Journal of Neurology
https://doi.org/10.1007/s00415-021-10674-8
REVIEW
Outcome measures assisting treatment optimization in multiple
sclerosis
Gabriel Pardo1
· Samantha Coates2 · Darin T. Okuda3
Received: 2 February 2021 / Revised: 14 June 2021 / Accepted: 16 June 2021
© The Author(s) 2021
Abstract
Objective To review instruments used to assess disease stability or progression in persons with multiple sclerosis (pwMS)
that can guide clinicians in optimizing therapy.
Methods A non-systematic review of scientific literature was undertaken to explore modalities of monitoring symptoms
and the disease evolution of MS.
Results Multiple outcome measures, or tools, have been developed for use in MS research as well as for the clinical management of pwMS. Beginning with the Expanded Disability Status Scale, introduced in 1983, clinicians and researchers have
developed monitoring modalities to assess all aspects of MS and the neurological impairment it causes.
Conclusions Much progress has been made in recent decades for the management of MS and for the evaluation of disease
progression. New technology, such as wearable sensors, will provide new opportunities to better understand changes in
function, dexterity, and cognition. Essential work over the decades since EDSS was introduced continues to improve our
ability to treat this debilitating disease.
Keywords Multiple sclerosis · Monitoring modalities · Function · Dexterity · Cognition
Introduction
Multiple sclerosis (MS) is an inflammatory neurologic disease with a varied presentation, and diagnosis is made clinically [1–4]. Once diagnosed, the type and speed of symptom
progression in MS vary, making the clinician’s job of assessing disease evolution and treatment responses a perpetual
challenge.
Multiple outcome measures, or tools, have been developed for use in MS research and clinical management of
persons with MS (pwMS). Such tools have been designed
to help determine the progression and severity of disease, including inflammatory activity [clinical relapses
or new magnetic resonance imaging (MRI) lesions] and
* Gabriel Pardo
gabriel-pardo@omrf.org
1
OMRF Multiple Sclerosis Center of Excellence, Oklahoma
Medical Research Foundation, 820 NE 15th Street,
Oklahoma City, OK 73104, USA
2
Excel Medical Affairs, Horsham, UK
3
Department of Neurology, University of Texas Southwestern,
Dallas, TX, USA
neurodegeneration (progression in absence of relapses).
These tools are also used to identify evidence of a response
to treatment. To ensure effective use, the practicing clinician
must first gain an understanding of the benefits and downsides of each tool to determine whether to incorporate it into
a patient’s evaluation and therapeutic decisions. If the tool is
to be incorporated, the clinician must then consider how to
effectively implement it and interpret the results. Currently,
only a few of the tools in existence are commonly used in
research and patient management [5].
Here we provide an overview of tools that can be used
to evaluate the functional (Table 1) and neuroanatomical
(Table 2) components of MS, highlighting new data on
potential MS biomarkers and how they may be utilized by
clinicians in the future. Some patient-reported outcome
tools are presented in Table 3 for reference, but they are
not detailed in this review. Our aim is to enable clinicians
to more accurately assess stability or progression in pwMS
and to guide treatment optimization, even in subclinical
progression.
The different instruments are presented in three categories: functional, describing evaluations of motor, ambulation, and cognitive performance; anatomical, reviewing
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Table 1 Commonly used tools for the assessment of functional change in individuals with multiple sclerosis
Test
Function tested
T25FW [19] Walking disability
6MWT [30] Gait
TUG [39]
Basic mobility
9-HPT [50]
Dexterity (upper extremity
[hand/arm] funsction)
Description
Measures time (in seconds) to walk 25 feet
Equipment
∙ Unobstructed open space
measuring 25 feet (no turns
permitted)
∙ Timer (e.g., stopwatch)
∙ Mechanism for recording
scores (e.g., pen and paper)
∙ Assistive walking devices
(optional)
Measures distance walked ∙ Unobstructed open space
(turns permitted)
(in meters) in 6 min
∙ Assistive walking devices
may be used
∙ Timer (e.g., stopwatch)
∙ Mechanism for recording
score (e.g., pen and paper)
∙ Assistive walking devices
(optional)
∙ 2-armed chair positioned
Measures the time taken
(in seconds) to stand
in a space that allows a
from a chair, walk a fixed 10-foot walk
∙ Assistive walking devices
distance, return, and sit
down
may be used
∙ Timer (e.g., stopwatch)
∙ Mechanism for recording
score (e.g., pen and paper)
∙ Assistive walking devices
(optional)
∙ Table and chair
Measures time taken (in
∙ Shallow container with 9
seconds) or speed (in
pegs/second) to complete pegs and a block containthe task
ing 9 holes for the pegs to
fit in
∙ Timer (e.g., stopwatch)
Process
Utility
∙ Ask individual to walk the
distance as quickly and safely as
possible, stopping beyond the
finish point to avoid a reduction
in speed
∙ Repeat once
∙ Routine management ∙ 20% change [19, 23, 24]
and clinical trials
∙ Ask individual to walk for 6 min
at maximal speed
∙ Clinical practice and
clinical trials
∙ Ask individual to rise from the
chair, walk to a mark 10 feet
away, turn, and return to a seated
position
∙ Repeat (once or twice)
∙ Clinical practice to
∙ Improvement of 23–24%
monitor effects of
and deterioration of
medical and rehabili30–31% [40]
tation treatment
∙ Ask the individual to sit and,
∙ Clinical practice and
using 1 hand, put pegs 1 at a
self-assessment, and
time into the holes as quickly as
as part of the MSFC
possible; once completed, ask
in clinical trials
the individual to remove the pegs
(with the same hand) 1 at a time
and place back in the container
∙ Repeat once with the same hand
∙ Repeat twice with the other hand
Threshold for clinically
meaningful change
∙ 20% change [22]
∙ 20% change [133]
Journal of Neurology
imaging of the brain, spinal cord and retina; and biological,
addressing the evolving area of biomarkers.
