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431076MSJ0010.1177/1352458511431076Langdon et al.Multiple Sclerosis Journal
Research Paper Multiple Sclerosis Journal0(0) 1 –8 Recommendations for a Brief
The Author(s) 2012Reprints and permissions: International Cognitive Assessment for
Multiple Sclerosis (BICAMS)
DW Langdon1, MP Amato2, J Boringa3, B Brochet4, F Foley5,
S Fredrikson6, P Hämäläinen7, H-P Hartung8, L Krupp9,
IK Penner10, AT Reder11 and RHB Benedict12
Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes.
Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative
data are not available for all languages and cultures.
Objective: To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with
one or few staff members, who may not have neuropsychological training and constructed to maximize international use.
Methods: An expert committee of twelve members representing the main cultural groups that have so far contributed
considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed
articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS.
Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and
sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients.
Results: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition
of the California Verbal Learning Test – Second Edition and the Brief Visuospatial Memory Test – Revised learning trials if
a further 10 minutes could be allocated for testing.
Conclusions: A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for
language groups and validation studies have commenced.
multiple sclerosis, cognition information processing, memory, assessment, psychometrics, neuropsychology, SDMT,
Date received 16th October 2011; accepted: 3rd November 2011 Introduction and rationale
Cognitive impairment in multiple sclerosis reduces patients' 1Royal Holloway, University of London, Surrey, UK.
life satisfaction and health-related quality of life. It is prob- 2Careggi University Hospital, Florence, Italy.
ably the most important determinant of employment status 3Meander Medisch Centrum, Amersfoort, The Netherlands.
and associated societal costs, and also adversely affects 4Universite de Bordeaux, France.
5 Yeshiva University, Bronx, NY, USA and Holy Name Hospital Multiple driving safety, household task completion, social activity, Sclerosis Center, Teaneck, NJ, USA.
physical independence, rehabilitation progress, coping, 6Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
treatment adherence and mental health.1 There is a high 7Masku Neurological Rehabilitation Centre, Masku, Finland.
functional impact on young adults in demanding environ- 8Heinrich-Heine-Universitat, Duesseldorf, Germany.
ments. Reported cognitive impairment prevalence rates are 9Albert Einstein College of Medicine New York, USA.
10University of Basel, Switzerland.
between 43% and 70%. They occur in all disease stages, 11University of Chicago, USA.
including clinically isolated syndrome (CIS) and early 12Jacobs Neurological Institute, New York, USA.
relapsing–remitting MS (RRMS). Cognition is only loosely related to disease duration2 and physical disability (in some Corresponding author:
Professor DW Langdon, Royal Holloway, University of London, Egham, instances clearly dissociated)3 and is more strongly related Surrey, TW20 0EX, UK. to brain MRI parameters, especially atrophy.4 Multiple Sclerosis Journal 0(0) Cognitive deficits typically involve a few cognitive making, including determining how best to support patients' domains, spare language and are often undetected at con- involvement in disease management. Information and sultation.5 Information processing speed is the most vulner- counselling could be offered, facilitating adjustment at able cognitive ability, followed by episodic memory, and work and home. The effect of a start or shift in Disease executive function.6 Deficits may be mild. There is high Modifying Drug (DMD) treatment on cognition could be interpatient variability, in part due to varying compensation monitored, and also the use of cognition enhancers (pro- capacities (cognitive reserve).7 Patients may not be fully vided that sufficient evidence of efficacy is achieved).17 aware of their deficits, or may not report them reliably: The brief cognitive tool could also be integrated into more depression results in over-reporting,8 whilst metamemory detailed, specialist cognitive assessments and used to indi- impairment and insight loss lead to underestimation in up cate which patients require expert evaluation, targeting this to a third.9 MS cognitive deficits occur in the context of resource more efficiently and equitably. From a global per- sensory and motor impairments10 and reduced functioning spective, there are currently no cognitive measures for MS and engagement is easily attributable to physical disabili- that are internationally validated and standardised, which is ties. Cognitive impairment is not always at the forefront of a challenge for international study design.
