Cover Story: Pediatric MS
Disease Course, Diagnosis, Treatment Options, and Overall Wellness
By Tom Garry, Medical Writer
Edited by Susan Wells Courtney, MSAA Senior Writer
Reviewed by Barry A. Hendin, MD, MSAA Chief Medical Officer
The last few years have seen plenty of welcome news regarding pediatric multiple sclerosis (MS). In 2018, Gilenya® (fingolimod) became the first disease-modifying therapy (DMT) approved by the United States Food and Drug Administration (FDA) for use in children and adolescents. Several other DMTs already approved for use in adults are in late stages of evaluation for pediatric MS. Researchers are investigating a role for stem-cell therapy, and are pursuing new classes of drugs that would restore the nerve-protecting myelin sheath that becomes damaged in MS. Experts report that the average time from onset of symptoms to diagnosis of pediatric MS is declining, which means that the medical community is considering the possibility of an MS diagnosis in young patients at an earlier time. Clinicians have more knowledge than ever about the course of MS in children and adolescents, risk factors for relapse, how to manage symptoms, and other aspects of medical management.
Mary Karpinski, LMSW, reviews those encouraging developments when she meets with the parents of a young person recently diagnosed with MS, but the most reassuring message she delivers concerns something that can’t be seen on magnetic resonance imaging (MRI) or quantified in an annualized relapse rate. “I remind parents that children are incredibly resilient. I explain that I’ve found young people with MS to be particularly strong, and that they can get through pretty much anything so long as parents give them the building blocks to succeed, and do not let their own worries lead them to impose well-intentioned but overly restrictive limits on what their child can do.”
Ms. Karpinski speaks from considerable experience. For the past 13 years she has served as the single point of access for young people with MS receiving care at the Pediatric MS Center of the UBMD Neurology/Jacobs Neurological Institute of the University at Buffalo. “I’ve been privileged to work with and assist many young people with MS as they’ve moved from childhood into adulthood. When parents first learn that their child has MS, one of the questions they inevitably ask is, ‘What will the future hold?’ I tell them about the many young people I’ve worked with who have earned college degrees, married, built meaningful careers, and had children of their own. Some have faced more challenges than others, and everyone’s path is different, but these children – and their parents – are the most inspiring people I have met,” the social worker says.
This cover story examines the progress that has been made in helping these young people deal with MS, developments on the near horizon, the key unanswered questions about pediatric MS, and experts’ advice on enhancing the health and quality of life for young people with MS.
Latest information about the course of pediatric MS
Exploring how – and why – pediatric MS is similar to and different from MS in adults has been a major focus of researchers. These investigators are analyzing the commonalities and contrasts for insights into everything from the factors that trigger the onset of MS in young people, to the way therapies approved for use in adults are likely to affect the course of MS in children and adolescents.
While relapsing-remitting MS is by far the most common form of the disease in newly diagnosed adults, it appears to be even more predominant in children and adolescents, representing 93% or more of all pediatric cases.1 Meanwhile, researchers at Partners Multiple Sclerosis Center in Boston have found that young people have relapses two to three times more often than adults, and that this difference persists over at least the first six years from onset of symptoms.2, 3 However, there is evidence that young people generally recover from relapses more quickly than adults.4
Research suggests that pediatric-onset MS takes longer to diminish physical abilities than does adult-onset MS, and also is slower to develop into secondary-progressive MS. British researchers who examined long-term outcomes in more than 2,000 MS patients found that those who developed the disease before 18 years of age, took on average, 23.8 years to reach an Expanded Disability Status Scale (EDSS) score of 4 (on the scale, 0 represents no disability, while progression toward higher numbers leading up to 10, indicates increasing disability) versus 15.5 years for people who developed MS as adults. Similarly, time to development of secondary-progressive MS was 32 years for pediatric-onset patients and 18 years for adult-onset patients.5
Conversely, compared to adult-onset MS, pediatric-onset MS appears to have a greater impact on cognitive function in the years following onset of symptoms.5, 6 Italian investigators who studied 48 pediatric MS patients found that 31% had some degree of cognitive impairment on initial evaluation, and that this proportion increased to 38% over five years.7, 6 Meanwhile, a recent study of more than 5,700 adults with MS found that those who developed the disease as children or adolescents were roughly 1.5-times more likely to have cognitive impairment in adulthood than people whose symptoms began when they already were adults, and that this increased risk was independent of the person’s age or duration of MS.8
Given these findings, Emmanuelle Waubant, MD, recommends neuropsychological testing of children and adolescents who are newly diagnosed with MS. “Getting a baseline is very helpful, and can help inform approaches to working with the child’s school and other aspects of comprehensive care,” explains Dr. Waubant, a professor of neurology at the University of California, San Francisco (UCSF) with extensive clinical and research expertise in pediatric MS. She advises follow-up testing two-to-three years later, unless a concern in the interim warrants earlier re-evaluation.
