Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)

 [bib_ref] Cognitive impairment in multiple sclerosisrecent advances and future prospects, Langdon [/bib_ref] [bib_ref] Sensitivity of conventional memory tests in multiple sclerosis: comparing the Rao Brief..., Strober [/bib_ref] [bib_ref] Intellectual enrichment lessens the effect of brain atrophy on learning and memory..., Sumowski [/bib_ref] [bib_ref] Relationship between depression, fatigue, subjective cognitive impairment, and objective neuropsychological functioning in..., Kinsinger [/bib_ref] [bib_ref] Awareness of deficit in multiple sclerosis, Sherman [/bib_ref] [bib_ref] Minimal neuropsychological assessment of MS patients: a consensus approach, Benedict [/bib_ref] [bib_ref] Neuroimaging in multiple sclerosis: neurotherapeutic implications, Sicotte [/bib_ref] [bib_ref] Quality indicators for multiple sclerosis, Cheng [/bib_ref] [bib_ref] Minimal neuropsychological assessment of MS patients: a consensus approach, Benedict [/bib_ref] [bib_ref] Minimal neuropsychological assessment of MS patients: a consensus approach, Benedict [/bib_ref] [bib_ref] Validity of performance scales for disability assessment in multiple sclerosis, Marrie [/bib_ref] [bib_ref] Three screening batteries to detect cognitive impairment in multiple sclerosis, Aupperle [/bib_ref] 

## Objective
Our objective was to recommend a clinical tool for neurologists and healthcare professionals working with people with MS, which was not designed to be either a cognitive screen or full assessment, but rather a brief monitoring instrument. It would be optimised for centres where neuropsychologists are not available. Identifying a brief measurement tool with adequate reliability, validity, sensitivity and specificity would allow for more widespread, accurate cognitive evaluations. A validated record of cognitive disability incorporated into routine clinical practise would be beneficial. Baseline ratings and regular follow-up assessments would optimise patient management. Data from this cognitive monitoring tool could assist therapeutic decision making, including determining how best to support patients' involvement in disease management. Information and counselling could be offered, facilitating adjustment at work and home. The effect of a start or shift in Disease Modifying Drug (DMD) treatment on cognition could be monitored, and also the use of cognition enhancers (provided that sufficient evidence of efficacy is achieved). [bib_ref] Treatment of cognitive impairment in multiple sclerosis: is the use of acetylcholinesterase..., Christodoulou [/bib_ref] The brief cognitive tool could also be integrated into more detailed, specialist cognitive assessments and used to indicate which patients require expert evaluation, targeting this resource more efficiently and equitably. From a global perspective, there are currently no cognitive measures for MS that are internationally validated and standardised, which is a challenge for international study design.

# Methods
A committee of seven neurologists and five neuropsychologists was convened, selected for their expertise in research and clinical aspects of MS cognition, and to represent the language groups who had so far contributed most significantly to the MS cognition literature. There were two cochairs (one European, one American). A list of 80 scientific articles from peer review journals (http://msj.sagepub.com/ content/early/recent) was assembled after a MEDLINE search in June 2010 by the co-chairs (D.L. and R.B.). These were chosen to represent a broad international spectrum of cognitive scales and their psychometric properties, including recent key review articles to allow the committee to identify any omissions. The full list was circulated to the committee and members were invited to suggest amendments and additions. Prior to the consensus meeting, a subset of articles was circulated to each committee member with standardised rating scales for completion. No member reviewed an article on which they were an author. Each article was rated independently by two committee members on three psychometric standards (reliability, validity and sensitivity) and four pragmatic standards (international applicability, ease of administration, feasibility in the specified 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 calculated, and then the mean overall rating (MOR) for psychometric and pragmatic qualities separately. Raters were also invited to submit qualitative comments and judgements. Ratings and comments were collated for each candidate measure, and all collated ratings, from individual to mean scores, were presented to the committee and fully discussed.

## Consensus criteria
To meet the specified objectives of the cognitive monitoring tool, it was decided that the recommended battery should be completed in 15 min and not require any special equipment (beyond papers, pen and stop watch) or specific 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 presentations can be seen clinically, [bib_ref] Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis, Prakash [/bib_ref] but it was felt that a battery of scales addressing the three domains identified would capture a reasonable proportion of significant cognitive impairment in large clinical samples.