the neurologist's mind, although cognitive decline could be as important to the patient as physical relapses or MRI Addressing cognitive dysfunction is recognised as a A committee of seven neurologists and five neuropsycholo- quality indicator in MS care.12 However, psychometric gists was convened, selected for their expertise in research assessment of cognitive status requires time-consuming and clinical aspects of MS cognition, and to represent the expert evaluation with specialist materials. The most language groups who had so far contributed most signifi- commonly utilised batteries of neuropsychological tests cantly to the MS cognition literature. There were two co- validated in MS are the 45-min Brief Repeatable Battery of chairs (one European, one American). A list of 80 scientific Neuropsychological tests (BRB-N)13 and the 90-min articles from peer review journals ( Minimal Assessment of Cognitive Function in MS content/early/recent) was assembled after a MEDLINE (MACFIMS).10 Comprehensive clinical cognitive assess- search in June 2010 by the co-chairs (D.L. and R.B.). These ment requires additional expertise in test selection, admin- were chosen to represent a broad international spectrum of istration and interpretation. This is not routinely available cognitive scales and their psychometric properties, includ- outside specialist centres.10 Non-specialist cognitive evalu- ing recent key review articles to allow the committee to ation tools are unsatisfactory. The Expanded Disability identify any omissions. The full list was circulated to the Status Scale offers only a rudimentary estimate of cognitive committee and members were invited to suggest amend- function.14 Widely used screening instruments, such as the ments and additions. Prior to the consensus meeting, a sub- Mini Mental State Examination, are insensitive to the MS set of articles was circulated to each committee member cognitive footprint.15 All of the above considerations point with standardised rating scales for completion. No member to a clear need for a short, well-validated and widely reviewed an article on which they were an author. Each accepted tool, which captures the cognitive performance of article was rated independently by two committee members MS patients, and can be used in everyday practice by clini- on three psychometric standards (reliability, validity and cal neurologists or administered by local healthcare sensitivity) and four pragmatic standards (international applicability, ease of administration, feasibility in the speci- fied context and acceptability to patients). All ratings were 3–1 (3 = excellent, 2 = satisfactory, 1 = unsatisfactory). The mean rating for each scale and each standard were calcu- Our objective was to recommend a clinical tool for neurol- lated, and then the mean overall rating (MOR) for psycho- ogists and healthcare professionals working with people metric and pragmatic qualities separately. Raters were also with MS, which was not designed to be either a cognitive invited to submit qualitative comments and judgements. screen or full assessment, but rather a brief monitoring Ratings and comments were collated for each candidate instrument. It would be optimised for centres where neu- measure, and all collated ratings, from individual to mean ropsychologists are not available. Identifying a brief meas- scores, were presented to the committee and fully discussed.
urement tool with adequate reliability, validity, sensitivity and specificity would allow for more widespread, accurate cognitive evaluations. A validated record of cognitive dis- Consensus criteria ability incorporated into routine clinical practise would be To meet the specified objectives of the cognitive monitor- beneficial. Baseline ratings and regular follow-up assess- ing tool, it was decided that the recommended battery ments would optimise patient management. Data from this should be completed in 15 min and not require any special cognitive monitoring tool could assist therapeutic decision equipment (beyond papers, pen and stop watch) or specific Langdon et al. assessor training. The battery should be easily performed in a clinical setting. Discussions at the consensus meeting led to agreement that the domains of information processing speed, verbal memory and visual memory could be included. Executive function scales were felt to be too long and too challenging to administer in the target context. It was acknowledged that a wide variety of cognitive presen- tations can be seen clinically,18 but it was felt that a battery of scales addressing the three domains identified would capture a reasonable proportion of significant cognitive ∫ ¬ ¤ §
Ħ ∫ ¬ §
Ξ Ħ ‡ ┌
impairment in large clinical samples.
