REvisión Sistemática 2023

Received: 27 January 2023 Revised: 27 March 2023 Accepted: 29 March 2023
DOI: 10.1002/brb3.3009
REVIEW
Instruments measuring change in cognitive function in multiple

sclerosis: A systematic review
Chigozie Ezegbe1 Amin Zarghami1 Ingrid van der Mei1 Jane Alty2,3
Cynthia Honan4 Bruce Taylor1
1
Multiple Sclerosis Research Flagship, Menzies
Institute for Medical Research, University of Abstract
Tasmania, Hobart, Tasmania, Australia
Background: Multiple sclerosis (MS) is a chronic demyelinating/neurodegenerative
2
Wicking Dementia Research and Education
Centre, University of Tasmania, Hobart,
disease associated with change in cognitive function (CF) over time. This systematic
Tasmania, Australia review aims to describe the instruments used to measure change in CF over time in
3
Neurology Department, Royal Hobart people with MS (PwMS).
Hospital, Hobart, Tasmania, Australia
4
Methods: PubMed, OVID, Web of Science, and Scopus databases were searched in
School of Psychological Sciences, University
of Tasmania, Launceston, Tasmania, Australia English until May 2021. Articles were included if they had at least 100 participants
and at least a 1-year interval between baseline and last follow-up measurement of
Correspondence
Dr Vincent Chigozie Ezegbe, Multiple Sclerosis
CF. Results were quantitatively synthesized, presented in tables and risk of bias was
Research Flagship, Menzies Institute for assessed with the Newcastle–Ottawa Scale.
Medical Research, University of Tasmania,
Hobart, Australia.
Results: Fifty-seven articles met the inclusion criteria (41,623 PwMS and 1105 con-
Email: Vincent.ezegbe@utas.edu.au trols). An intervention (drug/rehabilitation) was assessed in 22 articles. In the studies
that used a test battery, Visual and verbal learning and memory were the most fre-
quently measured domains, but when studies that used test battery or a single test
are combined, Information processing speed was the most measured. The Symbol Digit
Modalities Test (SDMT) was the most frequently used test as a single test and in a test
battery combined. Most studied assessed “change in CF” as cognitive decline defined
as 1 or more tests measured as ≥ 1.5 SD from the study control or normative mean
in a test battery at baseline and follow-up. Meta-analysis of change in SDMT scores
with seven articles indicated a nonstatistically significant –0.03 (95% CI –0.14, 0.09)
decrease in mean SDMT score per year.
Conclusion: This study highlights the slow rate of measured change in cognition in
PwMS and emphasizes the lack of a gold standard test and consistency in measur-
ing cognitive change at the population level. More sensitive testing utilizing multiple
domains and longer follow-up may define subgroups where CF change follows differ-
ent trajectories thus allowing targeted interventions to directly support those where
CF is at greatest risk of becoming a clinically meaningful issue
KEYWORDS
change, cognition, impairment, measurement, multiple sclerosis
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.
Brain Behav. 2023;13:e3009. wileyonlinelibrary.com/journal/brb3 1 of 38

https://doi.org/10.1002/brb3.3009
2 of 38 EZEGBE ET AL.
1 INTRODUCTION tered repeatedly to monitor change in CF though cognitive impairment

