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Received: 21 July 2021    Revised: 1 November 2021    Accepted: 2 November 2021

DOI: 10.1111/ane.13554

ORIGINAL ARTICLE

Multiple sclerosis impairment scale and brain MRI in secondary

progressive multiple sclerosis

Asta Theodorsdottir1,2  | Pia Veldt Larsen3 | Helle Hvilsted Nielsen1,4,5 | Zsolt Illes1,4,5  |

Mads Henrik Ravnborg6

1
Department of Neurology, Odense
University Hospital, Odense, Denmark Abstract
Objective: To examine the Multiple Sclerosis Impairment Scale (MSIS) in secondary
2
OPEN, Odense Patient Data Explorative
Network, Odense University Hospital,
Odense, Denmark
progressive MS (SPMS) in relation to the Expanded Disability Status Scale (EDSS),
3
Mental Health Services at the Region of magnetic resonance imaging (MRI) outcomes, and mobility.
Southern Denmark, Odense, Denmark Methods: In this observational single-­center study, 68 secondary progressive multiple
4
Department of Neurobiology Research,
sclerosis (SPMS) patients were examined by MSIS, EDSS, functional mobility tests of
Institute of Molecular Medicine,
University of Southern Denmark, Odense, upper/lower extremities, and multimodal MRI. Participants had EDSS ≥3.5, a decline
Denmark
5
in daily activities over the last year unrelated to relapses, and/or 6-­month confirmed
Department of Clinical Research, BRIDGE
-­Brain Research –­Inter Disciplinary disability progression.
Guided Excellence, University of Southern Results: Mean disease duration was 23.1 ± 8.3 years and mean age 54.4 ± 8.1 years.
Denmark, Odense, Denmark
6 MSIS, EDSS, and their corresponding motor, cerebellar, and sensory subscores corre-
Filadelfia Epilepsy Hospital, Dianalund,
Denmark lated (p < .0001). Motor subscores of MSIS correlated stronger with Timed-­25-­Foot-­
Walk (T25FW) than pyramidal functional system score (FSS) (p = .03), but EDSS had
Correspondence
Ásta Theódórsdóttir, Department of a stronger correlation to T25FW than the total MSIS score (p = .01). MSIS cerebel-
Neurology, Odense University Hospital,
lar subscore correlated stronger with 9-­Hole Peg Test (9-­HPT) than cerebellar FSS
J. B. Winsloews Vej 4, Odense 5000,
Denmark. (p = .04). The sensory MSIS subscore also showed correlation with 9-­HPT in contrast
Email: asta.theodorsdottir@rsyd.dk
to sensory FSS (p = .006). MSIS subscores had stronger correlations with MRI volume-
Funding information try measures than FSS scores (lesion volume and putamen, thalamus, corpus callosum
This study was funded by Novartis. The
volumetry, p = .0001–­0.0017).
funder had no influence on the study
design, data analysis, and interpretation Conclusion: In patients with SPMS, MSIS correlated with functional motor tests. MSIS
showed stronger correlations with atrophy of central nervous system areas, and may
be more sensitive to scale cerebellar and sensory function than EDSS.

KEYWORDS
9HPT, MRI, multiple sclerosis, MSIS, observational study, scale properties, secondary
progressive, T25FW

Zsolt Illes, Mads Henrik Ravnborg equal contribution

© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Acta Neurol Scand. 2021;00:1–16.  |

