Abstract
To improve care for children with multiple sclerosis (MS) and to advance understanding of the underlying biologic mechanisms through collaborative research studies, criteria for case definitions of pediatric MS and related CNS demyelinating disorders were proposed by the International Pediatric MS Study Group. Issues raised during development of these definitions and rationale behind criteria proposed are summarized in this article, as are potential international multicenter research studies that would be facilitated by the application of a uniform set of definitions.
The ultimate goal of the International Pediatric Multiple Sclerosis Study Group (Study Group) is to improve care for children with multiple sclerosis (MS) and related CNS demyelinating disorders through accurate and early diagnosis, promotion of a comprehensive multidisciplinary care model, and initiation of studies to advance our understanding of the biologic mechanisms at work in these disorders.
Although MS is considered an adult onset disease, current estimates suggest that children with MS account for up to 2.5 to 5% of all MS cases1,2 (10,000 childhood cases in the United States alone). This may be an underestimate given the lack of clear diagnostic criteria for cases of MS and other CNS demyelinating disorders occurring in children. In adult patients with MS, clinical trials show that disease-modifying therapies (DMT) can reduce the frequency and severity of MS attacks.3 Children should be afforded the same benefits of modern therapies. Yet, similar studies have not been conducted for children and adolescents younger than 18 years. At present, it is even unclear whether adult MRI diagnostic criteria apply to children. It also remains uncertain if conventional MS therapies are as effective in children as they are for adults, and if so, just when DMT should be initiated, which regimens used, and for what duration. Of equal importance are possible adverse medication effects and impact of DMT on future growth and development.
The answers to these questions require a greater understanding of the similarities and differences in the biology of adult and pediatric MS. Understanding how adults and children with MS differ epidemiologically, clinically, radiologically, and biologically may give us important insights into the underlying mechanisms of disease, including disease susceptibility, myelin repair, and regeneration. Moreover, because children may be closer to the inciting events resulting in MS, research in pediatric MS may ultimately hold the key to understanding the cause of the disease itself.
To conduct appropriate studies, clear diagnostic criteria to differentiate pediatric MS from other CNS demyelinating diseases in children is mandatory. At present, interpretation of the existing literature, especially the comparison of studies, is complicated by the myriad of terms and definitions used for pediatric MS and related disorders. For example, as reviewed by Tenembaum et al. in this conference report, over nine different definitions of acute disseminated encephalomyelitis (ADEM) have been used in publications.4 Furthermore, many of the studies are retrospective, have relatively small cohort size, and have short follow-up periods. Thus information is limited. Implementation of a uniform classification system for MS and CNS demyelinating disorders in children is an important first step to promote prospective, international, collaborative research. Equally important is enrolling a cohort of sufficient size. It will be critical to collect data from multiple centers given the relatively limited number of children with MS in any given geographic area.
Here we present some of the issues, dilemmas, and questions that arose during the development of the proposed definitions for pediatric MS and related childhood disorders by the Study Group.5 We offer an approach to test the validity of these definitions and delineate future research directions necessary to improve care for children with MS.
Classification controversies.
The Study Group critically reviewed the literature on pediatric MS, ADEM, neuromyelitis optica (NMO) and clinically isolated syndrome (CIS), and developed operational definitions for these disorders.5 The definitions do not encompass all possible clinical situations. The diagnostic criteria were made deliberately stringent, with the understanding that the Study Group’s goal was specificity at the expense of sensitivity. It was recognized that some patients will not meet the strict criteria for a case definition and will be excluded (low sensitivity); however, this will ensure greater confidence that the cases meeting inclusion criteria truly have the disorder in question. The definitions will need to be tested and validated in prospective multicenter studies and subsequently refined.
ADEM.
Controversies and dilemmas.
It is well acknowledged that a proportion of children with ADEM will go on to develop MS.6 Currently, for the child who presents with a first inflammatory demyelinating event, we are unable to predict if the child will subsequently remain asymptomatic, develop a variant of ADEM, or the lifelong disease MS. With the advent of DMT and recommended early use,3 the distinction between MS and ADEM (including ADEM variants) has become a major issue and is no longer a theoretical concern, since prognosis and currently recommended therapy for these disorders are markedly different. Accurate diagnosis is crucial. It remains unclear just what proportion of children who develop ADEM will later be diagnosed with MS, since numbers from published studies vary from 0 to 29%.7,8 It is also unclear if ADEM and MS are two distinct clinical disorders or part of a disease spectrum. Intrinsic to the difficulty in comparing studies attempting to address these questions is the use of differing clinical criteria for ADEM by different investigators. The definition of ADEM proposed by the Study Group is an attempt to strictly define an ADEM event, in contrast to CIS, which may carry a different prognosis for MS.
