Multiple sclerosis (MS) is an autoimmune inflammatory central nervous system disorder characterized by demyelinating lesion. MS mostly affects young adult which typically begins at 20-40 years old. It is more prevalent in female compared to man. In addition, it is the most common disabling disorder in young people [
MS does not only affect physical function but also cognitive function, which may impact on reduced productivity and quality of life (QOL) [
One challenge regarding the assessment of cognitive function is that neuropsychology assessment usually needs special expertise and is time-consuming, which hinders its application in daily practice. This situation hampers the detection of cognitive impairment, especially the subtle ones, in MS.
In 2012, an expert panel proposed Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) which focuses on cognitive processing speed and verbal and visual memory. BICAMS consists of three tests: Symbol Digits Modalities Test (SDMT) assessing processing speed/working memory, California Verbal Learning Test-Second Edition (CVLT-II) assessing learning and verbal memory, and Brief Visuospatial Memory Test-Revised (BVMT-R) assessing learning and visuospatial memory [
The objectives of our study were to validate and assess the reliability of BICAMS in Indonesia language and to evaluate the association between cognitive impairment with disease duration, relapse frequency, and physical disability. The secondary objective of this study was to observe the impact of cognitive impairment on quality of life using the MSQOL-54 instrument.
A cross-sectional study was performed in Dr. Cipto Mangunkusumo General Hospital Jakarta (RSCM) from September 2017 to June 2018. This study was approved by the Ethics Committee Faculty of Medicine Universitas Indonesia (Number:0381/UN2. F1/ETIK/2018).
We invited MS patients who had been registered in RSCM to participate in this study. Forty MS patients diagnosed using McDonald 2010 criteria [
We followed the BICAMS international standard validation procedure that consists of 5 steps: (1) standardization and translation of test stimuli; (2) standardization and translation of test instructions; (3) normalization; (4) test-retest reliability; (5) criterion-related validity [
BICAMS was translated into Indonesian by two different professional native speaking Indonesian translators blinded to each other. Words for CVLT-II were adapted to Indonesia culture. Translated version was compared and different words were reconciliated among neurologists. A preliminary version was tested to 10 MS patients and 10 HC. We noted all difficulties during the trial session. The preliminary version was then back-translated into English by two different English native speakers blinded to each other. The final version was developed by selecting words that have the closest meaning to the original version and are familiar in large populations in Indonesia.
The tests were administered in fixed order: SDMT, CVLT-II, and BVMT-R. SDMT was used to assess processing speed. Subjects were presented with a sequence of 9 symbols. Each symbol was paired with a single digit displayed on the top of the page. Participants were given a short practice session to recognize the symbol and the digit pair. Thereafter, they were asked to decrypt the symbols to the associated digits as rapidly as possible in 90 seconds. The maximum score for this test was 110. We performed the oral version of SDMT [
CVLT-II was used to assess auditory/verbal learning. Initially, examiner read aloud a list of 16 words. Participants listened to the list and repeated it as many as they can memorize. The number of words recalled was recorded and the trial was repeated for 5 times. The highest score for this test was 80 [
BVMT-R was used to evaluate visual/spatial memory. Six abstract figures were shown to the participants for 10 seconds. The figures were then removed, and participants were asked to draw those figures on paper manual responses. The time for drawing is not limited. Each figure was scored 0, 1, and 2 based on accuracy and location. Three trials were performed, and the total score was calculated from the sum of all 3 trial scores. The maximum score for this test was 26 [
On the same day with BICAMS examination, subjects were asked to fill the MSQOL-54 questionnaire which has already been validated into Indonesian. MSQOL-54 was transculturally adapted by performing a standardized forward-backward method and continued with assessing the reliability, internal validation, and external validation (unpublished). From 40 MS subjects, 3 subjects refused to fill the MSQOL questionnaire. This questionnaire consists of 54 questions measuring physical health, emotional well-being, role limitations due to physical problems, role limitations due to emotional problems, pain, energy, health perceptions, social function, cognitive function, health distress, sexual function, satisfaction with sexual function, change in health, and overall quality of life [
Before the BICAMS examination and filling the MSQOL-54 questionnaire, demographic and clinical data were collected including education level, duration of illness, relapse frequency, and treatment. Neurological examination, EDSS, and depression evaluation using mini-ICD-10 questionnaire were also performed.
