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Aims To assess the cognitive impairment of multiple sclerosis (MS) patients using the Brief
Repeatable Battery-Neuropsychology (BRB-N) test.
Methods The performance of 59 patients with MS in the BRB-N test was assessed and compared
with 152 matched healthy controls (HC).
Results In most tests, MS patients performed worse than controls. Age and educational level
strongly influenced the performance of the subjects. The Symbol Digit Modality Test (SDMT) best
correlated with the other individual tests and contributed most to the general BRB-N factor. Further-
more, a correlation between physical disability and performance in some BRB-N tests was observed.
Indeed, patients with progressive MS and greater physical disability performed worse in some tests
than less disabled patients with relapsing MS. By creating a global BRB-N Z score, we found that
patients generally performed 0.7 standard deviation (SD) below the level of controls. We obtained
cut-off values stratified by age and education to determinate cognitive impairment in MS patients.
Conclusions Our data show that cognitive impairment is prevalent amongst MS patients, and that a
single cognitive measurement might be useful for monitoring patients during the progression of this
illness. Multiple Sclerosis 2006; 12: 187 /195. www.multiplesclerosisjournal.com
Key words: Brief Repeatable Battery; cognitive impairment; multiple sclerosis; neuropsychology;
stratified cut-offs
1
Department of Neurology, Multiple Sclerosis Centre, Clinica Universitaria, University of Navarra, Navarra, Spain;
2
Neuroimmunology Clinic, Ramos Mejia Hospital, Argentina
Author for correspondence: Pablo Villoslada, Department of Neurology, Multiple Sclerosis Centre, Clı́nica
Universitaria de Navarra, Pio XII 36, 31008, Pamplona, Navarra, Spain. E-mail: pvilloslada@unav.es
Received 3 September 2004; accepted 6 July 2005
Patients and methods individuals had been previously studied with this
battery and none of the subjects refused to perform
We studied 59 consecutive patients with MS (Poser any of the tests (including PASAT 2-3). The BRB-N
criteria [14]) and 152 HC, proportionally matched was administered once, thus training-effects are
by sex, age and education in two MS centres. HC not applicable.
with cognitive impairment identified with Fol- Statistical analyses were performed using the
stein’s Mini-Mental [15], were also excluded. MS SPSS 11.0 software package (SPSS Inc., Chicago, IL,
related disability was evaluated with the Extended USA), applying the following tests: ANCOVA (ad-
Disability Status Scale (EDSS) [16], and the Multiple justed by age and education), unvaried correlation,
Sclerosis Functional Composite Measure (MSFC) multivariate analysis (multiple lineal regression-
[17,18], which includes: the Nine Hole Peg Test stepwise method, P to enter 0.05 and P to exit
(9-HPT); the Timed Walk Test (TWT); and PASAT 3. 0.1), factor analysis (principal components method)
Only one patient with complete paralysis of his and Z scores. A factor analysis was performed to
dominant hand was excluded for the 9-HPT. In this assess the principal distribution components of the
study, we included only individuals with no history battery in HC compared to MS, and not with the
of psychiatric or neurological disease other than intention to reduce variables. Correlation between
MS, no visual or auditory deficits, and no history the BRB-N tests and the patient’s disability scales
of alcohol or drug abuse, or any other major were assessed using the Pearson correlation test (all
medical illness. Individuals with psychiatric distur- variables had a normal distribution, as assessed by
bances identified with Cummings’ Neuropsychia- the Kolmogorov /Smirnov test). The level of sig-
tric Inventory [19], or Hamilton’s Depression Scale nificance was set at P B/0.05. To obtain cut-off
[20], were excluded from the study. values, we used three different criteria: 1 standard
MS patients were categorized by their EDSS as deviation (SD), 1.5 SD and 2 SD below the mean
follows: low disability (EDSS: 0 /3.0); medium dis- values of the HC in each test. We also defined the
ability (EDSS: 3.5 /6.5); and high disability (EDSS: pathological performance of MS patients at three
7.0 /9.0). The educational level of the subjects levels as the performance below the cut-off in at
was classified within one of four levels: low (B/8 least one, two or three tests of the battery. For the
years of education: elementary school); middle-low development of cut-off levels, the decimal values
(between nine and 12 years: high school), middle- were rounded up in the case of a decimal /0.5 and
high (between 13 and 16 years: college) and high down in the case of a decimal 5/0.5.
