The functional consequences of cognitive impairment in multiple sclerosis (MS) patients can be devastating. Cognitive impairment has a direct impact on health-related quality of life at all stages of MS [
Large studies of MS patients have reported cognitive impairment prevalence rates between 40 and 70% [
Traditionally, evaluation of cognitive deficits in MS patients has relied on “paper-and-pencil” neuropsychological batteries. Brief Repeatable Battery of Neuropsychological Tests (BRB-N) and Minimal Assessment of Cognitive Function in MS (MACFIMS) are the most widely used [
The aim of this study was to explore the efficacy of Central Nervous System Vital Signs (CNS VS) computerized battery in detecting cognitive dysfunction of MS patients in a district Greek population in Western Greece and try to designate differences in cognitive profile between RRMS and SPMS patients.
Eighty patients with MS, diagnosed according to McDonald criteria [
In addition, thirty-one Greek control participants were recruited in order to obtain a sample with similar demographic characteristics to our patients. Exclusion criteria for the control sample included nonnative Greek speakers, visual deficits, learning disabilities, psychiatric or neurological disorder, history of brain injury, cardiovascular illness, medication use that could interfere with cognitive performance, and drug and alcohol consumption.
All groups were assessed with Beck Depression Inventory-Fast Scale in order to exclude major depression as a concomitant factor that could interfere with cognitive performance.
Neuropsychological assessment was performed with Central Nervous System Vital Signs (CNS VS), a recently developed computerized cognitive screening battery which also provides a Greek adapted version. Brief Core assessment of CNS VS contains seven venerable neuropsychological tests: verbal and visual memory, finger tapping, symbol digit coding, stroop, shifting attention, and continuous performance test. Final results are automatically computed, expressing patient’s performance on specific domains such as composite memory, processing speed, psychomotor speed, executive function, reaction time, complex attention, and cognitive flexibility.
In addition, Greek versions of Trail Making Tests A and B, semantic and phonological verbal fluency tasks, and measuring executive function-information processing speed [
We classified as cognitively impaired, patients who failed on at least 33% of the included measures [
Differences between groups on clinical and demographic characteristics were analyzed using Kruskal-Wallis test for age and education, Mann-Whitney
RRMS patients were younger and had lower EDSS scores than SPMS. There were no significant differences in gender distribution and years of education between groups. Disease duration was longer for SPMS group, compared to RRMS (Table
Demographic and clinical characteristics of patients and controls.
Controls | RRMS | SPMS | Significant differences | |
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31 | 50 | 30 | |
Age (years) | 40.742 (2.695) | 41.760 (11.289) | 48.800 (6.228) |
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Education (years) | 12.935 (1.093) | 12.260 (3.556) | 12.667 (3.262) | n.s. |
Gender M/F, % | 38.7/61.3 | 22/78 | 26.7/73.3 | n.s. |
EDSS | 3.050 (0.810) | 6.183 (0.623) |
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Duration (years) | 8.840 (4.053) | 15.800 (5.135) |
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Hand, R/L % | 90.2/9.8 | 94/6 | 93.3/6.7 | n.s. |
Values are mean (SD);
RRMS: relapsing remitting multiple sclerosis, SPMS: secondary progressive multiple sclerosis.
n.s: nonsignificant.
Significant differences: RRMS < SPMS with
In the control sample, age and education did not correlate significantly with the performance in neuropsychological tests (Table
Correlations between age, education, and all neuropsychological measures in our control group. Pearson’s correlations for composite memory, executive function, and psychomotor speed. Spearman rank order correlations for all other measures.
Age | Educ. | Tmta | Tmtb | Vfsem | Vfphon | Reactime | Compatt | Cognflex | Procsp | Compm | Psysp | |
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Educ. | −0.11 | |||||||||||
Tmta | −0.07 | −0.14 | ||||||||||
Tmtb | 0.00 | −0.10 | 0.72*** | |||||||||
Vfsem | −0.09 | 0.12 | −0.44* | −0.59*** | ||||||||
Vfphon | 0.03 | 0.05 | −0.24 | −0.42** | 0.69*** | |||||||
Reactime | 0.14 | −0.23 | 0.16 | 0.01 | 0.13 | −0.03 | ||||||
Compatt | 0.04 | −0.04 | −0.02 | 0.30 | −0.31 | −0.30 | −0.42* | |||||
Cognflex | −0.03 | 0.18 | −0.47** | −0.65*** | 0.62*** | 0.49*** | −0.01 | −0.58*** | ||||
Procsp | 0.10 | −0.21 | −0.06 | −0.11 | −0.05 | −0.37* | 0.21 | 0.03 | −0.09 | |||
Compm | 0.12 | −0.02 | −0.10 | −0.33 | 0.08 | 0.30 | −0.22 | −0.25 | 0.40* | 0.10 | ||
Psysp | −0.11 | 0.02 | −0.44* | −0.51** | 0.32 | 0.12 | −0.30 | 0.14 | 0.31 | 0.09 | 0.41* | |
Exfunct | 0.23 | −0.03 | −0.15 | −0.09 | −0.06 | −0.23 | 0.12 | 0.00 | −0.12 | 0.69*** | 0.05 | −0.04 |
Correlation is significant at
Age; Educ.: education; tmta: trail making test a; tmtb: trail making test b; vfsem: verbal fluency semantic; vfphon: verbal fluency phonological; reactime: reaction time; compatt: complex attention; cognflex: cognitive flexibility; procsp: processing speed; compm: composite memory; psysp: psychomotor speed; exfunct: executive function.
