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To develop and propose a standardized battery of neuropsychological tests for the assessment of cognitive functioning of children and adolescents with pediatric systemic lupus erythematosus (pSLE).
A committee of health care professionals involved in the assessment of pSLE patients reviewed the literature to identify cognitive domains most commonly affected in pSLE and in adult SLE. They then reviewed the standardized tests available for children and adolescents that assess the cognitive domains identified. Through a structured consensus formation process the committee considered psychometric characteristics and duration of the tests.
A test battery was developed that appears suitable to provide a comprehensive assessment of cognitive domains commonly affected by pSLE with a 2.5 hour period.
It is hoped that the consistent use of this reliable and efficient battery increases the practicality of routine evaluations in pSLE, enabling between cohort comparisons and facilitating the longitudinal assessment of individual patients over time.
Cognitive dysfunction is commonly reported in adult SLE patients, based on studies employing non-standardized clinical assessment, as well as investigations that use standardized neuropsychological test batteries (1-5). In 1999, the ACR defined cognitive dysfunction in SLE as one of 19 neuropsychiatric syndromes of SLE (NPSLE) (6) and recommended a battery of standardized tests for use in adults with SLE (www.rheumatology.org/publications/ar/1999/499apc.asp). The recommended tests were selected by experts to assess impairment in the cognitive domains reported to be affected in SLE patients, i.e. attention, executive skills, memory, visual-spatial processing, language, and psychomotor speed (7-9). In the interim, this ACR test battery has been validated in a limited number of studies (10).
Cognitive dysfunction also is prevalent in pSLE patients and has been reported in 30 to 78% of pediatric SLE patients in small heterogeneous studies over the last 20 years (11-13). The wide range of numeric estimates reported in the literature is likely due to differences in design and case ascertainment between studies, because there is no standard comprehensive neuropsychological battery recommended for children and adolescents with pSLE, although such batteries have been developed for consistent use with other pediatric diseases, including cancer and multiple sclerosis (14, 15). The ACR test battery suggested for use in adult SLE (6) includes tests that either do not have well-established norms for children or have not been designed for use in children.
With increasing interest in the neurocognitive functioning with pSLE in recent years, there has been a small number of reports (most by members of this Committee), utilizing comprehensive batteries of standardized neuropsychological tests for the study of pSLE patients (16-19). It is, however, difficult to generalize findings across cohorts because the test batteries differed among studies (See Appendix).
Although neuropsychological testing remains the current criterion standard for the diagnosis of cognitive dysfunction (6), neuropsychological test batteries are not routinely used to assess the cognition of pSLE patients. Reasons include, but are not limited to, the length of time required for testing (20) (often as long as 6 to 8 direct contact hours), resulting in high cost of battery administration, scoring and interpretation, as well as the uncertainty as to which set of tests is the most appropriate for use in pSLE.
The Childhood Arthritis & Rheumatology Research Alliance (CARRA) Ad-Hoc Neurocognitive Lupus Committee recognized the need for such a battery, which was confirmed by a survey of pediatric rheumatologists organized in CARRA, using a Delphi questionnaire (21).
The objective of the Committee was to develop a battery of standardized neuropsychological tests for the future common use in the assessment of children and adolescents with pSLE. The rationale for using such a battery is as follows: (a) a concise but comprehensive battery will increase the practicality of routine evaluations of pSLE patients; (b) consistent baseline and follow-up evaluations may better gauge the effects of pSLE and its medical treatment in the individual patient; (c) a standard battery should enable generalizations across cohorts and, thereby, make it possible to assess the effects of factors such as demographics, disease activity, and medical therapies on cognition; and (d) testing results may be translated into interventions or modifications for individual patients within their educational settings. For example, if psychomotor processing speed is impaired, a student would be allowed extended time for tests and homework.
The Ad-Hoc Committee is comprised of four pediatric neuropsychologists and several pediatric rheumatologists, all of whom manage pSLE patients and recognized the need for a consistent, efficient, and comprehensive neuropsychological battery for children and adolescents with pSLE.