6MWT 6-Minute Walk Test, 9-HPT 9-Hole Peg Test, LCLA low-contrast letter acuity, SDMT Symbol Digit Modalities Test, T25FW Timed 25-Foot Walk, TUG Timed Up and Go
∙ 7-point change [76]
∙ Individual seated 2 m from chart
∙ Individuals read letters aloud top
to bottom and left to right
∙ Scores are quantified as the
number of letters identified on a
Sloan eye chart (maximum 70)
Visual disability
LCLA [76]
Measures impaired
low-contrast vision at
multiple letter sizes
∙ Clinical trials
∙ 4-point score change,
10% reduction in score,
or change in 0.5 standard deviations [63]
∙ Give the individual a set of sym- ∙ Clinical practice
bols corresponding to a series of
and trials assessing
numbers
cognitive processing
∙ Ask the individual to write down
speed
the symbols corresponding to the
series of numbers
∙ Set of symbols and numbers
∙ Timer (e.g., stopwatch)
∙ Mechanism for recording
score (e.g., pen and paper)
∙ Symbol test, including
mechanism for recording
response (electronic versions of the SDMT may be
available)
∙ Sloan Eye chart
∙ Retro-illuminated cabinet
or darkened room
∙ Mechanism for recording
score (e.g., pen and paper)
Cognition (processing
speed)
SDMT [65]
Measures time taken (in
minutes/seconds) to
complete the task
Function tested
Test
Table 1 (continued)
Description
Utility
Threshold for clinically
meaningful change
Process
Equipment
Journal of Neurology
Methods
A non-systematic review of scientific literature was undertaken to explore modalities of monitoring symptoms and the
disease evolution of MS. We searched PubMed in Jan-Feb
2020 using the following terms and limiting to English language and humans and papers since January 2000: “multiple
sclerosis” and “Expanded Disability Status Score”, “Timed
25-Foot Walk”, “Six-Minute Walk Test”, “Timed Up and
Go”, “9-Hole Peg Test”, “Symbol Digit Modalities Test”,
“Low-contrast letter acuity”, “magnetic resonance imaging”,
Optical Coherence Tomography”, “biomarkers”, and “neurofilament”. A similar procedure was followed in April–May
2021 to include “Multiple Sclerosis Functional Composite”
and “Paced Auditory Serial Addition Test”. A manual search
of papers included was also done to identify other possible references, including some that were relevant from the
period before January 2000.
Functional instruments
Expanded Disability Status Score (EDSS)
The EDSS was introduced in 1983 to quantify neurological impairment in pwMS [6]. It is used to score patients
across eight functional groupings on a step scale of 0–10.
The disability scoring can be simplified to mild [≤ 4.5; able
to walk without any aid (considered fully ambulatory)],
moderate [5–6.5; ranging from ambulatory without aid or
rest for ~ 200 m to requiring constant bilateral assistance
(canes, crutches, or braces) for walking ~ 20 m without resting], and severe (7–10; ranging from being unable to walk
beyond ~ 5 m even with aid, to death) [6]. Natural history
studies based on EDSS have shown an accelerated phase of
progression beginning around a score of 4.0 [7–9]. In an MS
population treated at a clinic in Ontario, Canada, Weinshenker et al. observed that patients spent the shortest mean times
at EDSS 4 and 5 (1.22 and 1.25 years, respectively) than at
any other EDSS score [9].
Since its introduction, EDSS has been a standard instrument for assessing patients with MS and charting status
changes. It is widely used in clinical trials to assess the effectiveness of clinical interventions and in the routine clinical
assessment of disease progression in pwMS [10]. A second
assessment of EDSS change is generally done at a minimum of 3 months to confirm that the progression was not
temporary for trials of 2- to 3-year duration [11]. Moreover,
confirmed persistence of progression at 3 months accurately
estimates irreversible progression in 70% cases at 5 years
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Journal of Neurology
Table 2 Commonly used tools for the assessment of neuroanatomical change in individuals with multiple sclerosis
Test
Function tested
Utility
Interpreting results
MS disease activity in the brain
∙ Routine clinical practice (diagnosis,
monitoring disease progression, prognosis); primary or secondary endpoint in
intervention trials[82, 87]
∙ New MRI lesion formation indicates
active inflammation/active disease in
relapsing MS and may indicate poor treatment outcome
∙ Presence of gadolinium-enhancing and
spinal cord lesions at diagnosis predict
long-term development of secondary progressive MS and physical disability and
may influence initial treatment selection
∙
∙
OCT [100] Neurodegenerative changes in the retina
Routine clinical practice and clinical trials Thinning of retinal nerve fiber layer indicates MS disease progression [99, 101]
MRI [81]
MRI magnetic resonance imaging, MS multiple sclerosis, OCT optical coherence tomography
Table 3 Commonly used
patient-reported outcome tools
Test
Function tested
Summary
MSQOL-54 [134]
Patient-reported quality of life
MFIS [135, 136]
Fatigue
SF-36 [137, 138]
Patient-reported quality of life
∙ Based on SF-36 with additional MS-specific
items
∙ Assessment of patient fatigue in terms of physical, cognitive, and psychosocial function
∙ Generic life questionnaire with limited utility for
MS parameters aside from cognitive function
MSQOL-54 54-item Multiple Sclerosis Quality of Life questionnaire; MFIS Modified Fatigue Impact
Scale, MS multiple sclerosis, SF-36 36-item Short Form Health Survey
(i.e., may result in the identification of temporary disability
changes in 30%). More accurate evaluation of irreversible
disability is seen when extending the confirmation periods
(6 months, 74%; 12 months, 80%, 24 months, 89%) [12].
