Cognitive functioning in children and adolescents with multiple sclerosis

Participants.

This study was approved by the Institutional Review Board for human subject research at the Stony Brook University Hospital. Subjects were recruited from all individuals with MS age 17 years 11 months and younger who were evaluated at the National Pediatric MS Center between October 2001 and August 2004. Written informed consent and assent were obtained.

Eligibility criteria included a diagnosis of childhood MS as jointly confirmed by an adult and pediatric neurologist using McDonald criteria⁹ (with the exception that age below 10 years was not an exclusion). Only patients with no other concurrent CNS disorder were included. Only two patients had a preexisting diagnosis of either attention deficit/hyperactivity disorder (ADHD) or a learning disability; these patients were included because it is not known whether these were a separate problem or represent a manifestation of white matter changes prior to the first recognized clinical event. As cognition may be affected by steroids, no patients were evaluated within 30 days of steroid use.

Of 84 individuals who were referred to the National Pediatric MS Center at Stony Brook for evaluation of possible MS, a diagnosis of clinically definite MS was confirmed for 40. Non-MS disorders were diagnosed in 44 children and included acute disseminated encephalomyelitis (n = 14), clinically isolated syndromes (n = 10), and other disorders (n = 16), such as nonspecific white matter changes, migraine, Syndenham’s chorea, and somatization disorder. Two of the patients initially identified as having experienced a clinically isolated syndrome went on to have a subsequent relapse, thus qualifying for a diagnosis of MS. As these patients were not considered to have definite MS at the time of the evaluation, they are not included in the present analyses. To date, 37 of the patients with confirmed MS received neuropsychological evaluation and a neurologic evaluation by both of the study neurologists. Demographic and historical data were collected by the study coordinator. All but three patients had normal vision bilaterally. Two patients had unilateral deficits: one had complete loss of vision of one eye (light perception only) and the other had moderate unilateral visual impairment of 20/80 in the right eye. The patient with bilateral visual loss had only mild impairment with visual disturbance of 20/30 in the right eye and 20/40 in the left, which is not of a severity to preclude valid neuropsychological assessment.

Procedure.

The patients were evaluated in the General Clinical Research Center of the State University of New York at Stony Brook. Neurologic data collected included current (i.e., measured within 1 week of cognitive evaluation) Expanded Disability Status Scale (EDSS),¹⁰ total number of relapses experienced, age at symptom onset, dichotomously scored (i.e., yes/no) subjective patient report of whether fatigue was problematic, and disease duration in whole months elapsed from symptom onset to time of cognitive evaluation.

Cognitive evaluation.

The participants received a brief standardized neuropsychological battery designed to assess all relevant cognitive domains. Although a global measure of cognitive function (i.e., IQ) may have provided interesting information, time constraints precluded inclusion of such instruments and, as declines on the WISC-III have been documented elsewhere,⁸ it was deemed more important to assess specific cognitive domains, including attention, language, memory, visual-spatial, and motor functions. The test battery included six tests. The Trailmaking Test¹¹ is a multifactorial task that is divided into two parts. Part A requires rapid visual scanning and motor speed, whereas Part B requires these skills as well complex attentional functions. The COWA¹² is a test of verbal fluency where the subject is asked to list words that begin with a target letter. The Boston Naming Test¹³ is a test of naming ability. To assess receptive language functions, the Listening to Paragraphs subtest of the Clinical Evaluation of Language Fundamentals–III¹⁴ was administered. With respect to memory, two subtests of the Wide Range Assessment of Memory and Learning were utilized: Verbal Learning and Visual Learning.¹⁵ Both immediate and delayed recall were assessed. Finally, the Beery Test of Visual Motor Integration¹⁶ provided an evaluation of graphomotor construction.

The battery required approximately 2 hours depending on the patient’s ability and was administered by a neuropsychologist in a single session. Breaks were provided when requested by the patient or if fatigue was evident. Performances were considered impaired when scores fell 1.5 SDs or more below the mean in comparison to published normative data. The cutpoint of 1.5 SDs was chosen as this is considered a deficient score by most neuropsychologists. As normative data are not available for the Boston Naming Test for children over 13,¹⁷ older children were compared to norms for 13-year-olds, likely resulting in a conservative estimate of their functioning in this domain. A patient was considered to have overall cognitive impairment if scores fell 1.5 SDs or more below published norms on at least two cognitive tasks (a criterion considered to be unlikely to be due to chance).¹⁸ All raw scores were converted into z-scores for subsequent correlational analyses to control for the effect of age and differing (i.e., age-appropriate) test forms. To represent overall cognitive functioning, a neuropsychological composite score was generated by calculating the mean of all test z-scores. Additionally, patients were administered the 9-hole Peg Test from the MS Functional Composite¹⁹ to adjust for fine motor functioning that may affect cognitive tests that require motor responses. One-year follow-up neuropsychological data were available for eight patients, and these data continue to be collected.

Psychological function.

A subset of the population (n = 13) was formally assessed for affective disorders by a psychiatrist utilizing the Schedule for Affective Disorders and Schizophrenia for School Aged Children.²⁰ The patients were not preselected for the evaluation, but rather were seen subsequent to the availability of the psychiatrist on the day of their study visit. Information regarding special educational services provided at school was also collected.

Statistical analyses.

