The onset of multiple sclerosis (MS) occurs before age 18 in up to 5% of cases.1 Based on various studies, it is estimated that cognitive impairment affects 30% to 50% of pediatric patients with MS2 compared with 45% to 65% of adult patients.3 While similar deficits have been observed in both adult and pediatric patients, there are also key differences.

“Factors such as age, maturation of the central nervous system, and cognitive reserve have different effects on cognition in childhood,” wrote Ozgul Ekmekci, MD, author of a 2017 review published in Behavioural Neurologythat describes the features of cognitive impairment in pediatric MS, based on the findings from relevant research.4

Using various neuropsychological tests and definitions of impairment, cross-sectional studies have found:

  • Impairments in general cognition, verbal and visual memory, language, and visuomotor integration in 10 children with MS5
  • Deficits in complex attention, naming, language, and delayed recall in 37 children and adolescents with MS6
  • Lower verbal and performance IQ scores in pediatric patients with MS vs healthy controls, with deficits in executive function, complex attention, visuospatial memory, and verbal comprehension7
  • Impairments in attention, processing speed, expressive language, and visuomotor integration, and significantly reduced full-scale and verbal IQ in children with MS8
  • Deficits in information processing speed (35%), visuomotor integration (50%), and fine motor coordination (54%) in a multicenter study of 231 pediatric patients with MS9

Across numerous studies, a higher risk for cognitive impairment was linked to lower age at MS onset and longer disease duration. In addition, several studies demonstrated an association between cognitive impairment and scores on the Expanded Disability Status Scale (EDSS), while other studies found no such connection.4

“Similar to adult patients, pediatric MS patients experience deficits in attention, information processing speed, memory, executive functions, and visuomotor integration,” Dr Ekmekci stated in the paper; however, “unlike in adults, MS affects language functions and intelligence” in patients who are particularly young.4

Observations from magnetic resonance imaging (MRI) studies in pediatric patients with MS have been consistent with those in adult patients, suggesting that a “relationship exists between cognitive impairment and gray matter atrophy, white matter atrophy, and global and regional brain volume,” Dr Ekmekci noted.4 The thalamus and the corpus callosum are 2 particular areas that have been implicated.

The findings from cross-sectional studies are further supported by longitudinal research, which also points to the potential role of cognitive reserve as a factor that may attenuate the impact of MS on cognitive function in some patients. In addition, children “are better able to compensate for brain damage because of the greater neural plasticity of the developing brain” compared with adults, Dr Ekmekci wrote.4

In longitudinal studies, follow-up ranged from 1 to 5 years. One study reported cognitive decline in 75% of patients at year 2. At year 5, the cognitive impairment index decreased in 56% of patients, improved in 25%, and remained stable in 18.8%.10,11 In other research, a greater number of healthy controls showed improvement on neuropsychological tests at 15-month follow-up compared with patients with MS (69.2% vs 17.9%, respectively).12

Noting that the studies described here used adult neuropsychological tests, Dr Ekmekci emphasized the need to develop testing that would identify cognitive deficits in pediatric patients with MS. “It is important to establish neuropsychological test batteries for evaluating cognitive domains that appear more frequently in children than adults and for assessing cognitive maturation in this age group,” she wrote.4

Related Articles

The following approaches have shown promise for use in this population:

  • One research group created a battery called the Brief Neuropsychological Battery for Children (BNBC) with MS, using the Symbol Digit Modalities Test (SDMT), the Trail Making Test B (TMT-B), the Selective Reminding Test-Consistent Long-Term Retrieval (SRT-CLTR), and the vocabulary test from the Wechsler Intelligence Scale for Children-Revised (WISC-R). They reported that the BNBC had a sensitivity of 96% and a specificity of 76%.13
  • Other investigators found significant differences between pediatric patients with MS (n=43) and healthy controls (n=45) on the SDMT and the Brief Visuospatial Memory Test-Revised (BVMT-R), indicating that “two relatively brief measures of visual-cognitive processing could be successfully applied to the pediatric population and could be useful in detecting and monitoring significant cognitive impairment.”1,14
  • In another study, the SMDT showed 77% sensitivity and 81% specificity when used as a screening tool for cognitive impairment in pediatric MS.15

For further discussion about cognitive deficits in pediatric MS, Neurology Advisor spoke with Christine Till, PhD, CPsychol, associate professor and director of clinical training, department of psychology, York University, Toronto, Canada, and Ann H. Tilton, MD, FAAN, professor of neurology and pediatrics and section chair of child neurology at Louisiana State Health Science Center in New Orleans.

Neurology Advisor: What are some of the cognitive deficits most commonly seen in pediatric MS and how do they effect patients’ lives?

Christine Till, PhD: Deficits are most commonly seen in memory, attention, and information processing speed, although changes in other domains, such as language and visuomotor ability, can also be observed. Cognitive impairment and fatigue are particularly disabling symptoms of the disease that can affect everyday and school activities. Approximately one-third of patients require a reduced class load, accommodations, and academic assistance due to fatigue and cognitive dysfunction.16 Cognitive impairment not only has a dramatic impact on quality of life, it may also affect an individual’s resources for enacting adaptive strategies for problem-focused coping. 