wileyonlinelibrary.com/journal/ane     1
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2      THEODORSDOTTIR et al.
1  |  I NTRO D U C TI O N
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and
degenerative disease of the central nervous system (CNS). Studies
of the natural course of MS have shown that up to 50% of patients
develop a secondary progressive course characterized by a slow
worsening of disability approximately 10–­15  years after disease
onset.1,2 This secondary progressive MS (SPMS) is presumed to be
due to quantitative and qualitative changes in the underlying disease
3
mechanisms.
SPMS is conventionally defined retrospectively as a sustained
progression in disability over a period of >6  months unrelated to
relapses and following an initial relapsing-­remitting disease course.
The definition has changed over the past years to include actual pro-
gression and/or activity.4,5 Thus, besides maintained worsening on
the Expanded Disability Status Scale (EDSS), the best performing
definition of SPMS has included a minimum EDSS score of 4, and a
minimum motor functional system score (FSS) of 3 in the Neurostatus
scoring system that is used to calculate the EDSS score.6 A new con-
cept of silent progression has recently been proposed based on the
argument that progression starts earlier than previously recognized,
7
that is, in the relapsing-­remitting (RR) phase.
The diagnosis of SPMS is often delayed by several years, and the
time between relapsing-­remitting and definite SPMS can be cate-
gorized as a transition.8 Although patients and neurologists showed
strong agreement regarding age at MS disease onset, patients re-
ported 2.7 years earlier conversion to SPMS than neurologists.9 The
long transition period and emerging treatments for active SPMS
emphasize the need for sensitive screening tools, including patient-­
10–­13
reported outcome measures for early detection of progression.
As the EDSS has notoriously low sensitivity for detecting progres-
sion in SPMS,7,14 a series of alternative clinical outcomes have been
developed. The MS Functional Composite (MSFC) measure is more
sensitive than EDSS partly because it better estimates hand func-
tion using 9-­HPT test besides assessing lower extremity function
using T25FW test.15 Lesion volume measured by MRI showed poor
correlation with EDSS score,16 but a stronger correlation of lesion
17
was seen with MSFC score. Measurements of the cross-­sectional
volume of the cervical spinal cord have shown a strong correlation
with disability in MS patients,18–­21 and even stronger in progressive
22,23
MS compared with RRMS patients.
The Multiple Sclerosis Impairment Scale (MSIS) was developed
in 1997, 24 motivated by the limited sensitivity of changes in the
higher EDSS scores in patients with progressive MS. The MSIS scale
has semi-­parametric properties and has shown better sensitivity in
25
moderate-­to-­severe impairment compared to EDSS.
With increased focus on the diagnosis of the progressive phase
of MS, there is a growing need for sensitive measures of progression
in clinical settings for early treatment decisions and in clinical trials
to monitor progression.
To investigate the efficacy of the MSIS in secondary progressive
MS, we examined its psychometric properties in a cross-­sectional
prospective study with a cohort of patients with SPMS or high risk
for SPMS (likely transition). We correlated the MSIS total score and
its subscores with EDSS and FSS scores, MRI outcomes, and func-
tional motor measures of mobility.
2  |  M E TH O DS ( DATA S O U RC E S A N D
P O PU L ATI O N )
2.1  |  Participants
The patients were recruited during routine out-­patient follow-­up
at the Department of Neurology, Odense University Hospital from
March 1, 2018, to April 1, 2019.
Inclusion criteria were SPMS, that is, a definite diagnosis of MS
according to the McDonald (2010) Criteria and progression based
on a minimum a 6  months confirmed increase in EDSS >1 point if
EDSS was between 3.5 and 5.0 or an increase of 0.5 point if EDSS
≥5.5 without interfering relapses, or EDSS ≥3.5 and a subjectively
assessed decline in daily activities over the last year with no inter-
fering relapses, that is, decline in walking distance, or worsening bal-
ance or cognitive decline.
Patients with other diseases that might influence clinical perfor-
mance or MRI outcomes, and patients with a confirmed relapse in
the last year were excluded.
In total, 84 patients were invited to participate, and 73 were
included. Five patients were excluded after entering the study; of
these, two patients did not meet the McDonald (2010) Criteria, one
patient was diagnosed with antiphospholipid antibody syndrome,
one patient had an infection at the baseline visit and was lost to
follow-­up, and one patient was excluded because of psychosomatic
symptoms influencing the clinical performance.
2.2  |  Data collection
The patient's history was explored at inclusion, and the last relapse
and current medication were recorded. A neurological examination
was performed with scoring on the EDSS and MSIS scales (the cogni-
tive data will be reported in another publication). The patients were
tested with 9-­HPT, Six Spot Step Test (6-­SST26), and T25FW. All ex-
aminations were conducted by a single neurologist trained in these
tests (AT).
The 9-­Hole Peg Test is a test of the upper extremities and coor-
dination. The patients were seated with a peg board in front of them
with 9 holes on one side and a shallow round dish on the other side.
They were asked to put the pegs, one at a time, in each hole on the
peg board, and remove them again one at a time, while the trial was
timed. The patients were tested twice for each arm, the dominant
arm first. An average time was calculated.
The Six Spot Step Test is a test of lower extremity function
and coordination. Five wooden cylinder blocks were placed on
marked circles on the floor, one at the end of the test field and 2