We classified as cognitively impaired patients, those who failed on at least 33% of the included measures [
The overall prevalence of cognitive dysfunction was 43/80 = 53.75%. Frequency of cognitive dysfunction observed for each group was for RRMS 19/50 patients (38.00%) and for SPMS 24/30 patients (80.00%) (Table
Frequency of impairment in each measure for each group of patients; number and percent %.
RRMS ( |
SPMS ( |
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Tmta | 17 (34%) | 19 (63.33%) |
Tmtb | 17 (34%) | 23 (76.67%) |
Vfsem | 12 (24%) | 16 (53.33%) |
Vfphon | 15 (30%) | 15 (50%) |
Compmem | 8 (16%) | 12 (40%) |
Psyspeed | 10 (20%) | 20 (66.67%) |
Reactime | 29 (58%) | 25 (83.33%) |
Compatt | 12 (24%) | 11 (36.76%) |
Cognflex | 14 (28%) | 20 (66.67%) |
Procspeed | 4 (8%) | 8 (26.67%) |
Exfunction | 12 (24%) | 7 (23.33%) |
tmta: trail making test a; tmtb: trail making test b; vfsem: verbal fluency semantic; vfphon: verbal fluency phonological; compmem: composite memory; psyspeed: psychomotor speed; reactime: reaction time; compatt: complex attention; cognflex: cognitive flexibility; procspeed: processing speed; exfunction: executive function.
RRMS: relapsing remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis.
Disease duration and EDSS had a weak negative correlation with measures of processing speed, composite memory, and psychomotor speed. Years of education correlated negatively with TMT A, TMT B, reaction time, and complex attention. Age was negatively correlated with performance on semantic and phonological verbal fluency, cognitive flexibility, processing speed, composite memory, psychomotor speed, and executive function. On the other hand, disease duration had a positive correlation with reaction time; age was positively correlated with TMT B and reaction time measures, while education had a significant positive correlation with performance on phonological and semantic verbal fluency tasks, processing speed, cognitive flexibility, and executive function (Table
(a) Correlation coefficients between demographic, clinical characteristics, and neuropsychological measures of RRMS patients. Pearson’s correlations for composite memory, psychomotor speed, and executive function and Spearman rank order correlations for all other measures. (b) Correlation coefficients between demographic, clinical characteristics, and neuropsychological measures of SPMS patients. Pearson’s correlations for composite memory, psychomotor speed, and executive function and Spearman rank order correlations for all other measures.
Age | Education | EDSS | Duration | |
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Education | −0.35* | |||
EDSS | 0.28 | 0.11 | ||
Duration | 0.58*** | −0.10 | 0.58*** | |
Tmta | 0.31* | −0.44** | 0.14 | 0.24 |
Tmtb | 0.43** | −0.41** | 0.21 | 0.30* |
Vfsem | −0.44** | 0.42** | −0.09 | −0.20 |
Vfphon | −0.41** | 0.46*** | −0.11 | −0.23 |
Reactime | 0.37** | −0.32* | 0.16 | 0.36** |
Compatt | 0.23 | −0.38** | 0.05 | 0.04 |
Cognflex | −0.30* | 0.40** | −0.13 | −0.19 |
Procspeed | −0.60*** | 0.47*** | −0.31* | −0.43** |
Compmem | −0.44** | 0.30* | −0.29* | −0.39** |
Psyspeed | −0.44** | 0.33* | −0.40** | −0.40** |
Exfunction | −0.34* | 0.44** | −0.13 | −0.20 |
Correlation is significant at
tmta: trail making test a; tmtb: trail making test b; vfsem: verbal fluency semantic; vfphon: verbal fluency phonological; reactime: reaction time; compatt: complex attention; cognflex: cognitive flexibility; procspeed: processing speed; compmem: composite memory; psyspeed: psychomotor speed exfunction: executive function.
