of intracortical lesions is
difficult to implement in most centres, a recommen-
dation was made to combine these lesions with the
juxtacortical topography [18,22].
1350-7540 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Multi ple sclerosis: clinical aspects Oh et al.
Laboratory tests
Blood tests are often requested as part of the routine
diagnostic work-up for multiple sclerosis. However,
routine testing of auto-antibodies is of limited util-
ity in patients presenting with a typical CIS [23].
Therefore, it would be reasonable to test for auto-
antibodies only when other symptoms suggestive of
other autoimmune diseases are also present.
The presence of IgG oligoclonal bands in CSF
that are absent in serum, together with an elevated
IgG index, are usually found in multiple sclerosis
patients. Although the CSF analysis is usually per-
formed to provide supportive evidence of multiple
sclerosis, with the 2010 McDonald diagnostic crite-
ria, CSF examination was not necessary to establish
the diagnosis. Two recent studies have evaluated the
role of CSF OB in multiple sclerosis diagnosis. Both
studies demonstrated that after presenting with a
CIS, the conversion rate to multiple sclerosis was
higher and within a shorter time interval in patients
presenting with CSF-specific oligoclonal bands
[24,25]. Demonstrating CSF-specific oligoclonal
bands was particularly of utility in patients with a
normal baseline brain MRI [24].
Recent modifications to the diagnostic
criteria
On the basis of accumulating evidence, many stud-
ies, which are summarized above, the McDonald
diagnostic criteria were recently reviewed and
&&
refined [26 ] to simplify and improve their diagnos-
tic utility. The main changes are: in a patient pre-
senting with a typical CIS and fulfilling DIS, the
presence of CSF-specific oligoclonal bands can be a
substitute to fulfilling DIT criteria, and can therefore
establish a diagnosis of multiple sclerosis, both
symptomatic and asymptomatic MRI lesions can
now be used to fulfil DIS and DIT, and cortical
and juxtacortical lesions can be used to fulfil MRI
&&
criteria for DIS [26 ] (Table 2). Regarding PPMS, the
diagnostic criteria remain largely unchanged, the
only exception being that the distinction between
symptomatic and asymptomatic lesions are no
longer needed.
DISEASE SUBTYPES AND COURSE OF
MULTIPLE SCLEROSIS
Traditionally, multiple sclerosis has been categorized
into four distinct clinical phenotypes: relapsing–
remitting (RRMS), secondary-progressive (SPMS), pri-
mary progressive (PPMS), and progressive relapsing
(PRMS) [27]. Although useful from a theoretical
standpoint, in clinical practice, this categorization
is often unable to adequately capture the complexity
www.co-neurology.com 3
CE: Tripti; WCO/310602; Total nos of Pages: 8;
WCO 310602
Special commentary
Table 2. 2017 revisions to the McDonald diagnostic criteria for multiple sclerosis
2010 McDonald criteria
Dissemination in space
Presence of at least one lesion in at least
two out of four CNS areas:
Periventricular
Juxtacortical
Infratentoriala
a
Spinal cord
Dissemination in time
A new T2 and/or Gd-enhancing lesion on follow-
up MRI, with reference to a baseline scan,
irrespective of the timing of the baseline MRI
Simultaneous presence of asymptomatic Gd-
enhancing and nonenhancing lesions at any time
CNS, central nervous system; CSF, cerebrospinal fluid; DIS, dissemination in space; DIT, dissemination in time; Gd, gadolinium; OB, oligoclonal bands.
a
If an individual has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the criteria and do not contribute to lesion count.
b
If an individual has a brainstem or spinal cord syndrome, the symptomatic lesions are NOT excluded from the criteria and CAN contribute to lesion count.
of disease phenotypes as there is often overlap
between clinical phenotypes, the transition between
