MULTIPLE
SCLEROSIS
Prognostic Factors in
Multiple Sclerosis
Prediction of highly active disease and rapid disability accumulation is crucial to
optimizing clinical outcomes over time.
By Adrian Espiritu, MD and Jiwon Oh, MD, PhD
Multiple sclerosis (MS) is a chron-
ic, inflammatory, predominantly
demyelinating condition of the
central nervous system (CNS)
that has a wide range of presenta-
tions, disease courses, and treat-
ment responses. Owing to the clinical heterogeneity of MS, an
awareness of key features that have predictive value to identify
those with a higher likelihood of having highly active disease
and developing rapid disability accumulation is crucial to opti-
mizing clinical outcomes over time. With the broad and con-
tinually increasing armamentarium of MS disease-modifying
treatments (DMTs), there is an opportunity to tailor treatment
decisions on an individual level to optimize clinical outcomes.
In this review, we discuss potential prognostic factors in MS,
including demographics, clinical characteristics, MRI measures,
and laboratory tests that may have utility in clinical practice
to predict conversion of clinically isolated syndrome (CIS) and
radiologically isolated syndrome (RIS) to MS (Table 1) and dis-
ease activity and disability accumulation (Table 2).
Demographic and Clinical Characteristics
Age at MS onset is known to impact MS disease course,
and increasing age at onset correlates with decreased time to
onset of specific disability milestones (eg, Expanded Disability
Status Scale [EDSS] scores of 4.0, 6.0 and 7.0).1 Although lower
age at onset is associated with a longer time to onset of dis-
ability milestone, individuals who present with MS earlier in
life often acquire significant disability at an earlier age com-
pared with individuals with onset later in life.1 Among people
with CIS, lower age of onset was associated with an increased
risk of conversion to clinically definite MS (CDMS).2 Similarly,
among people with RIS, lower age at diagnosis was indepen-
dently associated with a higher risk of developing a first clini-
cal event consistent with MS at 5 and 10 years of follow-up.3,4
Numerous studies have suggested that male sex negatively
influences long-term disability outcomes and is associated
with a shorter time to disability accrual in MS.1,5-7 This asso-
ciation may be dependent on disease subtype, considering
44 PRACTICAL NEUROLOGY FEBRUARY 2022
a study evaluating both relapsing-remitting MS (RRMS) and
primary progressive MS (PPMS) found median times from
disease onset to EDSS score of 6.0 were 18 and 22.7 years for
male and female individuals, respectively but not significant-
ly different between male and female persons with PPMS.6
Conversely, another study demonstrated in multivariate
analyses that sex was not a significant predictor of disability.8
Although epidemiologic studies show female persons
are more likely to develop MS, meta-analysis of 9 studies
(n=1,116) in people with CIS over approximately 4 years
showed no statistically significant increase in female per-
sons for conversion to CDMS (odds ration [OR], 1.2; 95%
CI, 0.98 to 1.46).9 Moreover, a large cohort study among
people with CIS showed that both sexes studied had simi-
lar risks of developing CDMS and disability progression.2
Conversely, among people with RIS followed for 5 years,
male sex was independently associated with a nearly two-
fold elevated risk of developing an initial clinical event.3
Subsequent 10-year follow-up of these individuals, how-
TABLE 1. FACTORS ASSOCIATED WITH
CONVERSION FROM CLINICALLY ISOLATED
OR RADIOLOGICALLY ISOLATED SYNDROMES
TO MULTIPLE SCLEROSIS
From clinically Younger age at onset
isolated High T2 lesion burden at baseline
syndrome to
Presence of cerebrospinal fluid-specific OCBs
multiple sclerosis
Presence of infratentorial lesions at baseline
From Younger age at diagnosis (< 37 years)
radiologically Male sex
isolated
Presence of infratentorial lesion at baseline
syndrome to
multiple sclerosis Presence of spinal cord lesion at baseline
Presence of cerebrospinal fluid-specific OCBs
Presence of gadolinium-enhancing lesions
on follow-up MRI
Abbreviations: OCBs, oligoclonal bands

