Dr Jan Hiller PhDJan Hiller, MD, PhD
Patients with pediatric-onset multiple sclerosis (MS) show a more rapid reduction in their information-processing skills over time and are more likely to experience cognitive impairment than their counterparts with adult-onset MS, new study findings suggest.1

The study group consisted of a national cohort of more than 5700 patients with MS, 300 of whom had pediatric-onset disease, and a databank of more than 46,000 prospective Symbol Digit Modalities Test (SDMT) scores. The investigators found that independent of age or disease duration, patients with pediatric-onset MS were more likely to experience cognitive impairment (odds ratio [OR], 1.44; 95% CI, 1.06 to 1.98).

Additionally, the investigators, including Jan Hillert, MD, PhD, professor, clinical neuroscience, Karolinska Institutet, observed that SDMT scores for patients with pediatric MS were significantly lower than those of patients with MS in adulthood (β coefficient, –3.59; 95%CI, −5.56 to −1.54), and similarly, SDMT scores for the pediatric group declined faster than their counterparts (β coefficient, −0.30; 95%CI, −0.42 to −0.17).

“Pediatric-onset multiple sclerosis appears to render persons particularly susceptible to impairments in information processing in adulthood,” Hillert and colleagues detailed. “Children and adolescents who develop multiple sclerosis should be monitored closely for cognitive changes and helped to manage the potential challenges that early-onset multiple sclerosis poses for cognitive abilities later in life.”

When SDMT scores were compared between the groups at age <30 years, the pediatric- and adult-onset groups were comparable, though past age 30, the score trajectories separated. As expected, both groups displayed their highest SDMT scores between ages 20 and 30 years. During the average follow-up period of 3 years, 70.7% (147 of 208 patients) of those in the pediatric group met the clinical definition for cognitive impairment, compared to 59.8% (2305 of 3852 patients) of those in the adult group.

Hillert et al. noted that prior efforts in the validation of the SDMT identified a number of vocational benchmarks with the scores. In this study, they found that the score of 55—the anchor for “employed but work challenged”—was achieved by age 34 for the pediatric group, on average, compared to age 50 for the adult-onset group.

“The differences observed in information-processing efficiency between the [pediatric-onset] MS and [adult-onset] MS groups may be a consequence of the heightened inflammation and axonal loss that has been reported in [pediatric-onset] MS,” the investigators wrote. They acknowledged that previous literature has shown that inflammation in the brain during developmental phases, such as myelinogenesis in adolescence, can led to irreparable neural network injury.2-4

“This damage may also lead to the reduced brain and deep gray matter volumes in adulthood that have been reported in [pediatric-onset] MS relative to sex- and age-matched patients with [adult-onset] MS independent of disease duration,” they wrote.

Ultimately, 97.6% (n = 5569) of patients in the cohort had a relapsing-onset disease course. As well, 98.8% of the 5704 total participants had been exposed to disease-modifying therapy (DMT). All told, 63.9% (n = 3647) of the total participants in both groups had been exposed to a second-line DMT, whereas only 1.2% (n = 67) of the full cohort were never exposed to
a DMT during follow-up.

The adult-onset group (n = 5404) had a higher proportion of patients receiving a first-line therapy, with 19.4% (n = 1048) of patients given first-line DMT during follow-up compared to 10.7% (n = 32) of patients in the pediatric group (P <.001). The pediatric group was more likely to have received only second-line therapy, with 75.3% (n = 226) of patients doing so compared to 63.3% (n = 3421) in the adult-onset MS group.

Hillert and colleagues identified a number of limitations, most notably that the SDMT is limited in its addressing only information-processing efficiency. As well, they noted that the true date of MS diagnosis is limited due to a basis on self-reported symptoms, and a lack of information on highest educational level achieved, and thus an inability to examine for or adjust the statistical models to account for the association of pediatric MS with educational attainment.

In an accompanying editorial from Lauren B. Krupp, MD, and  Leigh E. Charvet, PhD, the pair acknowledged that an increased awareness in the pediatric development of MS, and that those patients can experience cognitive-related difficulties, ought to lead to more rapid interventions.5

“A major advance in the management of MS has occurred with the advent of more effective treatments for individuals of all ages, and those with pediatric-onset are being identified and treated more promptly than in the past,” Krupp and Charvet wrote. “Additional research is necessary to determine whether these advances will lead to better long-term outcomes compared with those of patients treated in an earlier era.”
REFERENCES
1. McKay KA, Manouchehrinia A, Berrigan L, Fisk JD, Olsson T, Hillert J. Long-term cognitive outcomes in patients with pediatric-onset vs adult-onset multiple sclerosis. JAMA Neurol. Published online June 17, 2019. doi: 10.1001/jamaneurol.2019.1546.
2. Waldman A, Ness J, Pohl D, et al. Pediatric multiple sclerosis: clinical features and outcome. Neurology. 2016;87(9)(suppl 2):S74-S81. doi: 10.1212/WNL.0000000000003028
3. 14. Pfeifenbring S, Bunyan RF, Metz I, et al. Extensive acute axonal damage in pediatric multiple sclerosis lesions. Ann Neurol. 2015;77(4):655-667. doi:10.1002/ana.24364
4. Ozakbas S, Kaya D, Idiman E. Early onset multiple sclerosis has worse prognosis than adult-onset multiple sclerosis based on cognition and magnetic resonance imaging. Autoimmune Dis. 2012;2012:563989. doi: 10.1155/2012/563989.
5. Krupp LB, Charvet LE. Long-term cognitive consequences for patients with pediatric-onset multiple sclerosis. JAMA Neurol. Published online June 17, 2019. doi: 10.1001/jamaneurol.2019.0847