Age | Education | EDSS | Duration | |
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Education | 0.23 | |||
EDSS | 0.07 | 0.05 | ||
Duration | 0.30 | −0.11 | 0.35 | |
Tmta | 0.31 | −0.28 | 0.03 | 0.17 |
Tmtb | 0.00 | −0.17 | −0.11 | −0.07 |
Vfsem | 0.05 | 0.25 | 0.25 | 0.13 |
Vfphon | 0.13 | 0.37* | 0.10 | 0.09 |
Reactime | −0.13 | −0.07 | −0.22 | −0.31 |
Compatt | 0.20 | −0.43* | −0.08 | 0.37* |
Cognflex | 0.00 | 0.10 | 0.15 | −0.12 |
Procspeed | 0.02 | 0.04 | 0.00 | 0.04 |
Compmem | 0.10 | 0.07 | −0.32 | 0.14 |
Psyspeed | −0.32 | 0.17 | −0.28 | −0.26 |
Exfunction | −0.23 | 0.13 | 0.04 | −0.17 |
Correlation is significant at
tmta: trail making test a; tmtb: trail making test b; vfsem: verbal fluency semantic; vfphon: verbal fluency phonological; reactime: reaction time; compatt: complex attention; cognflex: cognitive flexibility; procspeed: processing speed; compmem: composite memory; psyspeed: psychomotor speed exfunction: executive function.
Education had a weak negative correlation with performance on complex attention and weak positive correlation on phonological verbal fluency task. Disease duration was only positively correlated with complex attention, while age and EDSS did not have any significant correlations with task performance (Table
Table
(a) Mean scores (SD) of RRMS, SPMS, and controls on neuropsychological tests. (b) Effect sizes for differences between controls and MS subgroups (RRMS, SPMS). For Cohen’s
RRMS | SPMS | Controls | |
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Tmta | 51.894 (19.549) | 63.436 (16.527) | 37.645 (12.547) |
Tmtb | 97.543 (39.400) | 141.537 (41.787) | 79.646 (22.946) |
Vfsem | 43.240 (10.413) | 36.967 (10.950) | 47.419 (8.865) |
Vfphon | 29.340 (12.327) | 21.800 (9.393) | 34.871 (9.552) |
Compmem | 90.940 (9.851) | 83.300 (9.675) | 97.903 (11.915) |
Psyspeed | 135.520 (26.301) | 103.267 (27.875) | 148.387 (24.204) |
Reactime | 827.360 (185.026) | 960.433 (143.748) | 618.516 (93.790) |
Compatt | 15.180 (10.435) | 19.733 (9.755) | 13.129 (6.820) |
Cognflex | 26.400 (22.707) | 14.200 (13.387) | 37.968 (15.070) |
Procspeed | 39.580 (15.617) | 26.800 (10.387) | 40.613 (14.986) |
Exfunction | 26.940 (22.835) | 15.733 (13.460) | 33.484 (16.442) |
RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; tmta: trail making test a; tmtb: trail making test b; vfsem: verbal fluency semantic; vfphon: verbal fluency phonological; compmem: composite memory; psyspeed: psychomotor speed; reactime: reaction time; compatt: complex attention; cognflex: cognitive flexibility; procspeed: processing speed; exfunction: executive function.
RRMS versus SPMS | RRMS versus Controls | SPMS versus Controls | |
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Tmta | Hedges’ |
Hedges’ |
Hedges’ |
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Tmtb | Hedges’ |
Hedges’ |
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Vfsem | Hedges’ |
Hedges’ |
Hedges’ |
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Vfphon | Hedges’ |
Hedges’ |
Hedges’ |
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Compmem | Hedges’ |
Hedges’ |
Hedges’ |
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Psyspeed | Hedges’ |
Hedges’ |
Hedges’ |
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Reactime | Hedges’ |
Hedges’ |
Hedges’ |
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Compatt | Hedges’ |
Hedges’ |
Hedges’ |
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Cognflex | Hedges’ |
Hedges’ |
Hedges’ |
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Procspeed | Hedges’ |
Hedges’ |
Hedges’ |
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Exfunction | Hedges’ |
Hedges’ |
Hedges’ |
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RRMS: relapsing remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; CONTR: controls; tmta: trail making test a; tmtb: trail making test b; vfsem: verbal fluency semantic; vfphon: verbal fluency phonological; compmem: composite memory; psyspeed: psychomotor speed; reactime: reaction time; compatt: complex attention; cognflex: cognitive flexibility; procspeed: processing speed; exfunction: executive function.