Limitations such as low sensitivity to change and underrepresentation of fatigue, visual function, and cognitive
impairment, however, have been noted and discussed [13].
The functional groupings of EDSS are largely contingent
on non-linear loss of ambulatory ability and do not include
scoring for loss of cognition or other neurological impairments. Although EDSS retains its place in the language of
MS assessment, numerous instruments and tests have been
proposed and validated to fill patient monitoring gaps.
Multiple sclerosis functional composite (MSFC)
The multiple sclerosis functional composite (MSFC) is a
multidimensional, three-component scale to assess the
degree of functional impairment in MS patients. It was
developed by the National MS Society (NMSS) in 1994 to
address the limitations and unidimensionality of other functional status outcomes [10, 14]. After a rigorous analysis
of candidate outcome measures, the following tests were
included: Timed 25-Foot Walk (T25W) for leg function and
ambulation, 9-Hole Peg Test (9HPT) for arm and hand function, and Paced Auditory Serial Addition Test (PASAT) for
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cognitive function, all of which are described separately in
this publication. An integrated MSFC score is calculated
using z scores from the three components. The entire composite measure takes approximately 20 min to complete [15].
The primary goal for creating the MSFC was to develop
a new clinical outcome measure for use in MS clinical trials
[15], and it has proven a useful outcome in Phase 3 trials
of disease-modifying agents for MS as both a primary and
secondary outcome measure [10].
There has been robust support for the validity of the
MSFC, with studies showing correlation with disability
as measured by the EDSS, disease course and patient selfreport measures of symptoms and QoL. Some studies have
also shown better correlation between MSFC and MRI
measures of cerebral lesion burden and atrophy than seen
with the EDSS, but this correlation is inconsistent [10, 16].
A systematic literature review evaluating the validity
of the MSFC compared with the EDSS found that while
the EDSS has some documented weaknesses in reliability
and sensitivity to change, the MSFC is limited in its learning effects of the PASAT, the z score method used to calculate the total score, low acceptance among patients and
lack of a visual dimension [10]. Both tools are suitable for
detecting the effectiveness of clinical interventions and to
monitor disease progression. Of the two measures, EDSS
appears to be the more widely used in clinical trials and
Journal of Neurology
its international acceptance facilitates comparison of data
between studies [10]. Despite some limitations, both instruments are accepted as endpoints although MSFC is often
used as a secondary parameter [10].
Gait
Timed 25‑foot walk (T25FW)
The T25FW has been used to measure gait speed in pwMS
for > 3 decades in both clinical and research settings [17].
It was initially part of the Ambulatory Index [18], supporting MS research and clinical practice, and was subsequently
incorporated into the MSFC for use in clinical trials [8].
The T25FW has been used to assess interventions in drug
and rehabilitation trials and is useful to assess ambulation
changes in the clinical setting [19]. The T25FW is conducted
using a premeasured, linear, unobstructed, 25-foot distance.
From an initial standing position, the individual is instructed
to safely walk the measured distance as quickly as possible,
going past the end measurement to avoid slowing down at
the end. A second measurement follows. Use of assistive
devices to accomplish the task is permitted. The time (in
seconds) to complete each segment is recorded and then
averaged to obtain a score. Speed can also be calculated in
feet per second [19].
A recent meta-analysis of T25FW studies identified 50
articles that included 6303 individuals with MS and 1377
healthy controls, providing evidence for the utility of the
T25FW as a gait assessment in MS [20]. Individuals with
MS were 55% slower in the T25FW than healthy controls
(mean difference − 2.4 s), with an effect size of − 0.92.
Performance on the T25FW was worse in those with greater
impairment as individuals with mild MS were 51% faster
than those of individuals with moderate to severe MS (mean
difference − 5.5 s), with an effect size of − 1.02. In addition,
performance on the T25FW was worse in individuals with
progressive MS compared with those who had a relapsing
clinical course. Those with a relapsing course had a 67%
faster completion on the T25FW (mean difference − 13.4 s),
with an effect size of − 1.36. All of these effect sizes are
indicative of clinically meaningful differences [20].
Standardized scoring of the T25FW calculates a z score
[8]. Because this scoring system is challenging to understand
and implement in clinical practice [21], alternative methods
of interpreting meaningful change have been suggested. For
instance, a minimum detectable change of 2.7 s in T25FW
time has been described [22]. A time of 6 to 7.99 s correlates with meaningful life changes due to disability, whereas
a time of ≥ 8 s is associated with a permanent disability,
use of a walker, and inability to perform daily tasks [17].
However, an approximately 20% change in the time needed
to complete the T25FW has most often been described as a
meaningful change [19, 23, 24] and was used in MS clinical
studies of dalfampridine for the improvement of walking
speed [24–26]. Minimum detectable changes of 21–36%
have been calculated in some studies, with the variation
explained by differences in MS severity [28, 27].
The T25FW correlates well with EDSS (Spearman coefficient 0.56; 95% CI 0.55–0.58) [21]. Nevertheless, some limitations have been suggested. For instance, directions provided must be clear and consistent in order to have the best
evaluation of the individual’s speed [8]. In addition, scores
on the T25FW separated by 1 week have been observed to
be consistently faster the second week, indicating a practice effect [29]. Researchers have also noted a floor effect,
by which results in patients with less disability are similar
to those of healthy controls [21]. Also, as the T25FW is
solely a measure of speed, gait quality is not captured and
clinicians need other measures to evaluate fall risk, endurance, and balance. Indeed, some recognize that the T25FW
is particularly effective as part of a group of evaluations in
MS rather than a standalone test [21].