relapsing–remitting and secondary-progressive mul-
tiple sclerosis is unclear, and classification is often
based on a patient’s recollection and description of
historical events. Further contributing to the com-
plexity of classification is that all multiple sclerosis
disease phenotypes share common characteristics,
and that there is no single clinical, imaging, or labo-
ratory characteristic that clearly differentiates
between disease subtypes. Although there can be
relative differences in a number of imaging and lab-
oratory markers between specific multiple sclerosis
subtypes (CSF and serum neurofilament levels, rate of
new lesion formation, rate of brain and spinal cord
&
atrophy [28–30,31 ,32,33]), none of these markers
can definitively differentiate accurately between
multiple sclerosis subtypes. As a result, multiple scle-
rosis disease subtype classification is still largely based
on clinical characteristics. A more accurate categori-
zation of multiple sclerosis subtypes would be useful
in numerous settings, including ensuring appropri-
ate patient selection in clinical trials, and for optimal
patient care in clinical practice.
Due to the recognition that traditional classifi-
cations of multiple sclerosis do not adequately cap-
ture the clinical spectrum of disease, recent
refinements have been proposed to traditional
descriptions of multiple sclerosis subtypes. Lublin
et al. [34] proposed that additional modifiers be
added to traditional categorizations, in an attempt
to add clinically relevant information to disease
4 www.co-neurology.com
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
New 2017 McDonald criteria
Dissemination in space
Presence of at least one lesion in at least two out of four CNS areas:
Periventricular
Cortical or juxtacortical
Infratentorialb
Spinal cordb
Dissemination in time
A new T2 and/or Gd-enhancing lesion on follow-up MRI, with
reference to a baseline scan, irrespective of the timing of the
baseline MRI
Simultaneous presence of asymptomatic Gd-enhancing and
nonenhancing lesions at any time
In patients fulfilling DIS, the presence of OB in CSF could
demonstrate DIT allowing MS diagnosis
categorizations. Specifically, each multiple sclerosis
subtype should include modifiers that convey addi-
tional information on disease activity (active vs. not
active) and disease progression, based on clinical
assessment and serial imaging (Fig. 1). For instance,
in a patient deemed to have RRMS, based on an
annual (or more frequent) clinical and imaging
assessment, additional modifiers confirming the
absence or presence of disease activity and disease
progression would assist in painting a more accurate
picture of the patient’s disease course. The same
should be done for patient deemed to have SPMS,
PPMS. The PRMS subtype can be eliminated, as this
phenotype is captured in PPMS with disease activity.
Although these modifications do not completely
capture the totality of a patient’s disease state, they
impart additional clarity to traditional definitions of
multiple sclerosis subtypes that can be helpful in
clinical and investigational settings.
Natural history studies have demonstrated that
the vast majority of patients present with relapsing–
remitting forms of multiple sclerosis, whereas 10–
20% of patients present with PPMS. In untreated
multiple sclerosis, the majority of RRMS patients
transition to SPMS after 10–20 years [35–39]. The
proportion of RRMS patients that transition to SPMS
in the modern era of increasing treatment options
with higher efficacies is unclear.
Recently, using MS Base, which is a large, Inter-
national Multiple Sclerosis Patient Registry, a num-
ber of definitions of SPMS were evaluated. The
definition of SPMS that performed best when
Volume 31  Number 00  Month 2018
CE: Tripti; WCO/310602; Total nos of Pages: 8;
WCO 310602

