Introduction
Multiple sclerosis (MS) is a chronic immune-mediated inflammatory and neurodegenerative disorder of the central nervous system characterised by demyelination, gliosis and progressive neuronal loss. It commonly affects young adults and may result in substantial long-term neurological disability. The Global Burden of Disease Study estimated approximately 2.22 million prevalent cases of MS worldwide in 2016, with considerable geographical variation in disease burden [1]. Although MS has traditionally been considered less common in India than in Western populations, institutional and community-based studies indicate that the disease is increasingly recognised, partly because of improved access to magnetic resonance imaging, greater clinical awareness and expanding neurological services [2,3].
The clinical course of MS is heterogeneous and is broadly classified into relapsing-remitting, secondary progressive and primary progressive phenotypes [4] Assessment of disability is commonly performed using the Expanded Disability Status Scale (EDSS), which primarily evaluates neurological impairment and ambulatory function [5]. However, physical-disability measures alone may not adequately represent the complete disease burden. Cognitive dysfunction can develop during the early stages of MS, including in patients with minimal apparent physical disability, and may worsen independently of overt motor impairment. Early cognitive abnormalities have also been associated with subsequent disability, impaired health-related quality of life, reduced occupational functioning and difficulties in social participation [6,7].
The cognitive domains most frequently affected in MS include information-processing speed, attention, verbal learning, episodic memory and visuospatial memory. Nevertheless, formal cognitive evaluation is not routinely incorporated into neurological practice because comprehensive neuropsychological batteries require considerable time, trained personnel and specialised resources. To address these limitations, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was developed as a brief and practical assessment battery suitable for routine clinical and research settings [8]. It comprises the Symbol Digit Modalities Test (SDMT) for information-processing speed, the first five learning trials of the California Verbal Learning Test–Second Edition (CVLT-II) for verbal learning and memory, and the first three learning trials of the Brief Visuospatial Memory Test–Revised (BVMT-R) for visuospatial learning and memory [9]. The battery can generally be administered within 15-30 minutes and does not require extensive neuropsychological training. Studies conducted in different linguistic and cultural populations have demonstrated the feasibility and reliability of BICAMS for assessing cognitive performance in patients with MS [10,11].
Despite the recognised clinical significance of cognitive dysfunction in MS, evidence concerning BICAMS-based cognitive performance among Indian patients remains limited. Furthermore, the relationships of processing speed, verbal learning and visuospatial memory with demographic characteristics, disease duration, relapse history and physical disability require further evaluation in local clinical settings. Therefore, the present study was undertaken to assess cognitive performance using BICAMS in patients with MS attending a tertiary-care centre and to examine its association with selected demographic and clinical variables, particularly disability measured using the EDSS.
Aim
To assess cognitive performance and its association with clinical disability in patients with multiple sclerosis attending a tertiary-care centre.
Objectives
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To assess information-processing speed, verbal learning and visuospatial memory in patients with multiple sclerosis using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS).
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To determine the association of BICAMS test scores with demographic variables, including age, sex and educational status.
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To evaluate the relationship of cognitive performance with clinical characteristics, including disease duration, number of clinical attacks and multiple sclerosis phenotype.
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To assess the association between BICAMS test scores and neurological disability measured using the Expanded Disability Status Scale (EDSS).
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To compare cognitive performance according to cerebrospinal fluid oligoclonal band status.
Materials and Methods
This hospital-based cross-sectional observational study was conducted in the Department of Neurology of a tertiary-care teaching hospital. A total of 44 patients aged 18–55 years, diagnosed with multiple sclerosis according to the 2017 McDonald criteria and clinically stable for the preceding 30 days, were included.
Demographic and clinical details, including educational status, disease phenotype, disease duration and number of attacks, were recorded. Cognitive performance was assessed using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), comprising the Symbol Digit Modalities Test, California Verbal Learning Test–Second Edition and Brief Visuospatial Memory Test-Revised. Neurological disability was assessed using the Expanded Disability Status Scale.
Patients with severe hearing impairment or neurological disability preventing completion of the BICAMS tests were excluded.