Six‑minute walk test (6MWT)
The 6MWT is a measure of motor fatigue validated in 1982
as a quicker alternative to the 12-min walk test for evaluating
pulmonary function [30]. It was validated for MS in 2008
[30] and since then has been broadly incorporated into clinical practice and has more recently been used as a primary
outcome measure in clinical trials of interventions aimed at
improving gait in MS [31]. For MS, general modifications
made to the original American Thoracic Society guidelines
include suggestions for rest during testing (participant may
lean against a wall) and standardization of language for
encouragement from evaluators [30, 32]. Since performance
on 6MWT is influenced by pulmonary function [32], it is
may be preferable to consider it as a measure of walking
endurance rather than a true measure of motor fatigue.
The 6MWT includes a measured course, either continuous or with a defined turning point, that is indoors, flat, and
without obstacles. The participant walks at a maximum safe
speed for 6 min, and the distance traveled is recorded. An
examiner may walk behind the individual with a measuring
wheel without setting a pace, and participants may use their
current walking assistance device if it is regularly used [30,
32]. When validated in MS patients, to maximize effort and
better assess motor fatigue, the script for the 6MWT was
modified from that used in patients with pulmonary orders;
namely, by eliminating instructions for permitted rest during
testing, emphasizing speed and excluding encouragement
phrases. Modified 6 MW instructions were read prior to each
walk. Subjects used their typical assistive device and walked
back and forth in a 175-foot hallway, pivoting at each end
of the hall. The floor was marked in 8.5-foot increments.
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Journal of Neurology
Distances walked during each minute and total distance were
recorded [30].
Measurement of the first minute of the 6MWT compared
to the final minute has been described as a way of identifying
motor fatigue, with a 15% decrease in distance during the
first minute to distance during the final minute indicating
motor fatigue [33]. The minimum detectable change in the
6MWT has been reported to be 88 m, and a 20% change
from one measurement to the next is clinically relevant [22].
A meta-analysis of studies employing the 6MWT identified 34 articles with results from 2683 pwMS and 521
healthy controls, confirming the utility of the 6MWT as
a measure of endurance in MS [34]. On average, pwMS
walked 177.92 m less than healthy controls, for a mean effect
size of − 1.87 [standard deviation (SD) 0.17; p < 0.001];
pwMS with mild disability walked 185.19 m farther than
pwMS with moderate to severe disability, for a mean effect
size of 1.83 (SD 0.10; p < 0.001). Moderators of response
were evident. The design of the course, continuous versus
straight with 180º turns at either end, impacted the effect
size, with larger effects between individuals with or without
MS and mild or moderate to severe disability noted when
a continuous course was used. In addition, a larger effect
size was noted between pwMS and healthy controls when
encouragement/feedback was provided [34].
Results from the 6MWT have been shown to correlate
with results on the T25FW [35, 36], and correspondence
with EDSS scales has been reported. Using a convenience sample, European researchers demonstrated that after
physical rehabilitation, individuals with MS and an EDSS
score ≤ 6.5 had better changes in scores with the 6MWT than
with the T25FW (0.64 vs 0.59) [37]. In addition, individuals identified as having moderate to severe disability (EDSS
4.5–6.5) rather than mild disability (EDSS ≤ 4) showed
superior responsiveness in the 6MWT compared with the
T25FW (0.62 vs 0.57). Hence, longer walking tests such
as the 6MWT may be a more sensitive measure than the
T25FW in detecting improvements in walking after physical rehabilitation in patients with mild and moderate-severe
levels of disability.
Balance
Timed Up and Go (TUG)
Balance is impaired in pwMS, and impairment can be more
severe than it is in individuals with other conditions such
as Parkinson’s disease [38]. TUG is a measure of balance
originally designed in 1986 for the frail elderly [39]. The test
used primarily to monitor the effects of treatment in clinical practice[35] is performed beginning with the individual
in a seated position in a two-armed chair. The individual
is instructed to rise from the chair, walk to a mark that is
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10 feet (3 m) from the chair, turn, and return to a seated
position in the chair. Time is measured in seconds from the
initial seated position to the return to sitting. The individual
should use any walking aid that they require in daily life
and wear their regular footwear, but no assistance is allowed
during the test [39]. The test may be repeated and the average time recorded. Some data suggest that a single attempt
is sufficient for evaluation [40], while other data support the
averaging of two consecutive measures [41].
TUG evaluates multiple aspects of daily living functionality: standing up, sitting down, and turning, in addition to
walking speed. Test–retest reliability and reproducibility
have been confirmed [35, 42], and TUG has been shown to
be reliable and responsive with no detected learning effect
[41]. TUG significantly correlates with EDSS (score 2.0–6.5
and no relapse within 30 days) and T25FW in individuals
with MS and is a stronger predictor of EDSS score than
the T25FW [35]. TUG also strongly correlates with other
measures of functionality, disability, and ambulatory mobility in pwMS, and significantly correlates with balance and
self-reported balance confidence [43]. TUG times strongly
correlate with 6MWT times [44] and with balance measurements among individuals with MS and low-minimal disability [45]. In adults with mild MS (EDSS ≤ 4) at two university
hospital outpatient centers, the mean TUG test time was 7.7
(range 5.0–12.5; SD 1.7) seconds [41]. Time to completion
for females was 32% longer than for males (time difference
1.9 s, p < 0.05). The minimum detectable change reported
for TUG was 10.6 s [40].
Although a study of the Khuzestan MS Patients’ Society
(Iran) demonstrated that TUG test scores were predictive
of falls in individuals with MS [46], other MS studies show
that TUG is unable to discriminate between those with and
without a fall history [47–49].
