pediatric multiple sclerosis

Pediatric multiple sclerosis

Anusha K. Yeshokumar, Sona Narula, and Brenda Banwell

Current Opionion in Neurology

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Purpose of review

This review discusses the epidemiologic factors involved in the pathogenesis of pediatric multiple sclerosis (MS), which have been the focus of numerous studies in the last several years. We also review the clinical features (including diagnostic evaluation and differential diagnosis) of, treatment approach to, and prognosis of pediatric MS.

Recent findings

Up to 10% of patients with MS have their initial demyelinating before the age of 18 years. Over the past 15 years, international and collaborative studies have identified an increasing number of genetic and environmental risk factors for pediatric MS. Identification of these risks and their interplay allow for better understanding of the pathophysiology of pediatric MS, which may inform subsequent treatment and disease management. Careful attention to the management of relapses and chronic symptoms, including implementation of lifestyle modifications and pharmacologic interventions, enables improved school performance and quality of life.

Summary

Ongoing research in the field of pediatric MS aims to better understand the epidemiologic factors involved in the pathobiology, safety and efficacy of disease-modifying treatments, and long-term prognosis, particularly of cognitive development and academic potential. Collaborative, multinational studies will enable the advancements needed to truly optimize clinical care for this population.

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INTRODUCTION

Up to 10% of patients with multiple sclerosis (MS) have their initial demyelinating before the age of 18 years [1,2]. Pediatric MS is characterized by a relapsing–remitting disease course at onset. The diagnosis is confirmed by recurrent clinical episodes consistent with demyelination of the central nervous system (CNS) and supported by MRI evidence for new lesions involving different regions of the CNS. Early consideration of MS in appropriate clinical cases is important for the timely confirmation of diagnosis and initiation of treatment. This review discusses the epidemiologic factors, clinical features (including diagnostic evaluation and differential diagnosis), treatment approach, and prognosis of pediatric MS.

 

EPIDEMIOLOGIC FACTORS

Over the past 15 years, international and collaborative studies have identified an increasing number of genetic and environmental risk factors for pediatric MS. Identification of these risks and their interplay allow for better understanding of the pathophysiology of pediatric MS, which may inform subsequent treatment and disease management. Given their young age of onset, pediatric MS patients likely experience their first clinical symptom at a time more proximate to a potential environmental exposure or trigger and are a valuable population to study epidemiologic factors.

Puberty/sex hormones

Adult onset and postpubertal pediatric MS is more common in women, however, the sex ratio is about equal in children whose disease onset occurs prior to the age of 12 years [3,4]. The clear increase in women representation after age 12 years has led to studies of the contribution of puberty, and menarche in particular, to MS in women. Earlier age of menarche is associated with an increased risk of MS in women [5]. It has also been shown that girls have increased number of relapses during their perimenarche period [6& ]. Conversely, later age of menarche may be protective, as evidenced by a decreased risk of MS in children presenting with acquired demyelinating syndromes [7& ]. The importance of puberty and hormonal change to the pathophysiology of MS is still unknown and requires further investigation.

Obesity

Obesity in adolescence is associated with an increased risk of MS by adulthood [8,9]. An association of obesity with increased risk of pediatric onset MS in girls has also been demonstrated [10]. Obesity allows for increased estrogenic exposure and supports a low-grade inflammatory state within the body and particularly in adipose tissue [11], which may contribute to MS pathogenesis. Obesity has also been associated with decreased bioavailability of vitamin D [12] and early age of menarche, which both may independently contribute to MS risk.

Vitamin D

The role of vitamin D insufficiency in pediatric MS is not fully understood, however, low vitamin D has been associated with an increased susceptibility to pediatric MS [13]. Lower vitamin D levels have also been associated with higher relapse rate in pediatric onset MS [14]. Studies have now revealed an association between MS risk and genes coding for enzymes involved in vitamin D metabolism, further supporting the interplay between genetics and environmental factors [15,16& ,17].

Viral exposures

Early viral exposure may play a key role in MS risk. Epstein–Barr virus (EBV) exposure has been associated with increased MS risk in both adults and children [13,18]. Remote cytomegalovirus (CMV) exposure has been associated with decreased risk [19]. In children presenting with an initial acquired demyelinating syndrome, those with evidence of remote EBV infection who were also seronegative for CMV were at highest risk of a forthcoming MS diagnosis [20& ].

Smoking

There is an increased risk of MS in smokers, and the cumulative dose (duration and amount) of smoking contributes to risk [21,22& ,23]. In children, passive smoke exposure (i.e., parental smoking) has been associated with a higher risk of MS [24]. Several pathogenic mechanisms have been suggested, including predisposition to autoimmunity, neurotoxic effects of components of cigarette smoke, and modulation of cell signaling within the CNS. Additional studies are needed to confirm these mechanisms.