Issues raised by the Study Group.
Encephalopathy, as defined in this supplement,5 is one of the required clinical features for a case definition of ADEM.
It can be argued that ADEM can present without encephalopathy, yet still satisfy the other defined clinical and MRI characteristics of the disorder. In this situation (absence of encephalopathy) the Study Group consensus was to use the term CIS.
It can also be argued that encephalopathy (mental status changes) is a possible complication of the first inflammatory demyelinating episode of early onset MS.9–11 While some investigators have then used terms such as ADEM-like to retrospectively describe the first attack, the Study Group recommendation was to avoid these terms completely as they add little except more confusion.
Case.
A 14-year-old boy has his fourth inflammatory demyelinating attack characterized by right sided weakness. At age 7 years he developed headache, lethargy, seizures, and right-sided weakness. Multiple bilateral asymmetric white matter lesions were visualized on T2-weighted MRI. CSF profile showed a mild pleocytosis, elevated protein, and the absence of oligoclonal bands. He was treated with IV methylprednisolone for 5 days and completely recovered. A diagnosis of ADEM was made. One year following the event his neurologic examination was considered normal. At 8.5 years of age, he developed unilateral optic neuritis from which he recovered. Two years later he had the new onset of ataxia. Brain T2-weighed MRI showed multiple lesions in the subcortical and periventricular white matter including the brainstem. The diagnosis of MS was made.
If the definitions for ADEM, CIS, and MS proposed by the Study Group are applied:
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ADEM is the diagnosis for a child whose initial CNS inflammatory demyelinating event includes encephalopathy (changes in mental status, behavioral changes).
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If this child subsequently experiences repeated (multiple) episodes (dissemination in time and space), the child would be reclassified with a diagnosis of MS.10
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CIS is the diagnosis for a child whose initial CNS inflammatory demyelinating episode does not include encephalopathy. If this child subsequently experiences a second episode (exhibiting dissemination in time and space), the child would be reclassified with a diagnosis of MS.10
ADEM variant, or is it MS?
Controversies and dilemmas.
ADEM typically follows a monophasic course. However, many clinicians and investigators acknowledge that the course can be 1) phasic, representing a protracted single episode rather than a new event; or 2) repeated with relapses within the first few months or years of the initial episode, as in recurrent or multiphasic ADEM; or 3) steroid dependent ADEM, with relapses occurring as glucocorticosteroids are tapered, and yet still have the same good outcome as monophasic ADEM.5 These variants, which may be more common in children than adults, pose a diagnostic dilemma since repeated CNS inflammatory demyelinating events could be confused with MS.
Controversy is heightened because some other investigators consider one episode of ADEM in children followed by a second demyelinating event to be consistent with a diagnosis of MS.8
Whereas other investigators require that two discrete episodes (each without encephalopathy) must follow ADEM to fulfill diagnostic criteria for MS. In this model one clinical event without encephalopathy following ADEM does not specify a diagnosis of MS, since it could still represent a self-limited disease process.7 These descriptions assume that the standard criteria used to define a discrete MS relapse have been met (e.g., a 1-month interval between relapses).
The Study Group acknowledged that a second episode of ADEM could develop without necessarily being followed by subsequent events (i.e., MS). It was decided to differentiate recurrent ADEM from multiphasic ADEM.5 However, it was also agreed that some patients initially classified as ADEM would go on to experience multiple repeated events and ultimately be reclassified as having MS. Since the risk for a development of MS might be higher in individuals who experienced multiphasic vs recurrent ADEM the use of these terms was judged to be of value and would allow for more meaningful outcome studies. To avoid excessive terminology, other terms for repeat episodes of ADEM were rejected, e.g., relapsing ADEM.
At this stage in definition development the question of treatment arose: Should DMT be recommended for the child with a history of ADEM who, in time, has a second demyelinating event, but according to the above definition will not yet be diagnosed with MS? The Study Group consensus was that treatment decisions, regardless of terminology/diagnosis, should be individualized and left to the discretion and judgment of the clinician and patient.
Unresolved questions.
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How many episodes of ADEM are allowed before the diagnosis should be changed to MS?