Dexterity
9‑Hole Peg Test (9‑HPT)
Impaired function of the upper extremities is a common consequence of MS [50, 51]. The 9-HPT is an evidence-based,
standardized, quantitative test of hand and arm function that
was first published in 1971 [52, 53] and was later incorporated into the MSFC [8]. To perform the timed test, an
individual is instructed to use one hand to insert nine pegs
into a block with nine holes [52]. Once the pegs are in the
holes, the individual removes them, one at a time, and places
them in a container. The score can be recorded as time taken
or speed (pegs per second) for dominant and non-dominant
hands individually [50].
The 9-HPT has high inter- and intra-rater reliability [54].
In 69 individuals with MS, intra-class correlation coefficient
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values for test–retest reliability over 1 week ranged from
0.902 to 0.972, exceeding the threshold for strong reliability (intra-class correlation coefficient > 0.80) [50].
However, performance on the 9-HPT may be sensitive to
practice effects, and three or four administrations should be
given prior to a baseline assessment if accurate assessments
of change over time are needed [16, 54]. The majority of
improvement on 9-HPT occurs within the first 2 months following a clinical MS relapse, but improvements have been
observed for up to 12 months following a relapse [55].
Increases in 9-HPT score are associated with long-term
MS-related disability [21, 56]. A 20% increase in 9-HPT
score indicates a clinical impact [53], with changes in 9-HPT
associated with diverse functional domains on Guy’s Neurological Disability Scale, including sexual, mood, upper- and
lower-limb disabilities, and fatigue [56]. In a study involving
105 people with MS treated with slow-release fampridine,
minimal clinically important difference for 9-HPT from preto post-treatment was 3.0 s (or 10.7% [range 0.0–15.3%])
[57]. Minimal detectable change for the 9-HPT is smaller for
speed measures than for time measures in the non-dominant
hand (20.5% and 29.1%), dominant hand (18.6% and 19.4%),
and globally (mean of both hands; 12.2% and 15.9%) [50].
The 9-HPT may be particularly sensitive in detecting
clinical changes in individuals with progressive MS [58].
A cohort study conducted among such individuals revealed
that early changes in 9-HPT score (identified over an initial
1–2 years) were significantly associated with walking limitations ≥ 5 years later [59]. In patients with MS, changes in
9-HPT score have been linked with grey matter damage in
the cerebellum, frontal cortex (specifically, Brodmann area
44), and spinal cord; and with damage to white matter in
brain areas such as the corpus callosum, cerebral peduncles,
internal capsule, and posterior thalamic radiations [60–62].
Cognition
Symbol Digit Modalities Test (SDMT)
Changes in cognitive function are commonly observed in
pwMS at any age; prevalence ranges from 34 to 65% in adults
and is approximately 33% in individuals aged < 18 years
[63]. Cognitive impairment, typically in the form of reduced
information-processing speed, occurs in all MS phenotypes
and may anticipate progression/conversion to secondary progressive MS or more severe disability (EDSS 4.0) [63, 64].
Identifying these deficits in their onset can support early
therapeutic intervention [63]. Indeed, cognitive impairment
at initial diagnosis predicts disability progression and conversion to secondary progressive MS [63, 64].
The SDMT takes about 5 min to administer. The subject
receives a reference key and has 90 s to pair specific numbers with given geometric figures, being scored on accuracy.
Scores are not subject to interpretation by the test administrator. Results are minimally affected by the individual’s age,
sex, and educational status; and the test shows only modest
practice effects [21, 65]. In addition, the SDMT shows no
evidence of skewing, or floor or ceiling effects [21]. The
SDMT is included in the Brief Repeatable Neuropsychological Battery, the Brief International Cognitive Assessment for
Multiple Sclerosis, and the Minimal Assessment of Cognitive Function in MS [63, 65]. The SDMT could serve as a
replacement for the PASAT in clinical trials or other settings
where a comprehensive assessment is needed [65].
Baseline cognitive screening with the SDMT (or alternative) when the patient is clinically stable is recommended
as a minimum requirement for all adults and children
aged ≥ 8 years. Baseline value could then be used to evaluate
changes in therapy or following relapse and recovery cycles
[63]. Clinically significant difference on the SDMT has been
defined as a 4-point score change, 10% reduction in score,
score change of 0.5 SDs, or use of Reliable Change Indices
[63]. Annual cognitive re-assessment with the same instrument is recommended for pwMS [63]; evidence from a longterm study in patients treated with natalizumab suggests a
practice effect when SDMT is performed on a monthly basis
[66].
Data from longitudinal studies ranging from 1 to 3 years
have shown progressive decline in cognitive functioning in
pwMS, suggesting that cognition could decline over longer
periods of time (10–20 years) [63]. Furthermore, correlation
between EDSS progression and reduction in SDMT performance has been demonstrated [67, 64]. Patient’s education
level should be considered when making decisions based on
test results [68].
A meta-analysis of studies performed in healthy subjects
associated regions of the frontoparietal attentional network
and occipital cortex, cuneus, precuneus, and cerebellum with
performing the SDMT [69]. In addition, a systematic literature review found six studies with statistically significant
confirmation of an association between decreases in SDMT
and brain volume loss [70]. Consequently, damage to these
brain areas or evidence of brain volume loss may indicate
increased likelihood of cognitive impairment occurring in
such individuals and highlight the importance of early initiation of disease-modifying therapy [70]. Another metaanalysis showed significant correlations between SDMT
and volume of T2 lesions (r = − 0.45; p < 0.001) and brain
atrophy (r = − 0.54; p < 0.001) [71].
The SDMT has been found to be the most sensitive individual cognitive measure for use in MS. Its many positive
features make is especially useful in clinical practice to
identify at-risk pwMS [72]. Some suggest it should also be
considered the measure of choice for MS trials in assessing
cognitive processing speed [72].
