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Paediatric MS

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No cognitive disadvantage in paediatric- vs adult-onset MS(12/09/14)

A new study suggests no cognitive disadvantage in the long term for patients with multiple sclerosis (MS) that began in childhood vs those with adult-onset disease.

Researchers are reporting that overall, cognitive outcomes were similar between the groups and that there were actually fewer patients in the paediatric-onset group, matched with adult-onset patients for age and education, who were classified as cognitively impaired. However, the difference between groups was not statistically significant.

"Since disease onset in a period of active brain growth and maturation may render pediatric-onset subjects more vulnerable to cognitive issues, our findings suggest good compensatory/recovery abilities in these subjects, possibly related with enhanced brain plasticity in early life," the researchers, with lead author Bahia Hakiki, from the University of Florence, Italy, concluded.

Dr. Hakiki presented their findings here at MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS).

Brain Plasticity

Paediatric-onset MS represents 3% to 5% of the overall MS population and "poses unique diagnostic and therapeutic challenges," she noted. Compared with patients developing adult-onset disease, pediatric patients have relapsing-remitting disease course at onset in more than 90% of cases, have higher clinical and MRI disease activity, and have a slower rate of disability accumulation, although disability is still seen at a younger age.

Cognitive issues are "particularly relevant" in this population, she added, because disease occurs during key periods of brain growth, active primary myelination, maturation of neural networks, and key academic training years. "But on the other hand, brain plasticity and recovery may be more efficient in this group," Dr. Hakiki said. "For this reason, final outcome of cognitive performance can be evaluated only in the long term."

Previous studies suggest a prevalence of cognitive impairment in paediatric-onset disease of 30% to 50%, with a neuropsychological pattern similar to that seen in adult-onset MS, including particular involvement of attention, information-processing speed, learning and memory, executive function, and visuospatial abilities, she noted. "Moreover, it has some peculiar aspects of cognitive impairment," she said, with involvement of linguistic skills, which is spared in adult-onset MS, and sometimes an effect on genera intelligence.

The aim of this study, then, was to determine whether the cognitive effects in adulthood are worse among paediatric-onset vs adult-onset cases and, if so, to what extent. They also looked to see whether they could identify any predictors of compensatory abilities in the paediatric-onset patients.

To do this, they compared cognitive performance between 2 groups of adults with MS: 1 that had paediatric-onset disease and 1 with adult-onset disease. Patients were matched for age, education, relapsing-remitting disease course, and scores on the Expanded Disability Status Scale. Patients with a history of conditions that would be expected to interfere with cognition, such as head trauma, learning disability, or drug and alcohol abuse were excluded.

All participants underwent neuropsychological assessment using Rao's Brief Repeatable Battery (which assesses learning memory, visuospatial abilities, attention and information-processing speed, and verbal fluency) and the Stroop test (which gauges executive function). Depression was also assessed by using the Montgomery-Asberg Depression Rating Scale and fatigue by using the Fatigue Severity Scale. Significant cognitive impairment was defined as failure on more than 2 cognitive tests.

Ongoing analyses include basal IQ, assessment of leisure activities, and parental education, Dr. Hakiki noted, which should allow the investigators to estimate cognitive reserve in the participants.

In addition to cognitive testing, conventional MRI was done, assessing T1 and T2 lesion volume as well as brain volume, white matter volume, and cortical volume. Resting-state functional MRI is ongoing in these groups.

For this analysis, the authors compared 30 adult-onset patients (9 men and 21 women) with 14 paediatric-onset patients (8 men and 6 women), with an average age of 25 and 27 years, respectively. As expected, the duration of disease was longer in the paediatric-onset patients than the adult-onset patients: 9.8 years vs 3.7 years. They were well matched in terms of EDSS scores, disease course, and use of disease-modifying therapies, she noted.