## Recommended monitoring tests
Information processing speed. There are two widely used tests of attention and processing speed in multiple sclerosis: the Paced Auditory Serial Addition Task (PASAT)and the Symbol Digit Modalities Test (SDMT, oral form).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 pragmatic MOR of 1.9. Discussion acknowledged that the 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. [bib_ref] Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the..., Drake [/bib_ref] The committee considered the evidence that the PASAT has detected therapeutic efficacy of disease modifying medication on cognition, [bib_ref] Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis, Fischer [/bib_ref] [bib_ref] Long-term effect of early treatment with interferon beta-1b after a first clinical..., Kappos [/bib_ref] but felt that the SDMT was the better choice for the specified context on feasibility grounds.
The SDMTwas recommended as the test of information processing speed. The test consists of single digits paired with abstract symbols [fig_ref] Figure 1: Example of stimuli of the SDMT type [/fig_ref]. Rows of the nine symbols are arranged pseudo-randomly. The patient must say the number that corresponds with each symbol. The SDMT can be completed within 5 min, including instructions, practice and testing. The good psychometric properties of the SDMT are well described. [bib_ref] Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS), Benedict [/bib_ref] The SDMT has a reported sensitivity of 82% and a specificity of 60%. [bib_ref] Screening for cognitive impairment in multiple sclerosis using the Symbol Digit Modalities..., Parmenter [/bib_ref] It has validations in several countries. [bib_ref] Relevance of cognitive deterioration in early relapsing-remitting MS: a 3-year follow-up study, Amato [/bib_ref] [bib_ref] Screening for cognitive impairment in multiple sclerosis using the Symbol Digit Modalities..., Parmenter [/bib_ref] [bib_ref] A Swedish national postmarketing surveillance study of natalizumab treatment in multiple sclerosis, Holmen [/bib_ref] [bib_ref] How to detect cognitive dysfunction at early stages of multiple sclerosis?, Deloire [/bib_ref] Estimates of practice effects and change indices are available. [bib_ref] Reliability, practice effects, and change indices for Rao's Brief Repeatable Battery, Portaccio [/bib_ref] The SDMT has a high sensitivity to cognitive impairment in MS. [bib_ref] Sensitivity of conventional memory tests in multiple sclerosis: comparing the Rao Brief..., Strober [/bib_ref] [bib_ref] How to detect cognitive dysfunction at early stages of multiple sclerosis?, Deloire [/bib_ref] [bib_ref] Cognitive function in primary progressive and transitional progressive multiple sclerosis: a controlled..., Camp [/bib_ref] It has been shown to be the best predictor of MS cognitive impairment in both the BRB-N and MACFIMS. [bib_ref] Sensitivity of conventional memory tests in multiple sclerosis: comparing the Rao Brief..., Strober [/bib_ref] The SDMT is reliable when administered by nursing staff over several months, with minimal practice effects (0.2). [bib_ref] Repeated assessment of neuropsychological deficits in multiple sclerosis using the Symbol Digit..., Benedict [/bib_ref] There is also evidence for the sensitivity of the SDMT to cognitive change in MS. [bib_ref] Relevance of cognitive deterioration in early relapsing-remitting MS: a 3-year follow-up study, Amato [/bib_ref] [bib_ref] A Swedish national postmarketing surveillance study of natalizumab treatment in multiple sclerosis, Holmen [/bib_ref] [bib_ref] Predicting loss of employment over three years in multiple sclerosis: clinically meaningful..., Morrow [/bib_ref] The SDMT is well validated against both conventional brain MRI parameters (including atrophy, 31 brain parenchymal fraction (BPF) and third ventricular width, 32 atrophy at baseline predicting SDMT change; 33 cortical lesion number and white matter lesion volume, [bib_ref] Identification and clinical impact of multiple sclerosis cortical lesions as assessed by..., Mike [/bib_ref] cortical lesion volume, cortical lesion volume change correlating with SDMT change, 36 correlation with some deep grey matter (DGM) nuclei, [bib_ref] Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial..., Benedict [/bib_ref] including thalamic fraction; [bib_ref] Thalamic atrophy and cognition in multiple sclerosis, Houtchens [/bib_ref] and fMRI (fractional anisotropy). [bib_ref] Transverse diffusivity of cerebral parenchyma predicts visual tracking performance in relapsing-remitting multiple..., Warlop [/bib_ref] The SDMT has also been shown to have external clinical validity, being significantly linked to both current 39 and future 30 employment status.