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Journal of Neurology
Paced auditory serial addition test (PASAT)
The PASAT is a useful cognitive tool with high sensitivity to
detect sustained attention and information processing speed
alterations [73]. It was originally developed to assess the
effects of traumatic brain injury on cognitive functioning
and subsequently was shown to have clinical utility in detecting impairments in cognitive processing in patients with a
wide variety of neuropsychological syndromes [74]. It is a
commonly employed neuropsychological test in pwMS and
has been added as a cognitive test to several widely used
batteries in this setting, such as the Brief Repeatable Neuropsychological Battery (BRN-B), the Minimal Assessment
of Cognitive Function in Multiple Sclerosis (MACFIMS),
and the MSFC.
For the PASAT, patients have to add pairs of digits
by adding each digit to the immediately preceding one.
[73]. Since its original format, specialized versions of the
PASAT have been developed to cater to specific populations
and presentations (aurally/visually). In MS patients, the
PASAT-3 is used as part of the MSFC, where each digit is
presented for either 3 or 2 s.[74]. The PASAT has good internal consistency and test–retest reliability [74]. Limitations of
the PASAT include practice effects that impact reliability, a
predisposition to ceiling effect, the impact of inherent math
ability, and test-related anxiety [75]. It is generally not used
either in clinical practice or clinical trials [75].
Comprehensive examination of the psychometric qualities
of the PASAT compared with SDMT revealed the SDMT
to be superior to the PASAT in terms of assessing cognitive processing speed, reliability, sensitivity, practicality and
cost-effectiveness [72].
Vision
Low‑contrast letter acuity (LCLA)
LCLA is the leading evaluation of vision loss in patients
with MS [76]. It uses a Sloan low-contrast chart to measure visual dysfunction. Sloan LCLA charts show gray letters of decreasing size against a white background. Each
letter correctly identified is given 1 point, for a maximum
score of 70. A change of 7 points is considered clinically
meaningful [76]. This test was first validated by Balcer et al.
[77], in a study comparing acuity at four contrast levels in
pwMS and healthy volunteers. The study demonstrated a
high level of inter-rater agreement (intra-class correlation
coefficient 0.86 ± 0.95) and confirmed LCLA as a reliable
test of both acuity and neurological dysfunction. Subsequent
research with LCLA has associated it with MRI-confirmed
T2 lesions and brain atrophy [78]. Additionally, decreased
LCLA scores have been correlated to retinopathy, visual
13
evoked potentials latency, and vision-related quality of life
in patients with MS [79].
LCLA has advantages over the Pelli-Robson contrast sensitivity chart which has letters of uniform size that decrease
in contrast [76, 80]. LCLA charts that decrease letter size
permit better assessment of impairments in low-contrast
vision at different letter sizes. [76]. LCLA also has advantages over the high-contrast visual acuity (HCVA) test a
measure considered a standard outcome in many ophthalmologic disorders which has proven a suboptimal measure
of visual dysfunction in MS [76]. The advantages of LCLA
over these other commonly used charts in MS patients mean
that Sloan LCLA has proven a useful visual outcome measure in MS clinical trials [76].
Anatomical instruments
Magnetic resonance imaging (MRI)
MRI is an objective measure of MS disease activity in the
central nervous system, which is more common than clinical relapses by an average ratio of 10–15:1 [81]. The role of
MRI in MS has developed exponentially as the technique
has evolved. MRI offers by far the most sensitive technique
for detecting MS lesions and has proved to be a powerful
tool across the whole spectrum of MS management in the
clinical setting, from diagnosis, monitoring disease activity/
clinical status, and prediction of prognosis; it has also proven
a useful adjunctive outcome measure in trials of diseasemodifying therapies (DMTs) [82].
Diagnosis MRI has become a well-established tool for
diagnostic purposes and facilitates the early diagnosis of
MS; it is performed after clinical examination and history
taking, facilitating early disease-modifying treatment. The
McDonald diagnostic criteria for MS include specific MRI
requirements for the demonstration of lesion dissemination
in space and time [83].
The diagnostic utility of MRI is high, with sensitivity and
specificity of up to 87 and 73 percent, respectively, for the
McDonald criteria requirement of dissemination in space
[84]. MRI detects many more MS lesions than computed
tomography (CT), and it is able to detect MS demyelinating plaques in regions that are rarely abnormal on CT [85].
Most lesions visualized by MRI correlate with pathologic
lesions [85].
Prognosis and disease progression monitoring A role of
MRI in monitoring relapsing MS disease progression has
evolved with use, and the evolution will continue with the
development of new techniques that increase the sensitivity
of the instrument.
Journal of Neurology
In an early meta-analysis by Kappos et al. [86], the standard deviation of the number of gadolinium-enhancing (Gd+)
lesions predicted relapse rates in the next year. However,
the researchers found no statistically significant association
between Gd+ lesion count at study initiation and EDSS score
at 1 or 2 years [86], A subsequent meta-analysis suggested
that MRI findings could serve as an alternative endpoint to
relapses in clinical trials of MS [87].
New lesion formation is the best MRI biomarker of active
inflammation in relapsing MS and predicts poor outcome
during interferon treatment [81]. A study of patients with
early-onset clinically isolated syndrome (n = 178) provided evidence that baseline Gd+ and spinal cord lesions
are independently associated with secondary progressive
MS at 15 years and showed a consistent association with
EDSS [88]. Based on these findings, the authors concluded
that spinal cord lesions observed on MRI anticipate poor
outcomes, disease progression, and relapse-onset MS [88].
Findings from MRIs may, therefore, be useful for discussing
long-term prognosis and treatment plans with patients [88].
Despite their diagnostic utility, MRI lesion scans are difficult
to quantify and pathology must be interpreted [81].