in people with above average baseline levels of intellectual functioning
Multiple sclerosis (MS) is an autoimmune disease that affects the cen- could be missed (Longley & Honan, 2022). Practice effect (more com-
tral nervous system with associated demyelination, inflammation, and mon between first and second assessments) can be an issue and can
irreversible axonal loss seen early in the disease (Oh et al., 2018). be minimized through dual baseline assessment before further regular
MS can present with protean clinical features including dysfunction assessments (Duff et al., 2001). The heterogeneity of these batteries
from the involvement of any part of the CNS with wide intra- and which includes having different tests measuring similar domain makes
interindividual variation (Katz Sand, 2015). Females are significantly the comparison of change in cognitive function problematic.
more susceptible to MS but the progression of the disease is worse Although each cognitive test is usually regarded as measuring a par-
in males with males getting to a specific disability level faster than ticular cognitive domain, they also tap into abilities in other functional
females (Golden & Voskuhl, 2017). domains. For example, while the Symbol Digit Modalities Test (SDMT)
People with MS (PwMS) can develop impairment of cognitive is primarily considered a test of information processing speed, it also
function in the early stages of the disease (Patti, 2009). Cognitive requires abilities in visual scanning and incidental memory (Sumowski
impairment has been observed in up to 65% of PwMS throughout et al., 2018). The SDMT, written or oral form, nonetheless has been
the disease course (Amato et al., 2006). While cognitive impairment observed to be a reliable and valid test for the measurement of infor-
may be present in all types of MS, it is more common in primary mation processing speed in PwMS (Benedict et al., 2017) and slowed
and secondary progressive MS (Amato et al., 2006; Brochet & Ruet, processing speed is considered a hallmark characteristic of MS due
2019). Attention, delayed memory and executive functions are mostly to the loss of myelin on neurons that facilitate neural communication
affected, but language, short-term memory and general intelligence are (Sivakolundu et al., 2020). Experts convened by The US National MS
not typically affected (Rao, 1995). In MS, cognitive change may not be Society recommended that the SDMT, or similarly validated test, be
linear and may involve different domains at different points in the MS used for an annual assessment of cognitive function in PwMS as it
disease course. Cognitive impairment due to MS is also usually mul- is sensitive to cognitive function changes and the best rapid clinical
tidomain and so has multidimensional adverse effects on a person’s life, assessment tool for cognitive function (Kalb et al., 2018). Therefore,
which include unemployment, and problems with communication and the SDMT may be referred to as the current gold standard to assess
education (Bose et al., 2022). cognitive function in MS.
Most studies of cognitive functioning in MS have examined a single This systematic review aims to evaluate how changes in cognitive
time point, which does not provide information about how cognition function occur in PwMS, over a minimum 1-year observation period,
may change over time (Sumowski et al., 2018). Examining change over and how this change was measured and quantified, in studies that
time is important since cognitive decline has been observed in PwMS included samples of at least 100 participants (PwMS and healthy con-
(Eijlers et al., 2018). A decline in cognition can also be an early symptom trols inclusive). The rationale in choosing these studies is to understand
of MS progression, secondary to potentially treatable inflammatory how change in cognitive function in PwMS occurs, and how it is mea-
disease activity (Pitteri et al., 2017; Shanmugarajah et al., 2017). There- sured, at a population or epidemiological level. The review will include
fore, there may be need for a comprehensive assessment by highly details of the assessment tools used, the cognitive domains these tools
trained clinicians (neuropsychologists), indicated by cognitive impair- measure, and the extent of change over time reported in studies using
ment on screening, to monitor change in cognitive function. But this these tools. A meta-analysis examining change in SDMT scores over
is often not feasible given the lack of specialist clinicians availability, time is also presented.
and because it is expensive, complex and time-consuming to under-
take (Longley & Honan, 2022). However, early detection is essential
given the potential for a “brain healthy lifestyle” to protect against fur- 2 METHODS
ther decline and the availability of rehabilitation to improve cognitive
functioning or assist with the development of cognitive compensation 2.1 Search strategy
strategies (Longley & Honan, 2022; Meca-Lallana et al., 2021).
Several clinical tools have been developed to assess cognitive func- PubMed, OVID, Web of Science, and Scopus were searched using
tion and/or screen for possible cognitive impairments specifically in the keywords “chang*” OR “trend*” OR “increase” OR “decrease” OR
MS. These are mostly pen and paper validated clinical tools and include “reduc*” OR “time” OR “follow-up” OR “longitudinal” OR “cohort” and
cognitive test batteries such as the Minimal Assessment of Cognitive “cogniti* function*” OR “cogniti* dysfunction*” OR “cogniti* impair-
Function in MS (MACFIMS), Rao’s Brief Repeatable Neuropsychology ment” OR “cogniti*” OR “memory” OR “cogniti* decline” OR “cogniti*
Battery (BRNB), Medical Outcomes Scale-Cognitive Functioning (MS- deficit” OR “processing speed” OR “attention” OR “executive func-
COG), Brief International Cognitive Assessment for MS (BICAMS), tion*” and “Multiple Sclerosis.” The search was undertaken on the
Multiple Sclerosis Functional Composite (MSFC) (Sumowski et al., May 31, 2021 and included all studies on change in cognitive func-
2018), and MSReactor (Merlo et al., 2019). Screening tools are easy to tion in MS without a date or MS patient group (relapsing-remitting MS
administer, easy to interpret with the use of cut-off scores, reflect the (RRMS), primary progressive MS (PPMS), secondary progressive MS
cognitive functioning of PwMS at a general level, and can be adminis- (SPMS)) restriction. Only articles published in English and on humans
EZEGBE ET AL. 3 of 38
were included. This systematic review was registered in PROSPERO: as one of the most reliable and valid tools for measuring cognitive
Registration CRD42021255389. function in MS. Cohen’s d of SDMT between baseline and follow-up
was calculated for all studies. A weighted average was applied depend-
ing on the sample size and the random-effects model used due to
2.2 Study selection study heterogeneity. The analysis was reported with a forest plot (with
95% confidence intervals). A negative value in the effect size indi-
Title and abstract screening was completed by one rater (CE) in Covi- cated a decline in cognitive function whereas a positive value indicated
dence using the following exclusion criteria: the study did not measure improvement. A p-value of < .05 was considered statistically signif-
cognitive function in MS, measured cognitive function at only one icant. The heterogeneity of the studies used for meta-analysis was
time point, measured cognitive function at less than a 1-year interval assessed with I2 with values of 25%, 50%, and 75% considered as low,
between baseline and follow-up, had less than 100 participants (study moderate, and high, respectively (Higgins et al., 2003). Publication bias
control inclusive), or were duplicates, case reports, brief reports, let- was assessed with Egger’s test.
ters to the editor, reviews, or a study protocol. The full-text screening
was completed by two researchers (CE and AZ) using the stated crite-
ria working independently. Conflicts were resolved by consensus or by 3 RESULTS
a third researcher (BT) when the first and second researchers could not
reach a consensus. The primary search yielded 11,023 publications. After duplicates were
removed, 5964 remained. Title and abstract screening yielded 97
papers. After full-text screening, 57 papers were included (Figure 1)
2.3 Data extraction of which 35 were observational studies (Table 1) and 22 were inter-
ventional studies (Figure 1 and Table 2). All the studies were published
Data were extracted by one reviewer (CE) with the following informa- between 1995 and 2021. North America contributed 22 papers,
tion: author, year of publication, country, cognitive domain measured, Europe 32, Oceania 2, and Asia 1. The sample size of PwMS and con-
corresponding cognitive test or battery, maximum interval between trols in the articles ranged from 100 (Raimo et al., 2020) to 11,222
baseline and follow-up measurement, study sample size, age range of (Crielaard et al., 2019) and included a total of 41,623 PwMS and
participants, patient group (RRMS, PPMS, and SPMS), MS duration 1105 controls. The interval between cognitive function measurement
(mean, median, range), baseline EDSS, how a change in cognitive func- at baseline and follow-up ranged from 1 to 30 (Crielaard et al., 2019)
tion was measured, study findings related to cognitive function, and the years. Five (Demakis & Buchanan, 2010; Demakis et al., 2009; Hughes
intervention/s used (if applicable). Although the information on many et al., 2018; Lincoln et al., 2020; McKay et al., 2019) out of the 57
cognitive domains and tests was extracted, only studies with SDMT included studies did not specify the Expanded Disability Status Scale
mean score and standard deviation at baseline and follow-up and sam- (EDSS) of their study participants. Among studies that specified the
ple size at baseline and follow-up were used for the meta-analysis. EDSS mean or median, all had a mean or median of less than 6.5 except
Fifteen authors were contacted through email for some missing infor- for one study that reported participants’ EDSS in the range of 6.0 to 9.5
mation for the meta-analysis but five responded. Only papers with (Ytterberg et al., 2008). The mean age ranged from 12.5 (Amato et al.,
complete data were used for the meta-analysis. SDMT was chosen 2010) to 57.5 years (Demakis & Buchanan, 2010) for all participants—
because it is sensitive to cognitive function changes and has been PwMS and controls. All MS groups in the included studies reported a
recommended as the best clinical practice tool for the assessment of mean disease duration of 6 months (Johnen et al., 2019) to 21 years
cognitive function in PwMS (Kalb et al., 2018). at baseline (Chan et al., 2017). After assessment of the risk of bias
The quality and risk of bias assessment of the included studies for all the 57 included publications, five were of high quality (7 to 9
was assessed by 2 reviewers (CE and AZ) independently using the stars/low risk of bias) while the rest were of moderate quality (4 to 6
Newcastle–Ottawa Scale (NOS). Stars were assigned to the included stars/moderate risk of bias) (Supplementary TablesS1 and S2).
publications based on three criteria: selection of cases/controls or
cohorts, comparability of cases/controls or cohorts, and outcome
assessment with a maximum of four, two and three stars respectively. 3.1 Change in cognitive function
For each publication, total stars ranging from 0 to 3, 4 to 6, and 7 to 9
were considered as low (high risk of bias), moderate (moderate risk of Most observational studies focused predominantly on cognitive
bias), and high quality (low risk of bias), respectively. impairment at baseline and follow-up or cognitive decline. However,
in some studies (interventional) the focus was on improvement in cog-
nitive function or both improvement and decline (from baseline to
2.4 Statistical analysis follow-up) (Benedict et al., 2018; Benedict et al., 2021; DeLuca et al.,
2021). There was significant heterogeneity in the definition of cog-
A meta-analysis was completed using STATA version 17 to examine nitive impairment in studies that used a cognitive test battery or a
change over time in SDMT scores. The SDMT has been recommended singular cognitive test. Most papers that used a test battery defined
TA B L E 1 Characteristics of studies measuring change in cognitive function in people living with multiple sclerosis without intervention.
4 of 38
Maximum EDSS
gap MS Definition of score
between duration cognitive (mean)
measure- Age (at Patient group (MEAN) at impairment (or at
Cognitive ment of baseline) (RRMS, PPMS, baseline: improve- baseline:
Author and domain cognition Study Mean (SD) SPMS) at Mean (SD) ment)/change in Mean Findings about
year Location measured (years) population years baseline years cognitive function (SD) cognitive function
Amato et al. Italy Verbal learning 2+ 106: 56 PwMS: (Age 56 RRMS 5.5 (3.7) < –2 SD in three or 1.7 (1.0) 75% of PwMS had a
(2010) and delayed PwMS and 10–15: more cognitive decline in cognitive
recall, 50 HC 12.5 (1.3), tests (study function compared
visuospatial Age ≥ 15: controls as to the study control.
learning, 17.9 (1.8)) norms)/ These were
complex HC: (Age comparison of the outstanding in
attention, 10–15: proportion of verbal memory,
planning, 11.2 (1.8), cognitively complex attention,
expressive Age ≥ 15: impaired/improved receptive language,
language 18.6 (2.4)) participants and verbal fluency
between baseline
and follow-up
Amato & Italy Memory, learning 4.53 120: 50 NA 44 Relapsing- 1.58 (1.62) < –2 SD on ≥5 1.98 PwMS scored lower
Ponziani and recall, PwMS (32 remitting, 6 cognitive tests (1.48) (statistically
(1998) abstract women chronic (study controls as significant) than the
reasoning and and 18 progressive norms) / healthy controls on
attention, men) and comparison of the all tests, except the
acquisition, 70 HC proportion of information-
and recall cognitively memory-
impaired/improved concentration
participants (IMC). Cognitive
between baseline decline predicted
and follow-up poor work
outcomes and social
activities
Amato et al. Italy Executive 4+ 120: 50 PwMS: 29.9 44 RRMS and 1.58 (1.62) ← 2 SD on a 2.55 PwMS scored lower
(1995) functions PwMS (18 (8.48) HC: 6 PMS cognitive test (2.41) than HC at baseline
males and 29.3 (study controls as and follow-up.
32 (1.15) norms))/ There was a
females) comparison of the statistically
and 70 HC proportion of significantly higher
cognitively number of failed
impaired/improved subtests at baseline
participants and follow-up in
between baseline PwMS compared to
and follow-up HCs.
(Continues)
EZEGBE ET AL.
EZEGBE ET AL.
TA B L E 1 (Continued)
Maximum EDSS
Amato et al. Italy Memory, learning 5 120: 50 PwMS: Relapsing- 11.34 (2.31) < –2 SD on ≥ 3 1.98 People living with MS
(2001) (recall), PwMS (32 29.90 remitting cognitive tests (1.48) performed worse
abstract women (8.48) HC: (44), (study controls as than the controls.
reasoning and and 18 29.30 Chronic norms)/ Physical disability,
attention, men) and (5.17) progressive comparison of the disease progression,
acquisition, 70 HC (44 (6) proportion of and older age
and recall women cognitively predicted cognitive
and 26 impaired/improved decline
males) participants
between baseline
and follow-up
Beckerman The Comprehension, 10 156 PwMS Median Relapse onset 10 Change in score over Median There was a 10%
et al. Nether- expression, (55 males (IQR): (128) and time (between (IQR): change or 3-point
(2013) lands social and 101 37.1 nonrelapse relapse or 2.5 change in 10 years
interaction, females) (29.6, onset (28) nonrelapse type (2.0, in FIM cognitive
problem- 45.2) MS) 3.0) function scale in all
solving and PwMS
memory
Bosma et al. NA 2 161 PwMS Not defined All primary Not defined 15% and 20% mean Range: Different cut-off
(2010) Netherlands, (sex ratio progressive change in score 2.0, points for cognitive
Spain not (PP) MS between baseline 6.5 decline may need to
and defined) and follow-up. be applied for
United different forms of
King- MS. PASAT is
dom suggested as not a
good scale to
measure disease
progression.
(Continues)
5 of 38
6 of 38
Maximum EDSS
Borghi et al. Italy Verbal memory 2 625: 322 41.98 89% of the 9.16 (7.13) < –1.5 SD on ≥ 2 2.37 The proportion of
(2016) (learning and PwMS (97 (11.37) PwMS cognitive tests (1.90) PwMS that had
delayed recall, males and participants (study controls as cognitive
learning and 225 had RRMS norms)/ impairment
delayed recall, females) while 11% comparison of the increased at 1 year
attention, and 303 had proportion of but came back to
speed of HC (93 progressive cognitively the baseline level at
information males and MS impaired/improved 2 years
processing, 210 participants
working females) between baseline
memory, and follow-up
sustained
attention, and
verbal fluency)
Bsteh et al. Austria NA 3 151 RRMS 35.1 (9.4) All RRMS 5.8 (2.7) ≥4-point loss Median Peripapillary retinal
(2019) (32 males or > 10% (range): nerve fiber layer
and 119 reduction in 1.5 (0, thickness ≤88 μm
females) SDMT score 6.5) was associated with
between baseline a 2.7-fold increased
and follow-up risk of cognitive
function decline in
the following 3
years
Chruzander Sweden Attention 10 118 PwMS: 49 (11) 55 RRMS, 63 18 (11) ← 1.5 SD from the EDSS: There was a decline in
et al. 33 males Progressive mean score of a 0−3.5 cognitive function
(2014) and 85 test)/ comparison (41 between baseline
females of the proportion PwMS), and follow-up (not
of cognitively 4.0−5.5 statistically
impaired/improved (24 significant).
participants PwMS), Cognitive
between baseline 6.0−9.5 impairment
and follow-up (51 predicted worse
PwMS) health-related
quality of life
(Continues)
EZEGBE ET AL.
EZEGBE ET AL.
Maximum EDSS
Crielaard Sweden Cognitive 30 11 222 Benign: 28.3 All RRMS Benign: 14.3 SDMT trajectory Benign: There was an
et al. processing PwMS (8.5) Non- (9.7) and compared (Median associated 0.3 (95%
(2019) efficiency and benign: Nonbe- (IQR)) CI: −0.39 to −0.18,
speed 32.9 nign: 6.8 –2 (1, p < .001) decline in
(10.4) (9.5) 2.5) SDMT raw score per
and year in nonbenign
Non- patients
be-
nign:
(Median
(IQR))
–2 (1,
4.0)
de Groot The Verbal learning 3 146 PwMS: 37.4 (9.7) Not defined < 6 months < –1 SD on ≥1 Median Age and gender and
et al. Nether- and memory, 53 males cognitive tests (IQR): T2- weighted
(2009) lands visuospatial and 93 (population 2.5 supratentorial
learning and females controls as norms) (2.0, lesion load are
delayed recall, / comparison of 3.0) predictors of
sustained the proportion of cognitive
attention, cognitively impairment
concentration, impaired/improved
information participants
processing between baseline
speed and and follow-up
verbal fluency
(Continues)
7 of 38
Maximum EDSS
8 of 38