Verbal memory (immediate recall). Again two candidate scales emerged: The California Verbal Learning Test-II (CVLT-II)and the Selective Reminding Test (SRT).The CVLT-II is in the MACFIMS and the SRT is in the BRB-N. The CVLT-II achieved a psychometric MOR of 2.9 and a pragmatic MOR of 2.6. In contrast, the SRT achieved a psychometric MOR of 2.5 and a pragmatic MOR of 2.2. It was noted that the SRT format required more expertise in administration and scoring, compared to the simple list recall format of the CVLT-II. The committee decided that the first five recall trials of the CVLT-II (CVLT-II T1-5) had sufficient psychometric rigour, in particular sensitivity to MS impairment, [bib_ref] Validity of the California Verbal Learning Test-II in multiple sclerosis, Stegan [/bib_ref] [bib_ref] The association between California Verbal Learning Test performance and fibre impairment in..., Fink [/bib_ref] to be suitable for inclusion in BICAMS. CVLT-II T1-5 has been previously recommended as part of a brief MS cognitive assessment. [bib_ref] Assessment of cognitive dysfunction in multiple sclerosis, Sartori [/bib_ref] The first five recall trials have a high degree of interdependence to other sections of the CVLT-II. [bib_ref] The association between California Verbal Learning Test performance and fibre impairment in..., Fink [/bib_ref] Although this renders conclusions from the validity data   based on the full CVLT-II inferential, it also reduces the range of cognitive processes involved. [bib_ref] Validity of the California Verbal Learning Test-II in multiple sclerosis, Stegan [/bib_ref] The recommendation carries the pragmatic advantage of reduced administration time (and possible patient fatigue effects), and a lesser requirement for assessor expertise and experience compared to the full CVLT-II, which suit our target context. The recommended verbal memory scale is the CVLT-II T1-5.This comprises a 16-item word list, with four items belonging to each of four categories, arranged randomly [fig_ref] Figure 2: Example stimuli of the CVLT-II type [/fig_ref]. The list is read aloud five times in the same order to the patient, at a slightly slower rate than one item per second. Patients are required to recall as many items as possible, in any order, after each reading of the list. The CVLT-II T1-5 can be completed in 5-10 min, including instructions, testing and responses. The CVLT-II T1-5 has been validated with brain MR total lesion area and right superior frontal atrophy, [bib_ref] Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis, Benedict [/bib_ref] MR T1 and FLAIR lesion volume, BPF and third ventricular width [bib_ref] Thalamic atrophy and cognition in multiple sclerosis, Houtchens [/bib_ref] and MR diffusion measures. [bib_ref] The association between California Verbal Learning Test performance and fibre impairment in..., Fink [/bib_ref] The full CVLT-II has been validated against brain MRI parameters (cortical lesion number; 34 correlation with some DGM nuclei volume, [bib_ref] Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial..., Benedict [/bib_ref] including thalamic fraction). [bib_ref] Thalamic atrophy and cognition in multiple sclerosis, Houtchens [/bib_ref] The full CVLT-II also has external clinical validity, in differentiating employed MS patients from patients not employed due to MS. [bib_ref] Validity of the California Verbal Learning Test-II in multiple sclerosis, Stegan [/bib_ref] Visual Memory (immediate recall). Once again, two major candidate scales emerged: the Brief Visuospatial Memory Test Revised (BVMT-R)and the 10/36 Spatial Recall Test.The BVMT-R is in the MACFIMS and the 10/36 is in the BRB-N. The BVMT-R achieved a psychometric MOR of 3.0 and a pragmatic MOR of 2.2. In comparison, the 10/36 achieved a psychometric MOR of 2.3 and a pragmatic MOR of 2.6. The committee's discussion highlighted the reliability of the BVMT-R, the special equipment needed for the 10/36 and the possible ceiling effect on the 10/36. [bib_ref] Intellectual enrichment lessens the effect of brain atrophy on learning and memory..., Sumowski [/bib_ref] [bib_ref] Cognitive function in primary progressive and transitional progressive multiple sclerosis: a controlled..., Camp [/bib_ref] As in the deliberations about the verbal memory scale, the conclusion was reached that the first three recall trials of the BVMT-R (BVMTR T1-3) would be the scale recommended for BICAMS, with similar advantages and caveats to those stated above in connection with the CVLT-II T1-5.
[formula]        1 2 3 4 5 6 7 8 9                                                                                                          [/formula]
The BVMT-R T1-3 45 is recommended. The BVMT-R T1-3 requires the patient to inspect a 2  3 stimulus array of abstract geometric figures [fig_ref] Figure 3: Example test stimuli of the BVMT-R type [/fig_ref]. There are three learning trials of 10 s. The array is removed and the patient is required to draw the array from memory, with the correct shapes in the correct position. The psychometric properties of the BVMT-R T1-3 are good.Validity of the BVMT-R T1-3 has been indicated by significant association with brain MR total lesion area, 44 T1 lesion and FLAIR lesion volume, BPF and third ventricular width [bib_ref] Thalamic atrophy and cognition in multiple sclerosis, Houtchens [/bib_ref] superior frontal atrophy [bib_ref] Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis, Benedict [/bib_ref] and correlation with some DGM nuclei, [bib_ref] Memory impairment in multiple sclerosis: correlation with deep grey matter and mesial..., Benedict [/bib_ref] including thalamic fraction. 32