In addition to imaging lesions, MRI can be used for volumetric analysis of both whole and regional brain atrophy,
which anticipates worsening ambulatory and cognitive function in pwMS [89]. Data from a 3-year prospective observational study in an MS population (n = 1052) showed a significantly increased prevalence of cognitive impairment in
patients with brain atrophy and high lesion volume. Patients
with brain parenchymal fraction < 0.85 and T2 lesion volume > 3.5 mL were more likely to have cognitive impairment compared with patients with brain parenchymal fraction > 0.85 and T2 lesion volume < 3.5 mL (odds ratio 6.5;
95% CI 4.4–9.5) [90]. In an MRI study in 61 patients with
relapsing–remitting MS, those with cognitive impairment
had significant differences in MRI-detected markers of brain
atrophy [91]. Volumetric analysis has also correlated wholebrain atrophy with dysarthria (r = 0.46; P < 0.001) [92].
Data from observational studies have confirmed that
thalamic atrophy is highly predictive of cognitive decline
and neurodegenerative processes [93–95]. A recent study in
patients with secondary progressive MS provided evidence
that atrophy of the corpus callosum also predicts cognitive
decline, with detriment to employment [96].
Assessing treatment response in clinical trials Most often,
clinical trials of pharmacologic treatments include MRI
findings as a secondary outcome measure, using changes
in the amount and size of T2-hyperintense and contrastenhanced T1-hypointense lesions [97]. One meta-analysis
of MS intervention trials assessed the effect of treatment
on lesion burden. The analysis of 31 studies revealed that
treatment effects on MRI lesions over 6–9 months can be
predictive of relapses over 12–24 months. Furthermore, new
or enlarging T2-hyperintense lesions and contrast-enhanced
T1-hypointense lesions were associated with the number of
relapses and MRI was subsequently suggested as a primary
outcome measure for treatment trials [87].
Optical coherence tomography (OCT)
OCT is a simple office-based measure that uses near-infrared
light for rapid cross-sectional imaging of the back of the eye
[98]. Visualization of retinal tissue is of specific interest in
MS because axons comprise a tissue layer in the retina, the
retinal nerve fiber layer (RNFL) [99]. Moreover, this is a
unique location within the central nervous system to assess
axonal volume exclusively as the ganglion cell axons are
unmyelinated (therefore, the volume change of myelin is a
non-factor). OCT allows visualization of neurodegenerative
changes in the retina and has the potential to be a useful tool
for measuring the impact of treatment on neurodegeneration in pwMS [100]. Advantages of OCT over MRI include
accessibility and technical ease [100]. The OCT can be performed at lower cost and with a shorter image duration.
Time domain was the first OCT technique used in pwMS
[101]. Spectral OCT has become the preferred technique
because it facilitates visualization of additional retinal layers
and quantification of their thicknesses [98]. RNFL thickness
indicates axonal injury independent of myelin sheath presence or thickness [102].
A meta-analysis of studies on time domain OCT and MS
published through May 2010 included 32 studies [99]. When
compared with healthy controls, RNFL loss was− 7.08 (95%
CI − 8.65 to − 5.52) μm in pwMS with no history of optic
neuritis and − 20.38 (− 22.86 to − 17.91) μm in pwMS
with associated optic neuritis. An updated meta-analysis
for data published on spectral OCT and MS through April
2016 included 40 studies [101]. Comparing eyes of pwMS
with and without associated optic neuritis, the inner nuclear
layer was thinner in individuals with optic neuritis-associated MS than those without. The RNFL layer was thinner
in both populations compared with the RNFL thickness in
healthy controls. Atrophy of the ganglion cell layer and inner
plexiform layer was greater in all pwMS (with and without
associated optic neuritis) than in healthy controls and was
greater in individuals with MS associated with optic neuritis
than in those without.
For pwMS from a single center who had OCT results
available, a lower total macular volume at baseline was
associated with a higher 10-year EDSS score [103]. This
association was stronger in the lowest one-third of the baseline macular volume score and for those individuals with
relapsing–remitting MS [103]. For each 1-year increase in
the duration of disease, there was an associated decrease of
0.2% in the superficial vascular plexus; and overall, lower
13
Journal of Neurology
density was associated with higher EDSS scores [104]. In
addition, optic nerve diameter and RNFL thickness were
significantly lower in individuals with an EDSS score > 2
than in those with an EDSS score ≤ 2 [105]. Moreover,
researchers have shown correlations between diminished
RNFL thickness on OCT and MRI volumetric degeneration
of the corpus callosum [106] and brain parenchymal fraction
and cerebrospinal fluid (CSF) volume [107] and correlation
between rates of ganglion cell + inner plexiform layer and
whole brain atrophy [108]. These findings provide evidence
that ocular damage occurs simultaneously to brain atrophy
in pwMS.
Some studies indicate that OCT may be less sensitive
than visual-evoked potentials (VEP) for detecting lesions of
the visual pathway in early relapsing–remitting MS patients
[109]. However, the two techniques may be useful when used
complementarily since VEP may be a better tool for detecting early demyelinating lesions whereas OCT may be a better tool for monitoring axonal loss and neurodegeneration.
Biological instruments
Specific biological markers that can assist the clinician in
monitoring specific MS treatments, such as natalizumab and
interferon beta, have been reviewed elsewhere [110, 111].
