Childhood multiple sclerosis often goes undetected but Lucy Wood's early diagnosis at the age of five has been crucial in reducing her disability over time.
A photograph of 11-year-old Lucy Wood taken last September shows her smiling in her new uniform, ready for her first day at secondary school. In another photo she is wearing the same smile but is hooked up to a hospital drip as she receives her monthly dose of Tysabri, the drug that controls her multiple sclerosis.
Diagnosed with MS at the age of five, Lucy is one of fewer than 10 per cent of patients who suffer their first symptoms in childhood: most of the 100,000 people with the disease in the UK develop it in their 20s and 30s. She was lucky, however, to receive an early diagnosis. New research from the University of Manchester has found that childhood MS often goes undetected, sometimes for years.
According to lead author Professor Susan Kirk, the delay is due to “low levels of awareness in the general public and doctors about the existence of childhood MS,” as well as there being only “a small group of paediatric neurologists with the necessary expertise to make the diagnosis.”
While some 125 children under 15 in the UK experience a first MS-like “attack” each year – commonly a problem with vision - only around 20 per cent subsequently develop paediatric MS.
Doctors do not know why an initial attack is followed by further attacks in some children but not in others.
Lucy, from Peterlee in county Durham, was three when she experienced a temporary loss of vision in her left eye. Doctors suspected a rare nervous system disease called ADEM (Acute Disseminated Encephalomyelitis), which can cause similar symptoms to MS and which was successfully treated with steroids. Further problems with Lucy’s vision, balance, coordination and speech followed, but her parents were still told MS was unlikely. This was even though Lucy’s father, Stuart, 46, had been diagnosed with MS aged 27 – and having a parent with MS increases the risk from 1 in 600 to 1 in 50.
“We were told MS was incredibly unusual at Lucy’s age, but to me it was like watching Stuart develop the disease all over again. We became convinced our daughter had it,” says Sharon, 45, Lucy’s mother. An MRI scan in August 2008 confirmed Lucy’s parents’ worst fears.
“We expected it but it still felt like a bombshell,” says Sharon. “Stuart blamed himself, believing he must have passed it on. In the end, Lucy’s positive attitude helped him accept it.” The couple’s other daughter, Katie, 17, shows no signs of MS.
Lucy experiences fatigue and sometimes needs to use a wheelchair. But Tysabri, prescribed four years ago to help dampen the immune system’s attack on myelin, has been “life changing”, says her mother.
Dr Cheryl Hemingway, a consultant paediatric neurologist at Great Ormond Street Hospital, runs one of the largest clinics in the country for children with MS and other rare myelin-attacking disorders. Early diagnosis is crucial, she says, for reducing the accumulation of disability over time and enabling children to “get on with their lives.”
Source: The Daily Telegraph © Copyright of Telegraph Media Group Limited 2015 (11/05/15)
Researchers in Denmark say children who have gone through a divorce could be at a slightly increased risk of developing multiple sclerosis.
The study, Stressful Life-Events In Childhood And The Risk Of Multiple Sclerosis: A Danish nationwide Cohort Study, looked at the cases of 2.9m Danes born between 1968 and 2011. A stressful life event (SFLE) was classed as divorce, parental death or the death of a sibling before the age of 18. MS cases in the cohort were identified in the Danish Multiple Sclerosis Registry. Associations of SFLE with MS risk were evaluated by incidence rate ratios (RR) of MS obtained in log-linear Poisson regression models.
Researchers found people exposed to any SFLE in childhood were at 11 per cent elevated risk of MS, compared to the “non-exposed”. Stratification by subtype of SFLE showed parental death and death of a sibling were not associated with MS risk. However, those exposed to divorce were at 13 per cent increased risk of developing MS compared to the “non-exposed”.
Source: University Of Southern Denmark (11/05/15)
Although the number of paediatric patients with multiple sclerosis has increased over the years, researchers recently revealed one of the first studies to offer population-based information.
Data from the Paediatric Health Information System (PHIS) has been presented at the 2015 annual meeting of the American Academy of Neurology in Washington, DC. Lead author Amy M. Lavery, MSPH, and her Department of child neurology in the Children’s Hospital of Philadelphia colleagues worked to shed light on a subject that doesn’t have a firm backing of research results.
