Wednesday, June 12, 2019

Long-term disability progression of pediatric-onset multiple sclerosis


McKay KA, Hillert J, Manouchehrinia A. Long-term disability progression of pediatric-onset multiple sclerosis. Neurology. 2019 Jun 11;92(24):e2764-e2773.doi: 10.1212/WNL.0000000000007647. Epub 2019 May 15.

Abstract

OBJECTIVE:
To evaluate long-term disability progression in pediatric-onset multiple sclerosis (POMS) and compare to adult-onset multiple sclerosis (AOMS).

METHODS:
This was a retrospective cohort study using prospectively collected clinical information from the Swedish MS Registry. Clinical features were compared and Kaplan-Meier and Cox proportional hazards regression were used to assess the risk of reaching sustained Expanded Disability Status Scale (EDSS) 3, 4, and 6 in POMS (multiple sclerosis [MS] onset <18 years) and AOMS (MS onset ≥18 years).

RESULTS:
A total of 12,482 persons were included; 549 (4.4%) were classified as POMS. The POMS cohort took longer to reach all 3 disability milestones from their MS onset, but did so at a younger age than the AOMS cohort. Primary progressive course (hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.46-14.7), higher relapse rate in the first 5 years of disease (HR 5.35; 95% CI 3.37-8.49), and complete remission from the initial relapse (HR 0.41; 95% CI 0.18-0.94) were associated with an altered risk of progression to EDSS 4 among POMS cases. The same pattern emerged for the risk of reaching EDSS 3 and 6.

CONCLUSIONS:
Patients with pediatric-onset MS follow a distinctive clinical course, which should be considered in the treatment and management of the disease.
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“POMS [pediatric-onset multiple sclerosis] differed from adult-onset cases in several ways, including an increased diagnostic delay and relapse rate and a higher proportion of cases with relapsing-onset MS,” researchers reported in the May 15 online edition of Neurology. “While the POMS cohort took longer to reach disability milestones from their MS onset, they did so at a younger age than the AOMS [adult-onset MS] cohort.”

The findings, which align fairly closely with previous smaller studies on the clinical course of pediatric MS, provide a decades-long view of a disease that usually strikes later in life, often in early adulthood. Pediatric-onset MS accounts for anywhere from 2 to 10 percent of all MS cases, according to background in the study…

“Persons who develop MS early in life appear to be vulnerable to heightened inflammation and axonal loss,” the study authors said. “At the same time, their younger age may provide protection through the brain's enhanced compensatory abilities.”…

Pediatric-onset patients with a higher annualized relapse rate in the first five years of disease were more likely to reach all three disability milestones, while those who had a complete remission from the initial relapse were less likely to reach EDSS 3, 4, and 6. Having a progressive course of disease at onset was associated with an elevated risk of disability compared to relapsing disease.

While overall trends aligned fairly closely with previous research, the researchers noted that the median time of 31 years from pediatric onset to EDSS 4 was much better than previous reports of 10.8 to 23.8 years.

“Disease progression appears to be slower than we previously thought,” study coauthor Kyla McKay, PhD, a postdoctoral researcher at Karolinska Institutet told Neurology Today in an email…
The new study hints that MS drugs may be making a difference. In a multivariate analysis of pediatric-onset cases, the researchers found that use of a second-line DMT was associated with a reduced risk of reaching EDSS 3 and 4, and they noted that “it's possible that DMT use has contributed to the extended period of time before reaching disability thresholds.”

But Dr. McKay reiterated a point made in the paper, that “this study was not designed to measure treatment effectiveness, nor the impact of interventions on disease outcomes.” Because of that, she said she could not comment “on disease management based on findings from this study.”

Dr. McKay said there is still much to be learned including “the longer-term socioeconomic consequences of pediatric-onset MS, the long-term effects of disease-modifying therapy exposure in terms of safety and effectiveness, as well as risk factors for the development of MS in childhood.”

Independent MS experts interviewed by Neurology Today said the new analysis of the Swedish registry data, which was collected during a time of changes in MS care, should help enhance the understanding of the expected course of pediatric-onset MS and perhaps provide some comfort to patients and families. And for the most part, they said it supports treating these children with early, aggressive therapy. 

“I think the optimistic message is that the time from the first attack to measurable disability is long,” said Brenda Banwell, MD, FAAN, chief of child neurology at The Children's Hospital of Philadelphia. At the same time, “the data show that patients with early relapses have an increased risk of disability, which emphasizes the importance of early treatment.”…

“The relapse rate in children is higher than in adults so it is even more pivotal to treat early,” she said. But she does not make light of safety considerations associated with the newer MS medications.

“I think we all use medications humbly, knowing we have to follow patients carefully,” Dr. Banwell said.

Leslie Benson, MD, assistant director of pediatric neuro-immunology at Boston Children's Hospital, said the findings from the Swedish registry raise some interesting questions that MS researchers like herself are interested in, including “why do kids recover better (from relapses) and take longer to hit EDSS landmarks.” She said kids may heal differently than adults from attacks, with their brains perhaps better able to rewire or develop work-around solutions.

When it comes to the use of second-line therapies, she said she tends “to be on the conservative side because these are young people with developing immune systems.”…

Emmanuelle Waubant, MD, PhD, FAAN, professor of neurology and pediatrics at University of California, San Francisco, said pediatric-onset MS “takes place during a very demanding time of life,” with challenging demands such as multitasking, and learning new material and skills in school.

She said that “cognitive problems related to MS with childhood onset can impair the ability to be successful in school and later become young adults with productive jobs.”

Dr. Waubant, director of the pediatric MS program at UCSF, said she is among the physicians who tend to treat pediatric MS aggressively early on, hoping to slow or prevent long-term impairment, and said evidence is starting to emerge from clinical trials on both the efficacy and tolerability of higher efficacy therapies in children…

She said what caught her eye the most in the new report was that “when they (researchers) did the regression analysis, going on a high-efficacy medicine was associated with a better outcome in the long run.” She said that suggestion supports her own tendency to favor aggressive treatment for pediatric patients.

Dr. Krupp said a conundrum that all doctors who treat MS face is that “at the moment we are not that great at figuring out who is going to do well and who is not. I can't say who is going to remyelinate, who can compensate, who can rewire.”


She said that her clinical experience has led her to believe that she'd rather over treat and assume the risk of possible a medication side effects, than leave a child at heightened risk of the life-long consequences of neurologic damage.


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