Biological biomarkers under investigation for prognostic
use in MS include oligoclonal bands (OCBs) and chitinase3-like protein 1 (CHI3L1) [112]. Levels of immunoglobulin
G (IgG) OCBs and neurofilaments in CSF have been shown
to anticipate conversion of demyelination symptoms to clinically isolated syndrome [113]. Prospective analysis of MRI
data in the Swedish Multiple Sclerosis Registry-associated
OCBs with whole-brain atrophy and decreased white matter [114]. In addition, retrospective and prospective studies
have shown: numerical differences in disease severity based
on the number of IgG OCBs [115], significantly higher levels of disease activity in patients with versus without IgM
OCBs [116], and aggressive disease development in patients
with IgM OCBs [117]. The glycoprotein CHI3L1 has also
been shown to be predictive of long-term impairment and
CDMS in patients whose first demyelinating event was optic
neuritis [118] and in patients with monophasic neurological
symptoms [119]. However, these markers may not be useful
in routine clinical practice.
One of the more promising biomarkers for monitoring
disease progression in MS is neurofilament light chain
(NfL). Neurofilaments—cytoskeletal components of neurons—are abundant in axons and include heavy, medium,
and light chain filaments [120]. In patients with axonal damage, neurofilament concentrations increase to abnormal levels [121]. Increased NfL concentrations in CSF have been
observed in individuals with MS compared with healthy
controls [122, 123]. Moreover, elevated concentrations of
13
NfL in CSF correlate with measures of MS disease progression [124] and treatment effects [123, 125].
Advances in the technological assessment of NfL concentrations have facilitated the measurement of NfL in
the serum (sNfL). Recent evidence suggests that sNfL has
the potential to be useful in the monitoring of response to
disease-modifying therapy in individuals with MS [124,
126–128]. Validation of a reliable assay coupled with further clarification of the relationship between sNfL and disease progression or treatment monitoring may position this
biological marker as a routine assessment of MS activity.
Summary
Since the introduction of the EDSS in 1983, numerous tests
and instruments have been developed for the assessment
of patient function and progression of MS. These instruments have enhanced the ability of the clinician to identify
changes in pwMS that otherwise might be missed in a purely
clinical assessment. Early identification of patient conditions
that require symptomatic interventions or optimization of
disease-modifying therapies may result in better outcomes.
Moreover, these instruments are objective measurements of
the disease evolution. Rather than evaluate and comment
on all available instruments, we have focused on those that
are most useful in clinical practice based on ease of administration, objective quantitative results, and applicability in
clinical practice.
As complexity and heterogeneity are hallmarks of MS,
the diagnosis and management of the disease require a
combination of clinical scales, imaging techniques and
laboratory findings to monitor and quantify symptomatic
complications as well as underlying pathological events.
Each technique has advantages and deficiencies and none
is an ideal outcome measure; thus, a combinatory approach
of both clinical rating scales and imaging techniques can
help to provide a more holistic picture of disease progression. Rating scales targeted at specific variables (e.g. motor
strength, spasticity, walking ability) can provide information about the symptomatic impact of the disease to the
individual patient while MRI is able to provide information
about the underlying pathology as well as essential prognostic detail. For diagnostic purposes, MRI evidence plays
a supportive role in what is ultimately a clinical diagnosis of
MS, since MRI abnormalities can be associated with other
diseases and non-specific MRI lesions are also common in
the general population. CSF analysis of oligoclonal bands,
visual evoked potentials, and OCT can all be used to support diagnosis in patients with typical presentation who have
insufficient clinical and MRI evidence to confirm the diagnosis [83].
Journal of Neurology
In addition to the instruments discussed in this review,
new tools continue to be validated for use in pwMS. Electronic self-assessment instruments provide innovative opportunities for patient engagement in the clinical setting. The
Performance Speed Test (PST) employs tablet software for
patient-administered screening of cognitive dysfunction
[129], and the MS Performance Test (MSPT) is tablet-based
with modules for cognition and motor function [130, 131].
The Multiple Sclerosis Partners Advancing Technology and
Health Solutions (MS PATHS) initiative, a learning health
system being developed by institutions in 10 countries in
collaboration with Biogen, is using the MSPT to standardize
information related to patient care in MS clinical practices
[132].
Wearable biosensors will also open new avenues for collecting patient data on ambulation, balance, and physical
activity or function. New technologies will add real-life
details that will allow clinicians to better understand disease progression in their patients and personalize treatment.
Ultimately, though, these technologies cannot take the place
of clinical evaluations by trained health care providers using
the validated modalities discussed in this review. In addition
to providing standardized methodology to record patient history, these modalities are well understood by the MS community. Essential work over the decades since EDSS was
introduced continues to improve our ability to treat this
debilitating disease.
Author contributions The first draft of the manuscript was written
by SC based on direction from GP and DTO. GP and DTO critically
reviewed the content. All authors gave their final approval of this manuscript and agree to be accountable for all aspects of the work, ensuring
that questions related to the accuracy or integrity of any part of the
work are appropriately investigated and resolved.
Funding The research for this review was sponsored by Biogen
(Cambridge, MA). Medical writing support for the development of
this manuscript was provided by Mark Poirier (Excel Medical Affairs,
Fairfield, CT); Nathaniel Hoover (Excel Medical Affairs, Fairfield, CT)
copyedited and styled the manuscript per journal requirements; funding
was provided by Biogen.
Availability of data and material Not applicable.
Code availability Not applicable.
Declarations
Conflicts of interest GP: speaker honoraria and/or consulting fees
from Alexion, Biogen, Celgene, EMD Serono, Greenwich Pharmaceuticals, Novartis, Roche/Genentech, and Sanofi-Genzyme, and research
support (to the institution) from AbbVie, Adamas, Alkermes, Biogen,
EMD Serono, Roche/Genentech, Sanofi Genzyme, Novartis, and Teva;
SC: funding for research and draft development from Biogen; DTO:
personal compensation for consulting and advisory services from
Alexion, Biogen, Celgene, Genzyme, EMD Serono, and TG Therapeutics, VielaBio and research support from Biogen and EMD Serono.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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