Data distribution was analysed using Kolmogorov-Smirnov test. The difference between SDMT, CVLT-II, and BVMTR score in MS and HC subjects was examined using paired student T-test. Test-retest reliability was performed following 1-3 weeks and analysed using Pearson correlation coefficient. The r-values for test-retest correlation were considered adequate if >0.70 and good if >0.80. Criterion-related validity of BICAMS was assessed by analysing the correlation between age, EDSS, disease duration, and relapse rate to BICAMS score using Spearman correlation. Pearson correlation was used to analyse the correlation between quality of life and cognitive function. The p-value less than 0.05 was considered significant. Statistical analysis was performed using SPSS-25.0 and GraphPad Prism 5.
There was no significant difference in sex, age, and education duration between MS and HC groups (Table
Demographic and clinical characteristics of MS and healthy control subjects.
MS (n=40) | Healthy control (n=66) |
|
|
---|---|---|---|
Sex – N(%) | 0.25# | ||
Female | 33 (82.5) | 48 (72.7) | |
Male | 7 (17.5) | 18 (27.3) | |
Education -N (%) | 0.05 | ||
≤12 years | 10 (25.0) | 7 (10.6) | |
>12 years | 30 (75.0) | 59 (89.4) | |
Age (years) – Median (range) | 31 (20-61) | 29 (22-51) | 0.15 |
EDSS – Median (range) | 3 (1-7.5) | ||
Depression -N(%) | 13 (32.5) | ||
Duration of illness (years) | 4 (0.1-15) |
#Fisher exact test,
In all tests, MS subjects had significantly lower scores than HC (Table
Comparison of BICAMS score between MS and HC subjects.
MS | HC |
| |
---|---|---|---|
Mean±SD | |||
SDMT | 40.9±14.8 | 64.8±16.2 | <0.0001 |
SDMT retest | 42.7±15.2 | 74.3±15.5 | <0.0001 |
Effect size (r) | 0.61 | ||
|
|||
CVLT-II | 52.0±12.8 | 61.5±9.7 | <0.0001 |
CVLT-II retest | 61.5±14.3 | 73.5±61.5 | 0.005 |
Effect size (r) | 0.36 | ||
|
|||
BVMT-R | 22.2±7.7 | 29.3±5.6 | <0.0001 |
BVMT-R retest | 25.8±8.6 | 33.4±2.8 | 0.003 |
Effect size (r) | 0.47 |
In MS group, male subjects had lower score compared to female with significant differences in SDMT and CVLT-II. In HC group, the difference was not apparent. In reverse, the effect of education was only observed in SDMT score on HC group (p=0.05). Negative correlation was also found between age and SDMT (r=-0.27; p=0.03) and BVMT-R score (r=-0.28; p=0.02) only on HC (Table
Association of BICAMS scores with sex, education, depression, age, MS subtype, EDSS, disease duration, and relapse rate.