Multi ple sclerosis: clinical aspects Oh et al.

Clinically Not acve* Relapsing- Not acve*

isolated reming
syndrome disease
(CIS) Acve*,** (RRMS) Acve*

Acve* and with progression**

Progressive accumulaon
of disability from onset (PP) Acve but without progression
Progressive
Progressive accumulaon disease Not acve but with progression
of disability aer inial
relapsing course (SP) Not acve and without progression
(stable disease)

FIGURE 1. 2013 multiple sclerosis phenotype descriptions (adapted from Lublin et al. [34]). Activity determined by clinical
relapses assessed at least annually and/or MRI activity (contrast-enhancing lesions; new and unequivocally enlarging T2
lesions). CIS, if subsequently clinically active and fulfilling. Current multiple sclerosis (MS) diagnostic criteria, becomes
relapsing–remitting multiple sclerosis (RRMS). Progression measured by clinical evaluation, assessed at least annually. If
assessments are not available, activity and progression are ‘indeterminate.’ MS 5 multiple sclerosis; PP 5 primary progressive;
PR 5 progressive relapsing; SP 5 secondary progressive. CIS, clinically isolated syndrome.

compared with a consensus diagnosis was one that
included all of the following: absence of a relapse,
confirmed ‘three strata’ disability progression at
3 months with an increase in disability in the domi-
nant functional system, an expanded disability sta-
tus scale (EDSS) at least 4, and pyramidal functional
&
system score at least 2 [40 ]. ‘Three strata’ disability
progression refers to an increase in EDSS by at least
1.5 points if the last EDSS prior to SPMS conversion
was 0, an increase at least 1 if the prior EDSS was
between 1 and 5.5, or an increase greater than 0.5 if
the prior EDSS was greater than 5.5.
Although the time of transition to SPMS may
differ for individual RRMS patients, upon transi-
tioning to progressive multiple sclerosis, a number
of studies have demonstrated that the trajectory of
disease progression is identical once a moderate
level of disability is attained [41,42]. This observa-
tion suggests that the distinction between SPMS
and PPMS may not be meaningful, and highlights
the importance of earlier treatment of RRMS, as
treatment may be beneficial during a specific
window of opportunity, before significant disabil-
ity has accrued.
Benign multiple sclerosis has also been a fre-
quently described phenotype of multiple sclerosis,
typically referring to individuals with RRMS who
have only minimal disability (EDSS score  3.0) after
having had disease for a minimum of 10 years
[34,43]. However, because of increasing recognition
that multiple sclerosis is rarely a ‘benign’ disease
entity, and that neurological disability that is not
adequately captured by the EDSS scale such as cog-
nitive impairment frequently accumulates in indi-
viduals with so-called ‘benign’ multiple sclerosis,
this clinical designation is falling out of favour.
With further study, biomarkers of disease sub-
type will likely emerge that will enable improved
classifications of multiple sclerosis phenotype,
which will have both clinical and scientific utility.
Furthermore, prognostic biomarkers may emerge
that will have predictive value in the clinical setting,
which will have significant treatment implications.
This topic is covered in the next section.

1350-7540 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-neurology.com 5

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: Tripti; WCO/310602; Total nos of Pages: 8;
WCO 310602

Special commentary

PROGNOSTIC ASPECTS OF MULTIPLE greatest challenges encountered in clinical practice

SCLEROSIS
Both natural history and recent studies have dem-
onstrated that individual patients with CIS/RRMS
and PPMS demonstrate striking differences in dis-
ease activity and progression. As a result, one of the
because of the extreme variability of multiple scle-
rosis disease course is difficulty with prediction and
optimizing treatment at presentation.
A number of clinical, imaging, and laboratory
markers have emerged as useful prognostic factors.

FIGURE 2. Predictive value of baseline MRI lesion load in clinically isolated syndrome patients in: (a) developing multiple
sclerosis and (b) accumulating disability (previously published in Tintore et al. [45], used with permission from Oxford
University Press).