on each side 1 meter apart. The patient was instructed to stand at
THEODORSDOTTIR et al.
the beginning of the field, and walk alternating from side to side,
without running, while shoving the wooden blocks out of their
circles with the same foot, alternating between the median and
lateral side of the foot. The test was timed from the moment the
patient lifted the foot until the last block was shoved of its circle.
The test was done twice for each foot. Assistive walking devices
were allowed if needed.
The Timed-­25 Feet Walk test is also a test of lower extremity
function. The patients were instructed to walk 25 feet as fast, but
safely, as possible. The test was timed from the moment the patient
crossed the start line and stopped when they had crossed the finish
line. An average score was calculated from two trials. Assistive walk-
ing devices were allowed if needed.
The MSIS (Appendix 1) is scored according to a full neurological
examination and is composed of 53 subscores. The subscores are di-
vided into five functional groups: (1) cognition (maximum 12 points);
(2) cranial nerve functions (maximum 23 points); (3) limb motor
functions (maximum 94 points); (4) sensory functions (maximum 48
points); and (5) complex functions (maximum 27 points), including
coordination, gait, and balance. The theoretical maximum total score
is 204 points. If the function is affected by impairment of another
function, the score is treated as a missing value. The total score is ad-
justed for missing values by multiplying the ratio between the total
subscore number (n = 53) and the actual number of subscores (53 -­x)
by the total score to give the MSIS score.
Study data were collected and managed using REDCap (Research
Electronic Data Capture) tools hosted at the University of Southern
Denmark.
2.3  |  MRI acquisition and analysis
Sixty-­two patients were scanned on a 3T Achieva dStream (Philips
Medical Systems), and five patients were scanned on a 3T Ingenia (Philips
Medical Systems). One patient was not scanned due to a cardiac pace-
maker. Scanning occurred within 34.9 ± 31.3 days after the first visit.
A 3D T1-­weighted scan was acquired with TE = 3.8 ms, TR = 8.4 ms,
image size 230  ×  288  ×  288, voxel size 0.87  ×  0.87  ×  0.87  mm,
and flip angle 8  degrees. A 3D T2-­weighted FLAIR series was ac-
quired with TE = 254.8 ms, TR = 4800 ms, TI = 1650 ms, image size
317 × 400 ×  400, and voxel size 0.63  × 0.63 × 0.63 mm. A diffu-
sion MRI series was acquired in all but one patient consisting of one
b  =  0 image and 32 volumes with b-­value 1000  s/mm2. Constant
parameters were TE = 80 ms, TR = 3100 ms, flip angle 90 degrees,
image size 128 × 128 × 60, and voxel size 1.75 × 1.75 × 2.5 mm. The
cross-­sectional icobrain pipeline was applied on the T1 and FLAIR
images. 27 After bias field correction28 and skull stripping, the FLAIR
and T1 images were co-­registered and used for joint segmentation
of the three main tissue classes (gray matter (GM), white matter
(WM), and cerebrospinal fluid (CSF)) and lesions (FLAIR hyperin-
tensities). This segmentation process includes a joint analysis of the
T1-­weighted images and FLAIR scans, as the segmentation of the
FLAIR scans benefits from knowledge of the tissue classes obtained
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from the T1-­weighted scans, while tissue segmentation benefits
from T1-­weighted lesion filling based on the FLAIR lesion segmen-
tations. FLAIR lesions were further subdivided into four categories,
according to the McDonald Criteria: juxtacortical, periventricular, in-
fratentorial, and deep white matter. The WM segmentation included
lesion filling. Mean upper cervical spinal cord area was computed
on the T1-­weighted brain scans, of which the field of view included
complete C2 and C3 vertebrae. The spinal cord was segmented mak-
ing use of the PropSeg algorithm. 29 After refinement, a multi-­atlas
registration approach was used to identify the spinal cord adjacent
to the C2 and C3 vertebrae. The cross-­sectional area was then com-
puted perpendicular to the spinal cord centerline. MRI analyses were
performed by IcoMetrix using pseudoanonymized data.
2.4  |  Statistics
The statistical analysis was done using STATA v.16.1. A threshold
of 0.05 was used for statistical significance. Descriptive analyses
of patient characteristics were presented as number (percent) or
mean (SD), as appropriate. Pairwise Spearman rank correlations (ρ)
were calculated between MSIS scores, EDSS scores, MRI outcome
measures, and functional motor measures of mobility. Pairwise par-
tial Spearman correlations were calculated to adjust for sex and age.
Differences in Spearman correlations between covariates and MSIS
and EDSS, respectively, were tested with standard errors of the dif-
ferences based on a bootstrap with 1000 replications. Holm's cor-
rections were applied to take multiple testing into account.
2.5  |  Ethics
The study was approved by the Danish Data Protection Agency
(journal no. 2017–­41–­5263) and the Danish Ethical Committee
(Acadre 17/31814, project-­ID S-­20170162).
3  |  R E S U LT S
3.1  |  Demographics, clinical and MRI
characteristics
The cohort included 68 patients with a mean age of 54.4 ± 8.1 years
at the time of inclusion. The mean time since first symptom was
23.1 ± 8.3 years, and mean time from diagnosis was 15.6 ± 7.3 years.
Seventy-­two percent of the patients had received disease-­modifying
treatment (DMT) during their disease course, but 30 patients (44%)
were not treated at inclusion. The reason for treatment discontinuation
was partly the patients´ choice, partly due to the diagnosis of SPMS.
The mean number of previous DMTs was 1.4 ± 1.3 (Table 1). At the time
of inclusion, various DMTs were used (Table  1). Mean EDSS score at
inclusion was 4.9 ± 1.4, and mean MSIS score was 50.0 ± 18.3. Mean
scores for functional tests and MRI measurements are shown in Table 1.
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4      THEODORSDOTTIR et al.