De Meijer Australia Psychomotor 1 106: 66 PwMS: 47.5 49 for 14.0 (10.8) Not defined Median Cognitive scores of
et al. function, PwMS (14 (12.4) and relapsing- (IQR): PwMS were
(2018) information males and HC: 35.2 remitting 2.5 significantly worse
processing 52 (14.7) multiple (1.25, compared to HCs.
speed, females) sclerosis, 17 4.0) CogState Brief
attention, and 40 HC for Battery was more
visual learning, (12 males secondary sensitive and
spatial and 28 progressive acceptable and with
problem- females) multiple less anxiety (based
solving, sclerosis, on scoring)
executive and 40 for compared to PASAT.
function and healthy
working controls
memory,
attention, and
calculation
ability.
Demakis & United Short-and 3 924 PwMS: 57.5 (13.5) MS (MS NA MDS Score of 2–4 NA MDS-Cog score at
Buchanan States long-term 72% without represents mild admission predicted
(2010) memory, female and psychiatric cognitive MDS-Cog scores
orientation, 28% male or impairment, 5−8 after 1 year.
and communi- neurological represents
cation comorbidi- moderately
ties), severe
MS-Neuro impairment, and
(MS with 9–10 very severe
neurological impairment/
comorbidi- comparison of the
ties), proportion of
MSPsyc (MS cognitively
with impaired/improved
psychiatric participants
comorbidi- between baseline
ties), and follow-up
MS-Comb
(MS with
neurological
and
psychiatric
comorbidi-
EZEGBE ET AL.
ties)
(Continues)
Maximum EDSS
EZEGBE ET AL.

Demakis United Short-and 3 924 PwMS: 57.5 (13.5) MS (MS NA MDS Score of 2–4 NA The MS-Neuro and
et al. States long-term 72% without represent mild the MS-Comb
(2009) memory, female and psychiatric cognitive groups had more
orientation, 28% male or impairment, 5 −8 cognitive decline
and communi- neurological represent compared to the
cation comorbidi- moderately MS-Psyc and the
pattern ties), severe MS groups
MS-Neuro impairment and
(MS with 9–10 very severe
neurological impairment/
comorbidi- comparison of the
ties), mean MDS score
MSPsyc (MS in participants
with between baseline
psychiatric and follow-up
comorbidi-
ties),
MS-Comb
(MS with
neurological
and
psychiatric
comorbidi-
ties)
Eijlers et al. The Executive 5 294: 234 PwMS: 181 RRMS, 33 14.77 (8.43) < –1.5 SD on ≥ 2 Median Statistically significant
(2018) Nether- functioning, PwMS 47.61 SPMS and cognitive domains (range): cognitive decline
lands verbal memory, –32% male (11.02) 20 PPMS. (study controls as 3 (0, 8) was observed in all
verbal fluency, and 68% and HC: norms) / MS phenotypes but
Information female, 60 46.45 comparison of the was three times
processing HC –29% (9.91) proportion of faster in progressive
speed, male and cognitively MS patients
visuospatial 71% impaired/improved compared to RRMS
memory, female) participants patients.
attention, between baseline
working and follow-up
memory
(Continues)
9 of 38
10 of 38
Maximum EDSS
Fuchs et al. United Processing speed 16 531 PwMS: RRMS: 43.4 455 RRMS, 76 Not SDMT age, sex, and RRMS— A decline of 0.22
(2020) States 22.2% (9.3) PMS: PMS specified education- median SDMT raw score per
male and 50.8 (9.0) corrected (IQR): year was observed
77.8% z-scores/SD that 2.5 in PwMS
female, is < 0 and > −1.5 (1.5, (statistically
455 RRMS, were considered 3.5) significant). Higher
76 PMS as mild PMS— trait
impairment and median Conscientiousness,
⩽−1.5 considered (IQR): being
as severe impair- 5.5 well-organized and
ment/Individual (3.5, goal driven was
subject 6.0) associated with a
trajectories slower decline in
shown with slopes SDMT
longitudinally
Healy et al. United NA 1+ (378 680 PwMS: 42.4 (10.8) Not defined 9.0 (8.1) Longitudinal cluster 1.7 (1.7) PwMS who had lower
(2021) States days 171 males trajectory of than average SDMT
(median and 509 SDMT/ score at baseline
time)) females trajectories had greater
shown in a graph worsening of SDMT
score compared to
PwMS who had
higher than average
score
(Continues)
EZEGBE ET AL.
Maximum EDSS
EZEGBE ET AL.

Heled et al. Israel Executive 8 183 PwMS: Assessment All RRMS Assessment Higher score There was an
(2021) functions, 158 males intervals: intervals: represented Assessment observed decline in
memory, and 25 2–3 2–3 better inter- executive functions,
visuospatial females years: years: performance/ vals: attention, and
perception, 38.48 7.58 comparison of 2–3 information
verbal (11.11), (7.21), means of years: processing speed
functions, 4–5 4–5 participant scores 1.97 (IPS) between the
attention, years: years: between baseline (1.61), two-time points of
information 38.81 8.68 and follow-up 4–5 assessment.
processing (12.38), (8.38), years:
speed 6–8 6–8 2.11
years: years: (1.57),
38.48 6.08 6–8
(12.41) (6.86) years:
1.92
(1.37)
Hoogervorst The Components of 1 120 PwMS: 47.1 years 40 RRMS, 37 NA Higher MSFC score Median MSFC had the highest
et al. Nether- Multiple 37% male (12.1 SPMS and represented (IQR)— correlation with
(2002) lands Sclerosis and 63% years) 43 PPMS better RRMS: cognitive function
Functional female; 40 performance/ 3.5
Composite RRMS, 37 MSFC score (2.0,
(MSFC) SPMS and between baseline 4.0)
43 PPMS and follow-up SPMS:
5.5
(4.0,
6.5)
PPMS:
6.5
(4.0,
7.5)
Hughes et al. United Perceived 3 234 PwMS: 53.83 136 RRMS, 58 15.88 (9.66) Higher score Range: There was a strong
(2015) States cognitive 35 males (10.54) SPMS, 28 represented 4.5– correlation between
impairment and 199 PPMS and better 6.5 in the University of
females 12 PRMS performance/ 47.4% Washington
comparison of of the Self-Efficacy Scale
participants’ mean partic- (UWSES) and ACGC
score between ipants and ACEF at
baseline and baseline and
follow-up follow-up
11 of 38
(Continues)
Maximum EDSS
12 of 38