The authors wrote that since “literature is lacking with respect to overall disease” when it comes to paediatric MS, it was time to “examine the prevalence of hospital admissions.”
From 2004 to 2013, the database revealed inpatient visits, emergency department encounters, and charges encountered from 44 children’s hospitals in the United States. The findings showed a trend in hospital visits among the affected children.
The 1,422 patients – made up of twice as many females – found in the database collectively had 2,068 hospital encounters and stayed for an average of 4 days. In 2004 paediatrics MS patients checked into the hospital an average of 2.37 times, however, that number jumped to 4.13 in 2013. Also, for every 10,000 hospital check-ins the cause associating with MS has increased from 3.47 to 5.95. The reason behind the rate surge, the authors noted, could be attributed to the addition of paediatric MS centres and awareness.
“A test for trend showed a steady, significant increase in encounters for MS,” the team said, which raises the question if that number will continue to grow. For children ages 11 and younger, the amount of MS cases has stayed the same while ages 11 to 15 and 15 and older has steadily increased. This study may be one of the first to address paediatric MS hospitalisations, however, it won’t be the last.
“Further analyses will incorporate pharmacy data and investigate factors contributing to healthcare utilization and hospital admission rates,” the study concluded.
Source: MS All Specialities Copyright HCPLive 2006-2015 Intellisphere, LLC (23/04/15)
Brain volumes in children with multiple sclerosis (MS) were smaller than in those without the disease due to a lack of age-expected brain growth and progressive atrophy, researchers reported.
Using longitudinal MRI data from patients with relapsing-remitting MS onset prior to age 18, Berengere Aubert-Broche, PhD, of McGill University in Montreal and colleagues noted that "significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes (P<0.10-4)." They also found that T2 lesion volume correlated with a greater reduction in age-expected thalamic volume compared with children without MS.
The findings provide compelling evidence that neurodegeneration is an early aspect of MS pathology, rather than a late effect of chronic disease, they wrote in Neurology.
"The marked impairment in age-expected growth and the subsequent brain atrophy indicates a clear failure of the anticipated resiliency of the maturing central nervous system to the brain injury mitigated by MS," they stated.
In previously reported cross-sectional analyses, patients with MS presenting before age 18 had reduced thalamic and brain volumes relative to their age- and sex-matched healthy peers.
"As MS is a chronic progressive illness, and childhood and adolescence are key periods of brain growth, longitudinal analysis is required to define the impact of MS disease on brain development, in order to determine whether these differences in brain volumes are due to failure of normal age-related brain growth or to progressive loss of volume, or both," the researchers wrote.
The current study included 185 scans from 36 children diagnosed with MS and 50 scans from 25 healthy children without MS.
Whole-brain and regional volumes were segmented in the MS patients (two to 11 scans per participant with 3-month to 2-year scan intervals). MRI scans of the 25 age-and sex-matched healthy controls were acquired at baseline and 2 years later using the same scanner as that used in the MS group.
A total of 874 scans from 339 pediatric participants in an NIH-funded MRI study of normal brain development acquired at 2-year intervals were also used as an age-expected healthy growth reference, and all data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures.
Mixed-effect models were built using age, sex, and group as fixed effects. The models were built using the MS and NIH brain development study groups. The MS group was also subdivided to study the impact of the age at onset of T2 lesion volume on growth. The MS group was divided into two groups by age of onset -- age
For a second model, the researchers computed a ratio of lesion volume to brain volume for each scan, where the total T2 infratentorial and supratentorial lesion volumes defined the lesion volume. They selected a threshold of 5 cm3 lesion volume to separate the MS cohort into two groups: a minimal lesion volume group and higher lesion volume group.
"The 5 cm3 threshold corresponds roughly to a 0.35% lesion-to-brain ratio," the researchers wrote. "Patients who have all scans with a lesion-to-brain ratio less than 0.35% fall into the minimal lesion group, and patients who had one or more scan with the lesion-to-brain ratio greater than 0.35% define the higher-lesion group."