6 www.co-neurology.com Volume 31  Number 00  Month 2018

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: Tripti; WCO/310602; Total nos of Pages: 8;
WCO 310602
Earlier studies demonstrated that a number of
clinical factors, including older age, male sex, race,
topology of presenting relapse, frequent relapses,
and accumulation of disability after disease onset,
presence of lesions on baseline MRI, presence of
CSF-specific oligoclonal bands, and presence of
lesions in the spinal cord were predictive of a more
active or aggressive disease course [44–49] in CIS or
early RRMS.
More recent studies have demonstrated that
amongst a spectrum of clinical and imaging factors,
in multivariate models, baseline MRI lesion load,
and presence of CSF-specific oligoclonal bands are
the most predictive of conversion of CIS to multiple
sclerosis, and disability accrual over the ensuing 5–8
years (Fig. 2) [49].
Emerging evidence is accumulating far more
advanced imaging measures (whole-brain atrophy,
brain grey matter volume, spinal cord grey matter
volume) [50,51] and other laboratory markers,
&
including serum and CSF neurofilaments [31 ];
however, these biomarkers are still in developmen-
tal stages and not yet available for widespread
clinical use, though this may change in the
near future.
A number of evidence-based recommendations
exist that can predict treatment response in patients
on disease-modifying therapies, and this will be
covered in detail in a subsequent chapter in this
series [52,53].
Although there is not yet a single biomarker that
accurately predicts disease course in all patients, at
the current time, a combination of these clinical,
imaging, and laboratory markers, together with clin-
ical judgement are utilized to influence treatment
decisions in clinical practice.
CONCLUSION
Multiple sclerosis is a chronic, predominantly
immune-mediated disease of the CNS that affects
younger adults globally. Multiple sclerosis is char-
acterized clinically, radiologically, and patholog-
ically by lesions disseminated both in time and
space. Advances in imaging technology and ongo-
ing refinements of diagnostic criteria have enabled
earlier diagnosis and treatment, and attempts are
being made to further refine definitions of disease
phenotypes. The prognosis of multiple sclerosis
varies substantially across individual patients.
Together with clinical judgement, a combination
of clinical, imaging, and laboratory markers can be
useful in predicting clinical course and optimizing
treatment in individual patients. Future research
will enable the development of more accurate bio-
markers of disease categorization and prognosis,
1350-7540 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Multi ple sclerosis: clinical aspects Oh et al.
which will enable timely personalized treatment; a
great unmet need in multiple sclerosis clinical
practice.
Acknowledgements
J.O. receives grant support from: The MS Society of
Canada, the National MS Society, Biogen-Idec, and
Brain Canada. J.O. has received personal compensation
for consulting or speaking from EMD-Serono, Genzyme,
Biogen-Idec, Novartis, Teva, and Roche.
A.V.-J. receives support for contracts Juan Rodes (JR16/
00024) from Fondo de Investigaciones Sanitarias, Insti-
tuto de Salud Carlos III, Spain; and has received speaking
honoraria or consulting fees from Novartis, Roche and
Genzyme- Sanofi.
X.M. has received personal compensation for activities
with Biogen, Celgene, Sanofi Genzyme, Merck, Novartis,
Roche and Teva Pharmaceutical.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372:1502–1517.
2. Amato MP, Derfuss T, Hemmer B, et al. Environmental modifiable risk
factors for multiple sclerosis: Report from the 2016 ECTRIMS focused
workshop. Mult Scler 2017; doi: 10.1177/1352458516686847. [Epub
ahead of print]
3. Belbasis L, Bellou V, Evangelou E, et al. Environmental risk factors and
multiple sclerosis: an umbrella review of systematic reviews and meta-ana-
lyses. Lancet Neurol 2015; 14:263–273.
4. Eskandarieh S, Heydarpour P, Minagar A, et al. Multiple sclerosis epidemiol-
ogy in East Asia, South East Asia and South Asia: a systematic review.
Neuroepidemiology 2016; 46:209–221.
5. Houzen H, Kondo K, Horiuchi K, et al. Consistent increase in the prevalence
and female ratio of multiple sclerosis over 15 years in northern Japan. Eur J
Neurol 2018; 25:334–339.