To achieve this goal, members of the Committee performed a systematic literature review of peer reviewed journal articles, review articles, and conference abstracts published from 1950 through the present on the neurocognitive status and outcomes of adult and pediatric SLE patients. Based on this review, the committee identified cognitive domains that are commonly affected in adults, children or adolescents with SLE and the tests most often used to assess neurocognition in those patients. In addition, the Committee reviewed a narrower band of literature regarding neurocognitive effects of other pediatric diseases and tests proposed to assess neurocognition in those populations (e.g., 15, 22-24).
Once members of the Committee identified those cognitive domains found to be affected in pSLE patients, they then reviewed, ranked, and selected neuropsychological tests appropriate for pediatric populations that specifically assess those domains of cognition described by the ACR (25). The criteria for test selection and ranking were as follows: (a) appropriate for the age range in question (9 to 18 years); (b) frequently used in a variety of pediatric populations and widely available; (c) good test-retest reliability; (d) standardized, so that scores can be compared across samples and with each other; (e) valid measurements of the aspect of cognition they purport to assess; (f) brief enough that the entire battery can be completed in a 2 to 2 ½ hour time period; (g) sufficient normative sample size; and (h) general ease of test administration.
In a series of structured teleconferences, Committee members considered a series of tests that previously had been used to assess neurocognition in pSLE patients and in other pediatric diseases and discussed alternate choices of tests that capture specific aspects of cognition. For example, the Color/Word Interference Test, a measure of executive function, was selected over the Stroop, a different measure of executive function, because the former test was normed on a larger patient sample). Discussions occurred on a monthly basis over a five month period, at which time a unanimous consensus was reached on those tests that were considered most appropriate for inclusion in the battery. The main strategy used to obtain consensus was structured, open discussion in which members presented their considered arguments for use of the various tests available. Decision to include specific tests into the batter was made based on unanimous agreement (consensus level 100%) of all members.
Based on this consensus, the Ad-Hoc Neurocognitive Lupus Committee proposes a concise, yet comprehensive battery of standardized tests that can be administered to pSLE patients ranging from 9 to 18 years of age. The battery is designed to assess domains of cognition thought to be vulnerable in pSLE, including attention, executive function, visual-spatial skills, memory, and psychomotor processing (13, 16-19), i.e. cognitive domains similar to those reported to be affected in adult SLE patients. Moreover, the battery includes measures of academic achievement, since school functioning is relevant to the daily functioning of pSLE patients.
Details on the proposed battery of standardized neuropsychological tests are provided in Table 1, including information on the cognitive domain assessed, normative sample size, duration of time needed for administration, and test-retest reliability.
Although the WASI (Wechsler Abbreviated Scales of Intelligence) (26) does not measure a specific aspect of cognition, it was included in the battery to provide an overall IQ as a reference standard against which it is possible to compare scores from the other tests and to gauge the presence of learning disabilities by comparison with academic achievement scores.
The Coding and Symbol Search subtests of the WISC-IV (Wechsler Intelligence Scales for Children – Fourth Edition), for patients ages 6 through 16 years and 11 months, as well as the WAIS-IV (Wechsler Adult Intelligence Scales, Fourth Edition), for patients ages 16 years and older, provide standardized measures of psychomotor speed and accuracy (27-29); whereas the Digit Span and Letter-Number Sequencing subtests of both Wechsler Scales assess verbal working memory (27-29). These four subtests (Coding, Symbol Search, Digit Span and Letter-Number Sequencing) are equivalent in the WISC-IV and WAIS-IV, so that the respective subtests of the WAIS-IV may be used for pSLE patients older than 16 years of age, while the WISC-IV subtests are for the testing of younger patients.
Visual attention and speed of response are assessed via the CPT-II (Continuous Performance Task II), a 15-minute computerized task, in which examinees must signal when target alphabet letters appear within a sequence of target and non-target letters (30). The academic achievement subtests chosen from the Woodcock-Johnson III Tests of Achievement measure word decoding, speed and accuracy of reading, numeric math calculation, and speed and accuracy of mathematical calculation (31).