Ms. Karpinski notes that the testing can help parents identify areas of strength and need – and, as a result – better understand the challenges their child may be facing, set realistic expectations, and advocate effectively for their son or daughter. She adds, however, that it is important for parents to meet with the specialist who evaluated their child to review the test results and their implications. “The reports containing the test results can be difficult to read, both in terms of the technical language employed, and sometimes, in terms of what the evaluation identified. Rather than trying to puzzle that out on their own, parents should sit with the specialist and get the background needed to avoid misunderstandings and put the results in context,” she says.
Parents also need to be aware of the heightened presence of anxiety and mood disorders in young people with MS, and to include mental-health professionals in their care team, as needed, Ms. Karpinski adds. A study of 23 young people aged 6 to 17 who had MS or another demyelinating disorder found that 48% met the criteria for a psychiatric diagnosis, with almost one-third having anxiety disorders and about 10% having depression.9 Another study, this one involving 45 young people, found that cognitive impairment is more common among pediatric MS patients with mood and anxiety disorders than among those without a psychiatric diagnosis. Eighty percent of the study participants who had been diagnosed with an anxiety disorder, a depressive disorder, or attention-deficit hyperactivity disorder (ADHD), had evidence of cognitive impairment. By contrast, 55% of the 20 participants who did not have a psychiatric disorder demonstrated cognitive impairment on testing.10
In exploring why the course of pediatric MS often differs from that of adult MS, researchers have noted that disease onset in young people is marked by a higher disease burden and more disease activity on MRI than is seen in adults. In a study of 41 individuals with pediatric-onset MS and 35 individuals who developed MS as adults, Dr. Waubant and colleagues found that the children had a median 21 T2-bright lesions, as opposed to six in adults, and had more T2-bright areas generally and focal points in enhancing lesions, indicating greater disease activity.11 Another study involving 19 children and 12 adults with MS found that the pediatric patients hadw more extensive acute damage to the axons that carry electrical impulses from the central nervous system’s main type of cell, the neuron.12 Those and other findings suggest that pediatric MS is more inflammatory in nature than adult-onset MS.13
Meanwhile, another age-related aspect of MS may offer important insights into factors contributing to onset of disease. While less than 1% of all cases of MS develop before age 10 to 12 years, the condition affects boys and girls in that age group in roughly equal proportion. By age 12 and older, however, the female:male ratio in pediatric MS shifts to 2.8:1, a gender split similar to that seen in adult-onset patients.1 Tanuja Chitnis, MD, a professor of neurology at Harvard Medical School and pediatric MS expert at Massachusetts General Hospital and Brigham and Women’s Hospital in Boston, noted in a 2013 article that this shift suggests a role for puberty in MS risk.14
Progress in making a timely diagnosis
E. Ann Yeh, MD, MA, FCRPC, says that just 15 years or so ago, the main challenge in diagnosing pediatric MS wasn’t necessarily obtaining an MRI to see what was happening in a child’s brain. Rather, she explains, the bigger issue often was what was not happening in a doctor’s brain.