TA B L E 1  Demographics, functional and MRI outcomes

compared (motor, rho = 0.5776; cerebellar, rho = 0.5845; sensory,
N = 68 rho = 0.7051; p < .0001 for all) (Table 2).
Female n (%) 44 (64.7)
Age at inclusion, mean (SD) 54.4 (8.1) (range 40.8–­83.2)
Years since first symptom, mean 23.1 (8.3)
3.3  |  Correlation of MSIS and EDSS with motor
(SD) functional tests
Years since diagnosis, mean (SD) 15.6 (7.3)
Delay from diagnosis to treatment 2.6 (6.1)
Total MSIS score was more highly correlated with performance on the
in years, mean (SD) 9-­HPT (rho  =  0.4840, p  <  .0001) compared to EDSS (rho  =  0.3906,
Patients that have received DMT 49 (72) p = .011), and similarly to EDSS regarding 6-­SST (MSIS: rho = 0.6943,
n (%) p < .0001, EDSS: rho = 0.7196, p < .0001). T25FW had a stronger corre-
Number of previous DMTs mean 1.4 (1.3) min-­max (0–­5) lation with EDSS than total MSIS score (MSIS: rho = 0.6483, p < .0001,
(SD) EDSS: rho = 0.8239, p < .0001), (Figure 1), and the difference in the rho
No current treatment 30 values (strength of correlation) was significant (p = .011).
Current treatment The MSIS motor subscore showed stronger correlation with
Teriflunomide 8 T25FW (rho = 0.6316, p < .0001) than pyramidal FSS (rho = 0.4339,
Fingolimod 10 p = .0002), and the difference in rho values was significant (p = .031).

Natalizumab 9
The MSIS motor subscore showed also stronger correlation with
6-­SST compared to pyramidal FSS (MSIS motor: rho  =  0.6164,
Others (Interferon β−1a, GA, 11
Rituximab, DF) p  <  .0001 and pyramidal FSS: rho  =  .4820, p  <  .0001) (Figure  2).

EDSS mean (SD)
MSIS mean (SD)
Functional tests (n  = 67)
9-­HPT (sec) mean (SD)
T25FW (sec) mean (SD)
6-­SST (sec) mean (SD)
Area volumes (n  = 67)
Corpus callosum cross-­sectional
areal (cm3)
Thalamus (cm3) mean (SD)
Putamen (cm3) mean (SD)
Hippocampus (cm3) mean (SD)
(n = 65)
Normal appearing cortical gray
matter (cm3) mean (SD)
MUCCA (cm3) mean (SD) (n = 66)
3
Total lesion volume (cm ) mean (SD)
(n = 64)
4.9 (1.4) (range 3.5–­7.0) The MSIS motor subscore did not correlate with performance on 9-­
HPT, while pyramidal FSS showed a weak correlation with 9-­HPT
50.0 (18.3) (range 14–­95)
(rho = 0.2497, p = .0416). (Figure 2).
The MSIS cerebellar subscore correlated more strongly with 9-­
30.6 (11.7)
HPT (rho  =  0.5793, p  <  .0001) than cerebellar FSS (rho  =  0.3743,
9.4 (8.5)
p = .0018), and the difference in strength of correlation was significant
15.6 (11.3)
(p  =  .041), while both were correlated with 6-­SST (MSIS cerebellar:
rho = 0.3240, p = .007; cerebellar FSS: rho = 0.2651, p = .029). The
518.6 (143.5) MSIS cerebellar subscore did not correlate with T25FW, in contrast to
a weak association with cerebellar FSS (rho = 0.2436, p = .045), but
14.4 (1.8)
the difference between rho values was not significant (Figure 3).
12.8 (1.0) The MSIS sensory subscore correlated with 9-­HPT (rho = 0.3683,
8.8 (0.7) p = .0022) in contrast to sensory FSS, and the difference of the rho
values was statistically significant (p = .006) (Figure 4).
831.9 (32.1)
68.6 (8.7)
3.4  |  Correlations of MSIS and EDSS with
16.2 (10.9) MRI outcomes

