We found that approximately one-third of pediatric patients with multiple sclerosis or clinically isolated syndrome met criteria for general cognitive impairment, defined here as having at least one-third of completed test scores falling 1 standard deviation or more below published normative data. The proportion of impairment in our sample is generally consistent with previous reports from much smaller studies,4,25
although direct comparisons are difficult across studies because of important differences in the assessment battery and criterion for cognitive impairment.
We report the first neuropsychological data from children and adolescents with clinically isolated syndrome. Cognitive impairment is well recognized in adults with clinically isolated syndrome. Cognitive impairment was identified in 8 of 44 (18%) children with clinically isolated syndrome and 69 (35%) children with multiple sclerosis. Identification of impairment at the early clinically isolated syndrome stage of disease is worrisome. The relative increased frequency of impairment among participants with multiple sclerosis compared to clinically isolated syndrome is consistent with the observation that cognitive impairments in children with multiple sclerosis progress over time.26,27
The test with the most frequent rate of impairment was the grooved pegboard, a measure of fine motor speed and coordination. We recognize that this finding may be attributable to the disease’s effects on motor as well as cognitive functioning. Future studies might specifically address the separate contributions of motor and cognitive functioning to multiple sclerosis patients’ performance on this measure.
Frequent impairment was also found on the Beery-Buktenica Developmental Test of Visual-Motor Integration, a measure that is dependent in part on fine motor coordination as well. In contrast, performances on a measure of visuospatial functioning that is not dependent on motor functioning (Wechsler Abbreviated Scale of Intelligence–Matrix Reasoning) were relatively normal. Previous studies of adults and children have documented visuomotor functions as vulnerable to impairment, both with respect to visuospatial functioning and visuospatial learning and recall. Therefore, assessments of this domain should include multiple measures, both with and without dependence on upper-extremity motor functioning.
Another area of impairment was identified by tests requiring speeded processing (Coding/Digit Symbol and Delis Kaplan Executive Function System trail making test). Slowed information processing is one of the most commonly observed domains of cognitive impairment in both adult and pediatric multiple sclerosis patients, and the results of this study confirm that this cognitive domain is highly susceptible to the effects of multiple sclerosis across the lifespan.
Other than the diagnosis of multiple sclerosis, neurologic disability as measured by the Expanded Disability Status Scale was the only variable significantly and independently associated with reduced cognitive function. Some studies,4
but not others,5,6
have found similar associations and it is likely that cognitive impairment progresses as does the neurologic burden of disease. This interpretation is also supported by the higher frequency of impairment in multiple sclerosis than in clinically isolated syndrome. There were also trends suggesting an association between reduced cognitive functioning with both fewer years of parent education as well as Hispanic ethnicity. Although race has been previously reported to be associated with cognitive impairment,28
we did not find it to be a significant predictor.
This study had several limitations. First, we used a relatively liberal cut-off point of 1 standard deviation below published norms to determine impairment on individual test scores. We chose this traditional benchmark in order to include children with even milder degrees of impairment that are likely clinically meaningful for academic performance and other aspects of functioning.20,22
However, we used a more stringent cut-off point to classify participants as cognitively impaired, with impaired performances on at least one-third of test scores from the completed battery (eg, at least 9 of 25 possible scores) in contrast to three impaired test scores used in prior studies.5
Second, although our neuropsychological battery was quite comprehensive, we excluded some tests in order to keep the battery brief; some excluded tests would have assessed domains that have been found to be sensitive indicators of cognitive status in both children and adults with multiple sclerosis, including measures of visuospatial learning and recall and measures of reading comprehension.4,8,9
Third, our multivariate analyses did not include detailed variables available regarding parent language status and socioeconomic status descriptors known to influence neuropsychological performance in children. In addition, fatigue and the presence of psychiatric distress were not included in these analyses but represent important characteristics influencing cognitive functions in multiple sclerosis.29,30
Aspects of disease burden as shown on magnetic resonance imaging (MRI)7,31,32
can also influence cognitive functions in pediatric multiple sclerosis. Finally, this study is cross-sectional; associations among sociodemographic and clinical variables in relation to cognitive function cannot be interpreted as causal relationships.
Despite these limitations, this is the largest study to date that uses a comprehensive neuropsychological battery to describe neuropsychological function in children and adolescents with multiple sclerosis. This study draws from a diverse catchment area across the United States and shows that cognitive impairment is a major feature of pediatric multiple sclerosis that can occur at the earliest stages of the disease. Cognitive impairment represents an important clinical problem for all patients with multiple sclerosis and confers specific challenges when it occurs during the context of childhood development. Further research is needed to develop strategies for prompt identification of children with multiple sclerosis at risk for cognitive problems so that treatment can be initiated.