(/17 years: advanced degrees). The age of the In order to obtain a global cognitive performance
individuals was classified within one of three levels: score, we created a Z score for each cognitive
B/35 years, between 35 and 49 years and /49 years. domain (Z verbal memory (Zv), Z visual memory
Trained personnel carried out the validated (Zvi), Z attention-executive functions (Za) and Z
Spanish translation of the BRB-N in both centres. fluency (Zf)) and Z global cognitive function (BRB-
The two alternative Spanish versions (A or B) of N Z; see equations below). We calculated two sets of
BRB-N were produced for the European Study Z scores, one based on the control group and the
Group on Interferon beta-1b in Secondary Progres- other based on the MS patient group and for each
sive MS [13], and both were administered in alter- cognitive domain, the different subtests were
nating order. The BRB-N includes: the Selective weighted by their Z score to balance the tasks
Reminding Test (SRT) to assess verbal memory; the (e.g., Z SRT-S, Z SRT-R and Z SRT-D to produce the
10/36 Spatial Recall Test (10/36) to assess visual Zv). We obtained the global cognitive function
memory; the Symbol Digit Modalities Test (SDMT) (BRB-N Z) by calculating the mean of the Z scores
to assess attention, visual precision search and from the four cognitive domains.
executive functions; the Paced Auditory Serial
Z-verbal memory (Zv)
Addition Task 2 and 3 seconds (PASAT 2-3) to assess
the maintenance of attention; and the Word List (Z SRT-SZ SRT-RZ SRT-D)=3
Generation (WLG) to assess associative verbal flu- Z-visual memory (Zvi)(Z 10=36Z 10=36D)=2
ency. These tests were selected to explore most Z-attentional=executive (Za)
of the cognitive functions while minimising the
overlap between them. (Z Pasat3Z Pasat2Z SDMT)=3
The SRT-S and SRT-R were performed over six Z-fluency (Zf)Z WLG
trials and the 10/36 over three trials. The delayed BRB-N Z or Z-global (Zg)(ZvZviZaZf)=4
SRT-D and 10/36-D were performed 15 minutes
later. The SDMT, the WLG semantic form (A: The local Ethical Committees of both centres
animals; B: fruits and vegetables), and PASAT 2-3 approved these studies and all participants gave
were performed only once. The SDMT and the WLG their informed consent before being included in
were each performed in 90 seconds. None of the the study.
is important to note that we only assessed the 8. Dujardin K, Donze AC, Hautecoeur P. Attention
semantic form of this fluency task, and this could impairment in recently diagnosed multiple sclerosis. Eur J
Neurol 1998; 5: 61 /66.
be responsible for the lack of sensitivity. 9. Ruggieri RM, Palermo R, Vitello G, Gennuso M,
Although it was not the primary aim of our study Settipani N, Piccoli F. Cognitive impairment in
and we might lack power, we found that subjects patients suffering from relapsing-remitting multiple
with progressive MS performed worse than those sclerosis with EDSS B/ or / 3.5. Acta Neurol Scand 2003;
108: 323 /26.
with relapsing MS, which is in agreement with 10. Beatty WW, Goodkin DE. Screening for cognitive
Huijbregts et al . [12] This poorer performance may impairment in multiple sclerosis. An evaluation of the
possibly reflect the amount of brain damage, as Mini-Mental State Examination. Arch Neurol 1990; 47:
highlighted in MRI studies [33]. 297 /301.
The creation of a unified cognitive BRB-N scale 11. Rao SM, in collaboration with the Cognitive
Function Study Group of the National Multiple
could prove to be a useful tool to screen cognitive Sclerosis Society. A manual for the Brief Repeatable
impairment in MS patients and to monitor changes Battery of Neuropsychological Tests in multiple sclerosis .
in cognitive functions over time. For this reason, we Section of Neuropsychology, Medical College of Wiscon-
created a BRB-N Z score. Through this BRB-N Z sin, 1000 N. 92 Street, Milwaukee, WI 53226, 1990.