Note: Lesion volume is based on joint analysis of T1 and FLAIR sequences.
Some of the MRI measurements could not be obtained for technical reasons
(number of the patients in the analyses are indicated).
Abbreviations: DMT, Disease-­modifying treatment; DF, Dimethyl fumarate;
EDSS, Expanded Disability Status Scale; GA, Glatirameracetate; MSIS,
Multiple Sclerosis Impairment Scale; 9-­HPT, 9-­Hole Peg test; T25FW,
Timed-­25 Foot Walk. 6-­SST, 6-­Spot Step Test; MUCCA, Mean upper
cervical spinal cord area; SD, Standard deviation.
3.2  |  Correlation of MSIS with EDSS and
correlations between their functional subscores
Multiple Sclerosis Impairment Scale showed strong correla-
tion with EDSS both for total scores (rho  =  0.7530, p  <  .001) and
when the functional subscores of the EDSS (FSS) and MSIS were
Total MSIS score showed significant negative correlation with the vol-
ume of thalamus (rho  =  −0.427, p  =  .0004) and mean upper cervical
spinal cord area (rho = −0.4309, p = .0004) similarly to EDSS (thalamus:
rho  =  −0.3278, p  =  .0077 and mean upper cervical spinal cord area:
rho = −0.4261, p = .0004) (Table 2). The partial correlations, adjusted
for age and sex, were slightly stronger than the unadjusted. When cor-
relations were compared, neither difference was statistically significant.
When subscores were correlated with CNS volumes, MSIS sub-
scores generally showed stronger correlations compared to FSS
(Table 2). The MSIS cerebellar subscore negatively correlated with cor-
pus callosum cross-­sectional area (rho = −0.3817, p = .0017) in com-
parison with cerebellar FSS (comparison diff = −0.139, p = .178). The
MSIS cerebellar subscore showed stronger correlation with volume of
putamen (rho  =  −0.3920, p  =  .0012) and thalamus (rho  =  −0.4897,
 THEODORSDOTTIR et al.