“Pediatricians, and even child neurologists, just weren’t trained to think in terms of children having MS. We were given the impression in residency and fellowship that MS did not occur in children, or that if it did, it was so rare that MS should not be high on the list of possibilities to consider when a young person presented with symptoms that could reflect a demyelinating event,” recalls Dr. Yeh. Today, as director of the MS and Demyelinating Disorders Program at The Hospital for Sick Children (SickKids) in Toronto, the physician sees dozens of children with MS from across Ontario and nearby Canadian provinces and American states.
Greater awareness that pediatric MS is a real – albeit quite uncommon – condition has contributed to significant improvements in the timeliness and accuracy of diagnosis, according to Dr. Yeh, who is also a senior associate scientist in Neurosciences & Mental Health at SickKids and a professor of pediatrics (Neurology) at the University of Toronto. Factors such as increased access to MRI and the development of a diagnostic pathway by the International Pediatric MS Study Group (IPMSSG) have been particularly important in this regard, notes Dr. Yeh, who estimates that the average child with MS is now diagnosed within about six months of symptom onset.
The IPMSSG guidance is intended to help clinicians evaluate young people who present with indications of a possible acquired demyelinating syndrome, meaning symptoms suggesting that the myelin sheath that coats nerves in the central nervous system has been damaged. Such symptoms may include visual loss, double vision, sensations of tingling or numbness, weakness, abnormal or uncoordinated movements, and urinary issues, similar to adults who develop relapsing-remitting MS.15
Acquired demyelinating syndromes (ADS) in pediatric patients include acute disseminating encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders (NMOSD), clinically isolated syndromes (CIS), and multiple sclerosis.16
Beyond distinguishing between the conditions within that group of disorders, however, pediatric neurologists also need to consider other conditions that may cause the same symptoms seen with demyelinating syndromes.
“The differential diagnosis for pediatric MS is quite broad, and includes a number of ‘MS mimics’ that are different from those that have to be considered when evaluating potential adult-onset MS,” notes Dr. Waubant. To help narrow that differential diagnosis, which essentially is a list of possible causes, the IPMSSG’s 2016 evaluation pathway identifies red flags that suggest a child may not have a demyelinating syndrome.16 The document also recommends a protocol for employing blood tests, assessment of cerebrospinal fluid (CSF), imaging, and other steps to identify specific demyelinating syndromes, including MS.16
The IPMSSG notes that a diagnosis of pediatric MS is warranted when a child or adolescent has two or more episodes presumed to be caused by inflammatory demyelination that do not represent ADEM and that occur more than 30 days apart. The episodes must involve more than one site in the central nervous system. The group also identifies three other, less-common scenarios that justify the diagnosis.16
However, Dr. Waubant notes that an intriguing, related question remains unanswered. “In the last 10 years or so, we’ve tended to see more patients with pediatric MS than we did previously. Greater awareness of the condition and improved diagnosis clearly play roles in this, but we just don’t know whether – beyond those factors – there also has been an increase in the actual number of children and adolescents who are developing MS,” she explains.
Dr. Yeh agrees, and notes that as physicians become more skilled at making an early diagnosis, along with greater patient access to magnetic resonance imaging, the proportion of cases of pediatric MS that go unrecognized will be reduced. According to Dr. Yeh, “We should be able to tell what’s happening.” She adds that even accounting for such issues, “the numbers do seem to be going up.” (See “Risk Factors for Pediatric MS Coming into Sharper Focus.”)
Recent study-based estimates of the incidence – or number of new cases per year – of pediatric MS vary from 0.07 to 2.9 per 100,000 children.15 Even the higher figure in that range represents an extremely small percentage of young people, however, and it is estimated that there are fewer than 5,000 pediatric MS patients in the United States.17
More treatment options and more patients receiving treatment
The FDA has approved 17 DMTs for use in adults with MS. Eight, including the longest-approved agents, are administered by injection, while five are taken orally, and four are infused intravenously. Only one of those medications, the oral-agent Gilenya® (fingolimod), is also approved for use in children and adolescents aged 10 years and older. The FDA expanded Gilenya’s indication to include pediatric MS patients in May 2018.18
Even before that approval, many pediatric MS specialists prescribed DMTs for their patients in an attempt to prevent relapses and disease progression. However, they often proceeded hesitantly because of a lack of data on the agents’ optimal dosing and safety profile in children and adolescents.
