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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