Pearson correlations were used to assess the interrelations of clinical variables and the neuropsychological composite score. A point biserial correlation was used to assess the relations between reported fatigue and cognitive function. Partial correlations were also conducted to control for the effects of dominant hand motor function. For the purpose of this exploratory study, a significance value of p < 0.05 was used throughout, although, despite the relatively small sample size, some reached significance at more stringent levels (e.g., p < 0.01). All analyses were performed with Statistical Package for the Social Sciences 11.5 software.

Demographic and neurologic data.

Patient characteristics and clinical data at the time of the neuropsychological evaluation are presented in table 1. The majority of patients had symptom onset and diagnosis during the teenage years. All but one patient presented with a relapsing remitting course. Fatigue was a concern for nearly half of the sample (48.6%). Most patients were on disease modifying therapy at the time of the evaluation; three were on combination therapies.

Neuropsychological performance.

This group of children with MS showed a range of cognitive deficits. A total of 35.1% (13/37) of the patients showed major cognitive impairment, defined by impaired performance on at least two cognitive tasks. A total of 59% (22/37) had an impaired performance on at least one neuropsychological test. Interestingly, neither the patient with a preexisting diagnosis of ADHD nor the patient with a preexisting learning disability showed objective cognitive impairment on the neuropsychological battery.

The most common impairment was in complex attention (e.g., rapidly shifting attention between competing stimuli), affecting 29.7% of patients (11/37). Language was deficient for many, with 18.9% showing impairment in naming (7/37), and 13.5% showing poor receptive language (5/37). Verbal fluency was intact for all of the patients. Immediate verbal memory was impaired for only 1 patient (2.7%), whereas delayed recall was deficient in 7 patients (18.9%). Immediate recall of visual information was impaired for 3 patients (8.1%) and 4 (11%) demonstrated visual memory impairment after a delay. Thus, both encoding problems and forgetting are suggested. Visual-spatial functions were impaired in 2 patients (5.4%).

Psychological functioning.

Six of the 13 patients who underwent a structured psychiatric evaluation received a formal diagnosis of an affective disorder. Specifically, two patients were diagnosed with both a major depressive disorder and anxiety disorder–not otherwise specified (NOS); two patients were diagnosed with a major depressive disorder; one had an anxiety disorder NOS; and one had panic disorder and a generalized anxiety disorder.

Correlations between neurologic factors and cognition.

As shown in table 2, there were clear relations between neurologic factors and cognitive performance. Current EDSS score accounted for almost 33% of the variance in cognition. The total number of relapses experienced accounted for about 28% of the variance in cognition and total disease length accounted for nearly 17% of the variance. Age at disease onset was also significantly related to cognitive dysfunction. However, as age at onset and total disease length share considerable variance, this should be interpreted with caution. When multiple regression assessed the relative contributions of these factors to cognition, disease length emerged as the more salient predictor (pr = −0.288, p = 0.089) and age at onset no longer accounted for much variance (pr = 0.132, p = 0.442).

After controlling for dominant hand fine motor functioning, the relations of both EDSS and number of relapses with cognition remained significant. Though the correlation between disease length and cognitive function was no longer significant after controlling for motor function, a trend was evident. Subjective report of fatigue did not significantly correlate with cognition.

A hierarchical multiple regression assessing the relative contribution of the clinical variables in predicting cognition while controlling for dominant hand manual dexterity showed that EDSS was the strongest predictor (pr = −0.452, p = 0.006). Number of relapses was the second strongest predictor (pr = −0.336, p = 0.045) and the other variables did not add any additional significant predictive power.

Academic consequences.

For the 22 children for whom data were available, the average number of school days missed due to MS was 24.73, ranging from 0 to 225. Three of the patients required homeschooling. A total of 13 of 37 patients (35.1%) required some type of assistance or change in their school curriculum as a result of cognitive dysfunction. As an example, one patient was unable to memorize her locker combination at school, which led to her being continually late to a class and failing the course. This difficulty was obviated by providing her with a lock and key, rather than a traditional combination lock. She also required increased time to complete her examinations. Other children reported difficulty maintaining focus at school due to attention deficits. Many of these cognitively impaired children required academic accommodations at school to aid them in their studies. In the majority of cases, such accommodations have been adequate to overcome most of their cognitive limitations.

For some of the children, however, the effect of MS on academic performance was severe. For example, one 13-year-old girl had been under consideration for the gifted program prior to developing MS. Following onset of MS and subsequent acquired cognitive deficits, she required remedial classes after only 1 year of disease duration.

Two girls dropped out of school. One patient dropped out of a community college due to multiple hospitalizations for frequent relapses, cognitive deficits, and inability to handle the workload. As her disease course stabilized she was able to return to school. The other patient permanently dropped out of high school due to severe depression. Two boys, one in elementary school and the other in high school, repeated a year in school due to cognitive difficulty and multiple missed school days.

One year follow-up.

Of the 37 children who were initially evaluated for this study, eight have received 1-year follow-up neuropsychological re-evaluations. Three of the eight were cognitively impaired at baseline and all three went on to decline further. Among the five children who were cognitively intact at baseline, two declined at follow-up. During the interim period, both of these boys experienced relapses; one had five more relapses and the other had three. At follow-up, one manifested impairment across numerous domains, including attention, memory, language, visual-spatial functions, and motor functions. The other now demonstrated mild word finding deficits and verbal memory problems.