Multiple Sclerosis (N=40) | Healthy Control (N=66) | |||||
---|---|---|---|---|---|---|
SDMT | CVLT-II | BVMT-R | SDMT | CVLT-II | BVMT-R | |
Sex - median (range) | ||||||
Female | 48 (12-69) | 56 (25-71) | 25 (4-34) | 62 (40-110) | 64.5(36-77) | 31.5(14-36) |
Male | 30 (8-49) | 34 (23-72) | 18 (7-32) | 64.5(42-92) | 60(43-75) | 30 (17-36) |
|
|
|
0.15 | 0.92 | 0.41 | 0.58 |
|
||||||
Education - median (range) | ||||||
>12 years | 47 (15-69) | 54 (23-72) | 24.5(4-32) | 63 (42-110) | 63 (36-77) | 31 (14-36) |
≤12 years | 34 (8-57) | 54.5 (25-64) | 20.5 (6-34) | 53 (40-71) | 62 (37-74) | 28 (19-33) |
|
0.10 | 0.47 | 0.36 |
|
0.69 | 0.14 |
|
||||||
Depression–median (range) | ||||||
Yes | 36 (12-57) | 56 (25-64) | 23 (4-34) | |||
No | 46 (8-69) | 46 (8-69) | 24 (7-32) | |||
|
0.98 | 0.83 | 0.89 | |||
|
||||||
Age |
-0.004(0.98) | -0.11 (0.5) | 0.02(0.89) | -0.27( |
-0.11(0.39) | -0.28 |
|
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MS Subtype – median (range) | ||||||
RRMS (N=31) | 49 (8-69) | 58 (23-72) | 26 (4-34) | |||
SPMS (N=9) | 29 (12-39) | 42 (25-68) | 17 (6-29) | |||
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|
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EDSS |
-0.5 |
-0.46( |
-0.49( |
|||
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Disease duration |
-0.23 (0.15) | -0.19 (0.23) | -0.18 (0.27) | |||
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Relapse rate |
0.04 (0.78) | -0.15 (0.93) | 0.18 (0.25) |
All BICAMS scores were significantly lower in SPMS subtype subjects. All tests also showed significant negative correlation with EDSS, but this was not found on the relation to disease duration and relapse rate (Table
Test-retest reliability was performed on 16 MS patients and 42 HC (Table
Test-retest reliability.
SDMT | CVLT-II | BVMT-R | ||||
---|---|---|---|---|---|---|
r | p | r | p | r | p | |
All subjects | 0.88 | <0.0001 | 0.75 | <0.0001 | 0.77 | <0.0001 |
MS Patient | 0.86 | <0.0001 | 0.81 | <0.0001 | 0.83 | <0.0001 |
Healthy control | 0.76 | <0.0001 | 0.49 | 0.01 | 0.51 | 0.008 |
Using the
The impact of cognitive impairment on QOL was mostly seen in physical functions. SDMT, CVLT-II, and BVMT-R score significantly correlated with physical function (r=0.43, 0.43, and 0.45, respectively). SDMT also correlated with role limitation due to both physical and emotional problems (Table
Correlation between MSQOL-54 item score and BICAMS score.
SDMT | CVLT-II | BVMT-R | ||||
---|---|---|---|---|---|---|
r |
p | r |
p | r |
p | |
Physical function | 0.43 |
|
0.43 |
|
0.45 |
|
Health perceptions | -0.14 | 0.4 | -0.18 | 0.27 | -0.20 | 0.24 |
Energy/fatigue | -0.14 | 0.4 | -0.21 | 0.22 | -0.18 | 0.27 |
Role limitations - physical | 0.34 |
|
0.21 | 0.21 | 0.20 | 0.23 |
Pain | -0.03 | 0.8 | -0.19 | 0.25 | -0.12 | 0.47 |
Sexual function | -0.12 | 0.7 | 0.30 | 0.92 | -0.43 | 0.14 |
Social function | -0.3 | 0.2 | -0.15 | 0.36 | -0.23 | 0.17 |
Health distress | -0.12 | 0.5 | -0.10 | 0.56 | -0.18 | 0.27 |
Overall quality of life | -0.14 | 0.41 | -0.12 | 0.48 | -0.14 | 0.41 |
Emotional well-being | -0.07 | 0.7 | -0.07 | 0.67 | -0.20 | 0.24 |
Role limitation-emotional | 0.36 |
|
-0.001 | 0.99 | 0.14 | 0.42 |
Cognitive function | 0.19 | 0.25 | -0.38 | 0.83 | 0.10 | 0.55 |
PHC | 0.12 | 0.47 | 0.07 | 0.68 | 0.02 | 0.88 |
MHC | 0.07 | 0.67 | 0.005 | 0.97 | -0.07 | 0.68 |
Indonesia is a tropical country in which the prevalence of MS is estimated low [
There are several batteries proposed for assessing cognitive function in MS. Minimal Assessment of Cognitive Function in MS (MACFIMS) contains seven neuropsychology tools that cover five domains of cognitive function [
BICAMS is a brief cognitive evaluation tool that is recommended for MS and can be used worldwide. It is valid and reliable with high sensitivity and specificity. BICAMS can be administered by a physician for only 15 minutes [