TA B L E 2  Correlations between clinical outcomes and MRI volume measures

EDSS FSS-­P FSS-­C FSS-­S CC † Put† HC† Thal† NACGM† MUCCA† TLV†

MSIS 0.753*** −0.196 −0.076 −0.175 −0.427* −0.056 −0.431* 0.170

EDSS −0.023 0.042 −0.099 −0.328 −0.041 −0.426* 0.039
MSIS-­M 0.578*** −0.056 0.117 −0.135 −0.183 0.032 −0.380 −0.022
MSIS-­C 0.585*** −0.382 −0.392 −0.143 −0.490*** −0.208 −0.083 0.485**
MSIS-­S 0.705*** −0.146 −0.154 −0.143 −0.339 0.009 −0.254 0.125
FSS-­P −0.080 0.001 −0.193 −0.249 −0.131 −0.281 0.133
FSS-­C −0.217 −0.299 −0.083 −0.374 −0.123 −0.091 0.267
FSS-­S 0.103 0.092 −0.060 −0.169 0.011 −0.151 −0.091
9-­HPT −0.344 −0.232 −0.211 −0.460** −0.148 −0.334 0.376
T−25FW −0.170 0.032 −0.220 −0.391 −0.042 −0.433* 0.194
6-­SST −0.193 −0.066 −0.201 −0.422* −0.150 −0.428* 0.250
†
Note: Spearman's correlation were used, adjusted for age and sex. Measurements are given in rho. Total lesion volume is based on joint analysis of T1 and FLAIR sequences.
Abbreviations: 6-­SST, 6-­Spot Step Test; 9-­HPT, 9-­Hole Peg test; CC, Corpus callosum total volume; EDSS, Expanded Disability Status Scale; FSS-­C, Functional systems score—­cerebellar; FSS-­P, Functional systems
score—­pyramidal; FSS-­S, Functional systems score—­sensory; HC, Hippocampus total volume; MRI, magnetic resonance imaging; MSIS, Multiple Sclerosis Impairment Scale; MSIS-­C, Multiple Sclerosis Impairment
Scale—­cerebellar scores; MSIS-­M, Multiple Sclerosis Impairment Scale—­motor scores; MSIS-­S, Multiple Sclerosis Impairment Scale—­sensory scores; MUCCA, Mean upper cervical spinal cord area; NACGM, Normal
appearing cortical gray matter; Put, Putamen total volume; T-­25FW, Timed-­25 Foot Walk; Thal, Thalamus total volume; TLV, Total lesion volume.
*p < .05 after Holm´s correction.
**p < .01 after Holm´s correction.
***p < .001 after Holm´s correction.
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6      THEODORSDOTTIR et al.
p  <  .0001) compared to cerebellar FSS (putamen: rho  =  −0.2985,
p = .0166 and thalamus (rho = −0.3741, p = .002), though the differ-
ence in rho values was not significant. Mean upper cervical spinal cord
area showed stronger correlations with motor (rho = −0.3796, p = .002)
and sensory MSIS subscores (rho = −0.2536, p = .043) than pyramidal
FSS (rho = −0.2807, p = .025) and sensory FSS (non-­significant), but
the strength of correlations was not significantly different. The vol-
ume of thalamus negatively correlated with the sensory subscore of
MSIS (rho = −0.3386, p = .006) but not with sensory FSS. Finally, the
total lesion volume strongly correlated with the cerebellar subscore of
MSIS (rho = 0.4846, p = .0001) and slightly less with the cerebellar FSS
(rho = 0.2671, p = .037) (comparison diff = 0.190, p = .134).
3.5  |  Correlations of functional motor tests and
MRI outcomes
We found significant negative correlations between the 9-­HPT and
the volume of thalamus (rho = −0.4602, p = .0001), cross-­sectional
F I G U R E 1  Correlation of MSIS and
EDSS with motor functional tests. A.
Correlation between MSIS and 9-­HPT,
T25FW, and 6-­SST, respectively. B.
Correlation between EDSS and 9-­HPT,
T25FW, and 6-­SST, respectively. C.
Difference of correlations. MSIS: Multiple
Sclerosis Impairment Scale. EDSS:
Expanded Disability Status Scale. 9-­HPT:
9-­Hole Peg test. T25FW: Timed-­25 Foot
Walk. 6-­SST: 6-­Spot Step Test. Rho:
Spearman correlation coefficient. CI:
confidence interval
corpus callosum (rho = −0.3443, p = .005), and mean upper cervical
spinal cord area (rho  =  −0.3342 p  =  .007), and a positive correla-
tion with the total lesion volume (rho = 0.3761, p = .003). T25FW
and 6-­SST negatively correlated with the volume of thalamus
(rho = −0.3906, p = .001 and rho = −0.4220, p = .0005) and with
mean upper cervical spinal cord area (rho = −0.4330, p = .0004 and
rho = −0.4279, p = .0004) (Table 2).
4  |  D I S C U S S I O N
A previous study reported a non-­linear correlation between MSIS
and EDSS in all phases of MS. 24 Here, we examined MSIS in a spec-
trum of patients with SPMS and in transition to SPMS and investi-
gated the correlation of MSIS with EDSS, functional system scores,
MRI, and functional motor outcomes in a cross-­sectional cohort.
In this single-­center study, SPMS was defined clinically or sus-
pected to be, judged by the patient's symptoms. The challenge of
identifying the start of the secondary progressive phase of MS
THEODORSDOTTIR et al. |
      7

F I G U R E 2  Correlation of MSIS and

EDSS motor subscores with motor
functional tests. A. Correlation between
MSIS motor subscores and 9-­HPT,
T25FW, and 6-­SST, respectively. B.
Correlation between FSS pyramidal
subscores and 9-­HPT, T25FW, and 6-­SST,
respectively. Difference of correlations
is given for each comparison. MSIS:
Multiple Sclerosis Impairment Scale.
EDSS: Expanded Disability Status Scale. 9-­
HPT: 9-­Hole Peg test. T25FW: Timed-­25
Foot Walk. 6-­SST: 6-­Spot Step Test. Rho:
Spearman correlation coefficient. CI:
confidence interval