TABLE 2. FACTORS ASSOCIATED WITH A
HIGHER RISK OF POOR CLINICAL OUTCOMES
IN MULTIPLE SCLEROSIS
Demographic Older age at onset
and clinical Sex (male)
features
Social construct of race /ethnicity
(Black and Hispanic/Latinx people and those
with Middle Eastern, North African, or Asian
ancestry compared with white people or those
of Northern European ancestry)
Cardiovascular comorbidities (eg, diabetes,
hypertension, heart disease, peripheral
vascular disease, hypercholesterolemia)
Psychiatric co-morbidities (eg, depression,
anxiety, bipolar disorder)
Smoking
Disease- Number of relapses during initial years after onset
related
Brief interattack intervals
clinical
Poor recovery from first relapse
features
Pyramidal symptoms at onset
Cerebellar symptoms at onset
Sphincteric symptoms at onset
Cognitive symptoms at onset
Clinical presentation other than optic neuritis
Multifocal presentation at onset
Progression at onset
Rapidly worsening disability
MRI features New T2 lesions over time
Gadolinium-enhancing lesions at baseline
Infratentorial lesions at baseline
Spinal cord lesions at baseline
Laboratory Presence of cerebrospinal fluid-specific
measures oligoclonal bands
ever, showed that male sex was no longer a significant pre-
dictor of developing CDMS.4
In a US-based study, Black and Hispanic/Latinx people with
MS had more rapid disability accumulation than white peo-
ple with MS, even after adjusting for age, gender, and insur-
ance type.10 In a study from Toronto, Ontario, Canada, peo-
ple with MS of Middle Eastern or North African ancestry had
disease phenotypes that were different compared with an
age- and sex-matched group of people with MS of Northern
European ancestry. Those of Middle Eastern or North African
ancestry had greater disability progression over time, despite
evidence of inflammatory disease activity, based on clinical
MULTIPLE
SCLEROSIS
relapses and MRI lesions, that was similar to individuals of
Northern European ancestry.11 Another study found that
white people with MS were only half as likely as the rest of
the population studied (ie, those of African or Asian ancestry,
Hispanic/Latinx people, and others) to have an early clinical
event within the first year of MS disease onset.12
A large cohort study of 8,983 people with MS showed hav-
ing cardiovascular comorbidities at MS onset or diagnosis
significantly correlated with more rapid disability accumula-
tion.13 In addition, the presence of 1 or more vascular comor-
bidities (eg, diabetes, hypertension, heart disease, peripheral
vascular disease, or hypercholesterolemia) at any point in
the disease course independently increased the risk of early
gait disability (EDSS 4.0) and needing unilateral (EDSS 6.0) or
bilateral (EDSS 6.5) assistance to walk by 58%, 54%, and 38%,
respectively.13 Another cohort study showed that a 1-point
increase in Framingham risk score was associated with a 31%
elevated relapse risk, 19% increased risk of reaching EDSS score
of 6.0, and 62% higher risk of DMT escalation over a 5-year
follow-up period.14 Obesity at age 11 to 20 years has been
shown to increase the risk of developing MS.15 Finally, psychi-
atric comorbidities in people with MS, including depression,
anxiety, and bipolar disorder, independently correlate with
higher disability over a 10-year follow-up period.16
Several studies have identified a link between smoking and
increased risk of disability progression in MS. A meta-analysis
of 8 studies that including various subtypes of MS and CIS
(n=4,030), with follow-up periods ranging from 2 to 5.2 years,
showed that smoking increases EDSS score by 0.15 points.17
Disease-Related Clinical Features
Higher relapse activity in the initial few years of MS is asso-
ciated with an elevated risk of reaching disability milestones
(ie, EDSS scores 3.0, 6.0, or 8.0) or having secondary progres-
sion.6.,18,19 Relapses during the first year of treatment are pre-
dictive of disability progression within the next 3 years; the
likelihood increases twofold with 1 relapse and threefold with
2 or more relapses in the first year.20
The interval between relapses and recovery from relapses
has also been shown to be relevant to clinical outcomes. A