6. Koch-Henriksen N, Sorensen PS. The changing demographic pattern of
multiple sclerosis epidemiology. Lancet Neurol 2010; 9:520–532.
7. Thormann A, Sorensen PS, Koch-Henriksen N, et al. Comorbidity in multiple
& sclerosis is associated with diagnostic delays and increased mortality. Neu-
rology 2017; 89:1668–1675.
This article analyses the effect of chronic comorbidity on the time of multiple
sclerosis diagnosis and mortality.
8. Koch-Henriksen N, Laursen B, Stenager E, et al. Excess mortality among
patients with multiple sclerosis in Denmark has dropped significantly over the
&
past six decades: a population based study. J Neurol Neurosurg Psychiatry
2017; 88:626–631.
This population-based study investigates life expectancy in multiple sclerosis
during a 60-year observation period.
9. Lunde HMB, Assmus J, Myhr KM, et al. Survival and cause of death in multiple
sclerosis: a 60-year longitudinal population study. J Neurol Neurosurg Psy-
&
chiatry 2017; 88:621–625.
This work investigates survival and causes of death in a 60-year population-based
multiple sclerosis cohort.
10. Montalban X, Tintore M, Swanton J, et al. MRI criteria for MS in patients with
clinically isolated syndromes. Neurology 2010; 74:427–434.
11. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple
sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;
69:292–302.
www.co-neurology.com 7
CE: Tripti; WCO/310602; Total nos of Pages: 8;
WCO 310602
Special commentary
12. Brownlee WJ, Hardy TA, Fazekas F, et al. Diagnosis of multiple sclerosis:
progress and challenges. Lancet 2017; 389:1336–1346.
13. Rovira A, Wattjes MP, Tintore M, et al. Evidence-based guidelines: MAGNIMS
consensus guidelines on the use of MRI in multiple sclerosis-clinical imple-
mentation in the diagnostic process. Nat Rev Neurol 2015; 11:471–482.
14. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria
for multiple sclerosis: guidelines from the International Panel on the diagnosis
of multiple sclerosis. Ann Neurol 2001; 50:121–127.
15. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple
sclerosis: 2005 revisions to the ‘McDonald Criteria’. Ann Neurol 2005;
58:840–846.
16. Brownlee WJ, Swanton JK, Miszkiel KA, et al. Should the symptomatic region
be included in dissemination in space in MRI criteria for MS? Neurology 2016;
87:680–683.
17. Tintore M, Otero-Romero S, Rio J, et al. Contribution of the symptomatic
lesion in establishing MS diagnosis and prognosis. Neurology 2016;
87:1368–1374.
18. Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of
multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 2016;
15:292–303.
19. Arrambide G, Tintore M, Auger C, et al. Lesion topographies in multiple
sclerosis diagnosis: a reappraisal. Neurology 2017; 89:2351–2356.
20. Brownlee WJ, Miszkiel KA, Altmann DR, et al. Periventricular lesions and MS
diagnostic criteria in young adults with typical clinically isolated syndromes.
Mult Scler 2017; 23:1031–1034.
21. Filippi M, Rocca MA, Calabrese M, et al. Intracortical lesions: relevance for
new MRI diagnostic criteria for multiple sclerosis. Neurology 2010;
75:1988–1994.
22. Preziosa P, Rocca MA, Mesaros S, et al. Diagnosis of multiple sclerosis: a
multicentre study to compare revised McDonald-2010 and Filippi-2010
criteria. J Neurol Neurosurg Psychiatry 2017; 89:316–318.
23. Negrotto L, Tur C, Tintore M, et al. Should we systematically test patients with
clinically isolated syndrome for auto-antibodies? Mult Scler 2015;
21:1802–1810.
24. Huss AM, Halbgebauer S, Ockl P, et al. Importance of cerebrospinal fluid
analysis in the era of McDonald 2010 criteria: a German-Austrian retro-
spective multicenter study in patients with a clinically isolated syndrome. J
Neurol 2016; 263:2499–2504.
25. Arrambide G, Tintore M, Espejo C, et al. The value of oligoclonal bands in the
multiple sclerosis diagnostic criteria. Brain ; 141:1075–1084.
26. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis:
&& 2017 revisions of the McDonald criteria. Lancet Neurol 2017; 17:162–173.
New multiple sclerosis diagnostic criteria.
27. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis:
results of an international survey. National Multiple Sclerosis Society (USA)
Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis.
Neurology 1996; 46:907–911.
28. De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a