Institutional Ethics Committee approval was obtained vide letter number BREC/21/18, dated 19 August 2021. Written informed consent was obtained from all participants. Continuous variables were expressed as mean ± standard deviation and categorical variables as frequencies and percentages. A p value <0.05 was considered statistically significant.
Results
A total of 44 consecutive patients with multiple sclerosis who either attended the neurology clinic or admitted in the neurology ward were serially screened and enrolled in the study.
| Sr. No. | Characteristic | Category | Frequency, n (%) |
| 1 | Age group | 18–20 years | 4 (9.1) |
| 21–30 years | 20 (45.5) | ||
| 31–40 years | 13 (29.5) | ||
| 41–50 years | 7 (15.9) | ||
| 2 | Sex | Male | 23 (52.3) |
| Female | 21 (47.7) | ||
| 3 | Marital status | Married | 22 (50.0) |
| Unmarried | 21 (47.7) | ||
| Divorced | 1 (2.3) | ||
| 4 | Educational status | Primary education | 15 (34.1) |
| Secondary education | 15 (34.1) | ||
| Graduate and above | 14 (31.8) |
The mean age of the participants was 30.47 ± 8.02 years, with most belonging to the 21–30-year age group. Males constituted 52.3% of the study population. Half of the participants were married, while primary and secondary education were each reported in 34.1% of cases.
| Sr. No. | Characteristic | Category | Frequency, n (%) / Mean ± SD |
| 1 | MS phenotype | Relapsing-remitting MS | 42 (95.5) |
| Secondary progressive MS | 1 (2.3) | ||
| Primary progressive MS | 1 (2.3) | ||
| 2 | Disease duration | <1 year | 7 (15.9) |
| 1–3 years | 21 (47.7) | ||
| 3.1–5 years | 5 (11.4) | ||
| >5 years | 11 (25.0) | ||
| Mean duration, years | 2.98 ± 1.67 | ||
| 3 | Number of clinical attacks | 1 attack | 9 (20.5) |
| 2 attacks | 14 (31.8) | ||
| 3 attacks | 7 (15.9) | ||
| 4 attacks | 3 (6.8) | ||
| 5 attacks | 9 (20.5) | ||
| 6 attacks | 1 (2.3) | ||
| 7 attacks | 1 (2.3) | ||
| Mean number of attacks | 2.91 ± 1.62 | ||
| 4 | Disease-modifying therapy | Dimethyl fumarate | 40 (90.9) |
| Interferon beta | 4 (9.1) | ||
| 5 | MMSE score | >24 | 32 (72.7) |
| ≤24 | 12 (27.3) | ||
| 6 | EDSS score | Mean ± SD | 1.59 ± 1.13 |
| 7 | CSF oligoclonal bands | Positive | 31 (70.5) |
| Negative | 13 (29.5) |
Abbreviations: CSF, cerebrospinal fluid; EDSS, Expanded Disability Status Scale; MMSE, Mini-Mental State Examination; MS, multiple sclerosis; SD, standard deviation.
Most participants had relapsing-remitting multiple sclerosis (95.5%), with a mean disease duration of 2.98 ± 1.67 years. Two clinical attacks were most common, and 90.9% were receiving dimethyl fumarate. The mean EDSS score was 1.59 ± 1.13, while 70.5% were positive for CSF oligoclonal bands.
| Sr. No. | BICAMS Test | Cognitive Domain | Mean ± SD | Minimum-Maximum | Median (IQR) |
| 1 | SDMT | Information-processing speed | 31.36 ± 10.63 | 15–60 | 32 (20.5–39.75) |
| 2 | CVLT-II | Verbal learning and memory | 38.18 ± 6.26 | 22–56 | 37.5 (35–42) |
| 3 | BVMT-R | Visuospatial learningand memory | 23.95 ± 4.48 | 13–36 | 24 (21–27) |
Abbreviations: BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; SDMT, Symbol Digit Modalities Test; CVLT-II, California Verbal Learning Test–Second Edition; BVMT-R, Brief Visuospatial Memory Test–Revised; SD, standard deviation; IQR, interquartile range.