## Implementation
For those health professionals with little experience of cognitive assessment, prior review of instructions and practice is recommended. Testing should take place in a quiet room, with just the patient and the assessor present. The purpose of BICAMS should be explained to the patient and if appropriate, some background information explaining cognitive difficulties in MS should have been made available to the patient in advance (e.g. www.stayingsmart.org.uk). It is recommended that BICAMS should not be used within 1 month of recovery from relapse (or if used, the data should not be interpreted as indicating long-term decline), [bib_ref] Reversible focal cognitive impairment in multiple sclerosis, Rozewicz [/bib_ref] or within 1 month of steroid therapy, which has a proven reversible detrimental effect on memory function. [bib_ref] Effect of high-dose cortisol on memory functions, Brunner [/bib_ref] The recommended order of administration is first the SDMT, then if time allows the CVLT-II T1-5 and BVMT-R T1-3. In most clinical situations, yearly or bi-annual BICAMS evaluations will be appropriate.

# Confounds and limitations
BICAMS is not intended to replace a full neuropsychological assessment, which provides important additional insights to the patient, family, and clinician. These more detailed evaluations are necessary for in depth rehabilitation and vocational counselling and disability determination.
Neuropsychological test performance, including measures such as the SDMT, CVLT-II, and BVMT-R, is influenced by MS physical symptoms, demographic factors, the presence of concurrent neurological disorders other than MS, some concurrent medications, and to a modest degree depression.
Physical symptoms of MS. Whilst the BICAMS component scales have been selected to minimise the impact of physical impairments on cognitive test performance, 10,13 the assessor should remain aware of confounds from MS symptoms. For example, dysarthria reduces performance on tests requiring a spoken response, especially if timed. [bib_ref] Dysarthria predicts poorer performance on cognitive tasks requiring a speeded oral response..., Smith [/bib_ref] Even mild MS visual impairments can also affect cognitive tests with visual stimuli. [bib_ref] Mild visual acuity disturbances are associated with performance on tests of complex..., Bruce [/bib_ref] The experienced clinician can infer how a patient's physical difficulties prejudice their test scores. Aside from the sensory and motor interface with the test situation, there are a number of physical symptoms of MS that can interfere with cognitive test performance, notably pain. [bib_ref] Minimal neuropsychological assessment of MS patients: a consensus approach, Benedict [/bib_ref] Demographic factors. Demographic factors (age, education, and gender) affect cognitive performance. Many tests have normative data taking account of these variables. [bib_ref] The brief repeatable battery of neuropsychological tests: normative values allow application in..., Boringa [/bib_ref] [bib_ref] The Rao's Brief Repeatable Battery and Stroop Test: normative values with age,..., Amato [/bib_ref] It is also well established that pre-morbid optimal level will affect how far current deterioration is detectable (cognitive reserve). [bib_ref] Intellectual enrichment lessens the effect of brain atrophy on learning and memory..., Sumowski [/bib_ref] Some countries have reading scales that estimate pre-morbid level. [bib_ref] Minimal neuropsychological assessment of MS patients: a consensus approach, Benedict [/bib_ref] If testing materials are not available in the patient's native language, particularly with respect to verbal learning and memory, published normative data cannot be used with any precision to evaluate the patient's performance. The limited value of BICAMS for patients who are not native speakers is as a baseline against which to measure future change.
Concurrent neurological/medical disorders. If an MS patient has cognitive dysfunction, consideration must be give to whether other co-morbid neurological or medical conditions exist. In the context of learning disability, most mainstream intellectual assessments are inappropriate. It is helpful to ask whether or not a diagnosis of learning difficulty or attention deficit disorder was present prior to the MS diagnosis, or their characteristic features, since these conditions may have been present without formally diagnosis. Questions regarding difficulties in school performance or with reading can yield helpful information. The medical history should include questions regarding past head trauma, cerebrovascular disease, and other medical conditions such as sleep apnoea.
Concurrent medications. Certain medications commonly used in MS can adversely affect cognitive functioning. [bib_ref] Cognition and fatigue in multiple sclerosis: Potential effects of medications with central..., Oken [/bib_ref] Benzodiazepines can interfere with vigilance and memory. [bib_ref] Cognitive toxicity of pharmacotherapeutic agents used in social anxiety disorder, Hindmarch [/bib_ref] For many patients high doses of anti-spasticity agents such as baclofen are associated with cognitive impairments. [bib_ref] Relationship between intrathecal baclofen and the central nervous system, Dario [/bib_ref] Anticonvulsants are also known to reduce cognitive function. [bib_ref] Pharmacotherapy of epilepsy: newly approved and developmental agents, Stephen [/bib_ref] Antidepressant medication can cause cognitive inefficiency to varying degrees. 52 Cannabis, whether prescribed or self-medicated, can influence cognition. [bib_ref] Multiple sclerosis and cannabis: a cognitive and psychiatric study, Ghaffar [/bib_ref] It is also important to be alert to other non-prescribed medication. Recent changes in cognition should be considered in the context of any concurrent medication changes.
Depression. Depression is highly prevalent in MS and may have mild effects on cognitive functioning, possibly mediated by coping styles. [bib_ref] A longitudinal analysis of cognitive dysfunction, coping, and depression in multiple sclerosis, Rabinowitz [/bib_ref] It is likely that severe depression could interfere with either willingness to undergo testing or ability to concentrate. An important aspect of depression's influence on the clinical management of cognition, is that depression affects self-report of cognitive problems. Patients' self-report of cognitive impairment does not reliably correlate with their performance at objective cognitive testing; in contrast, the relative's report of the patient's cognitive status does correlate with the patient's performance at objective cognitive testing. [bib_ref] Reliable screening for neuropsychological impairment in multiple sclerosis, Benedict [/bib_ref] Treatment of depression (and fatigue) improves patients' self report of cognitive function, but not their objective cognitive test performance. [bib_ref] Relationship between depression, fatigue, subjective cognitive impairment, and objective neuropsychological functioning in..., Kinsinger [/bib_ref] Fatigue. Over 80% of MS patients experience fatigue and also have the impression that this symptom interferes with their cognitive functions. [bib_ref] Multiple sclerosis-associated fatigue, Krupp [/bib_ref] This association has not been consistently confirmed in studies of objective cognitive test performance. However, it is known that heat, infections, pain and depression can increase fatigue and these contributory factors should be managed to ensure optimum cognitive performance. When feasible, patients should be allowed to rest after arriving, before their cognitive assessment, to minimise the effects of fatigue. [bib_ref] Long-term followup of the original interferon-beta 1b trial in multiple scelrosis: design..., Ebers [/bib_ref] Those undergoing repeated testing should if possible be evaluated at the same time of day as the original assessment, to avoid variance from time of day fatigue effects.