Hughes et al. United Perceived 1 163 PwMS: 52.2 (10.1) 91 RRMS, 34 12.0 (9.0) A higher score NA Self-reported Sleep
(2018) States cognitive 21 males SPMS, 28 represented problems are
impairment and 142 PPMS and 8 better associated with
females PRMS and 2 performance perceived cognitive
not dysfunction
reported
Jakimovski United Processing 5 199: 127 PwMS: 48.4 127 PwMS: 85 PwMS: 16.3 < −1.5 SD on ≥ 1 (Median Baseline higher serum
et al. States speed, verbal PwMS (11 (10.9) RRMS, 42 (10.4) cognitive test (IQR)) neurofilament light
(2020) learning and males and CIS: 42.6 PMS CIS: 5.1 (study controls as PwMS: chain level
memory, 89 (10.7) HC: (5.7) norms) 2.5 predicted reduced
visuospatial females), 43.8 (1.5, cognitive
learning, and 20 CIS (3 (15.4) 5.5) processing speed
memory males and CIS:
17 1.5
females) (1.0,
and 52 HC 1.5)
(12 males
and 38
females)
Johansson Sweden Processing speed 10 264 PwMS: 71% were 149 RRMS, > 10 (10 < 32 correct 54% had SDMT score of ⩾32
et al. 85 males more 115 PMS years responses at a correct responses
(2020) and 179 than 41 follow-up) baseline and score predicted sustained
females years follow-up between participation in
0–3.5 social/lifestyle
activities
Johnen et al. Germany Processing 1 1123 PwMS 34.12 (9.67) 622 RRMS and 0.57 (0.61) < –2 SD on ≥ 2 1.49 Baseline
(2019) speed, divided and CIS: 501 CIS (Years cognitive tests (0.99) characteristics and
attention and 348 males since (population initiation of
working and 775 symptom controls as treatment with
memory females onset) norms)/ disease-modifying
comparison of the therapies did not
proportion of predict cognitive
cognitively changes within the
impaired/improved follow-up period
participants
between baseline
and follow-up
(Continues)
EZEGBE ET AL.
EZEGBE ET AL.
Maximum EDSS
Jonsson et al. Denmark Verbal 5 155: 80 Mean and 75 RRMS, 3 Months: 7 < −1.5 SD on a Mean Of all the measured
(2006) Intelligence, PwMS (19 (range): PPMS, 2 (1, 24) cognitive test (range): domains only, Visual
attentional males 61 35 SPMS (study controls as 2.7 (0, Organization had a
Control, females) (20–59) norms) / 6) significant linear
mental and 75 HC comparison of the deterioration over 3
processing proportion of years
speed, cognitively
visuospatial impaired/improved
memory, participants
problem- between baseline
solving, visual and follow-up
organization
and naming
Lopez- Spain Verbal memory 1 294: 237 PwMS: 38.5 All RRMS 7.4 (7.1) < −1.5 SD on ≥ 2 Median PwMS with cognitive
Gongora acquisition and PwMS (80 (10.2) and cognitive tests (range): impairment
et al. delayed recall, males and HC: 40.5 (study controls as 1.5 (0, increases from
(2015) visual memory 157 (9.4) norms) / 6) 27.6% at baseline to
acquisition and females) comparison of the 31.6% at follow-up.
delayed recall, and 57 HC proportion of
sustained and (13 males cognitively
complex and 44 impaired/improved
attention, females) participants
information between baseline
processing and follow-up
speed, working
memory, verbal
fluency and
executive
function
(Continues)
13 of 38
14 of 38
Maximum EDSS
McKay et al. Sweden Information 3+ 5704 PwMS Adult onset, 99% of Adult onset: < −1.5 SD below the NA SDMT score
(2019) processing (1689 median Pediatric 5.2 normative mean/ statistically
speed males and (IQR): onset and (1.7-11.0) trajectory plotted significantly
4015 38.3 97.6% of Pediatric in a graph with the declined faster for
females): (31.4, adult onset onset: mean score for pediatric onset than
5404 45.2) were RRMS 10.2 (5.3– each group adult-onset MS.
adult- pediatric 15.7)
onset MS onset,
and 300 median
pediatric (IQR):
onset MS 25.6
(21.0,
31.7)
Motyl et al. Czech Processing speed 1 1091 PwMS: 38.4 (9.0) 90.8% were 9.9 (7.3) < −1.5 SD on a All Only 4% of PwMS
(2021) Republic (332 males RRMS and cognitive test groups: experienced
759 9.2% were (study controls as Median, isolated cognitive
females) SPMS norms) / (IQR) decline and this
comparison of the 2.0 occurred without a
proportion of (1.5, corresponding
cognitively 3.5) neurological clinical
impaired/improved activity
participants
between baseline
and follow-up
(Continues)
EZEGBE ET AL.
EZEGBE ET AL.
Maximum EDSS
Raimo et al. Italy Global cognitive 2+ 100 PwMS Not Not defined Not defined A higher score on NA A higher degree of
(2020) functioning, (gender specified Cognitive apathy at baseline
verbal learning not Impairment Index predicted cognitive
(immediate specified) (CII) represents a changes (CII) at
and delayed poorer cognitive follow-up.
recall), function. Higher
visuospatial CII depends on a
memory higher number of
(delayed SD from the
recall), control mean.
short-term (Population
(verbal) controls as
memory, norms)/
visuospatial Comparison of
functions, mean score
executive between
functions, participants from
abstraction, baseline to
mental follow-up
flexibility,
motor
Programming,
sensitivity to
interference by
conflicting
instructions
test, Inhibitory
control,
environmental
autonomy),
executive
domain
(Continues)
15 of 38
Maximum EDSS
16 of 38

Roy et al. United NA 5 182 (82 PwMS: Not defined 9.56 (6.61) 0.8 reliable change Median, Personality changes
(2018) States PwMS (17 45.96 indices (decline) in (range): were observed in
males and (8.13), at least one 2.75, PwMS with
65 HC: 45.42 BICAMS (0.00, cognitive decline
females) (11.68) measure/graph of 6.50)
and 100 trajectory
HC (29 between baseline
males and and follow-up
71
females))
Strober et al. United Cognition SDMT: 2 1512 PwMS 36.5 (9.79) Both SDMT 3.6 (4.71) ≤ 4-point worsening Both A ≤4- point worsening
(2019) States PASAT: 5 (441 males and PASAT: of SDMT SDMT of SDMT was the
and 1071 All RRMS and strongest predictor
females): PASAT: of worsening in the
Both 2.5 Physical
SDMT and (1.23) Component
PASAT Summary
Uher et al. Czech Processing 2 1052 PwMS: Cognitively Not defined Cognitively < –1.5 SD on a Low brain
(2017) Republic speed, memory 770 pre- pre- cognitive test Cognitively parenchymal
(visual Cognitively served: served: (study controls as pre- fraction and high T2
modality), preserved 37.6 (8.8) 8.8 (6.7) norms) / served: lesion volume were
memory (29% male, Cogni- Cogni- comparison of the 2.2 associated with an
(auditory 71% tively tively proportion of (1.1) increased risk of
sphere) female) impaired: impaired: cognitively Cogni- cognitive decline
and 282 39.6 (8.8) 11.6 (7.6) impaired/improved tively over the follow-up
Cognitively participants impaired: period
impaired between baseline 3.4
(33% male, and follow-up (1.4)
67%
female)
Wallach et al. United NA Mean: 1.8+ 616 PwMS SDMT Not defined SDMT < –1 SD on a 14.1% of PwMS had
(2020) States years (217 males decline: decline: cognitive test Score: < 2.0 SDMT decline at
and 399 14.3 2.7 [0.6, (SDMT) over time (274 follow-up predicted
females): (13.2, 3.8] (population PwMS) by older age and
Adminis- 16.6) SDMT controls as ⩾2.0 male gender
tered SDMT stable or norms)/ (109
SDMT stable or improve: comparison of the PwMS)
improve: 2.9 [0.8, proportion of
13.3 4.2] cognitively
(11.9, impaired/improved
15.8) participants
EZEGBE ET AL.
between baseline
and follow-up
(Continues)
EZEGBE ET AL.
Maximum EDSS
Wu et al. Australia NA 2.5 1958 PwMS 45.0 (10.2) RRMS, SPMS < 5 years: Perceived cognitive NA Persistent Perceived
(2020) (367 males, and PPMS 904; 5- 10 impairment: cognitive
1591 years: cognitive function impairment was
females): 450 sub-score ≤66.7 associated with a
1313 and > 10 points/ significantly higher
RRMS, 214 years: comparison of the risk of sexual
SPMS, 170 602 proportion of dysfunction at
PPMS and cognitively follow-up.
253 unsure impaired/improved
participants
between baseline
and follow-up
Ytterberg Sweden 1. NA 2 200 PwMS 47 (12) 119 RRMS, 73 14 (10) Not defined/ mean Range: 0 A higher mean
et al. (65 males SPMS and 8 score at baseline (1 number of correct
(2008) and 135 PMS and follow-up PwMS), answers in SDMT
females) 1 −3.5 was observed in
(122 PwMS in the EDSS
PwMS), category 1–3.5
4– compared to PwMS
5.5 (34 with EDSS 4 and
PwMS) above
and 6–
9.5 (43
PwMS)
RRMS: relapsing-remitting multiple sclerosis; PPMS: primary progressive multiple sclerosis; SPMS: secondary progressive multiple sclerosis; PwMS: people living with multiple sclerosis. SDMT: Symbol Digit
Modalities Test; PASAT: Paced Auditory Serial Addition Test; SD: standard deviation; NA: not available; IQR: interquartile range; HC: healthy control; EDSS: Expanded Disability Status Scale; BICAMS: Brief
International Cognitive Assessment for Multiple Sclerosis; ACGC: applied cognition—general concerns. ACEF: applied cognition—executive function; MSFC: multiple sclerosis functional composite.
17 of 38
18 of 38
TA B L E 2 Characteristics of studies measuring change in cognitive function in people living with multiple sclerosis after intervention.
The
maximum Definition of
gap Patient cognitive
between the group MS duration impairment (or
measure- Age (at (RRMS, (mean) at improvement)/ EDSS score
ment of baseline) PPMS, baseline: Change in (mean) at Findings about Any inter-
Author and cognition Study Mean (SD) SPMS) at Mean (SD) cognitive baseline: cognitive vention/
year Location Cognitive domain (years) population years baseline years function Mean (SD) function medication
Amato et al. Italy Verbal memory 3 105: 49 PwMS: 36.9 All 2.9 (1.7) < −1.5 SD on ≥ 2 1.7 (0.7) Moderate Therapy
(2010) acquisition and PwMS (8.9) and Relapsing- cognitive tests cognitive with
delayed recall, (11 males HC: 38.1 remitting (study controls impairment inter-
visual memory and 38 (9.0) as norms)/ at baseline feron β
acquisition and females) Comparison of predicted (IFNB)-
delayed recall, and 56 mean scores more 1b.
attention, HC (20 for each test cognitive
concentration, males among decline later
and speed of and 36 participants at follow-up
information females) between
processing, verbal baseline and
fluency on follow-up
semantic stimulus,
and Cognitive
control and
inhibition
Benedict et al. United Processing speed, 2 1651 48.0 (7.9) All 12.6 (7.8) 4-point sustained Median: 6.0 Patients Siponimod
(2021) States working memory, PwMS secondary increase treated with versus
episodic memory (659 progres- (improvement) siponimod placebo
(visuospatial males sive (SP) or decrease had
memory) and 992 MS (deterioration) significant
females) in SDMT. improve-
Impairment is ment in
defined as SDMT
SDMT ≥2 SD
below the
mean of study
controls/mean
change in
SDMT score
from baseline
to follow-up
(Continues)
EZEGBE ET AL.
The
EZEGBE ET AL.
Benedict et al. United Cognitive 2+ 1841 Range: 18, All RRMS Not defined 3-point or 4-point Range: 0, 5.0 Clinically Daclizumab
(2018) States processing speed (144 weeks) PwMS 55 years change in meaningful β com-
(919 SDMT score improve- pared to
daclizumab from baseline ment (an intramus-
β and to follow-up/ increase cular
922 IM mean change in from inter-
Inter- SDMT score baseline of feron
feron from baseline ⩾3 points) in (IFN)
β-1a) Sex to follow-up cognitive β-1a
ratio not function
defined. (SDMT)
observed
from
daclizumab β
compared to
intramuscu-
lar
interferon
(IFN) β-1a
Benesova & Czech NA 2 300 PwMS: 36.33 All 5+ (61.6 Increase in mean 2.85 (1.10) Improvement All PwMS
Tvaroh Repub- 300 (10.04) relapsing- months) PASAT score in cognition were on
(2017) lic relapsing- remitting from baseline (PASAT different
remitting MS to follow-up score) in doses of
MS patients (not patients subcuta-
(RRMS) statistically taking sub- neous
patients significant)/ cutaneous IFN β-1a
(102 proportion of IFN β-a
males participants (change in
and 198 with increased, PASAT
females) stable or compared to
but 272 decreased stable PASAT
analyzed PASAT at score)
baseline and
follow-up
(Continues)
19 of 38
20 of 38
The
Chan et al. United Premorbid 2 140 PwMS: 51⋅3 (6⋅9) All 21⋅2 (8⋅6) < −1.5 SD on a 5⋅8 (0⋅8) There was a Simvastatin
(2017) King- Intelligence 70 on secondary cognitive test significant versus
dom Quotient (IQ), Simvas- progres- (study controls decline in placebo
intellectual tatin and sive as norms) verbal
function, verbal 70 on multiple /mean change memory and
IQ, nonverbal IQ, placebo sclerosis in test scores nonverbal
verbal from baseline memory in
intelligence, to follow-up all PwMS.
abstract verbal FAB score
reasoning, spatial higher in the
perception and Simvastatin
visuomotor skills, group
nonverbal compared to
abstract the placebo
reasoning, group
semantic memory,
verbal episodic
memory, verbal
episodic memory,
visuoperceptual
functioning,
nonverbal
episodic memory,
nonverbal
episodic memory,
spatial perception,
executive
functions,
information
processing,
attention, and
working memory
(Continues)
EZEGBE ET AL.
EZEGBE ET AL.
The
Cinar et al. Turkey Verbal learning and 1 263: 161 PwMS: 30.4 All RRMS 2.02 (2.6) < −1.5 SD on a Score: < 5.5 Cognitive test Glatiramer
(2017) memory, PwMS (11.2) HC: cognitive test scores were acetate
visual-spatial (51 males 31.5 (14.3) (study controls significantly and β-
memory and 110 as poorer in the interferon
females) norms)/mean PwMS The
and 102 test scores at proportion
HC (34 baseline and of
males follow-up cognitively
and 68 impaired
females) PwMS
reduced
after a year
of the admin-
istration of
glatiramer
acetate and
β-interferon
Comi et al. Italy Executive functions 1.5 (18 157 PwMS Fingolimod: All RRMS Fingolimod: < −1.5 SD on ≥ 1 Fingolimod: Both treatment Fingolimod
(2017) months) (106 for 40.23 4.97 (6.67) cognitive test 2.78 (1.34) groups and inter-
fin- (9.09) and and (population and showed feron
golimod Interferon Interferon controls as Interferon significant β-1b
and 51 B: 37.64 B: 4.71 norms based on B: 2.09 improve-
for Inter- (9.29) (6.47) age and (1.05) ment in
feron gender)/mean cognitive
B) change in test function. No
scores between significant
baseline and differences
follow-up were
observed
between the
treatment
groups
(Continues)
21 of 38
22 of 38
The
DeLuca et al. United Processing speed 1 830 PwMS: Ozanimod: All RRMS 6.9 4-point or greater PwMS on Ozanimod Ozanimod
(2021) States 418 took 34.8 years increase Ozani- significantly com-
ozani- and (SDMT mod: enhanced pared to
mod and Interferon improved) or SDMT cognitive Inter-
412 β-1a: 35.9 decrease improved: scores feron
inter- years (worsened) in 2.5 (1.0), compared β-1a
feron SDMT score worsened: with
β-1a from baseline 2.5 (1.2) Interferon
(63.3% to follow-up and PwMS β-1a
and 67% was observed Interferon
in each as β-1a:
group improvement SDMT
were or worsening improved
females, respectively/ 2.5 (1.2),
respec- Proportion of worsened:
tively) participants 2.7 (1.2)
with improved
or worsened
SDMT score at
baseline and
follow-up
(Continues)
EZEGBE ET AL.
The
EZEGBE ET AL.