study showed an interval of fewer than 2 years between a first
and second relapse was associated with an 80% increased risk
of reaching an EDSS score of 3.0.19 Another showed that MS
with short (0-2 years) or intermediate (3-4 years) interattack
periods had a significantly shorter time from disease onset to
reaching an EDSS score of 6.0 compared with longer interattack
intervals (≥6 years) at 18.2, 21.0, and 25.9 years, respectively.18
Poor recovery after the first attack was also independently
associated with increased risk of progression to EDSS scores of
3.0 and 6.0 by a factor of 13.2 and 5.3, respectively, even after
adjusting for a wide range of potential confounders, including
relapse frequency and the interval between relapses.19
FEBRUARY 2022 PRACTICAL NEUROLOGY 45
 MULTIPLE
SCLEROSIS
Relapse topology has prognostic value in MS. Initial
relapses characterized by involvement of pyramidal, cerebel-
lar, sphincter, or cognitive domains are associated with poor
outcomes. The risks of developing EDSS 6.0 (median time
12 years from onset) and secondary progression (median
time 11 years from onset) nearly triple when the initial
relapse involves the pyramidal or cerebellar systems.19 Over
almost 10 years of follow up from onset, the risks of reach-
ing an EDSS of 4.0 or 6.0 are increased by nearly 70% and
100% in those with sphincteric symptoms at onset.21 Among
those with cognitive impairment at MS onset, the risk of
acquiring global disability based on an increase in EDSS
was higher than in those without cognitive impairment at
8 years.22 Finally, a multifocal presentation at onset is linked
to an elevated risk of poor clinical outcomes with a 1.6 and
2.2 times higher risk of reaching EDSS scores of 4.0 and 6.0,
respectively, over nearly 10 years from onset.21
The topology of the clinical presentation may also have
prognostic relevance in CIS. Individuals with CIS presenting
with optic neuritis at onset have a 40% and 50% lower risk of
converting to CDMS and reaching an EDSS score of 3.0, respec-
tively. Furthermore, when adjusted for other relevant variables,
optic neuritis was not significantly associated with conversion
to CDMS, and was only marginally significant for risk of an
EDSS of 3.0. (adjusted hazard ratio [HR] 0.6, 95% CI 0.4-1.0).2
People with PPMS have an earlier median time to acquir-
ing disability milestones compared to those with RRMS.7 In
natural history studies, median time to EDSS score 6.0 in PPMS
is 10 years compared with almost 22 years in RRMS.6,21,23 The
rate of disability progression is strongly associated with overall
disability accumulation in the long term. Multivariate analyses
showed that baseline EDSS scores and change in EDSS scores
from baseline to 2 years are associated with an increased risk of
EDSS of 6.0 or more after 8 years.24 In addition, a shorter time
to reaching moderate disability in a single neurologic domain
(ie, EDSS 3.0) independently predicts a shorter time to severe
global disability with EDSS scores of 6.0, 8.0, and 10.0.18
MRI Features
Numerous MRI measures have prognostic value in MS,
including the number of T2-hyperintense lesions at baseline—
among the most important factors influencing development
of disability milestones. In people with CIS/MS who have
0, 1 to 3, 4 to 9, and 10 or more T2 lesions at baseline, the pro-
portions with EDSS 6.0 or more 20 years later were 6%, 18%,
35%, and 45%, demonstrating the relevance of baseline MRI
lesion load.25 A large 6-year study of persons with MS who
presented with optic neuritis found correlations with sub-
sequent disability accumulation with, in decreasing order of
importance, new T2 lesions, new gadolinium-enhancing (Gd+)
lesions, baseline enhancing lesions, baseline T2 lesion number,
and baseline T2-lesion volume.26,27 A 7-year cohort study of
46 PRACTICAL NEUROLOGY FEBRUARY 2022
people with CIS showed baseline MRI lesion load was among
the most important predictors of developing MS and dis-
ability progression. In this study, the presence of 1 to 3, 4 to 9,
and more than 10 T2 lesions independently correlated with
5.1-, 7.5-, and 11.3-times increased risk of developing CDMS.