patients is well known and is complicated by the lack of biomark-
ers and the psychological burden of communicating the diagnosis
to the patient.30 Several approaches have been proposed to diag-
nose SPMS earlier and more accurately, since EDSS is not sensitive
7
enough to measure silent progression in RRMS and has a low sen-
sitivity as an assessment tool.31,32 Therefore, a few SPMS predictor
tools have been developed6,10,11 taking different parameters into ac-
count. In the search for a more homogenous definition of SPMS for
clinical trials, clinical retrospective data of 17.356 patients with MS
were used to define the “best definition” of SPMS in 2016, based on
changes in EDSS and FSS over a 3 months period.6 MSFC, also used
in many clinical trials, contains EDSS, T25FW, 9-­HPT and a cognitive
measure, Paced Auditory Serial Addition Test.33,34 EDSS-­Plus has
also been proposed,35 although it only differs from MSFC by lacking
Paced Auditory Serial Addition Test. There is furthermore a need for
tools for accurate evaluation of subtle signs of progression in clinical
practice, and for that purpose, MS Progression Discussion Tool36 has
been developed.
The most promising biomarkers for detection of early diagnosis
of SPMS at the moment are atrophy measures of the brain and spi-
nal cord7,37 and the measurement of the thickness of retinal nerve
fiber layer.38 Although elevated levels of neurofilament light chain
in blood and cerebrospinal fluid have been suggested as potential
markers for progressive MS,39 recent data including a meta-­analysis
have not found differences between relapsing-­remitting and pro-
gressive MS.40,41
In our study, we examined correlation of MSIS with clinical and
MRI outcomes in a SPMS cohort, including patients with high risk
to convert and possibly in the transition phase. In addition, we also
compared the correlation of MSIS and EDSS with these outcomes
to test their sensitivities. We found that MSIS correlated well
with EDSS, both as total scores and as subscores of motor, cere-
bellar and sensory function. A general feature was that the MSIS
scores had a wide range in comparison with the EDSS and FSS,
a difference that weakens direct statistical comparisons between
the MSIS and EDSS scales. However, we observed the lowest
 |
8      THEODORSDOTTIR et al.
correlation for the cerebellar scores, possibly because these are
highly dependent on motor disabilities in both functional scoring
systems. Within a progressive cohort, the motor abilities are highly
affected, which also was the case in our cohort, where motor FSS
scores were 3–­4 in most patients and MSIS scores mainly around
20–­4 0 points. This artificially lowers the cerebellar scoring in both
systems because it cannot be evaluated properly. The scales are
differently constructed—­w hile in the EDSS, the patient is given
an approximate cerebellar FS score, marked with an X, the MSIS
excludes the subscores that cannot be evaluated properly due to
motor disabilities and proportionally weights the other subscores
higher in the total score. This also leads to an artificially low cere-
bellar score on the MSIS.
The MSIS is less dependent on ambulation compared to EDSS.
The MSIS score increases linearly with each objective deficit in the
neurological examination. However, we expected the observed
stronger correlation of T25FW with EDSS compared to MSIS.
On the contrary, the correlation between MSIS and 9-­HPT was
higher than expected. MSIS motor scores showed a significantly
F I G U R E 3  Correlation of MSIS and
EDSS cerebellar subscores with motor
functional tests. A. Correlation between
MSIS cerebellar subscores and 9-­HPT,
T25FW, and 6-­SST, respectively. B.
Correlation between FSS cerebellar
subscores and 9-­HPT, T25FW, and 6-­SST,
respectively. Difference of correlations
is given for each comparison. MSIS:
Multiple Sclerosis Impairment Scale.
EDSS: Expanded Disability Status Scale. 9-­
HPT: 9-­Hole Peg test. T25FW: Timed-­25
Foot Walk. 6-­SST: 6-­Spot Step Test. Rho:
Spearman correlation coefficient. CI:
confidence interval
stronger correlation with T25FW and better correlation with 6-­
SST (strength of difference although not significant) compared to
pyramidal FSS, indicating that the ambulation that drives EDSS
scores above 3 is not fully explained by motor deficits. The cor-
relations of motor scores with 9-­HT, indicating hand function,
were low for both scales although it was slightly higher for pyra-
midal FS scores of EDSS.
The 9-­HPT correlated stronger with MSIS cerebellar scores than
with cerebellar FSS. However, 9-­HPT correlated poorly with the
motor subscore of MSIS, suggesting that 9-­HPT may primarily be
determined by coordination and ataxia in this cohort. 9-­HPT has
a ceiling effect for patients with EDSS<3.0 and a large variability
when EDSS exceeds 6.0.42 This is illustrated for the current cohort
in Figure 1A.
We examined the correlation of both MSIS and EDSS with dif-
ferent MRI outcome measures and found only significant negative
correlations with the volume of thalamus, and with mean upper cer-
vical spinal cord area when the total score of each scale was exam-
ined. When we examined the subscores of each scale, however, we
THEODORSDOTTIR et al. |
      9