Ħ ¤ ¬ Ξ Ħ ¦
Recommended monitoring testsInformation processing speed. There are two widely used tests of attention and processing speed in multiple sclero- Ħ ∫ ¤ §
Ξ ┌ ‡ §
sis: the Paced Auditory Serial Addition Task (PASAT)13 and the Symbol Digit Modalities Test (SDMT, oral form).19 Both are included in the BRB-N and the MACFIMS. The ┌ ‡ § ¦
SDMT achieved higher ratings, with a psychometric MOR of 2.8 and a pragmatic MOR of 3.0. In comparison, the PASAT achieved a psychometric MOR of 2.6 and a prag- matic MOR of 1.9. Discussion acknowledged that the § Ξ ¦
SDMT is more congenial for both patient and assessor, takes less time to complete, requires less expertise and experience of the assessor and unlike the PASAT, does not require special equipment for auditory presentation of stimuli. It has equal psychometric validity to the PASAT.20 The committee considered the evidence that the PASAT has Figure 1. Example of stimuli of the SDMT type.
detected therapeutic efficacy of disease modifying medica- tion on cognition,21,22 but felt that the SDMT was the better choice for the specified context on feasibility grounds.
volume change correlating with SDMT change,36 correla- The SDMT19 was recommended as the test of informa- tion with some deep grey matter (DGM) nuclei,37 including tion processing speed. The test consists of single digits thalamic fraction;32 and fMRI (fractional anisotropy).38 The paired with abstract symbols (Figure 1). Rows of the nine SDMT has also been shown to have external clinical valid- symbols are arranged pseudo-randomly. The patient must ity, being significantly linked to both current39 and future30 say the number that corresponds with each symbol. The employment status.
SDMT can be completed within 5 min, including instruc- tions, practice and testing. The good psychometric proper- Verbal memory (immediate recall). Again two candidate ties of the SDMT are well described.23 The SDMT has a scales emerged: The California Verbal Learning Test-II reported sensitivity of 82% and a specificity of 60%.24 It (CVLT-II)40 and the Selective Reminding Test (SRT).13 The has validations in several countries.2,24–26 Estimates of prac- CVLT-II is in the MACFIMS and the SRT is in the BRB-N. tice effects and change indices are available.27 The SDMT The CVLT-II achieved a psychometric MOR of 2.9 and a has a high sensitivity to cognitive impairment in MS.6,26,28 pragmatic MOR of 2.6. In contrast, the SRT achieved a psy- It has been shown to be the best predictor of MS cognitive chometric MOR of 2.5 and a pragmatic MOR of 2.2. It was impairment in both the BRB-N and MACFIMS.6 The noted that the SRT format required more expertise in admin- SDMT is reliable when administered by nursing staff over istration and scoring, compared to the simple list recall for- several months, with minimal practice effects (0.2).29 There mat of the CVLT-II. The committee decided that the first five is also evidence for the sensitivity of the SDMT to cogni- recall trials of the CVLT-II (CVLT-II T1-5) had sufficient tive change in MS.2,25,30 The SDMT is well validated psychometric rigour, in particular sensitivity to MS impair- against both conventional brain MRI parameters (including ment,41,42 to be suitable for inclusion in BICAMS. CVLT-II atrophy,31 brain parenchymal fraction (BPF) and third T1-5 has been previously recommended as part of a brief MS ventricular width,32 atrophy at baseline predicting SDMT cognitive assessment.43 The first five recall trials have a high change;33 cortical lesion number and white matter lesion degree of interdependence to other sections of the CVLT- volume,34 cortical lesion volume,32,34.35 cortical lesion II.42 Although this renders conclusions from the validity data Multiple Sclerosis Journal 0(0) Figure 2. Example stimuli of the CVLT-II type.
based on the full CVLT-II inferential, it also reduces the Figure 3. Example test stimuli of the BVMT-R type.
range of cognitive processes involved.41 The recommenda- tion carries the pragmatic advantage of reduced administra- Test Revised (BVMT-R)45 and the 10/36 Spatial Recall tion time (and possible patient fatigue effects), and a lesser Test.13 The BVMT-R is in the MACFIMS and the 10/36 is requirement for assessor expertise and experience compared in the BRB-N. The BVMT-R achieved a psychometric to the full CVLT-II, which suit our target context.