## Future work and development of bicams
An international validation protocol for BICAMS is under development. Several national validation and standardisation projects are under way. It is envisaged that over time, many nations will be able to utilise BICAMS as part of routine clinical MS practice, referring to appropriate national norms. International MS natural history studies and treatment trials with cognition outcomes will be assisted by an internationally standardised battery. In order to support this process and facilitate access to materials and norms, the BICAMS committee is working to publish BICAMS updates in scientific and professional journals and meetings. The BICAMS website (www.BICAMS.net) will be a focus for this process, with a commitment to open access whenever possible.

## Summary
An expert consensus committee of neurologists and neuropsychologists, with extensive research and clinical experience of MS cognition, have recommended a Brief International Assessment of Cognition for MS (BICAMS). [bib_ref] The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): first consensus steps..., Langdon [/bib_ref] The battery takes 15 min to complete, requires no specialist equipment and no specialist expertise in cognitive assessment. BICAMS comprises:
- The Symbol Digit Modalities Test - The California Verbal Learning Test -II, first five recall trials - The Brief Visuospatial Memory Test -Revised, first three recall trials.
[fig] Figure 1: Example of stimuli of the SDMT type. [/fig]
[fig] Figure 2: Example stimuli of the CVLT-II type. [/fig]
[fig] Figure 3: Example test stimuli of the BVMT-R type. [/fig]