Having 10 or more T2 lesions was associated with a nearly
threefold elevated risk of disability progression.2
The development of new T2 lesions on serial MRI is widely
used as a marker of treatment response because studies
have shown the prognostic value of T2 lesion development
while using DMTs. Developing new lesions beyond a certain
threshold is associated with disability progression over time.
This has led to the development of treatment algorithms that
are used in clinical practice, including the modified Rio score,
the Canadian MS Working Group Treatment Optimization
Recommendations, and many others.28,29 These scoring sys-
tems incorporate clinical features (relapses) and MRI findings
to aid clinical decision-making in RRMS.
Gd+ lesions also have prognostic value. Meta-analysis of
31 randomized controlled trials comprising 18,901 cases of
MS found having Gd+ or new/enlarging MRI lesions within
6 to 9 months of initiating treatment correlated with relapses
within 12 to 24 months.30 Among those with CIS, a baseline
MRI with 2 or more Gd+ lesions independently increased the
risk of secondary progressive MS by a factor of 3.2 after 15 years
of follow-up.31 The presence of Gd+ lesions may have predic-
tive value in RIS as well. Although Gd+ lesions at baseline do
not appear to predict RIS converting to MS over 5 to10 years
of follow up, the presence of Gd+ lesions on a follow-up MRI
seemed to elevate the risk of clinical evolution by 80% in a uni-
variate analysis at 10-year follow up.3,4
Having infratentorial lesions at baseline is associated with
future disability accumulation in CIS or RIS. In a small study
of 42 people with CIS followed for 8.7 years, having 2 or more
infratentorial lesions at baseline increased the risk of an EDSS
score of 3.0 approximately sixfold.32 A larger study of 246 peo-
ple with CIS observed for 8 years revealed that those with
infratentorial lesions within 3 months of onset had a 3.3‑times
higher risk of conversion to CDMS and a 2.4-times higher
likelihood of reaching EDSS score 3.0.33 Similarly, in RIS, there
may also be prognostic value of baseline infratentorial lesions.
Although an initial 5-year follow-up study did not show pre-
dictive value of an infratentorial lesion in developing an initial
demyelinating event, a 10-year follow-up study showed base-
line infratentorial lesions are predictive of conversion to MS.3,4
A higher number of spinal cord lesions at baseline has
been associated with a higher risk of relapse over approxi-
mately 3 years.34 In those with CIS, baseline spinal cord
lesions and new spinal cord lesions at 1 year independently
elevate the risk of developing MS by 4.7 and 5.7 times after
15 years, respectively.31 The presence of cervical or thoracic
cord lesions raises the risk of a first clinical event by threefold

according to a 5-year cohort study of RIS,3 and the prognos-
tic value persisted in a 10-year follow-up study.4
T1-hypointense lesions or T1-black holes are identifiable
on conventional MRI and known to be associated with high-
er disability in MS.35 A meta-analysis that pooled 27 stud-
ies comprising 1,919 cases showed a moderate correlation
between T1 hypointense lesion volume and EDSS score.35 T1
lesion volume, however, can be difficult to ascertain in clini-
cal practice. Development of T1 lesions on subsequent MRI
has not been definitively validated as useful in clinical prac-
tice; therefore, this measure is not used routinely.26
Whole brain atrophy or atrophy of smaller structures
affected by MS in the CNS (eg, brain substructures and spi-
nal cord) are associated with clinical disability in numerous
studies.36,37 Whole-brain atrophy is associated with cognitive
impairment and mood disturbance,22 and spinal cord cross-
sectional area and gray matter atrophy correlate with clinical
disability.38,39 Whole-brain atrophy has also been widely used
in phase 3 clinical trials, and there is a clear association with