MOR of 3.0 and a pragmatic MOR of 2.2. In comparison, The recommended verbal memory scale is the CVLT-II the 10/36 achieved a psychometric MOR of 2.3 and a T1-5.40 This comprises a 16-item word list, with four items pragmatic MOR of 2.6. The committee's discussion high- belonging to each of four categories, arranged randomly lighted the reliability of the BVMT-R, the special equip- (Figure 2). The list is read aloud five times in the same order ment needed for the 10/36 and the possible ceiling effect to the patient, at a slightly slower rate than one item per sec- on the 10/36.7,28 As in the deliberations about the verbal ond. Patients are required to recall as many items as possi- memory scale, the conclusion was reached that the first ble, in any order, after each reading of the list. The CVLT-II three recall trials of the BVMT-R (BVMTR T1-3) would T1-5 can be completed in 5–10 min, including instructions, be the scale recommended for BICAMS, with similar testing and responses. The CVLT-II T1-5 has been validated advantages and caveats to those stated above in connec- with brain MR total lesion area and right superior frontal tion with the CVLT-II T1-5.
atrophy,44 MR T1 and FLAIR lesion volume, BPF and third The BVMT-R T1-345 is recommended. The BVMT-R ventricular width32 and MR diffusion measures.42 The full T1-3 requires the patient to inspect a 2 × 3 stimulus array of CVLT-II has been validated against brain MRI parameters abstract geometric figures (Figure 3). There are three learn- (cortical lesion number;34 correlation with some DGM nuclei ing trials of 10 s. The array is removed and the patient is volume,37 including thalamic fraction).32 The full CVLT-II required to draw the array from memory, with the correct also has external clinical validity, in differentiating employed shapes in the correct position. The psychometric properties MS patients from patients not employed due to MS.41 of the BVMT-R T1-3 are good.45 Validity of the BVMT-R T1-3 has been indicated by significant association with Visual Memory (immediate recall). Once again, two major brain MR total lesion area,44 T1 lesion and FLAIR lesion candidate scales emerged: the Brief Visuospatial Memory volume, BPF and third ventricular width32 and right Langdon et al. superior frontal atrophy44 and correlation with some DGM reserve).7 Some countries have reading scales that estimate nuclei,37 including thalamic fraction.32 pre-morbid level.10 If testing materials are not available in the patient's native language, particularly with respect to verbal learning and memory, published normative data can- not be used with any precision to evaluate the patient's per- For those health professionals with little experience of cog- formance. The limited value of BICAMS for patients who nitive assessment, prior review of instructions and practice are not native speakers is as a baseline against which to is recommended. Testing should take place in a quiet room, measure future change.
with just the patient and the assessor present. The purpose of BICAMS should be explained to the patient and if appro- Concurrent neurological/medical disorders. If an MS patient priate, some background information explaining cognitive has cognitive dysfunction, consideration must be give to difficulties in MS should have been made available to the whether other co-morbid neurological or medical conditions patient in advance (e.g. It is exist. In the context of learning disability, most mainstream recommended that BICAMS should not be used within 1 intellectual assessments are inappropriate. It is helpful to ask month of recovery from relapse (or if used, the data should whether or not a diagnosis of learning difficulty or attention not be interpreted as indicating long-term decline),46 or deficit disorder was present prior to the MS diagnosis, or within 1 month of steroid therapy, which has a proven their characteristic features, since these conditions may have reversible detrimental effect on memory function.47 The been present without formally diagnosis. Questions regard- recommended order of administration is first the SDMT, ing difficulties in school performance or with reading can then if time allows the CVLT-II T1-5 and BVMT-R T1-3. In yield helpful information. The medical history should include most clinical situations, yearly or bi-annual BICAMS eval- questions regarding past head trauma, cerebrovascular dis- uations will be appropriate.
ease, and other medical conditions such as sleep apnoea.