Less Cognitive Impairment

No difference was found between the groups in terms of mean scores on the neuropsychological tests or in the number of tests failed, Dr. Hakiki reported. Interestingly, more patients in the adult-onset group than the paediatric-onset group met criteria for cognitive impairment: 27% vs 14%. No differences were found in measures of fatigue or depression.

The cognitive profile across tests was similar between the 2 groups, she said, "showing a prominent involvement of tests exploring information processing speed, followed by tests exploring executive function and memory."

In a subset of 22 patients who underwent MRI (11 pediatric and 11 adult-onset patients), the paediatric-onset patients showed a nonsignificant trend toward higher white-matter lesion load, but no differences were seen between the groups in terms of brain volumes.

"The comparable brain volumes, despite a longer disease duration and tendency to accumulate more lesions, may suggest a greater repair capability in these patients," Dr. Hakiki concluded.

Going forward, they hope to extend the study sample, complete the assessments of cognitive reserve as well as MRI analysis, and then integrate the cognitive and MRI data, she said.

Brenda L. Banwell, MD, chief of neurology at the Children's Hospital of Philadelphia, Pennsylvania, who comoderated the Young Investigators session where these results were presented, pointed out that the age at onset for the paediatric-onset patients was 15.6 ± 2.1 years.

"The resiliency to cognitive impairment may be very different of course in patients who start much younger," Dr. Banwell said. "Obviously you can't address that in this cohort, and you only had 14% cognitive impairment, which is what about half of studies that included younger kids have shown. Are you going to repeat this now with younger-onset patients?"

Dr. Hakiki noted they are planning to include younger-onset patients in the extended study sample to address this question.

Dr. Banwell told Medscape Medical News that both groups were relatively intact even though the paediatric-onset patients had a longer disease duration.

"The low proportion of impaired patients limits the ability to correlate with imaging," she noted. "Further work in a larger group whose MS onset occurred at a younger age — especially prepuberty — would be of great value."

Primary Source: MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract YI2.3. Presented September 10, 2014.

Source: Medscape Multispeciality © 1994-2014 by WebMD LLC (12/09/14)

Severe optic nerve damage in MS not a hurdle to some children(12/09/14)

There is a clear subset of pediatric patients with demyelinating disease who have substantial damage to the nerve layer in the retina but nevertheless have no vision loss, a new study shows.

"Understanding how this subset of patients recover functionally after optic nerve damage could lead to great insight into best acute treatment options and a better understanding of brain plasticity and neural networking," lead author Samuel Hughes, BS, UT Southwestern Medical Center, Dallas, Texas, concluded.

"We need to analyse other variables in these children, including age, sex, time to acute treatment, and type of treatment to see if we can shed light on how this is occurring."

He presented their findings here at MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.

"This is a really crazy cohort of kids that no one has identified before who can see normally but from looking at their retina they should be blind," Hughes said.

"Maybe there is some kind of mechanism that children have but adults don't to compensate for the loss of nerve fibres in the retina," he speculated. "We need to understand better what it is about these children that helps them recover functionality. Something could be happening in the visual cortex of the brain causing it to rewire."

He added that this could have implications for understanding neural networking and finding treatments for the adult population with demyelinating disease. "If we could pinpoint what is happening in the brains of these children we may be able to figure out some functional stimulation to enhance that process."

Cochair of the session at which the study was presented, Patrick Vermersch, MD, PhD, Centre Hospitalier Régional Universitaire de Lille, France, called this an "interesting observation. It certainly appears that the optic nerve in some children is more resilient than in adults. We need to learn why this is the case," he told Medscape Medical News.

As background, Hughes noted that in adults visual acuity (especially low contrast) correlates to retinal nerve fiber layer thinning as measured by optical coherence tomography (OCT), and a threshold of 75 microns predicts persistent visual dysfunction. But these measures have not been well established in children.

For the current study, OCT data and corresponding visual acuities were obtained from a total of 378 eyes of children with demyelinating disease, including multiple sclerosis, acute disseminated encephalomyelitis, or idiopathic optic neuritis.