The mean SDMT, CVLT-II and BVMT-R scores were 31.36 ± 10.63, 38.18 ± 6.26 and 23.95 ± 4.48, respectively. These scores represented participants’ performance in information-processing speed, verbal learning and visuospatial memory.
| Sr. No. | Clinical variable | Statistical measure | SDMT | CVLT-II | BVMT-R |
| 1 | Disease duration | Spearman’s ρ | −0.194 | −0.310 | −0.065 |
| p value | 0.230 | 0.051 | 0.690 | ||
| 2 | Number of clinical attacks | Group-comparison p value | 0.617 | 0.386 | 0.498 |
| 3 | EDSS score | Spearman’s ρ | 0.385 | 0.025 | 0.108 |
| p value | 0.014* | 0.877 | 0.509 |
*Statistically significant at p < 0.05.
Abbreviations: BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; SDMT, Symbol Digit Modalities Test; CVLT-II, California Verbal Learning Test–Second Edition; BVMT-R, Brief Visuospatial Memory Test–Revised; EDSS, Expanded Disability Status Scale; ρ, Spearman’s rank-correlation coefficient.
Disease duration showed a negative correlation with SDMT, CVLT-II and BVMT-R scores; however, none of these correlations were statistically significant. The number of clinical attacks was also not significantly associated with any BICAMS component. EDSS demonstrated a statistically significant positive correlation with SDMT score (ρ=0.385, p=0.014), whereas its correlations with CVLT-II and BVMT-R scores were not significant.
| Sr. No. | BICAMS test | OCB positive (n = 31), Mean ± SD | OCB negative (n = 13), Mean ± SD | p value |
| 1 | SDMT | 37.03 ± 12.29 | 41.50 ± 3.32 | 0.478 |
| 2 | CVLT-II | 39.31 ± 4.18 | 36.00 ± 1.16 | 0.127 |
| 3 | BVMT-R | 24.11 ± 6.33 | 23.50 ± 3.32 | 0.851 |
No statistically significant differences were observed between OCB-positive and OCB-negative participants.
Abbreviations: BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; CSF, cerebrospinal fluid; OCB, oligoclonal bands; SDMT, Symbol Digit Modalities Test; CVLT-II, California Verbal Learning Test–Second Edition; BVMT-R, Brief Visuospatial Memory Test–Revised; SD, standard deviation.
Among OCB-positive participants, the mean SDMT, CVLT-II and BVMT-R scores were 37.03 ± 12.29, 39.31 ± 4.18 and 24.11 ± 6.33, respectively, compared with 41.50 ± 3.32, 36.00 ± 1.16 and 23.50 ± 3.32 among OCB-negative participants. None of these differences were statistically significant (p = 0.478, 0.127 and 0.851, respectively).
| Sr. No. | BICAMS test | RRMS (n=42), Mean ± SD | SPMS (n=1), Mean ± SD | PPMS (n=1), Mean ± SD | p value |
| 1 | SDMT | 37.21 ± 11.78 | 26.00 ± 0.00 | 48.00 ± 0.00 | 0.371 |
| 2 | CVLT-II | 38.90 ± 4.12 | 38.00 ± 0.00 | 42.00 ± 0.00 | 0.462 |
| 3 | BVMT-R | 24.11 ± 6.33 | 19.00 ± 0.00 | 23.50 ± 3.32 | 0.993 |
Abbreviations: RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; SDMT, Symbol Digit Modalities Test; CVLT-II, California Verbal Learning Test–Second Edition; BVMT-R, Brief Visuospatial Memory Test–Revised; SD, standard deviation.