De Giglio Italy Verbal memory 2 142 PwMS All RRMS < –1 SD on ≥ 2 The proportion
et al. (2016) acquisition and (All Subcutaneous Subcutaneous cognitive tests Subcutaneous of Subcutaneous
delayed recall, female) IFN-b-1a: IFN-b-1a: (population IFN-b-1a: cognitively IFN-b-1a
visuospatial 30.4 (7.0) 4.2 (4.5) controls as 1.7 (0.7) impaired and
memory Subcuta- subcuta- norms)/proportion subcuta- PwMS less in ethinyl
acquisition and neous neous of participants neous subcuta- estradiol
delayed recall, IFN-b-1a IFN-b-1a with cognitive IFN-b-1a neous
sustained and and ethinyl impairment at and IFN-b-1a and
attention, ethinyl estradiol baseline and ethinyl ethinyl
Concentration, estradiol 20 μg: 3.3 follow-up estradiol estradiol 40
processing speed, 20 μg: (3.0) and 20 μg: 1.8 μg groups
and verbal fluency 29.1 (6.4) Subcuta- (0.9) and
on semantic and Sub- neous Subcuta-
stimulus. cutaneous IFN-b-1a neous
IFN-b-1a and ethinyl IFN-b-1a
and estradiol and
ethinyl 40 μg: 3.5 ethinyl
estradiol (3.9) estradiol
40 μg: 40 μg: 1.6
30.6 (5.9) (1.0)
Fischer et al. United Information 2 166 PwMS Interferon All RRMS Interferon Having a score Interferon RRMS patients Interferon
(2000) States processing, visual (128 β-1a: 36.1 β-1a: 6.7 that is less than β-1a: 2.3 performed β-1a
learning/recall, females, (6.4) (5.7) 0.5 SD relative (0.8) better versus
verbal 38 males Placebo: Placebo: to week 0 Placebo: cognitively placebo
learning/recall, and 83 36.2 (6.8) 6.4 (5.1) (baseline) score 2.4 (0.9) (information
visuospatial Interferonβ- (after adjust- processing
abilities, 1a, 83 ment)/mean z and learn-
problem-solving, placebo) score at ing/recent
visual scanning, baseline and memory
plan- follow-up measures,
ning/sequencing, visuospatial
deductive abilities, and
reasoning, general executive
verbal abilities, functions)
attention span, while on
Information Interferon
processing, β-1a
general verbal compared to
abilities those on a
23 of 38
placebo
(Continues)
24 of 38
The
Iaffaldano Italy Verbal memory Main group: 100 PwMS 34.55 (9.25) All RRMS 11.09 (7.52) < 2 SD on ≥ 3 3.66 (1.14) Cognitively
et al. (2012) acquisition and 1 year. (main (main cognitive tests impaired Natalizumab
delayed recall, Smaller group): group) (population participants
visual memory group: 2 28 males controls as decreased
acquisition and years and 72 norms)/proportion significantly
delayed recall, females of participants between
attention, with Cognitive baseline and
concentration and Impairment at follow-up (1
speed of baseline and year)
information follow-up
processing, verbal
fluency on
semantic stimulus,
frontal lobe
executive
functions
Koch et al. Canada NA 2 889 PwMS: 47.2 years All SPMS Has had Four-point (Median There was an
(2021) 339 (7.6) SPMS for change in (IQR)): 6.0 increased Natalizumab
males two or SDMT and (5.0, 6.5) improve-
and 550 more years PASAT score ment in
females between SDMT score
baseline and in about 75%
follow-up of the
participants
from
baseline to
104 weeks.
(Continues)
EZEGBE ET AL.
EZEGBE ET AL.
The
Lincoln et al. United Total recall and 1 449 PwMS 49 (SD 9.9) 291 RRMS, 11.7 (8.4) < −1 SD on a NA No long-term Cognitive
(2020) King- delayed recall, (123 46 PPMS cognitive test benefits on rehabili-
dom total recall and males and 112 (study controls quality of life tation
delayed recall, and 326 SPMS as were versus
information females) norms)/mean observed in usual
processing speed, test scores at MS patients care
easy total and baseline and at after the
hard total, word follow-up cognitive
fluency, memory rehabilita-
function, tion
attention, and program
executive abilities
Patti et al. Italy NA 3 459 PwMS: 33.3 (8.13) All RRMS 3.8 (4.47) < −1 SD on a 1.8 (1.0) For PwMS on
(2010) 236 on sc years cognitive test 44 μg, subcutaneous
IFNb-1a (population cognitive IFNb-1b
(44 μg) controls as impairment (Interferon-
and 223 norms)/proportion remained 1b)
on sc of cognitively stable at
IFNb-1a impaired 15.2% from
(22 μg) participants at baseline to
baseline and follow-up.
follow-up For PwMS on
22 μg
cognitive
impairment
increased
from 23.5%
to 24.8%
(Continues)
25 of 38
26 of 38
The
Patti et al. Italy NA 5+ 265 PwMS 39 (8.2) All RRMS 8 (4.4) < −1 SD on ≥ 3 NA The proportion
(2013) (99 males cognitive tests with Subcutaneous
and 166 (population cognitive (sc) inter-
females) controls as impairment feron
norms)/proportion remained so (IFNb-1b)
of cognitively at 3 years 44 or
impaired and at 5 22 mg
participants at years
baseline and however
follow-up men were
more
affected.
Perumal et al. United NA 2 222 PwMS 34.0 (8.97) All RRMS 1.6 (0.77) Higher scores 2.0 (1.13) PwMS had a
(2019) States (61 males indicate better significant Natalizumab
and 161 cognitive increase in
females) function/ SDMT score
change in between
SDMT score baseline and
between follow-up (2
baseline and years)
follow-up
(Continues)
EZEGBE ET AL.
EZEGBE ET AL.
The
Rudick et al. United NA 2 942 PwMS AFFIRM‡ : AFFIRM: All AFFIRM‡ : A ≥ 20% AFFIRM‡ : A ≥ 20%
(2009) States (627 on Natal- RRMS Natalizumab— worsening of Natal- worsening of Natalizumab
natalizumab median MSFC† score izumab 2.3 MSFC score and
izumab 35.6 (8.5) (range) 5.0 (PASAT-3) (1.2) was placebo
and 315 Placebo (0, 34); sustained for 3 Placebo significantly
on 36.7 (7.8) Placebo— months at 2.3 (1.2) associated
placebo median follow-up with EDSS
(AFFIRM)) (range) 6.0 compared to change.
(0, 33) the baseline
score/
proportion of
participants
that had the
worsening of
MSFC from
baseline to
follow-up
Schwartz United Verbal and spatial 1 130 PwMS 43.2 (8.93) 41.5% 8.26 (6.71) Number of 4.74 (1.74) The interven- Two psy-
et al. (1996) States memory, complex (27.4% RRMS and cognitive tions had no chosocial
attention, verbal male and 58.5%Chronic tests < −1 differential interven-
fluency, executive 72.6% Progres- SD, ← 2, ← 3 of effect on tions (not
function/cognitive female) sive normative neuropsy- explained
flexibility, complex mean/ mean T chological but
attention, and score at function reference
sequencing baseline and over time provided)
follow-up
(Continues)
27 of 38
The
28 of 38