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At what point after a single event has been followed by a relapse-free interval is the risk of MS no longer a consideration?
Clinically isolated syndrome.
Controversies and dilemmas.
CIS is a first acute clinical episode of CNS symptoms with a presumed inflammatory demyelinating cause for which there is no prior history of a demyelinating event. The term CIS has been variably applied to patients with purely monofocal presentations as well as multifocal presentations (symptoms that cannot reasonably be explained by a single lesion). According to the consensus definitions, CIS can be either monofocal or multifocal, but cannot include encephalopathy.
Case.
A 12-year-old girl developed tingling and numbness in her left hand and arm. The following day she stated that her left leg felt heavy. She denied any other symptoms. She was able to continue attending school and had no problems with her academic work. Sleep–wake cycle was normal. There were no recent infections or immunizations. T2-weighted MRI of the brain showed scattered white matter lesions, of which three lesions showed gadolinium enhancement. CSF profile was normal. Oligoclonal bands were absent.
In this scenario the child has the new onset of focal neurologic symptoms and signs, with no evidence of behavioral or mental status changes. MRI was consistent with demyelination. This was her first demyelinating episode (isolated in time). Her signs and symptoms are consistent with a diagnosis of CIS.
For research purposes, the Study Group recommended subcategories for specific syndromes, such as transverse myelitis and unilateral vs bilateral optic neuritis.
Unresolved questions.
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Is encephalopathy specific for ADEM?
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Is the long-term prognosis for development of MS the same or different for children with monofocal vs multifocal CIS events; transverse myelitis; unilateral optic neuritis; bilateral optic neuritis?
Application of the McDonald criteria for the diagnosis of childhood onset MS.
The Recommended Diagnostic Criteria for MS: International Panel on the Diagnosis of MS report12 states that MRI criteria apply to individuals between 10 and 59 years old and are based on data and experience available primarily from adults. However, one study of small cohort size found that the majority of pediatric MS cases, as defined by Poser’s criteria,13 did not fulfill the McDonald criteria for a positive MRI.14 Despite this limitation, the Study Group agreed to apply the McDonald criteria to pediatric MS, including children <10 years of age, until additional neuroimaging experience is gained or MRI criteria for children, particularly those <10 years of age, are developed. The consensus was that an event of CIS followed by MRI evidence of new lesion formation at 3 months would be used to diagnose MS. Clearly the role of MRI in pediatric MS diagnosis requires further study.
Future research studies in pediatric MS and related disorders.
Testing the definitions.
A major objective of the Study Group is to promote research to further our understanding of the clinical features and underlying biologic mechanisms of pediatric MS. A critical first step is to test, validate, and refine the consensus definitions by conducting prospective, longitudinal, multicenter international clinical studies.
Specific issues to be addressed.
Specific issues to be addressed include, but are not limited to, the following:
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Long-term outcome of ADEM and CIS with respect to development of MS
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Role of encephalopathy in distinguishing ADEM from CIS
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Correlation of ADEM and CIS events with neuroimaging and biologic markers (thereby possibly identifying surrogate markers to define events)
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Validity of proposed diagnostic criteria for pediatric MS
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Is the definition of pediatric MS too stringent?
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Is proof of dissemination in time, by additional clinical events, or MRI changes required?
Hypotheses to be tested.
Hypotheses to be tested would include but are not limited to the following:
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Children who present with CIS are more likely to develop MS than children who present with ADEM
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Children with prolonged steroid–dependent events are more likely to develop MS than children with rapid recovery ADEM
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Children with multiphasic ADEM compared to children with recurrent ADEM are at increased risk of developing MS
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Children with recurrent ADEM are at increased risk of developing MS than children with ADEM
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Neuroimaging features and biologic markers can be identified to distinguish among ADEM, ADEM variants, CIS, and MS
Study design.
Subjects.
Children under 18 years of age experiencing neurologic events consistent with inflammatory CNS demyelination (other causes excluded) would be included. A comprehensive structured neurologic history and examination (uniform measures of neurologic function) would take place at the time of enrollment (first demyelinating event). The event would be classified as either ADEM or CIS. Information which might predict the subsequent development of recurrent ADEM, multiphasic ADEM, or MS would be recorded, e.g., details of the anatomic distribution (optic nerve or spinal cord, monofocal or multifocal distribution), CSF findings, and neuroimaging results. Longitudinal follow-up, 5 to 10 years, should include uniform neurologic examinations (uniform measures of neurologic function), neurocognitive evaluations, and neuroimaging studies. Biologic and genetic testing would augment these evaluations. It is anticipated that they would yield additional prognostic markers.