Participants with RRMS had mean SDMT, CVLT-II and BVMT-R scores of 37.21 ± 11.78, 38.90 ± 4.12 and 24.11 ± 6.33, respectively. The corresponding scores were 26.00, 38.00 and 19.00 in the SPMS participant and 48.00, 42.00 and 23.50 in the PPMS participant. No statistically significant differences were observed across MS phenotypes for SDMT (p = 0.371), CVLT-II (p= 0.462) or BVMT-R (p = 0.993).
| Sr. No. | Investigation | Finding | Frequency, n | Percentage (%) |
| 1 | MRI brain and spine | Periventricular lesions | 43 | 97.7 |
| 2 | Cortical/subcortical lesions | 34 | 77.3 | |
| 3 | Infratentorial lesions | 23 | 52.3 | |
| 4 | Spinal cord lesions | 18 | 40.9 | |
| 5 | VEP | Normal P100 latency | 4 | 9.1 |
| 6 | Unilaterally prolonged P100 latency | 15 | 34.1 | |
| 7 | Bilaterally prolonged P100 latency | 25 | 56.8 | |
| 8 | BAER | Normal | 41 | 93.2 |
| 9 | Unilaterally affected | 2 | 4.5 | |
| 10 | Bilaterally affected | 1 | 2.3 |
Abbreviations: MRI, magnetic resonance imaging; VEP, visual evoked potential; P100, positive wave occurring approximately 100 milliseconds after visual stimulation; BAER, brainstem auditory evoked response.
The MRI lesion categories were not mutually exclusive; therefore, their percentages do not total 100%.
Periventricular lesions were the most frequent MRI finding, observed in 43 (97.7%) participants, followed by cortical/subcortical lesions in 34 (77.3%), infratentorial lesions in 23 (52.3%) and spinal cord lesions in 18 (40.9%). On VEP testing, P100 latency was bilaterally prolonged in 25 (56.8%) participants and unilaterally prolonged in 15 (34.1%), while only 4 (9.1%) had normal findings. BAER was normal in 41 (93.2%) participants, whereas unilateral and bilateral abnormalities were observed in 2 (4.5%) and 1 (2.3%) participants, respectively.
| Sr. No. | Clinical assessment | Finding | Frequency, n | Percentage (%) |
| 1 | MMSE score | ≤24 | 12 | 27.3 |
| 2 | >24 | 32 | 72.7 | |
| 3 | Speech | Normal | 41 | 93.2 |
| 4 | Affected | 3 | 6.8 | |
| 5 | Vision | Normal | 18 | 40.9 |
| 6 | Unilaterally affected | 20 | 45.5 | |
| 7 | Bilaterally affected | 6 | 13.6 | |
| 8 | Motor system | Normal | 35 | 79.5 |
| 9 | Monoparesis | 2 | 4.5 | |
| 10 | Hemiparesis | 1 | 2.3 | |
| 11 | Paraparesis | 6 | 13.6 | |
| 12 | Sensory system | Normal | 28 | 63.6 |
| 13 | Abnormal | 16 | 36.4 | |
| 14 | Cerebellar function | Normal | 25 | 56.8 |
| 15 | Abnormal | 19 | 43.2 | |
| 16 | Bowel function | Normal | 44 | 100.0 |
| 17 | Affected | 0 | 0.0 | |
| 18 | Bladder function | Normal | 42 | 95.5 |
Abbreviation: MMSE, Mini-Mental State Examination.
Most participants had an MMSE score >24 [32 (72.7%)], while 12 (27.3%) had scores ≤24. Speech was normal in 41 (93.2%) participants. Visual involvement was unilateral in 20 (45.5%) and bilateral in 6 (13.6%) participants. Motor examination was normal in 35 (79.5%), while sensory and cerebellar abnormalities were observed in 16 (36.4%) and 19 (43.2%) participants, respectively. Bowel function was normal in all participants, whereas bladder dysfunction was present in 2 (4.5%) cases.
| Sr. No. | Disease duration | SDMT, Mean ± SD | CVLT-II, Mean ± SD | BVMT-R, Mean ± SD |
| 1 | <1 year | 40.25 ± 19.09 | 41.75 ± 6.55 | 23.25 ± 4.50 |
| 2 | 1–5 years | 38.31 ± 11.48 | 39.31 ± 4.06 | 24.81 ± 6.26 |
| 3 | >5 years | 34.20 ± 9.68 | 37.00 ± 2.16 | 22.40 ± 6.28 |
Abbreviations: BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; SDMT, Symbol Digit Modalities Test; CVLT-II, California Verbal Learning Test–Second Edition; BVMT-R, Brief Visuospatial Memory Test–Revised; SD, standard deviation.