Since there is a statistically significant difference between mean ages of RRMS and SPMS patients (Table
The statistical comparison (ANOVA, Kruskal-Wallis test) of task performance between RRMS, SPMS, and controls showed statistically significant differences in all measures.
To compare task performance between group pairs, we conducted
Pairwise comparisons demonstrated that control group performed significantly better than SPMS group in all measures except complex attention. In addition the control group performed better than RRMS group in reaction time, TMT A and B, phonological verbal fluency task, composite memory, psychomotor speed, and cognitive flexibility (Table
Large effect sizes were present when SPMS patients were compared to controls on TMT A, TMT B, phonological verbal fluency, composite memory, psychomotor speed, reaction time, and cognitive flexibility. Medium effect sizes were present when the same groups were compared on semantic verbal fluency and executive function, while small effect size was present on processing speed. Comparison between RRMS patients and controls revealed large effect size on reaction time, medium effect size on TMT A and small on TMT B, phonological verbal fluency task, composite memory, psychomotor speed, and cognitive flexibility. Between patient groups (RRMS and SPMS), medium effect sizes were present on TMT B and psychomotor speed, while small effect sizes were present on composite memory and processing speed (Table
The present study allowed the recognition of cognitive impairment in RRMS and SPMS patients in a district Greek population in Western Greece, using CNS VS computerized battery as well as Trail Making Tests A and B and semantic and phonological verbal fluency tasks. The overall prevalence of cognitive dysfunction in our patients was 53.75%, thus in accordance with the estimated prevalence of previous studies that was ranging from 40% up to 70% [
Higher percentages of impaired RRMS patients were found in TMT A and B (34%), phonological verbal fluency (30%), and in reaction time (58%) with large effect size in reaction time, medium in TMT A (Table
SPMS patients performed significantly worse than control group in all tasks except complex attention. Higher percentages of cognitively impaired SPMS patients were found in reaction time (83.33%), TMT A and B (63.33% and 76.67% resp.), psychomotor speed and cognitive flexibility (66.67%), semantic and phonological verbal fluency tasks (53.33% and 50% resp.), and in composite memory (40%), all with large effect size except from semantic verbal fluency task that had medium effect size (Tables
It appears that deficits in reaction time, TMT A and B, and phonological verbal fluency task are the hallmarks of cognitively impaired RRMS and SPMS patients followed by impaired cognitive flexibility, psychomotor speed, and composite memory. Our findings are consistent with previous studies highlighting that the most affected cognitive domains in MS are processing speed, executive function, and memory with relative preservation of language [
Comparison between RRMS and SPMS patients demonstrated medium effect sizes on TMT B and psychomotor speed, while small effect sizes were present on composite memory and processing speed (Table
In the present study, cognitive assessment was performed with CNS VS, a battery that uses computerized forms of traditional tests such as Symbol Digit Modalities and Stroop and can provide even nonneuropsychologist clinician with a reliable, highly sensitive screening tool for detecting cognitive deficits in MS patients. Computerized batteries have demonstrated comparable results to traditional neuropsychological batteries. They are easy to use, require significantly less time to administer, produce instant scoring and can incorporate alternate forms, necessary to minimize learning effect on follow-up. Computerized cognitive screening batteries have also the capacity to accurately-automatically quantify “speed factor” via multiple parameters such as reaction time, psychomotor speed, and processing speed, increasing their sensitivity in detecting even subtle changes in information processing speed [
However, it is important to address few disadvantages of computerized cognitive assessment screening such as reliance on the visual modality and familiarity of the participant with computers. Moreover, there are many potential sources of error including use of various configurations and operating systems. There is also a provision of less qualitative information compared with paper and pencil tests [
In order to broaden the neuropsychological assessment and try to designate differences in cognitive profile between RRMS and SPMS patients, we also administered four traditional tests TMT A and B semantic and phonological verbal fluency tasks. A face to face parallel testing by a traditional paper and pencil versus its computerized form will be of great importance to address the actual efficacy of computerized neuropsychological tests in detecting cognitive impairment.
In conclusion, the present study clearly demonstrated cognitive decline in RRMS and SPMS patients of a district Greek population in Western Greece, using a computerized battery (CNS VS) and traditional neuropsychological tests (TMT A and B semantic and phonological verbal fluency tasks). CNS VS appears to be sensitive in detecting cognitive impairment in RRMS and SPMS patients. Significant impairment occurs in almost all studied cognitive domains such as episodic memory, executive function, and processing speed with gradual increment of the frequency as disease progresses. We did not detect distinct patterns of impairment between MS subtypes. This suggests a relatively broad pattern of cognitive deficits in MS, independently of the disease course, but with gradual augmentation of the frequency as disease progresses.
The authors declare that there is no conflict of interests regarding the publication of this paper.