F I G U R E 4  Correlation of MSIS and

EDSS sensory subscores with motor
functional tests. A. Correlation between
MSIS sensory subscores and 9-­HPT,
T25FW, and 6-­SST, respectively. B.
Correlation between FSS sensory
subscores and 9-­HPT, T25FW, and 6-­SST,
respectively. Difference of correlations
is given for each comparison. MSIS:
Multiple Sclerosis Impairment Scale.
EDSS: Expanded Disability Status Scale. 9-­
HPT: 9-­Hole Peg test. T25FW: Timed-­25
Foot Walk. 6-­SST: 6-­Spot Step Test. Rho:
Spearman correlation coefficient. CI:
confidence interval

found stronger correlations with MSIS subscores compared to FSS.
Particularly, MSIS cerebellar subscores correlated with corpus callo-
sum and cortical normal appearing gray matter volumes in contrast to
cerebellar FSS; putaminal, thalamic, and lesion volumes also showed
stronger correlation with cerebellar MSIS. The stronger correlations
of cerebellar MSIS subscore with volumetry compared to cerebellar
FSS somewhat mirrored its stronger correlation with the functional
motor tests. The volume of mean upper cervical spinal cord area also
showed stronger correlation with MSIS motor subscore compared to
pyramidal FSS and was also correlated with sensory MSIS subscore in
contrast to sensory FSS. The volume of the basal ganglia correlated
with the cerebellar deficits in our cohort, and the motor symptoms
were highly affected by the volume of the spinal cord. The cross-­
sectional area of the cervical spinal cord correlates stronger with
43
MSIS scores for RRMS and SPMS patients than with EDSS.
The volumes of thalamus and putamen have previously been
44,45
found to correlate with T25FW. In our study, we only found
correlations of T25FW with the volume of thalamus and mean
upper cervical spinal cord area. Thalamic volume has also previ-
ously been correlated with 9-­HPT in RRMS patients.45,46 In our
SPMS cohort, we found a correlation of 9-­HPT with thalamic,
corpus callosum, mean upper cervical spinal cord area, and total
lesion volumes. This indicates that hand function may be highly
complex and dependent on multiple cerebral areas. For the 6-­SST,
we found correlations with the thalamic and mean upper cervical
spinal cord area volumes, which perhaps is surprising because the
coordination required for 6-­SST is most likely as complex as the
hand function needed for 9-­HPT.
Similar to other studies, we used the cervical cross-­sectional
area for atrophy measure of the spinal cord, since it is the technically
easiest method. However, a study of the thoracic volume measures
of white and gray matter showed a specific correlation with certain
motor disabilities in the lower extremities, not explained by the
cervical atrophy,47 indicating that total spinal cord volume measure
might be needed to explain the full disability progression within MS
patients.
 |
10      THEODORSDOTTIR et al.
In conclusion, we found a significant correlation between
MSIS and EDSS, and correlations with functional motor tests.
Although both disability scales detect motor symptoms, MSIS may
be more sensitive for scoring cerebellar and sensory deficits. We
also found that the subscores of MSIS were better correlated with
brain volume measures on MRI compared to EDSS. Our data in-
dicate that MSIS is a sensitive tool to detect disease progression
in SPMS that is worthy of further investigation in longitudinally
multicenter studies.
AC K N OW L E D G E M E N T S
The authors would like to thank Lisbeth Hoegedal and Ljubo
Markovic for their contribution to aquire brain MRI for this study.
C O N FL I C T O F I N T E R E S T
AT has served on a scientific advisory board for Roche, has received
research grant from Novartis Healthcare, and support for congress
participation from Roche, Biogen, Novartis Healthcare, Merck, and
Sanofi Genzyme. PVL and MHR have nothing to disclose. HHN has
received financial compensation for travels and consultations from
Novartis Healthcare, Biogen, Teva, Sanofi-­Genzyme, and Roche, has
received a research grant from the Danish MS society, and served as
a board member on the MS Society Research Council. ZI has received
speakers’ honoraria and/or research grants from Biogen, Roche,
Sanofi, Novartis, Merck, Lundbeckfonden, and Scleroseforeningen,
has been member of advisory boards at Alexion, Biogen, Sanofi,
Merck, Roche, and Novartis, was member of the adjudication re-
lapse committee in the SAKuraStar and SakuraSky trials, and has
been principal investigator in studies sponsored by Biogen, Merck,
and Sanofi.
PEER REVIEW
The peer review history for this article is available at https://publo​
ns.com/publo​n/10.1111/ane.13554.
DATA AVA I L A B I L I T Y S TAT E M E N T
Anonymized data will be shared on request from any qualified inves-
tigator under approval from the Danish Protection Agency and the
board of the DMSR.
ORCID
Asta Theodorsdottir  https://orcid.org/0000-0001-7894-611X
Zsolt Illes  https://orcid.org/0000-0001-9655-0450
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How to cite this article: Theodorsdottir A, Larsen PV,
Nielsen HH, Illes Z, Ravnborg MH. Multiple sclerosis
impairment scale and brain MRI in secondary progressive
multiple sclerosis. Acta Neurol Scand. 2021;00:1–­16.
doi:10.1111/ane.13554
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APPENDIX 1
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      13
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14      THEODORSDOTTIR et al.
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16      THEODORSDOTTIR et al.