Significant group and age interactions found with the adjusted models fitting brain volumes and normalized thalamus volumes "indicate a failure of age-normative brain growth for the MS group, and an even greater failure of thalamic growth," the researchers wrote.
A clear difference was seen in the growth trajectories between male and female participants and between the MS and NIH growth study groups. Growth in brain volume and normalized thalamic volume was significantly attenuated in the MS group relative to the NIH brain study group, as was growth in the normalized globus pallidus.
MS and Thalamus Growth
Looking at the impact of age-at-onset and the lesion volumes on growth curves, the authors reported that brain or internal structures mean models did not differ significantly between the patients with MS with onset before age 11 years and the patients with MS with onset after age 11 years.
Using the arbitrarily selected threshold of 5 cm3 as an indicator of low lesion volume, which represents approximately 0.35% of the normalized brain volume in a 1,400 cm3 brain, the brain, normalized caudate, putamen and globus pallidus mean models did not differ significantly between patients with MS who had at least one scan with a lesion-to-brain ratio exceeding 0.35% versus patients with MS with low lesion volumes, they explained.
There was a significant group difference between the NIH study group, minimal lesion volume MS group, and high lesion volume MS groups in the thalamus longitudinal fitting models, where higher lesion lead was associated with significantly smaller thalamic volumes over time.
"The low normalized thalamus volumes in the MS group compared to the (NIH study group) indicate that the thalamus is more impacted by the disease than the brain overall," the researchers wrote. ""Vulnerability of the thalamus has also been noted in in adult-onset MS cohorts, in which loss of volume in the thalamus is one of the earliest and most prominent signs of subcortical gray matter pathology, evident even at the time of a first attack."
They noted that further research is needed to determine how the findings impact cognitive performance and whether the trajectories of cognitive function will mirror changes in brain volume over time.
They also pointed out that the findings have implications for the study of MS pathobiology and treatment options, suggesting that neuroprotective strategies may need to be implemented as early as possible following an MS diagnosis.
In an accompanying editorial, Tanuja Chitnis, MD, of MassGeneral Hospital for Children in Boston, and Mark Gorman, MD, of Boston Children's Hospital, wrote that the results have important implications for patients with pediatric MS.
The study also demonstrates for the first time the effect of a chronic inflammatory demyelination disease during a critical window of central nervous system and cognitive development, they noted.
The finding that thalamic growth is impaired in children with MS prior to significant physical disability "reinforces the importance of closely monitoring cognitive outcomes, which were not included in this study, but were evaluated by the same group in separate work demonstrating the correlation of thalamic volume and cognitive impairment in children with MS," Chitnis and Gorman wrote.
They noted that future clinical trials should include whole-brain and thalamic atrophy measures to assess the potential benefit of disease-modifying treatments in pediatric MS.
The study was funded by the Canadian Institutes of Health Research and the Canadian Multiple Sclerosis Scientific Research Foundation.
Aubert-Broche disclosed no relevant relationships with industry.
Some co-authors disclosed relevant relationships with NeuroRx Research, Teva Neuroscience Canada, Biogen Idec Canada, Coronado Biosciences, Consortium of Multiple Sclerosis Centers, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MS Forum, NeuroRx Research, Novartis, Opexa Therapeutics, Roche, Merck Serono, Serono Symposia International Foundation, Canadian Institutes of Research Health, and Multiple Sclerosis Society of Canada.
Chitnis disclosed relevant relationships with Merck-Serono, Biogen-Idec, Novartis, National MS Society, Peabody Foundation, Guthy-Jackson Charitable Foundation, and the NIH.
Gorman disclosed no relevant relationships with industry.
Primary source: Neurology
Source reference: Aubert-Broche B, et al "Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth" Neurology 2014; DOI: 10.1212/WNL.000000000000.1045.
Additional source: Neurology
Source reference:Chitnis T, Gorman M "Impact of MS during the critical window of brain development" Neurology 2014; DOI: 10.1212/WNL.0000000000001056
Source: MedPage Today © 2014 MedPage Today, LLC. (02/12/14)
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).
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)
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
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)