12. Huijbregts SCKN, de Sonneville LM, de Groot V,
score, we found that patients performed close to 1 Reuling IE, Polman CH. Differences in cognitive
SD worse than HC and that the BRB-N Z score also impairment of relapsing remitting, secondary, and pri-
correlated well with physical disability. One limita- mary progressive MS. Neurology 2004; 63: 335 /39.
tion of our study was that our results were obtained 13. European Study Group on interferon beta-1b in
secondary progressive MS. Placebo-controlled multi-
after a single administration of the battery in
centre randomised trial of interferon beta-1b in treat-
each subject, and the psychometric properties of ment of secondary progressive multiple sclerosis. Lancet
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14. Poser CM, Paty DW, Scheinberg L, McDonald WI,
Davis FA, Ebers GC et al . New diagnostic criteria for
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15. Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental
We would like to thank the individuals who state’. A practical method for grading the cognitive state
of patients for the clinician. J Psychiatr Res 1975; 12:
participated in our study, the Navarra MS Society
189 /98.
and the Argentina MS Society for their collabora- 16. Kurtzke JF. Rating neurologic impairment in multiple
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Masdeu, Dr Teresa Gomez-Isla, Dr Manuel Alegre Neurology 1983; 33: 1444 /52.
and Dr Isabel Lamet from the Department of 17. Fischer JS, Rudick RA, Cutter GR, Reingold SC,
Baier ML, Cookfair DL et al . The Multiple Sclerosis
Neurology at the University of Navarra, for their Functional Composite Measure (MSFC): an integrated
advice in the design and analysis of this study. approach to MS clinical outcome assessment. National
MS Society Clinical Outcomes Assessment Task Force.
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Appendix 1 Proposed BRB-N cut-off scores stratified by age and education using the criteria of 1 SD below the mean values of the
HC in each test (see methods for details)
Age
Appendix 1 (Continued)
Age
SRT-S, Selective Reminding Test Long-Term Storage; SRT-R, Selective Reminding Test Long-Term Retrieval; SRT-D, Selective Reminding
Test Delayed Recall; 10/36, 10/36 Spatial Recall Test; 10/36 D, 10/36 Spatial Recall Test Delayed; SDMT, Symbol Digit Modalities Test;
PASAT 2-3, Paced Auditory Serial Addition Task 2 and 3 seconds; WLG, word list generation.
Appendix 2 Proposed BRB-N cut-off scores stratified by age and education using the criteria of 1.5 SD below the mean values of the
HC in each test (see methods for details)
Age
SRT-S, Selective Reminding Test Long-Term Storage; SRT-R, Selective Reminding Test Long-Term Retrieval; SRT-D, Selective Reminding
Test Delayed Recall; 10/36, 10/36 Spatial Recall Test; 10/36 D, 10/36 Spatial Recall Test Delayed; SDMT, Symbol Digit Modalities Test;
PASAT 2-3, Paced Auditory Serial Addition Task 2 and 3 seconds; WLG, word list generation.
Appendix 3 Proposed BRB-N cut-off scores stratified by age and education using the criteria of 2 SD below the mean values of the
HC in each test (see methods for details)
Age
SRT-S, Selective Reminding Test Long-Term Storage; SRT-R, Selective Reminding Test Long-Term Retrieval; SRT-D, Selective Reminding
Test Delayed Recall; 10/36, 10/36 Spatial Recall Test; 10/36 D, 10/36 Spatial Recall Test Delayed; SDMT, Symbol Digit Modalities Test;
PASAT 2-3, Paced Auditory Serial Addition Task 2 and 3 seconds; WLG, word list generation.
HC MS P values*
SRT-S 50.919/11.34 40.129/14.5 B/0.001
SRT-R 42.459/13.24 28.469/15.91 B/0.001
SRT-D 9.79/2.04 7.759/2.61 B/0.001
10/36 20.869/5.43 17.059/5.98 B/0.001
10/36D 7.169/2.23 5.669/2.39 B/0.001
SDMT 49.239/14.64 36.869/16.87 B/0.001
PASAT 3 45.969/10.71 36.339/13.93 B/0.001
PASAT 2 36.979/10.69 26.839/11.43 B/0.001
WLG 28.159/7.32 26.159/8.47 NS