The mean SDMT and CVLT-II scores showed a gradual decline with increasing disease duration, from 40.25 ± 19.09 and 41.75 ± 6.55 among participants with disease duration of less than 1 year to 34.20 ± 9.68 and 37.00 ± 2.16 among those with disease duration exceeding 5 years. The mean BVMT-R scores were 23.25 ± 4.50, 24.81 ± 6.26 and 22.40 ± 6.28 across the three disease-duration groups, respectively. However, these differences were not statistically significant for SDMT (p = 0.581), CVLT-II (p = 0.113) or BVMT-R (p = 0.557).
| Sr. No. | Number of clinical attacks | n | SDMT, Mean ± SD | CVLT-II, Mean ± SD | BVMT-R, Mean ± SD |
| 1 | 1–2 | 23 | 38.42 ± 13.88 | 40.16 ± 5.11 | 24.53 ± 5.88 |
| 2 | 3–4 | 10 | 37.17 ± 10.50 | 37.67 ± 2.54 | 23.67 ± 6.20 |
| 3 | 5–6 | 10 | 37.63 ± 8.04 | 38.25 ± 2.96 | 24.63 ± 6.50 |
| 4 | >6 | 1 | 22.00 ± 0.00 | 38.00 ± 0.00 | 15.00 ± 0.00 |
| p value | 0.617 | 0.386 | 0.498 |
Abbreviations: BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; SDMT, Symbol Digit Modalities Test; CVLT-II, California Verbal Learning Test–Second Edition; BVMT-R, Brief Visuospatial Memory Test–Revised; SD, standard deviation.
Participants with 1-2 clinical attacks had mean SDMT, CVLT-II and BVMT-R scores of 38.42 ± 13.88, 40.16 ± 5.11 and 24.53 ± 5.88, respectively. The corresponding scores were 37.17 ± 10.50, 37.67 ± 2.54 and 23.67 ± 6.20 among those with 3–4 attacks, and 37.63 ± 8.04, 38.25 ± 2.96 and 24.63 ± 6.50 among those with 5–6 attacks. The participant with more than six attacks had SDMT, CVLT-II and BVMT-R scores of 22.00, 38.00 and 15.00, respectively. However, no statistically significant differences were observed across the groups for SDMT (p = 0.617), CVLT-II (p = 0.386) or BVMT-R (p = 0.498).
Discussion
The mean age of the participants was 30.47 ± 8.02 years, with most belonging to the 21–30-year age group. This was comparable with Rima et al.,[12] and Estiasari et al.,[11] but lower than the mean age reported by Giedraitiene et al.,[13] A slight male predominance was observed, which was inconsistent with these studies, as they reported female predominance. Half of the participants were married, while primary and secondary education were each reported in 34.1% of cases. The differences may be related to the small sample size and regional variation.
Most participants had RRMS (95.5%), which was consistent with the findings of Rima et al.,[12] and Estiasari et al.,[11] The mean disease duration was 2.98 ± 1.67 years and the mean EDSS score was 1.59 ± 1.13, both of which were lower than those reported by Rima et al.,[12] and Giedraitiene et al.,[13]. This indicates that the present study mainly included patients with relatively early disease and mild neurological disability.
The mean SDMT, CVLT-II and BVMT-R scores were 31.36 ± 10.63, 38.18 ± 6.26 and 23.95 ± 4.48, respectively. Compared with Rima et al.,[12] the present study showed higher SDMT and BVMT-R scores, whereas Estiasari et al.,[11] reported higher SDMT and CVLT-II scores but a comparable BVMT-R score [24,28]. These findings demonstrate involvement of information-processing speed, verbal learning and visuospatial memory; however, cognitive impairment could not be classified because locally validated normative cut-offs were unavailable.