The screening subtests of the WRAML2 (Wide Range Assessment of Memory and Learning-2) provide a measure of overall memory, as well as scores for verbal memory and visual memory (32). Lastly, the Color/Word Interference test of the D-KEFS (Delis-Kaplan Executive Function System) yields an index of executive functioning that samples the ability to shift cognitive sets and inhibit pre-potent responses (33, 34).
In addition to the test battery of standardized neuropsychological tests, the Committee recommends the completion of a standardized, self-administered parent questionnaire, the Child Behavior Checklist (CBCL/6-18), that is easily completed in clinical or research settings (35). The CBCL/6-18 is a measure of behavior problems and emotional internalization that provides standardized indices of eight behavior problem syndromes and yields measures of the following DSM-IV type categories: affective problems; anxiety problems; somatic problems; attention deficit/hyperactivity problems; oppositional defiant problems; and conduct problems. The results of the CBCL can provide additional guidance about possible patient school or behavioral interventions, complementing the results of the proposed battery.
In conclusion, the CARRA Ad-Hoc Neurocognitive Lupus Committee has proposed a relatively brief battery of neuropsychological tests to comprehensively assess cognitive function of children with pSLE. This battery includes neuropsychological test that are widely used and easily obtainable; normative standards for the U.S. population between the ages of 9 to 18 years are available; and previous research suggests good test-retest reliability and validity in assessing the different domains of cognition that are reported to be most commonly affected in pSLE. Due to the selection of tests considered in the battery, a targeted yet comprehensive assessment of neurocognition of children with pSLE can be limited to 2 ½ hours, thereby decreasing patient burden and reducing cost compared to other currently employed testing batteries. Although the proposed neuropsychological battery represents a practical means of assessing pSLE patients, it requires validation as a tool for characterizing neurocognitive deficits in this population, as was performed with the adult test battery following its recommendation by the ACR in 1999. We believe that consistent utilization of a uniform battery, such as the one proposed, is important as it will provide the possibility of comparing findings among cohorts of pSLE patients, as well as the effects of exposures to and impact of therapies in both individual and groups of patients. Moreover, results of such testing may be used to suggest educational interventions for individual patients.
Dr. Brunner is supported by grant funded NIAMS P60-AR047884
Dr. Muscal is supported by NICHD K12 HD41648 and the NINDS Pediatric Research Loan Repayment Program.
Dr. Levy is supported by NIAMS K23AR053202.
|Levy et al.a||Difrancesco et al. b||Brunner et al. c||Geisinger et al. d||Klein-Gitelman et al. e|
|Memory||- WRAML Screening Test||X|
|- Children's Memory Scale:||X||X|
|Stories Subtest, Immediate and Delayed Recall Trials||X|
|Dot Locations, Stories, Faces||X|
|- Wechsler Memory Scale III:||X||X|
|Logical Memory Subtest, Immediate and Delayed Recall|
|- Rey Osterrieth Complex Figure (ROCF)|
|Immediate Recall Trials||X||X||X|
|Delayed Recall Trials|
|- Stanford Binet Intelligence||X|
|Test (IV), Memory Subtests -Wechsler Memory Scale||X|
|Executive function/Attention||- Animal Naming||X|
|-Verbal Fluency “FAS”||X||X|
|- Comprehensive Trail-Making Test, Parts 4, 5||X|
|- Stroop Color-Word||X|
|- WISC/WAIS Letter-Number Sequencing||X|
|- Delis-Kaplan Executive Function System (D-KEFS)||X||X|
|Trail Making Test, Part B||X||X|
|-California Verbal Learning Test||X|
|-WISC- III, Spatial Span||X|
|-Brief Test of Attention||X|
|Visual spatial||- WASI Block Design||X|
|- Woodcock Johnson, Cognitive Ability||X||X|
|- ROCF (copy trial)||X|
|- Test of Visual Motor Integration|
|Processing speed||- CTMT Parts 1,2,3||X|
|- WISC/WAIS Code Substitution||X|
|- Stroop Color Test||X|
|- Stroop Word Test||X|
|- Purdue Pegboard||X|
|Trail Making Test, Part A, Children's Version||X|
|Broad Cognitive Measure||WISC||X||X|
|Expressive Language Vocabulary Test||X|