Recent years have seen that hesitancy yields to a more pro-active approach, according to Dr. Waubant. “There has been a trend over time to treat pediatric MS more aggressively,” she notes, explaining that several factors are propelling the trend. One, she notes, is growing evidence that early intervention in the MS-disease process can favorably impact not only a patient’s current health, but also long-term well-being. At the same time, clinical trials, observational studies, and patient registries are providing reassuring data about the safety profiles of DMTs in children and adolescents.
Expanded options, particularly in terms of route of administration, also has helped. “Teenagers very often are reluctant to consider agents that require an injection, but are willing to take an oral agent,” the pediatric MS expert notes. The fact that one agent has been approved by the FDA for use in children and adolescents, and that other DMTs approved for adults are in late stages in clinical evaluation in pediatric populations, has also made both parents and payers (insurance companies) more receptive to DMTs for young patients, Dr. Waubant adds.
Gilenya secured its pediatric indication on the basis of the Phase III PARADIGMS trial, which studied more than 200 young people with pediatric MS.19 Other pediatric studies of DMTs already approved for use in adults include ongoing Phase III trials of Aubagio® (teriflunomide) and Tecfidera® (dimethyl fumaric acid), an ongoing open-label trial of Lemtrada® (alemtuzumab), and completed open-label trials of Tysabri® (natalizumab) and Tecfidera.17
However, Dr. Waubant and several of her colleagues belonging to the IPMSSG note that enrollment challenges and other obstacles mean that “Phase III trials for every newly approved therapy for adult MS in the pediatric MS population are simply not feasible.” Writing in the journal Neurology earlier this year, they noted, “In the last years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span. As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency. There are also ethical considerations on conducting clinical trials in this age group including the use of placebo owing to highly active disease. It is imperative to reconsider study design and implementation based on what information is needed.” The group went on to propose recommendations that would enable future studies to adequately assess the safety of DMT use in pediatric patients while avoiding some of the trial-design issues that made it difficult to obtain timely, meaningful results.17 (See sidebar on Clinical Trials)
Such studies are all the more important given the above-referenced trend toward the increased use of DMTs in children and adolescents. An analysis of 748 pediatric MS patients receiving care at practices in the US Network of Pediatric MS Centers found that 78% had received a DMT before reaching 18 years of age.20 However, there are indications that the more-proactive approach being taken by clinicians at pediatric MS centers is not being uniformly adopted nationwide. An analysis of claims data for 288 children and adolescents diagnosed with pediatric MS from 2010 to 2017 found that 65% did not receive a DMT in the 12 months following their diagnosis.21
Other research into treatment of pediatric MS is looking beyond DMTs. Several small studies have evaluated the safety and efficacy of Rituxan® (rituximab) in pediatric MS. This monoclonal antibody, which depletes certain types of B cells, primarily is used in the treatment of leukemias and lymphomas. It is not approved for use in either adult or pediatric MS, but has been employed by some clinicians to treat multiple sclerosis.
Investigators are also exploring the role that stem-cell therapy may play in treating pediatric MS, and are pursuing other treatments that would have remyelinating and neuroprotective effects. “One of the greatest unmet needs in pediatric MS relates to the fact that we don’t have a sufficient understanding of why there is disease progression even with adequate control of inflammation. Figuring out a way to control that progression is super important,” says Dr. Yeh. She adds that agents with mechanisms of action different from those of current DMTs will likely be needed to halt the disease progression not driven by inflammation and, hopefully, to exercise a regenerative effect.