Diet

To date, there are no clear associations between diet and MS risk. Salt intake has been investigated with no confirmed association [25& ].

Genetics

Several studies have shown that the presence of the human leukocyte antigen (HLA)-DRB1 15 allele confers increased MS risk. More recently, genome wide associate studies have identified a number of loci outside of the HLA complex that may contribute to MS risk in children and adults [26,27]. With increased identification of genetic and environmental risk factors, additional studies can be done to determine combined risk. For example, in a cohort of children presenting with an initial acquired demyelinating syndrome, more than half of the study participants (57%) with the presence of HLA-DRB1 15 allele, remote EBV infection, and low vitamin D were ultimately confirmed to have MS. Conversely, less than 5% of children with acute demyelination who did not have HLA DR1501 alleles, were EBV naı¨ve, and whose vitamin D concentrations were robust were diagnosed with MS [13].

 

CLINICAL FEATURES

Pediatric MS often presents initially with optic neuritis, transverse myelitis, brainstem syndromes, or an acute disseminated encephalomyelitis (ADEM)- like event. They may also present with sensory loss or dysesthesia or cerebellar symptoms including impaired coordination. About one third of children who present with an acute demyelinating syndrome will demonstrate evidence of a relapsing disease such as MS, neuromyelitis optic spectrum disorder, or other. The remaining two thirds will have either a monophasic event or be found to have another diagnosis.

Although many of the focal or multifocal neurologic syndromes that pediatric MS presents with can be similar to those seen in adult MS, brainstem, and cerebellar syndromes are particularly prominent in young children and adolescent patients [28,29]. Children are also much more likely to present initially with encephalopathy, fever, seizures, and/ or polyfocal symptoms [30], which rarely can result in residual cognitive and motor impairments. This presentation may be indistinguishable from ADEM [31].

MS in children follows a relapsing–remitting disease course, though a shorter interval between the initial and second demyelinating event and higher relapse rate as compared with MS in adults is seen [32]. Approximately, 40% of children experience their second demyelinating event within one year of their initial presentation, 60% by 2 years, and 66% by 3 years [29]. Conversely, residual deficits following demyelinating events are much less likely in children, present in less than 10% [31].

 

DIAGNOSIS OF MULTIPLE SCLEROSIS IN CHILDREN

When evaluating children who present with an acute demyelinating syndrome, factors predictive of a diagnosis of MS include adolescence at the time of onset (as opposed to early childhood), imaging findings characteristic of MS (discussed below), and involvement of the optic nerve [31]. Factors suggestive of a monophasic illness or other diagnosis include age of onset less than 10 years, syndrome of transverse myelitis, and acute encephalopathy. In children with symptom onset before the age of 10 years, time from the initial to subsequent demyelinating episode can be long, and therefore, prolonged observation is required to ensure the correct diagnosis has been made.

MRI

Children presenting with concern for an acute demyelinating syndrome should have an MRI of the brain and spinal cord completed, which may show one or multiple lesions in the white matter consistent with demyelination and with or without contrast enhancement. A diagnosis of MS can be confirmed by the presence of recurrent clinical demyelinating events and/or MRI evidence for new lesions involving different regions of the CNS. Implementation of the 2010 revised McDonald criteria may allow for diagnosis to be made at the time of the first demyelinating syndrome if imaging demonstrates silent lesions in two of the four regions typical for MS, at least one of which enhances with gadolinium [33]. When criteria are not met at the time of the first event, new clinical attacks and/or serial imaging demonstrating accrual of lesions are needed to confirm the diagnosis of MS.

Studies have evaluated other imaging findings during the first demyelinating event that may be predictive of a future diagnosis of MS. In a study of 116 children with an initial acute demyelinating syndrome, MRI features associated with eventual diagnosis of MS included lesions oriented perpendicular to the long axis of the corpus callosum and the sole presence of well defined lesions (100% specificity with 21% sensitivity) [34]. Lesions involving the deep gray nuclei were seen equally in children with monophasic illness and those with MS.

In a study of 35 children presenting with optic neuritis who underwent MRI of the brain, 13 of the 18 children with asymptomatic white matter lesions on imaging subsequently met criteria for diagnosis of MS as compared with none of the 17 children with normal imaging outside of the optic nerves [35]. For children who present with an ADEM phenotype, no single MRI feature reliably distinguishes those with monophasic illness from those who will eventually receive an MS diagnosis [36].