Schwid et al. United Verbal learning and 10+ 153 PwMS 34.6 (6.1) All RRMS 6.9 (5.2) A 0.5 SD 2.6 (1.2) Cognitive test Glatiramer
(2007) States memory, (gender reduction in score acetate
visuospatial propor- test scores changes in 2 and
memory and tion not compared to years placebo
learning, speci- the norm in a predicted
attention, fied) cognitive 10-year
information test/the changes
processing, and proportion of
working memory, the cognitively
verbal fluency impaired in
baseline and
follow-up
Stephenson United NA 1 333 PwMS 46.8 (10.4) Not defined 10.6 (7.9) One point change NA Natalizumab
et al. (2012) States (21.9% in scale reduced the Natalizumab
male and (MS-COG) effect of MS
78.1% between on cognitive
female) baseline and function.
follow-up 65% to 69%
of PwMS
showed
improve-
ment at
follow-up
compared to
baseline.
Weinstein United Verbal learning and 2 251 PwMS Glatiramer: All RRMS Glatiramer: < −2 SD on a Glatiramer: Mean cognitive Glatiramer
et al. (1999) States recall, visuospatial (67 males 34.6 (6.0) 7.3 (4.9) cognitive test 2.8 (1.2) test function and
learning and and 184 Placebo: Placebo: (population Placebo: scores were Placebo
delayed recall, females) 34.3 (6.5) 6.6 (5.1) controls as 2.4 (1.3) higher at
perceptual norms/mean follow-up (1
processing and test scores at and 2 years)
attention, baseline and compared to
information follow-up the baseline
processing speed
and sustained
attention,
semantic retrieval
and production
EZEGBE ET AL.
(Continues)
EZEGBE ET AL.
The
Weinstock- United NA 2 856 PwMS: Not All RRMS Not specified Cognitive decline Range: Natalizumab Intravenous
Guttman States 574 on specified progression: 0.0−5.0 reduced the natal-
et al. (2012) natal- 0.5 SD risk of izumab
izumab worsening in observed 300 mg,
group PASAT-3 score progression intramus-
and 282 observed for of cognitive cular (IM)
on 12 weeks deficits by IFNb-1a
placebo 43% 30 lg and
(AFFIRM‡ ). compared placebo
887 with the
PwMS: placebo
459 on
natal-
izumab
and
IFNb-1a
and 428
on
placebo
and
IFNb-1a
group
(SENTINEL§ ).
†
MSFC: multiple sclerosis functional composite.
‡
AFFIRM: natalizumab safety and efficacy in relapsing-remitting multiple sclerosis.
§
SENTINEL: safety and efficacy of natalizumab in combination with interferon β-1a in patients with relapsing-remitting multiple sclerosis.
Abbreviations: RRMS: relapsing-remitting multiple sclerosis; PPMS: primary progressive multiple sclerosis; SPMS: secondary progressive multiple sclerosis; PwMS: people living with multiple sclerosis; SDMT:
Symbol Digit Modalities Test; PASAT: Paced Auditory Serial Addition Test; SD: standard deviation; NA: not available; IQR: interquartile range; HC: healthy control; EDSS: Expanded Disability Status Scale; MS-COG:
Medical Outcomes Scale-Cognitive Functioning; FAB: Frontal Assessment Battery.
29 of 38
FIGURE 1 Flowchart of the literature search and study selection process.
impairment as failure in 1 or more tests with a cut-off score of < −1.5 3.2 The cognitive function domains measured,
SD from the mean (normative or study healthy control). However, there and the tests and batteries used
was heterogeneity in the use of a cut-off score with −2.0, −1.5, and
−1.0 SD from the mean (normative or study healthy control), and het- Visual learning and memory (21/57) and verbal learning and memory
erogeneity in the number of qualifying failed tests (1 to 5 or more tests), (20/57) were the most frequently measured domains when a bat-
to define “impairment.” Decline or improvement was shown by com- tery was used (Table 3). Information processing speed and complex
paring the percentage/proportion of cognitively impaired to improved attention (34/57) was the most measured domain when cumula-
participants between baseline and follow-up (Amato & Ponziani, 1998; tively a single test or a battery was used. Rao’s BRNB and BICAMS
Andravizou et al., 2020; Chruzander et al., 2014; Johnen et al., 2019) were the predominant batteries used in the measurement of change
and reliable change index was used to report meaningful change as it in cognitive function in PwMS (19/57). Other studies used Randt’s
corrects for measurement error and practice effects (Andravizou et al., memory battery, Birt Memory and Information Processing Battery
2020). For some papers that used one cognitive test, a 10% or 20% (BMIPB), and Visual Object and Space Perception (VOSP) battery
change in mean score (Bsteh et al., 2019) or a 4-point change (SDMT (Chan et al., 2017). In some cases, it was a combination of cogni-
mostly) in the score (Benedict et al., 2018; DeLuca et al., 2021; Koch tive tests from different batteries that were used (Jonsson et al.,
et al., 2021) were used. 2006).
TA B L E 3 Cognitive function domains and the cognitive tests and batteries that were used in included studies.
Domains Cognitive test (Cognitive test battery† )