Promoting wellness for the whole person as well as for family members
“Yes, MS is a part of your life, but it needn’t define your life,” Ms. Karpinski tells the young people she works with at UBMD Neurology in Buffalo. Often, she adds, parents need to hear that message more than their children do, given a parent’s increased concerns.
The concerns that parents have for a child newly diagnosed with MS are often accompanied by a tendency to be over-protective, and even to feel a sense of guilt, experts say. “Parents often ask, ‘Did I do something that put my child at risk for this?’” notes Dr. Yeh. Beyond allaying parents’ unfounded fears that they are responsible for their child’s MS, she uses the question to refocus parents on ways to optimize their daughter’s or son’s health. The pediatric neurologist explains that those steps include participating in physical activity, ensuring sufficient sleep, and eating a balanced diet while avoiding extreme eating plans not supported by scientific evidence. “I particularly stress the importance of the child staying active and leading a normal life. If parents unnecessarily limit a child’s activities because of concerns about their MS, it can have a negative impact in terms of forging friendships and developing socially,” she adds.
Dr. Waubant counsels parents along the same lines, and notes the importance of having a smoke-free household, and also
recommends Vitamin D supplementation. In many cases, she adds, the parents’ concerns about MS extend to their newly diagnosed child’s siblings. When asked about the chances that another of their children will also develop MS, Dr. Waubant explains to parents that people who have a first-degree relative with MS have a 2% to 3% lifetime chance of having MS.
“Where is my child going to be 10 years from now?” is another question Dr. Waubant hears frequently. “I explain that children with MS are less likely to have problems with physical disability than adults and, for reasons we don’t entirely understand, children are better able to recover from relapses,” the neurologist says. She also urges parents to connect with support networks for families affected by MS. (See “Support and Resources for Families Facing Pediatric MS”)
Ms. Karpinski agrees that these support groups and networks are valuable resources for parents, and can help them obtain insights into handling practical issues. One example is to work with school officials to accommodate their child’s educational needs.
“School districts often have many children with a diagnosis of ADHD or seizure disorder, and so they have experience with formulating educational plans centered around those conditions. But it is not unusual for a child at our clinic to be the only student in his or her district with multiple sclerosis, and educators may not appreciate the need for certain accommodations, such as extended time for test-taking or standing permission to use the restroom,” says Ms. Karpinski.
After more than a decade of working with children at UBMD, Ms. Karpinski has helped several patients make the adjustment from grammar school to high school, and then to college. Along the way, she has addressed issues ranging from compliance with medication regimens to what and how a teen with MS may want to tell classmates, or a boyfriend or girlfriend, about the condition. She also has worked with patients and parents on family dynamics and practical approaches to dealing with symptoms such as fatigue and heat sensitivity. The experience, she says, has left her in awe of children with MS. “It is a privilege to work with them, and to see them flourish. They’re just amazing people, and they give me so much hope.”
Support and Resources for Families Facing Pediatric MS
Learning that your child has a serious, lifelong condition can be overwhelming. When that condition is so uncommon that you do not know of anyone else in the same situation, a sense of isolation can add to a parent’s anxiety. Resources including the Multiple Sclerosis Association of America (MSAA) are available to assist. Parents may call MSAA’s toll-free Helpline at (800) 532-7667, extension 154, to speak to an MSAA specialist. Parents and others also can obtain information from MSAA’s Helpline by emailing MSquestions@mymsaa.org, and by using the online MS Chat feature on MSAA’s website at mymsaa.org/chat. MSAA’s website also has numerous other resources of interest to people of all ages who are coping with the challenges of MS.
Other MS advocacy organizations also offer resources and support for young people with MS and their relatives. One group – the Pediatric Multiple Sclerosis Alliance – is dedicated exclusively to connecting, supporting, and advocating for children and adolescents with MS and their families. The Alliance’s website, at pediatricms.org, includes a directory of centers specializing in pediatric MS, a resource center where visitors can download parents’ guides to understanding the condition, information about camps for young people with MS, and more. This organization also helps the parents of children with MS connect with one another online.
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