Spinal fluid analysis

A lumbar puncture to evaluate cerebrospinal fluid (CSF) can be helpful in elucidating a diagnosis in certain clinical cases. If a child presents with fever or encephalopathy, it is important to exclude infectious etiologies for encephalitis. Cytologic analysis may be considered to exclude malignancy in children with tumefactive lesions or with leptomeningeal enhancement on imaging. In a study of 136 children with acute demyelinating syndromes, mild CSF pleocytosis (defined as CSF leukocyte counts >5 cells/ml) was noted in 66%, and no child had more than 60 cells/ml [37]. In this study, oligoclonal immunoglobulin G bands (OCBs) specific to the CSF and not present in serum were detected in 92% of all children. Conversely, OCBs have only been detected in 5–30% of children with ADEM [31,36]. Presence of OCBs alone cannot confirm (nor may their absence rule out) MS in children.

Evoked potentials

Evoked potentials evaluate the function of the optic nerve, brainstem, or somatosensory pathways and may provide additional insight into the presence of a recurrent demyelinating disease. Prolongations in the peak latency may be seen in demyelinating lesions and can be used to confirm localization and/or as evidence for prior demyelination. Studies are abnormal in 95% of children with optic neuritis [38] and in over 60% of children with MS who have not had overt clinical optic nerve involvement. Brainstem and somatosensory studies are abnormal in 75% of children with MS who have clinical brainstem syndromes and in 40% of those without clinically apparent brainstem symptoms [30]. Somatosensory studies are abnormal in 60% of children with MS who have sensory complaints and in 50% of those without clinically apparent sensory disturbances [30].

 

DIFFERENTIAL DIAGNOSIS

MS must be distinguished from acute monophasic or transiently multiphasic demyelination, as there are major treatment and prognostic differences between these entities. ADEM, the classic monophasic demyelinating disease, should be considered when a child presents with acute, multifocal neurologic symptoms in the setting of encephalopathy and fever [31,39]. MRI will demonstrate bilateral, asymmetric increased T2 signal lesions with poorly defined borders affecting both the white matter and deep gray nuclei. Rarely, children may have transient multiphasic presentations [39], however, there is not ongoing CNS autoimmunity, as is seen in MS. As discussed above, a proportion of children who present initially with ADEM will subsequently have recurrent episodes of CNS demyelination not consistent with ADEM, leading to a diagnosis of MS [31,36].

Acute CNS infection, bacterial or viral, must be considered in children who present with an acute demyelinating syndrome. Demyelinating lesions may be seen in the context of acute CNS infection of EBV, Mycoplasma, enteroviruses, and other pathogens. Inherited disorders affecting CNS white matter, or leukodystrophies, may be considered, though will have a different clinical history characterized by chronic and progressive symptoms, characteristic MRI findings, and involvement of other organ systems. Such disorders include metachromatic leukodystrophy, globoid cell leukodystrophy, adrenoleukodystrophies, infantile Refsum’s disease, Alexander’s disease, mitochondrial cytopathies, glutaric aciduria type I, and Pelizaeus–Merzbacher disease [40]. Vanishing white matter disease is a progressive, genetic disorder in which children present with catastrophic deterioration in the face of acute viral infection, minor trauma, or fever [41].

Inflammatory vasculopathies, including systemic lupus erythematosus, CNS vasculitis, and isolated angiitis of the CNS, can all present with polyfocal neurologic deficits, headache, and MRI features of white matter involvement [42–44]. Children with systemic lupus erythematosus and vasculitis may demonstrate autoantibodies against nuclear antigens. Isolated angiitis of the CNS, a rare disorder presenting primarily in children, can be diagnosed with brain biopsy [42].

 

TREATMENT

There are an increasing number of disease-modifying treatment options available for patients with MS, including now 10 that have been Food and Drug Administration (FDA) approved for use in adults. There are no medications that have been FDA approved for use in children, though studies of many medications in children are currently underway. Information on their efficacy, tolerability, and safety in children has thus far mostly resulted from anecdotal experience and retrospective analyses.

The most commonly used treatments for MS in children are the injectables interferon-b and glatiramer acetate, both of which have a favorable safety profile in children and adults. A second-line treatment must often be considered because of intolerable first-line medication side-effects or treatment failure, defined as continued clinical and radiographic relapses on first-line medication. These medications may include natalizumab, rituximab, or newer oral agents. Changes in medications require careful counseling and consideration of safety given risks of infection (including the often fatal disease, progressive multifocal leukoencephalopathy).