Premorbid intelligence National Adult Reading Test (Chan et al., 2017)
Intellectual functioning Wechsler Abbreviated Scale of Intelligence (WASI; Full-Scale IQ, Performance IQ, and Verbal IQ) (Chan et al., 2017)
Wechsler Adult Intelligence Scale–Revised (WAIS-R) (Fischer et al., 2000)
Short-term storage Digits Forward (Jonsson et al., 2006)
capacity or attention Wechsler Memory Scale–Revised (WMS-R) (Fischer et al., 2000)
span
Complex attention— Symbol Digit Modalities Test (single test and in a battery) (RBRB† ) (Amato et al., 2010; Amato et al., 2010; Benedict
information et al., 2018; Benedict et al., 2021; Borghi et al., 2016; Bsteh et al., 2019; Chruzander et al., 2014; Crielaard et al.,
processing speed 2019; De Giglio et al., 2016; de Groot et al., 2009; DeLuca et al., 2021; Eijlers et al., 2018; Fuchs et al., 2020; Healy
and visual tracking et al., 2021; Iaffaldano et al., 2012; Jakimovski et al., 2020; Johansson et al., 2020; Jonsson et al., 2006; Lincoln
et al., 2020; Lopez-Gongora et al., 2015; McKay et al., 2019; Motyl et al., 2021; Patti et al., 2010; Perumal et al.,
2019; Roy et al., 2018; Schwartz et al., 1996; Schwid et al., 2007; Uher et al., 2017; Wallach et al., 2020; Weinstein
et al., 1999; Ytterberg et al., 2008)
The Trail Making Test—Part A (Raimo et al., 2020; Schwartz et al., 1996)
California Computerized Assessment Package (CALCAP) Sequential reaction time (Fischer et al., 2000)
Memory Comparison Test (Eijlers et al., 2018)
Working memory Paced Auditory Serial Addition Test (single test and in a battery) (Amato et al., 2010; Benedict et al., 2021; Benesova
& Tvaroh, 2017; Borghi et al., 2016; Bosma et al., 2010; Chan et al., 2017; Comi et al., 2017; De Giglio et al., 2016;
de Groot et al., 2009; De Meijer et al., 2018; Fischer et al., 2000; Hoogervorst et al., 2002; Iaffaldano et al., 2012;
Johnen et al., 2019; Koch et al., 2021; Lincoln et al., 2020; Lopez-Gongora et al., 2015; Patti et al., 2010; Rudick
et al., 2009; Schwartz et al., 1996; Schwid et al., 2007; Strober et al., 2019; Weinstein et al., 1999;
Weinstock-Guttman et al., 2012)
Serial Seven Subtraction Test (Jonsson et al., 2006)
Arithmetical Operations (Jonsson et al., 2006)
Digits Backward (Jonsson et al., 2006)
Visual scanning Visual search number of trials (Fischer et al., 2000)
Mesulam Cancellation Test (Jonsson et al., 2006)
Visual perception and Street Gestalt Completion Test (Jonsson et al., 2006)
organization
Visual construction Rey– Osterrieth Complex Figure Test (ROCF)—Copy (Jonsson et al., 2006; Raimo et al., 2020) (see also Executive
Function—planning)
Block Design (Wechsler Abbreviated Scale of Intelligence) (Chan et al., 2017)
Figure Copying (BIRT† Memory and Information Processing Battery) (Chan et al., 2017)
Clock Drawing Test (CDT) (Raimo et al., 2020)
Language The Aachener Aphasie Test (Amato et al., 2010)
Vocabulary (WASI/WAIS) (Chan et al., 2017; Jonsson et al., 2006)
Boston Naming (split half version, odd-numbered tasks) (Jonsson et al., 2006)
Graded Naming Test (Chan et al., 2017)
Verbal learning and Selective Reminding Test (RBRB† ) (Amato et al., 2010; Amato et al., 2010; Borghi et al., 2016; Comi et al., 2017; De
memory Giglio et al., 2016; de Groot et al., 2009; Eijlers et al., 2018; Iaffaldano et al., 2012; Jonsson et al., 2006; Lincoln
et al., 2020; Lopez-Gongora et al., 2015; Patti et al., 2010; Schwartz et al., 1996; Schwid et al., 2007; Weinstein
et al., 1999)
Story: Immediate and Delayed Recall (BIRT† Memory and Information Processing Battery) (Chan et al., 2017)
The California Verbal Learning Test-II (BICAMS† ) (Cinar et al., 2017; Fischer et al., 2000; Jakimovski et al., 2020; Uher
et al., 2017)
Word List Learning (2 trials), Interference Word List Learning, and Word List Recall (Raimo et al., 2020)
Rey Auditory Verbal Learning Test (RAVLT) (Raimo et al., 2020)
Visual learning and 10/36 Spatial Recall Test (SPART) (RBRB† ) (Amato et al., 2010; Borghi et al., 2016; Comi et al., 2017; De Giglio et al.,
memory 2016; de Groot et al., 2009; Eijlers et al., 2018; Iaffaldano et al., 2012; Jonsson et al., 2006; Lincoln et al., 2020;
Lopez-Gongora et al., 2015; Patti et al., 2010; Schwartz et al., 1996; Schwid et al., 2007; Weinstein et al., 1999)
7/24 Spatial Recall Test (Jonsson et al., 2006)
Brief Visuospatial Memory Test—Revised (BICAMS† ) (Benedict et al., 2021; Cinar et al., 2017; Jakimovski et al., 2020;
Roy et al., 2018; Uher et al., 2017)
Rey–Osterrieth Complex Figure Test (ROCF)—Delay Recall (Jonsson et al., 2006; Raimo et al., 2020)
Figure Copying: Delayed recall (BIRT† Memory and Information Processing Battery) (Chan et al., 2017)
(Continues)

Cognitive control Modified Stroop Task, Stroop Test-interference task (Raimo et al., 2020)
The Stroop Test (Amato et al., 2010)
Stroop Color Naming Test (simplified version) (Jonsson et al., 2006)
Stroop Color-Word Task (Iaffaldano et al., 2012; Lopez-Gongora et al., 2015) (Eijlers et al., 2018) (Patti et al., 2010)
Inverse Motor Learning Test (IML) (Raimo et al., 2020)
Cognitive Category Fluency Switch Condition (Raimo et al., 2020)
flexibility/divided The Trail Making Test—Part B (Schwartz et al., 1996)
attention Trail Making: Part B—Part A (DKEFS† ) (Lincoln et al., 2020)
Trail Making Test (TMT: B, TMT: B-A) (Raimo et al., 2020)
Motor performance Constructional Apraxia Task (CAT) (Raimo et al., 2020)
Executive Tower of London Test (Amato et al., 2010; Fischer et al., 2000; Jonsson et al., 2006)
function—planning Rey—Osterrieth Complex Figure Test (ROCF)—Copy (Raimo et al., 2020) (see also visual construction)
Executive Word List Generation (Amato et al., 2010; Borghi et al., 2016; Comi et al., 2017; De Giglio et al., 2016; de Groot et al.,
function—fluency 2009; Eijlers et al., 2018; Iaffaldano et al., 2012; Lopez-Gongora et al., 2015; Patti et al., 2010; Schwid et al., 2007)
Word Fluency Total Score (Lincoln et al., 2020)
Controlled Oral Word Association Task (Schwartz et al., 1996)
Words starting with letter “s” (Jonsson et al., 2006)
Phonological verbal fluency task, and semantic verbal fluency task (Raimo et al., 2020)
Animals (Jonsson et al., 2006)
Design Fluency (Jonsson et al., 2006)
Ruff Figural Fluency Test (Fischer et al., 2000)
Executive Raven’s Colored Progressive Matrices (RCPM) (Raimo et al., 2020)
function—visual Raven Progressive Matrices (Jonsson et al., 2006)
concept formation Matrix Reasoning (WASI/WAIS) (Chan et al., 2017; Lopez-Gongora et al., 2015)
or abstract Cube Analysis Task (The Visual Object and Space Perception battery) (Chan et al., 2017)
reasoning
Executive Similarities (WAIS) (Chan et al., 2017; Jonsson et al., 2006)
function—verbal 20 Qs % good hypothesis Qs (Fischer et al., 2000)
concept formation
or abstract
reasoning
Executive Free Sorting and Sort Recognition—Sorting Test (DKEFS† ) (Comi et al., 2017)
function—set The Concept Shifting Test (Eijlers et al., 2018)
shifting The Wisconsin Card Sorting Test (WCST) (Fischer et al., 2000; Lopez-Gongora et al., 2015; Schwartz et al., 1996)
Social cognition Famous Faces (naming %) (Jonsson et al., 2006)
Multiple Blessed Information-Memory Concentration Test (“Information Test”—personal orientation; “Memory”—personal
domains—global and nonpersonal knowledge and remembering a name and address; and “Concentration”—saying months of year
cognition backward and counting 1–20 forward and backward (Amato & Ponziani, 1998; Amato et al., 1995; Amato et al.,
2001) Digit forward, Five items and paired word acquisition (Amato & Ponziani, 1998; Amato et al., 1995; Amato
et al., 2001) (Randt’s Memory Battery† )
Frontal Assessment Battery (Chan et al., 2017) Similarities task, lexical fluency, Luria’s motor series, Conflicting
instructions test, Go/no go test and Prehension Behavior Test (Frontal Assessment Battery† ) (Raimo et al., 2020)
Mini-Mental State Examination Italian version (Raimo et al., 2020)
GO-NOGO Response Inhibition Test, Stroop interference test, catch game, verbal memory, nonverbal memory,
staged information processing speed, finger tapping, verbal function, visual-spatial processing (NeuroTrax (NT;
NeuroTrax Corp, Modiin)) (Heled et al., 2021)
Comprehension, Functional Independence Measure (Beckerman et al., 2013)
expression, social
interaction,
problem-solving, and
memory
Episodic memory Brief Visuospatial Memory Test—Revised (Benedict et al., 2021)
Short- and long-term MDS-Cognition Scale (11-point scale) (Demakis & Buchanan, 2010; Demakis et al., 2009)
memory, orientation,
and communication
(Continues)