Disease duration and number of clinical attacks were not significantly associated with BICAMS scores, which was consistent with Giedraitiene et al.,[13] and Estiasari et al.,[11] However, EDSS showed a significant association with SDMT, indicating that information-processing speed may be related to neurological disability. This was partially consistent with Giedraitiene et al.,[13] and Drulović et al.,[14] although they reported significant associations with additional BICAMS components.
No significant differences in SDMT, CVLT-II or BVMT-R scores were observed between OCB-positive and OCB-negative participants. As no directly comparable study was available in the thesis references, this finding should be considered exploratory and may have been influenced by the small number of OCB-negative participants.
No significant differences in BICAMS scores were observed among RRMS, SPMS and PPMS phenotypes. However, because 42 participants had RRMS and only one participant each had SPMS and PPMS, a reliable comparison among clinical phenotypes was not possible. The predominance of RRMS was consistent with Rima et al.,[12] and Estiasari et al.,[11]. Periventricular lesions were the most common MRI finding, followed by cortical/subcortical, infratentorial and spinal cord lesions. Visual evoked potential abnormalities were frequently observed, whereas brainstem auditory evoked responses were normal in most participants. These findings indicate frequent involvement of visual pathways, while auditory brainstem pathways were relatively preserved. As directly comparable data were unavailable in the thesis references, these findings should be interpreted descriptively.
Most participants had MMSE scores above 24 and had normal speech and motor examination. However, abnormalities of vision, cerebellar function and sensory examination were commonly observed. These findings demonstrate the variable neurological involvement seen in multiple sclerosis. BICAMS provided additional domain-specific cognitive information that may not be adequately detected using MMSE alone.
Although SDMT and CVLT-II scores showed a numerical decline with increasing disease duration, the differences were not statistically significant. This finding was consistent with Giedraitiene et al.,[13] and Estiasari et al.,[11] who also found no significant association between disease duration and BICAMS performance but was inconsistent with Drulović et al.,[14] who reported significant associations with SDMT and BVMT-R.
No significant differences in SDMT, CVLT-II or BVMT-R scores were observed according to the number of clinical attacks. This finding was consistent with Giedraitiene et al.,[13] and Estiasari et al.,[11] who reported that relapse frequency did not significantly predict BICAMS performance. However, the subgroup with more than six attacks included only one participant, which limited the reliability of the comparison.
Conclusion
The present study demonstrated the feasibility of using BICAMS for the assessment of information-processing speed, verbal learning and visuospatial memory in patients with multiple sclerosis. A significant association was observed between neurological disability measured by EDSS and SDMT performance, suggesting that information-processing speed may be related to physical disability in patients with multiple sclerosis. However, BICAMS scores were not significantly associated with disease duration, number of clinical attacks, CSF oligoclonal band status or multiple sclerosis phenotype.
These findings support the incorporation of brief, multiple-sclerosis-specific cognitive assessment into routine clinical practice, including among patients with relatively mild physical disability. However, because the study had a small sample size, lacked a healthy control group and did not use locally validated normative cut-offs, the prevalence of cognitive impairment could not be determined. Larger multicentric and longitudinal studies are required to validate these findings and evaluate changes in cognitive performance over time.
Declarations
Conflicts of Interest
The authors declare that there is no conflict of Interest
Acknowledgements
The authors wish to express their sincere gratitude to the Head of Department, Neurology, for granting permission to conduct this study.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request and subject to institutional approval.
Authors' Contribution Statement
All authors have read and agreed to the published version of the manuscript:
Conceptualization: Dr. Neeraj Kumar, Dr. Surekha Dabla; Methodology: Dr. Surekha Dabla, Dr. Dr Beerbhan; Validation: Dr. Surekha Dabla, Dr Kiran Bala; Formal Analysis: Dr. Sunil Kumar Dahiya; Investigation: Dr Kiran Bala, Dr. Surekha Dabla; Resources: Dr. Surekha Dabla; Data Curation: Dr. Neeraj Kumar; Writing (Original Draft): Dr. Neeraj Kumar; Writing (Review and Editing): Dr Naveen Ranga, Dr. Sunil Kumar Dahiya.