large population of untreated multiple sclerosis subtypes. Neurology 2010;
74:1868–1876.
29. Gass A, Rocca MA, Agosta F, et al. MRI monitoring of pathological changes in
the spinal cord in patients with multiple sclerosis. Lancet Neurol 2015;
14:443–454.
30. Kidd D, Thorpe JW, Kendall BE, et al. MRI dynamics of brain and spinal cord in
progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;
60:15–19.
31. Novakova L, Zetterberg H, Sundstrom P, et al. Monitoring disease activity in
& multiple sclerosis using serum neurofilament light protein. Neurology 2017;
89:2230–2237.
This work examines the serum neurofilament light as a potential biomarker for
disease activity.
8 www.co-neurology.com
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
32. Rocca MA, Horsfield MA, Sala S, et al. A multicenter assessment of cervical
cord atrophy among MS clinical phenotypes. Neurology 2011;
76:2096–2102.
33. Moccia M, de Stefano N, Barkhof F. Imaging outcome measures for pro-
gressive multiple sclerosis trials. Mult Scler 2017; 23:1614–1626.
34. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of
multiple sclerosis: the 2013 revisions. Neurology 2014; 83:278–286.
35. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis
assessed by the computerized data processing of 349 patients. Brain 1980;
103:281–300.
36. Debouverie M, Laforest L, Van Ganse E, et al. Earlier disability of the patients
followed in Multiple Sclerosis centers compared to outpatients. Mult Scler
2009; 15:251–257.
37. Tedeholm H, Skoog B, Lisovskaja V, et al. The outcome spectrum of multiple
sclerosis: disability, mortality, and a cluster of predictors from onset. J Neurol
2015; 262:1148–1163.
38. Tremlett H, Yinshan Z, Devonshire V. Natural history of secondary-progressive
multiple sclerosis. Mult Scler 2008; 14:314–324.
39. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple
sclerosis: a geographically based study. I. Clinical course and disability. Brain
1989; 112(Pt 1):133–146.
40. Lorscheider J, Buzzard K, Jokubaitis V, et al. Defining secondary progressive
& multiple sclerosis. Brain 2016; 139(Pt 9):2395–2405.
Performance evaluation of different objective definitions for secondary progressive
multiple sclerosis.
41. Kremenchutzky M, Rice GP, Baskerville J, et al. The natural history of multiple
sclerosis: a geographically based study 9: observations on the progressive
phase of the disease. Brain 2006; 129(Pt 3):584–594.
42. Leray E, Yaouanq J, Le Page E, et al. Evidence for a two-stage disability
progression in multiple sclerosis. Brain 2010; 133(Pt 7):1900–1913.
43. Reynders T, D’Haeseleer M, De Keyser J, et al. Definition, prevalence and
predictive factors of benign multiple sclerosis. eNeurologicalSci 2017;
7:37–43.
44. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progres-
sion of irreversible disability in multiple sclerosis: an amnesic process. Brain
2003; 126(Pt 4):770–782.
45. Tintore M, Rovira A, Rio J, et al. Defining high, medium and low impact
prognostic factors for developing multiple sclerosis. Brain 2015; 138(Pt
7):1863–1874.
46. Degenhardt A, Ramagopalan SV, Scalfari A, et al. Clinical prognostic factors
in multiple sclerosis: a natural history review. Nat Rev Neurol 2009;
5:672–682.
47. Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis inci-
dence cohort with twenty-five years of follow-up. Brain 1993; 116(Pt
1):117–134.
48. Sombekke MH, Wattjes MP, Balk LJ, et al. Spinal cord lesions in patients with
clinically isolated syndrome: a powerful tool in diagnosis and prognosis.
Neurology 2013; 80:69–75.
49. Kuhle J, Disanto G, Dobson R, et al. Conversion from clinically isolated
syndrome to multiple sclerosis: a large multicentre study. Mult Scler 2015;
21:1013–1024.
50. Perez-Miralles F, Sastre-Garriga J, Tintore M, et al. Clinical impact of early
brain atrophy in clinically isolated syndromes. Mult Scler 2013;
19:1878–1886.
51. Schlaeger R, Papinutto N, Panara V, et al. Spinal cord gray matter atrophy
correlates with multiple sclerosis disability. Ann Neurol 2014; 76:568–580.
52. Freedman MS, Selchen D, Arnold DL, et al. Treatment optimization in MS:
Canadian MS Working Group updated recommendations. Can J Neurol Sci
2013; 40:307–323.
53. Sormani MP, Rio J, Tintore M, et al. Scoring treatment response in patients
with relapsing multiple sclerosis. Mult Scler 2013; 19:605–612.
Volume 31  Number 00  Month 2018