clinical disability and treatment effect.36 Despite their clinical
relevance and use in clinical trials, however, no quantita-
tive measures of atrophy are widely used in clinical practice
because of several obstacles, including the need for specific
MRI sequences, time and technical expertise needed to uti-
lize volume quantification software, and lack of clear guide-
lines for use in clinical practice, among other challenges.40
Laboratory Measures
The only laboratory measure widely available and with
clearly demonstrated prognostic value at this time for MS
is cerebrospinal fluid (CSF)-specific oligoclonal band (OCB)
testing. A meta-analysis of 4 studies comprising 1,918 cases
showed the presence of CSF-specific OCBs increased risk of
reaching clinical disability landmarks (ie, EDSS 4.0 or 6.0 or an
increase in EDSS) by nearly twofold.41
The presence of CSF-specific OCBs in CIS independently
elevated the risk of conversion to CDMS by 30% and the risk of
disability accumulation twofold.2 In addition, in RIS, the 10-year
risk of developing an initial clinical event was 1.7 times higher
in those with more than 2 unique OCB or greater than a 0.7
IgG index in the CSF after adjusting for other factors.4
Neurofilament light chain (NfL) is a neuronal cytoskeletal
protein that can be measured in the CSF or blood and indi-
cates neuronal injury when elevated. In MS, elevated NfL likely
reflects neuroaxonal damage driven by inflammation, and
emerging studies suggest this may have prognostic value.42 In
clinical trials and longitudinal cohorts, serum NFfL correlated
with relapses, Gd+ lesions, disability progression, and short-
term treatment response.43-45 Longer term correlations are less
established, although a number of studies support serum NfL
as a weak predictor of longer-term disability accumulation.46,47
Serum NFL is not yet used in clinical practice owing to a num-
MULTIPLE
SCLEROSIS
ber of obstacles, including access to testing, cost, and lack of
validated clinical algorithms for use in individuals. Considering
the emerging data, however, it seems likely that NfL measure-
ments may be integrated with clinical and other paraclinical
measures in the near future for use in clinical practice.
Conclusions
In the past few decades, there has been a substantial para-
digm shift regarding treatment approaches in MS that is likely
a result of increased understanding of the pathophysiology
and disease course of MS and accumulating evidence of the
importance of early treatment and rapid treatment optimiza-
tion.28,29 The need for personalized medicine has become all
the more apparent with the ever-increasing range of treat-
ment options with markedly different risk-benefit profiles.
A knowledge of prognostic factors in MS, which range from
demographic, clinical, imaging based, and laboratory based,
is essential for practitioners. Understanding how to apply
these factors in clinical practice is necessary to enable a more
refined therapeutic approach. Prognosis for individual patients
will likely require integrating these factors, as well as clinical
judgment to make optimal treatment decisions, which will
ultimately improve clinical outcomes in MS. n
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Adrian I. Espiritu, MD
Division of Neurology, Department of Medicine
St. Michael’s Hospital, University of Toronto
Toronto, Ontario, Canada
Department of Neurosciences
Department of Clinical Epidemiology
College of Medicine and Philippine General Hospital
University of the Philippines Manila
Manila, Philippines
Jiwon Oh, MD, PhD
Waugh Chair in MS Research
Division of Neurology, Department of Medicine
St. Michael’s Hospital, University of Toronto
Toronto, Ontario, Canada
Department of Neurology
Johns Hopkins University
Baltimore, MD
Disclosures
AIE reports no disclosures
JO has disclosures at www.practicalneurology.com

48 PRACTICAL NEUROLOGY FEBRUARY 2022