Concurrent medications. Certain medications commonly Confounds and limitations used in MS can adversely affect cognitive functioning.52 BICAMS is not intended to replace a full neuropsychologi- Benzodiazepines can interfere with vigilance and mem- cal assessment, which provides important additional insights ory.53 For many patients high doses of anti-spasticity agents to the patient, family, and clinician. These more detailed such as baclofen are associated with cognitive impair- evaluations are necessary for in depth rehabilitation and ments.54 Anticonvulsants are also known to reduce cogni- vocational counselling and disability determination.
tive function.55 Antidepressant medication can cause Neuropsychological test performance, including measures cognitive inefficiency to varying degrees.52 Cannabis, such as the SDMT, CVLT-II, and BVMT-R, is influenced by whether prescribed or self-medicated, can influence cogni- MS physical symptoms, demographic factors, the presence of tion.56 It is also important to be alert to other non-prescribed concurrent neurological disorders other than MS, some con- medication. Recent changes in cognition should be consid- current medications, and to a modest degree depression.
ered in the context of any concurrent medication changes.
Physical symptoms of MS. Whilst the BICAMS component Depression. Depression is highly prevalent in MS and may scales have been selected to minimise the impact of physical have mild effects on cognitive functioning, possibly medi- impairments on cognitive test performance,10,13 the assessor ated by coping styles.57 It is likely that severe depression should remain aware of confounds from MS symptoms. For could interfere with either willingness to undergo testing or example, dysarthria reduces performance on tests requiring ability to concentrate. An important aspect of depression's a spoken response, especially if timed.48 Even mild MS influence on the clinical management of cognition, is that visual impairments can also affect cognitive tests with visual depression affects self-report of cognitive problems. stimuli.49 The experienced clinician can infer how a patient's Patients' self-report of cognitive impairment does not reli- physical difficulties prejudice their test scores. Aside from ably correlate with their performance at objective cognitive the sensory and motor interface with the test situation, there testing; in contrast, the relative's report of the patient's cog- are a number of physical symptoms of MS that can interfere nitive status does correlate with the patient's performance at with cognitive test performance, notably pain.10 objective cognitive testing.58 Treatment of depression (and fatigue) improves patients' self report of cognitive function, Demographic factors. Demographic factors (age, educa- but not their objective cognitive test performance.8 tion, and gender) affect cognitive performance. Many tests have normative data taking account of these variables.50,51 It is also well established that pre-morbid optimal level will Fatigue. Over 80% of MS patients experience fatigue and affect how far current deterioration is detectable (cognitive also have the impression that this symptom interferes with Multiple Sclerosis Journal 0(0) their cognitive functions.59 This association has not been Conflict of interest statement
consistently confirmed in studies of objective cognitive test Professor Langdon has received funding for travel to scientific performance. However, it is known that heat, infections, meetings from Bayer Healthcare; serves on a Steering Committee pain and depression can increase fatigue and these contrib- for Bayer Healthcare; has served/serves as a consultant to Merck- utory factors should be managed to ensure optimum cogni- Serono, Bayer Healthcare; served on speaker bureau for Bayer tive performance. When feasible, patients should be Healthcare, Roche, Serono Symposia, TEVA Germany; receives allowed to rest after arriving, before their cognitive assess- research contract funding from Bayer Healthcare; receives edu- cational grants from Bayer Healthcare.
ment, to minimise the effects of fatigue.60 Those undergo- Professor Amato received personal compensation from ing repeated testing should if possible be evaluated at the Merck Serono, Biogen Dompè, Sanofi Aventis, Bayer Schering same time of day as the original assessment, to avoid vari- for serving on scientific advisory board and for speaking. ance from time of day fatigue effects.