This study found significantly lower score in all BICAMS tests on MS than HC (p<0.0001). SDMT has the largest effect size (r=0.61), followed by BVMT-R (r=0.47). This result was similar with previous studies which reported that SDMT and BVMT-R were more sensitive in distinguishing the cognition in MS and healthy subjects [
Our study found good correlation between test and retest score in SDMT (r=0.86), CVLT-II (r=0.81), and BVMT-R (r=0.83). In the HC group, the strongest correlation was observed in SDMT (r=0.76). BVMT-R and CVLT-II had weaker correlation (r=0.51 and 0.49). This result showed that BICAMS is reliable for assessing cognitive function in Indonesian MS patients.
Based on MS subtype, SPMS patients in this study had significantly lower score in all tests compared with RRMS. This result was in line with the negative correlation between EDSS and BICAMS score in those subjects. This proved the criterion-related validity of BICAMS for Indonesian MS patients. Studies in Japan and Brazil also found correlation between EDSS, disease duration, and BICAMS score [
Based on our result, SDMT and CVLT-II were affected by sex in the MS group, but it was not found in HC. This result was in conjunction with the correlation to the EDSS score since MS male subjects had higher EDSS score compared to female. This study did not find association between age, education, and BICAMS score in MS subjects, which was partially seen in HC groups. This might be due to the distribution of age and education in our subjects, most of which were younger than 40 year and had high education.
The prevalence of cognitive impairment on each test using
In this study, we found significant correlation between SDMT score with physical functioning and role limitation due to physical and mental problems. CVLT-II and BVMTR only significantly correlated with physical functioning. This finding was different with Sandi et al. who found significant correlation between BICAMS score with cognitive, physical, and social functioning subscales, overall quality of life and general health subscales, sexual function, and satisfaction with sexual function [
There were numbers of limitation in our study including a small sample size. Patients with relapse during the study were not excluded, and we have two patients who received high dose of methylprednisolone recently. We used the same form for CVLT-II retest which may lead to the practice effect. An alternate form is needed for the implementation of BICAMS in Indonesia. In this study we did not exclude subjects with depression and did not screened for fatigue status. However, there was no significant BICAMS score difference between MS subjects with and without depression. Fatigue might influence the subjects’ performance during the test as another study showed significant correlation with SDMT score [
BICAMS is valid and reliable for Indonesia MS patients which is short and easy to be performed. It can be widely used in Indonesia. Correlation between cognitive function and QOL described the importance of cognitive evaluation in MS care.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that there is no conflict of interest regarding the publication of this paper.
The authors were grateful to members of Yayasan Multiple Sclerosis Indonesia (Indonesia Multiple Sclerosis Foundation) for participating in this study. They thank Sarah Shafa Marwadhani, M.D., and Ausi Mutiara, M.D., for managing the research schedule. They also thank Prof. Dawn Langdon, Ph.D., who has given permission for us to translate and validate BICAMS into Indonesian version. The use of all tools in this research has been permitted by all publishers. This study is supported by Hibah PITTA 2018 funded by DRPM Universitas Indonesia [PITTA/214/FK/2018]