Results showed that while there was a relationship between the thickness of the retinal nerve layer and visual acuity in most patients, a small subset of 9 eyes had a very thin retinal nerve layer (55 to 59 microns) but the patients had normal high and low visual acuity.

Hughes noted that it is important to validate the normative data in the pediatric population.

"OCT is well validated in adults. It is a ubiquitous tool for understanding optic nerve damage and is starting to be used as a proxy for disease progression. It is being used in the pediatric population but our data begs the question that we may need different parameters in children."

MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) Meeting. Abstract Y12.4 Presented September 10, 2014.

Source: Medscape Multispeciality © 1994-2014 by WebMD LLC (12/09/14)

Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research(19/08/14)

Amy Waldman MD, Prof Angelo Ghezzi MD, Amit Bar-Or MD, Yann Mikaeloff MD, Prof Marc Tardieu PhD, Prof Brenda Banwell MD

Summary

The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years.

National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis.

The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume.

Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis.

Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.

Source: The Lancet Neurology, Volume 13, Issue 9, Pages 936 - 948, September 2014 Copyright © 2014 Elsevier Ltd (19/08/14)

Children with MS have higher disease activity but better myelin repair than adults(14/04/14)

Quantitative determination of regional lesion volume and distribution in children and adults with RRMS.

Abstract

INTRODUCTION: Onset of MS occurs during childhood in about 5% of cases. It is unclear whether very young age at MS onset, when the nervous system is still myelinating, affects MS lesion accrual or regional distribution.

OBJECTIVE: To compare the frequency, volume and distribution of T2 and T1 lesions in children and adults with relapsing-remitting multiple sclerosis (RRMS).

METHODS: Lesions were segmented on T2- and T1-weighted MRI images from 29 children and 29 adults with RRMS, matched for disease duration.

RESULTS: All subjects exhibited T2-weighted brain lesions. Children had higher whole-brain T2-weighted-lesion-volume (T2LV) compared to adults (mean (SD) in cm(3): 12.76(2.7) vs. 10.03(3.4), p<0.0013). The supratentorial-T2LV was similar in children and adults (8.45(1.7) vs. 7.94(1.7), mean (SD), p?=?0.2582), but adults were more likely to have supratentorial lesions (96.5% vs. 68.9%, p<0.012). Children were more likely to have infratentorial-T2-weighted lesions (75.9% vs. 43.4%, p<0.03), specifically in the brainstem (62.1% vs. 26.7%, p<0.019) and the pons (48.3% vs. 17.24%, p<0.024), had higher infratentorial-T2-weighted-lesion counts (4.1(5.6) vs. 1.45(2.3), p<0.021), a greater infratentorial-T2LV (4.31(2.7) vs. 2.08(2.4), p<0.0013), and a greater infratentorial-T1-weighted-lesion-volume (T1LV) (3.7(2.5) vs. 1.08(1.9), p<0.0007). Whole-brain-T1LV was higher in children (9.3(2.5) vs. 6.43(2.1), p>0.001). Adult MS patients had higher supratentorial-T1LV (5.5(0.92) vs. 6.41(2.1), mean (SD), p<0.034), whereas children were more likely to have infratentorial-T1-weighted lesions (58.6% vs. 23.3%, p<0.015).

DISCUSSION: Onset of MS during childhood is associated with a higher volume of brain lesions in the first few years of disease relative to adults. Children with MS are more likely than adults to have T2 and T1 lesions in the infratentorial white matter, raising the possibility of preferential immune targeting of more mature myelin. Children with MS have a lower supratentorial T1 lesion burden, possibly reflecting more effective remyelination and repair in brain regions that are still engaged in active primary myelination.

Ghassemi R, Narayanan S, Banwell B, Sled JG, Shroff M, Arnold DL; Canadian Pediatric Demyelinating Disease Network.

Full Article  

Source: PLoS One. 2014 Feb 26;9(2):e85741. doi: 10.1371/journal.pone.0085741. eCollection 2014. & PMID: 24586244 (14/04/14)