Professor Amato received financial support for research activi- ties from Merck Serono, Sanofi Aventis, Biogen Dompè, Bayer Future work and development of
Dr Boringa has consulted for Bayer Healthcare served on speaker bureau for Exencia Pharma Academy.
Dr Brochet serves on scientific advisory boards for Bayer An international validation protocol for BICAMS is under Schering Pharma, Novartis, and Merck Serono; has received fund- development. Several national validation and standardisation ing for travel and speaker honoraria from Bayer Schering Pharma, Merck Serono, Biogen Idec, AB Sciences, and Teva Pharmaceutical projects are under way. It is envisaged that over time, many Industries Ltd./Sanofi-Aventis; and serves as LEN editor for SEP nations will be able to utilise BICAMS as part of routine et Neurosciences.
clinical MS practice, referring to appropriate national norms. Dr Foley has received honoraria for speaking at scientific and International MS natural history studies and treatment trials patient-education meetings, serving on scientific advisory boards with cognition outcomes will be assisted by an internation- and consulting activities from Bayer–Schering, Biogen, and Teva ally standardised battery. In order to support this process and Neuroscience.
facilitate access to materials and norms, the BICAMS com- Dr Fredrikson has received honoraria for lectures, educational mittee is working to publish BICAMS updates in scientific activities and consultancy from Bayer, Biogen Idec and Sanofi– and professional journals and meetings. The BICAMS web- Aventis during the past year.
site ( will be a focus for this process, Dr Hämäläinen received personal compensation from Bayer with a commitment to open access whenever possible.
Healthcare and Novartis for serving on scientific advisory boards; consulting for Sanofi–Aventis; served on speaker bureau for Bayer Healthcare and Sanofi–Aventis.
Professor Hartung received honoraria with approval by the Rector of Heinrich-Heine-University from Bayer Healthcare An expert consensus committee of neurologists and neu- GmbH, Octapharma GmbH, Novartis, Teva Sanofi Aventis, ropsychologists, with extensive research and clinical expe- Biogen Idec GmbH and Merck Serono GmBH for consulting and rience of MS cognition, have recommended a Brief speaking at scientific symposia.
International Assessment of Cognition for MS (BICAMS).16 Dr Krupp has served on speaker bureaux, scientific advisory The battery takes 15 min to complete, requires no specialist boards and/or been a consultant for Teva Neurosciences, BiogenIdec, equipment and no specialist expertise in cognitive assess- EMD Serono, Multiple Sclerosis Association of America, Betaseron/ Bayer Healthcare Pharmaceuticals, Pfizer, Sanofi–Aventis, Axon ment. BICAMS comprises: Advisors; she has received royalties from Genzyme, ER Squibb & Sons, NMSS, Novartis, MedImmune, Abbott Laboratories, • The Symbol Digit Modalities Test Johnson&Johnson, Roche, Health Professions Conferencing Corp.
• The California Verbal Learning Test –II, first five Dr Penner has received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activ- • The Brief Visuospatial Memory Test –Revised, first ities from Bayer–Schering, Biogen, Merck Serono, Roche, Novartis.
three recall trials.
Dr Reder has recently submitted two articles to Neurology and his disclosures remain the same.
Professor Benedict has acted as a consultant or scientific advi- sory board member for Bayer, Biogen Idec, Merk Serono, EMD This group of authors first came together in a Bayer sponsored Serono, Pfizer, Novartis; royalties from Psychological Assessment meeting, which inspired the foundation of the (independent) Resources, Inc; financial support for research activities from Shire BICAMS committee. We acknowledge Bayer's scientific contri- Pharmaceuticals, Biogen Idec.
bution in the area of cognition.
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