Ann Tilton, MD: The primary cognitive areas that are affected in pediatric MS range from deficits in general cognition to specific areas involving language and information processing. In addition, there may be an impact on memory in both the verbal and visual domains. Visual-motor integration abnormalities have also been reported.

Cognitive deficits have a significant impact on a child’s life. They are going to school and continuously facing academic demands. Although heterogenous in the degree of impairment, improvement, and stability, nearly 40% of patients have been reported to have cognitive impairment 5 years after diagnosis.17 The social impact is also understandable.

Neurology Advisor: How should clinicians screen for and address these deficits, and what are other relevant treatment implications or takeaways for our clinician audience?

Dr Till: The Symbol Digit Modalities Test (SDMT) has been shown to be an effective screening measure for identifying cognitive impairment in pediatric MS and this measure is considered a good screening tool for assessing cognitive decline over time. A more comprehensive neuropsychological evaluation is often needed for identifying an individual’s overall profile — which varies from person to person — and for establishing a baseline level of functioning with which to compare future results should the child or adolescent experience cognitive decline in the future.

Dr Tilton: Awareness is always the first step. Screening begins with asking the child and family if they are aware of deficits that are affecting their daily lives. Understandably, school performance is an important measure. Cognitive deficits do not necessarily correlate with deterioration in physical parameters and may occur independently. However, it is anticipated that more significant deficits in cognitive skills may be seen based on increased disease duration and severity. Formal assessments of cognitive function are an essential component of clinical management. Neuropsychological evaluations at baseline and periodically over time are necessary to monitor the patient’s clinical course and function adequately. 

Neurology Advisor: What are some of the remaining research needs in this area?

Dr Till: We need more research examining the impact of pediatric MS on long-term outcomes, such as educational, vocational, and psychosocial outcomes in adulthood. In addition, further research can help us better understand risk and protective factors in the context of cognitive and brain-related changes in order to improve early identification and the management of these changes.

Dr Tilton: With the heterogeneous finding of cognitive outcomes in patients with pediatric MS, research to determine predictors and potential interventions is essential. Of note, it is reported that some patients remain stable or improve cognitively while a significant percentage of patients continue to deteriorate. If this can be predicted early on, opportunities for altering the clinical course might be possible.

References

1.      Duquette P, Murray TJ, Pleines J, et al. Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr. 1987;111(3):359-363.

2.      Bobholz JA, Rao SM. Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol. 2003;16(3):283-288.

3.      Rao SM. Neuropsychology of multiple sclerosis. Curr Opin Neurol. 1995;8(3):216-220.

4.      Ekmekci O. Pediatric multiple sclerosis and cognition: a review of clinical, neuropsychologic, and neuroradiologic features. Behav Neurol. 2017;2017:1463570.

5.      Banwell BL, Anderson PE. The cognitive burden of multiple sclerosis in children. Neurology. 2005;64(5):891-894.

6.      Macallister WS, Belman AL, Milazzo M, et al. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology. 2005;64(8):1422-1425.

7.      Amato MP, Goretti B, Ghezzi A, et al. Cognitive and psychosocial features of childhood and juvenile MS. Neurology. 2008;70(20):1891-1897.

8.      Till C, Ghassemi R, Aubert-broche B, et al. MRI correlates of cognitive impairment in childhood-onset multiple sclerosis. Neuropsychology. 2011;25(3):319-332.

9.      Julian L, Serafin D, Charvet L, et al. Cognitive impairment occurs in children and adolescents with multiple sclerosis: results from a United States network. J Child Neurol. 2013;28(1):102-107.

10.  Amato MP, Goretti B, Ghezzi A, et al. Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up. Neurology. 2010;75(13):1134-1140.

11.  Amato MP, Goretti B, Ghezzi A, et al. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology. 2014;83(16):1432-1438.

12.  Till C, Racine N, Araujo D, et al. Changes in cognitive performance over a 1-year period in children and adolescents with multiple sclerosis. Neuropsychology. 2013;27(2):210-219.

13.  Portaccio E, Goretti B, Lori S, et al. The brief neuropsychological battery for children: a screening tool for cognitive impairment in childhood and juvenile multiple sclerosis. Mult Scler. 2009;15(5):620-626.

14.  Smerbeck AM, Parrish J, Serafin D, et al. Visual-cognitive processing deficits in pediatric multiple sclerosis. Mult Scler. 2011;17(4):449-456.

15.    Charvet LE, Beekman R, Amadiume N, Belman AL, Krupp LB. The Symbol Digit Modalities Test is an effective cognitive screen in pediatric onset multiple sclerosis (MS). J Neurol Sci. 2014;341(1-2):79-84.

16.  MacAllister WS, Belman AL, Milazzo M, et al. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology. 2005; 64(8):1411-1455.

17.  Amato MP, Goretti B, Ghezzi A, et al. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology. 2014; 83(16):1432-1438.