Epidemiology of pediatric MS.
The true incidence of pediatric MS is unknown. Estimates vary and are likely influenced by regional and ethnic differences in MS incidence as well as the source population.1,4 The lack of uniform criteria to define pediatric MS could account for some of the variability. In considering future research, however, it is important to recognize that without an adequate follow-up duration, patients with single demyelinating events, whose second clinical event is years later, could be missed, which would result in underestimation of the frequency of pediatric MS. The Study Group believes the consensus definitions will facilitate and improve epidemiologic studies, which will ultimately improve the care provided to children and adolescents through increased awareness and preparedness.
Disease course and prognosis.
Several groups have initiated studies examining the disease course of pediatric MS.1,2,8,15,16 In general, cohort sizes have been relatively small and follow-up limited. Further studies are needed to confirm observations and to fully delineate the characteristics of the disease course in children. It is critical to understand the similarities to and differences from adult MS, in order to appropriately draw on the already existing vast adult MS knowledge base. The few studies that have compared the course and prognosis between childhood and adult onset MS suggest that children experience a longer relapsing-remitting phase of disease than adults, with a prolonged comparative time to reach particular levels of disability.15,16 If this general trend is confirmed, understanding the origin may provide insights into lesion evolution and possibly repair and regeneration mechanisms.
Furthermore, understanding the differences between MS in children and adults is necessary, since research findings in adults have been extrapolated to children and teenagers. As new therapies emerge it will be essential to understand the appropriateness of use in children.
Psychosocial issues.
There is a paucity of information concerning psychosocial aspects of pediatric MS, including developmental issues, body image issues, cognitive function over time, overall effects on education, and quality of life. Depression, anxiety, and other psychiatric problems may occur as part of the disease, as a side effect of MS medications or as the child’s or teenager’s reaction to having a chronic illness. Studies will require an interface between child and adolescent psychologists, neuropsychologists, psychiatrists, and MS neurologists. Evaluations of educational interventions and development of new assessment tools and therapy strategies geared specifically to this population may be required.
Treatment of pediatric MS.
There have been no studies (clinical trials) documenting the efficacy of DMT in pediatric MS. Several small studies demonstrated that children treated with DMTs seem to experience some of the same adverse effects as adults.17–21 Studies documenting efficacy of therapy use in children are needed, as are large detailed safety studies. There is also a need for documentation of long-term side effects, including effects on development and psychosocial outcomes. Some children will fail treatment with the standard DMTs, necessitating use of second-line agents. Studies examining the use and effects of rescue or escalation therapies are likewise required.
Conclusion.
The use of standardized definitions for pediatric MS and related demyelinating disorders will greatly facilitate clinical care and promote a platform for future research. Collaborative international multicenter studies will be essential to achieve the cohort size necessary to address unresolved questions given the limited number of patients in any given geographic area. Such information will help to address several key questions such as whether CNS inflammatory demyelinating diseases have specificities in children as compared to adults (for example, are younger patients more prone to develop encephalopathy?), second, whether clinical presentation during the first demyelinating event can predict a mono vs multiphasic course, and third, whether ADEM and MS represent distinct entities.
To better care for these youngsters and to advance our understanding of the biologic mechanisms underlying pediatric MS and related disorders, prospective, collaborative studies will be required.
Appendix
The International Pediatric MS Study Group: Lauren Krupp, MD (chair), Brenda L. Banwell, MD, Anita Belman, MD, Dorothee Chabas, MD, PhD, Tanuja Chitnis, MD, Peter Dunne, MD, Andrew Goodman, MD, Jin S. Hahn, MD, Deborah P. Hertz, MPH, Nancy J. Holland, EdD, RN, MSCN, Douglas Jeffery, MD, PhD, William MacAllister, PhD, Raul Mandler, MD, Maria Milazzo, RN, MS, CPNP, Jayne Ness, MD, PhD, Jorge Oksenberg, PhD, Trena L. Pelham, MD, Daniela Pohl, MD, PhD, Kottil Rammohan, MD, Mary R. Rensel, MD, Christel Renoux, MD, Dessa Sadovnick, PhD, Steven Robert Schwid, MD, Silvia Tenembaum, MD, Cristina Toporas, Emmanuelle Waubant, MD, PhD, Bianca Weinstock-Guttman, MD.
Footnotes
References
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