Self-reported cognitive Applied Cognition—General Concerns and Applied Cognition—Executive Function (Neurological Disorders
function (NeuroQoL) measurement system) (Hughes et al., 2015), (Applied Cognition–General Concerns Short Form
Version 1 (NeuroQoL) measurement system) (Hughes et al., 2018), Medical Outcomes Scale-Cognitive Functioning
(MOS-Cog) (Stephenson et al., 2012), MS Quality of Life-54 (MSQOL-54) (Wu et al., 2020)
No mention of (RBRB† ) (Patti et al., 2013)
cognitive domain or
test
Abbreviations: RBRB: Rao’s Brief Repeatable Battery; BICAMS: Brief International Cognitive Assessment for Multiple Sclerosis; DKEFS: Delis-Kaplan
Executive Function System.
†Cognitive test battery.
Thirty-nine studies used cognitive test batteries and nineteen stud- ment intervals of cognitive function in the 7 papers ranged from 1 year
ies used individual cognitive tests. Among the studies that used only to 3 years. The results showed that there was an associated −0.03
one cognitive test, most used either the SDMT (13 articles) or Paced (95% CI −0.14, 0.09) decrease in SDMT mean score per year in PwMS,
Auditory Serial Addition Test (PASAT) (5 articles). Both were addi- although this was not statistically significant. Sensitivity analysis using
tionally reported by some authors to measure attention (sometimes linear regression that included the 7 papers did not show any statisti-
qualified as sustained attention) and/or concentration (Amato et al., cally significant difference between 1 and 3 years in terms of change
2010; De Giglio et al., 2016; Iaffaldano et al., 2012) Overall, considering in SDMT score. The heterogeneity test I2 at 66.77% was considered
both studies that used batteries or a single test, the SDMT was used in moderate and the Egger test for publication bias was not statistically
the highest number of studies (n = 31). significant (p = .318).
3.3 Results related to change in cognitive 4 DISCUSSION

function from the included papers
This systematic review found that changes in cognitive function in MS
Most longitudinal studies without any intervention reported cognitive are more often measured at the population level using a battery of tests
decline between baseline and follow-up and some occurred with- rather than a single test. The domains most measured using a test bat-
out associated clinical neurological deterioration based on EDSS and tery were visual learning and memory, and verbal learning and memory.
relapse (Motyl et al., 2021). Other observed findings include that Many papers defined cognitive impairment as failure in 1 or more tests
the trend of cognitive decline in PwMS depended on the associated with a cut-off score of < −1.5 SD from study control or normative
comorbidities: psychiatric conditions such as depression, bipolar dis- mean and change in cognitive function as the proportion with cogni-
order, schizophrenia, or neurological conditions such as Alzheimer’s tive impairment or improvement between baseline and follow-up. This
and Parkinson’s diseases, or both (Demakis et al., 2009). Cognitive illustrates that there was no uniformity in the assessment of change in
decline in PwMS is associated with poorer work outcomes (Amato & cognitive function in MS. The SDMT was the most frequently used cog-
Ponziani, 1998), poorer health-related quality of life (Chruzander et al., nitive test, either as a sole test or as part of a battery in all the papers.
2014) and personality changes (Raimo et al., 2020). A decline in cog- The meta-analyses did not find a clinically or statistically significant
nitive function was theorized to occur gradually over time in PwMS change in SDMT scores over a period of three years in PwMS.
as opposed to it occurring in a step-wise manner (as would occur for The findings suggest that there is no uniform method for measuring
example in stroke) (Demakis & Buchanan, 2010; Healy et al., 2021). change in cognitive function over time. Nor is there a uniform or agreed
There was also a greater decline in progressive MS than RRMS (Eijlers method to denote the presence of cognitive impairment. Most papers
et al., 2018), older PwMS, and males with MS (de Groot et al., 2009; included in this review defined cognitive impairment as a test score less
Wallach et al., 2020). Pediatric onset (i.e., < 18 years of age) is also asso- than 1.5 standard deviations from a study or normative sample mean
ciated with greater cognitive decline than adult-onset MS (McKay et al., in one or more cognitive function tests, and a decline was defined by a
2019). Cognitive dysfunction is also more likely to occur in PwMS with comparison of the proportion that was impaired at baseline and follow-
an EDSS of more than 3.5 compared to those with an EDSS of 1 to 3.5 up. However, cut-off scores varied with some papers using a criterion
(Ytterberg et al., 2008). of more than 2 or as low as 1 standard deviation. Other studies used
a 10 or 20% change (decrease for impairment) in the mean score or a
3- to 4-point SDMT score change between baseline and follow-up to
3.4 Meta-analysis of SDMT denote change in cognitive ability. While it can be argued that part of
this inconsistency may be due to the individual specifics of the test and
In the meta-analysis of SDMT, 2594 participants were pooled from 7 the cognitive domains being assessed in the study, there is a clear need
observational study papers (Figure 2). Baseline and follow-up measure- for a consistent definition of what constitutes a meaningful change in
FIGURE 2 Forest plot of the effect size of change in Symbol Digit Modalities Test between baseline and follow-up.
cognitive function. However, this consistent definition needs to con- of change may not be easily differentiated from cognitive decline in
sider the heterogeneity that exists between PwMS in the profile of normal aging though older PwMS decline faster than younger PwMS
cognitive impairments that they experience and whether the assess- (Wallach et al., 2020).
ment is for screening purposes or is part of a more comprehensive An alternative explanation for the lack of change over 3 years is
assessment of cognitive functioning. The lack of consistency may be that there is likely to be considerable heterogeneity in the trajectories
problematic insofar as developing or progressive cognitive impairment of cognitive change over time. While some PwMS may experience no
may be missed or conversely over-interpreted. change (i.e., cognition remains stable with no excess changes compared
This study observed that the SDMT is popularly used in studies and to background normal cognitive aging), others may experience cogni-
that there is more emphasis in the literature on assessing information tive decline over time. Indeed, there is now emerging evidence that
processing speed in PwMS. This may be because it has been reported early cognitive impairments (assessed using the SDMT) are an impor-
to be a reliable measure (Sumowski et al., 2018). By implication, the tant prognostic marker of future cognitive decline and cortical thinning
use of reliable and sensitive tools to assess change in other domains (Healy et al., 2021; Pitteri et al., 2017). It is also possible that future
of cognitive function has become important, particularly for the clini- decline may be minimized in response to changes in disease-modifying
cian who is conducting a more comprehensive assessment of cognitive therapies or that practice effects on the tests may exist in the published
function. However, while poor processing speed is often thought to studies or due to natural fluctuations. As supported by other studies,
underlie poor functioning in other domains of cognition (e.g., it may a decline in SDMT scores among PwMS is very slow, a 1-point change
impair learning processes), this is not always the case (Chiaravalloti & in SDMT score in 10 years (Chruzander et al., 2014) and a decline of
DeLuca, 2008). Hence, one cannot infer dysfunction in everyday liv- 0.22 in SDMT score per year (Fuchs et al., 2020), although not as slow
ing based on poor processing speed alone. It may also be that specific as our meta-analysis suggest, which found that SDMT score decreased
impairments in learning and memory occur without the presence of by 0.03 mean score per year.
poor processing, i.e., as would occur if there are specific lesions in the There are several limitations of this study. First, only studies with
brain in areas that govern these learning and memory processes. 100 or more participants were evaluated and thus the present results
This study pooled and evaluated longitudinal change in SDMT may not be entirely representative of the broader population of peo-
scores in PwMS across studies which spanned from 1 year to 3 years. ple with MS. This was done to evaluate the use of cognitive tests and
No significant change in the SDMT score was observed over three batteries in large population groups. After the full-text screening, data
years. However, this meta-analysis would suggest that to detect a clini- were extracted by one rater though the risk of bias assessment was
cally meaningful change in cognitive function using SDMT, researchers done by two independent raters. There was no analysis of how change
may need to aim for a longer interval than three years. This raises occurred across groups of PwMS (i.e., according to the type of MS,
two important considerations. First, it may be that cognitive change measures of cognitive reserve, sex-specific or age-related changes or
in MS proceeds at such slow a rate that meaningful change is not extent of baseline impairments). This is owing to this diversity not
detected over a short-to-moderate period. Second, it may be that the being characterized in the larger samples. Only studies in English were
SDMT is not a sensitive marker of change in cognition. Such a slow rate included due to convenience though studies with a different language
could be informative. However, no article was screened out in full-text ology; writing—review & editing. Bruce Taylor: conceptualization;
screening based on not being written in English. methodology; supervision; writing—review & editing.
A meta-analysis was conducted for the SDMT as it has been rec-
ommended as one of the most reliable and valid tools for measuring FUNDING
cognitive function in MS. A meta-analysis was not conducted for other No funds were received for this review.
domains of cognitive functioning because of the high heterogeneity
(in tests used) in the studies included. Change in SDMT could not be PROSPERO
reported between RRMS and the progressive types of MS because Registration CRD42021255389.
most papers either did not define the MS group or reported a combined
SDMT without differentiation. CONFLICT OF INTEREST STATEMENT
There is no conflict of interest to declare. There was no financial
support for this review.
5 CONCLUSION
ORCID
This study highlights the slow rate of change of cognition in PwMS at Chigozie Ezegbe https://orcid.org/0000-0003-1858-1360
the population level, the plethora of tests used for measuring cogni- Amin Zarghami https://orcid.org/0000-0002-1135-0255
tive change, and the need for uniformity in the measurement of change
in cognitive function in PwMS both when a battery of tests or a single PEER REVIEW
cognitive test is used for a comprehensive assessment or screening for The peer review history for this article is available at https://publons.
change in CF. There is a clear need to establish clinically meaningful com/publon/10.1002/brb3.3009.
change for each cognitive test in the measurement of different cog-
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Received: 27 January 2023 Revised: 27 March 2023 Accepted: 29 March 2023

Instruments measuring change in cognitive function in multiple

Brain Behav. 2023;13:e3009. wileyonlinelibrary.com/journal/brb3 1 of 38

1 INTRODUCTION tered repeatedly to monitor change in CF though cognitive impairment

between duration cognitive (mean)

between duration cognitive (mean)

measure- Age (at Patient group (MEAN) at impairment (or at

gap MS Definition of score

Cognitive ment of baseline) (RRMS, PPMS, baseline: improve- baseline:

measure- Age (at (RRMS, (mean) at improvement)/ EDSS score

gap Patient cognitive

FIGURE 1 Flowchart of the literature search and study selection process.

Domains Cognitive test (Cognitive test battery† )

Domains Cognitive test (Cognitive test battery† )

Domains Cognitive test (Cognitive test battery† )

3.3 Results related to change in cognitive 4 DISCUSSION

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