For acute relapses, IV corticosteroids may be given with the goal of accelerating the speed of symptom recovery [45,46], however, administration does not alter long-term outcome. IV immunoglobulin may be considered for patients with incomplete response to steroid treatment [47] and plasma exchange for patients with severe clinical syndromes such as brainstem or spinal cord involvement [48]. Physical, occupational, and speech therapy consultations should be considered during a relapse to determine whether a patient would benefit from outpatient or inpatient rehabilitation. Careful attention to the management of relapses and chronic symptoms, including implementation of lifestyle modifications and pharmacologic interventions, will enable improved school performance and quality of life.

 

PROGNOSIS OF MULTIPLE SCLEROSIS IN CHILDREN

90% of children with MS have no evidence of physical disability in the first 5 years after their initial demyelinating event [31]. The remaining 10%, however, will require ambulatory aid after an average of only 3 years. Some of these children will develop significant gait impairment or wheelchair dependence within the first 5 years [49]. This outcome has not been demonstrated to be associated with age at presentation but is more likely to occur in children with polyfocal involvement, residual sequelae after the initial event, progression of disability between attacks, and/or frequent relapses in the first 2 years of disease [31,50].

In a cohort of 116 patients with pediatrics MS, 50% entered the secondary progressive phase of MS after 23 years, as compared with after 10 years in adults with MS [51]. In total, 60% of children with MS in this cohort followed for a mean of 19 years were found to reach an expanded disability status scale score of 3 or more, and 40% had an expanded disability status scale of 6 or more. Although the latency between first demyelinating episode and the development of secondary progressive disease and/or neurologic disability may be longer in pediatric MS, these patients are likely to experience progressive disease and disability at a younger age.

Cognitive sequelae of pediatric MS can conversely be seen much earlier in disease course, and this may in part be related to interruption of the crucial neurodevelopment that occurs during adolescence and early adulthood. Studies have demonstrated impairment in working memory, executive function, and processing speed in children with earlier onset and longer duration of MS [52& ,53,54]. These impairments occur without association to physical disability. Further studies are needed to better understand cognitive consequences of MS in children and what can be done to prevent and address them.

 

CONCLUSION

The review discusses the current understanding of epidemiologic factors, clinical features (including diagnostic evaluation and differential diagnosis), treatment approach, and prognosis of pediatric MS. Ongoing research aims to better understand the epidemiologic factors involved in the pathobiology, safety and efficacy of disease-modifying treatments, and long-term prognosis, particularly of cognitive development and academic potential, of pediatric MS. Collaborative studies involving centers around the world will enable the advancements needed to truly optimize clinical care for this population.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

& of special interest

&& of outstanding interest

1. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6:773–781.

2. Chitnis T, Glanz B, Jaffin S, et al. Demographics of pediatric-onset multiple sclerosis in an MS center population from the North-eastern United States. Mult Scler 2009; 15:627–631.

3. Tintore M, Arrambide G. Early onset multiple sclerosis: the role of gender. J Neurol Sci 2009; 286:31–34.

4. Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007; 356:2603–2613.

5. Ramagopalan SV, Valdar W, Criscuoli M, et al. Age of puberty and the risk of multiple sclerosis: a population based study. Eur J Neurol 2009; 16:342– 347.

6. & Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Mult Scler 2016; 22:93–200. The article explores the role of puberty in the MS course of female patients, noting that girls have an increased number of relapses during their perimenarche period.

7. & Ahn JJ, O’Mahony J, Moshkova M, et al. Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous autoimmunity in mice. Mult Scler 2015; 21:735–748. The article explores the role of puberty in the MS course of female patients, noting that a later age of menarche is associated with a decreased risk of subsequent MS diagnosis in patients with acquired demyelinating syndrome.

8. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology 2009; 73:1543–1550.

9. Hedstrom AK, Olsson T, Alfredsson L. High body mass index before age 20 is associated with increased risk of multiple sclerosis in both men and women. Mult Scler 2012; 18:1334–1336.

10. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 80:548–552.

11. Tam CS, Clement K, Baur LA, Tordjman J. Obesity and low-grade inflammation: a paediatric perspective. Obes Rev 2010; 11:118–1126.

12. Wortsman J, Matsuoka LY, Chen TC, et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72:690–693. 13. Banwell B, Bar-Or A, Arnold DL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol 2011; 19:436–446. 14. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010; 67:618– 624. 15. Agnello L, Scazzone C, Ragonese P, et al. Vitamin D receptor polymorphisms and 25-hydroxyvitamin D in a group of Sicilian multiple sclerosis patients. Neurol Sci 2016; 37:261–267. 16. & Lin R, Taylor BV, Charlesworth J, et al. Modulating effects of WT1 on interferon-b-vitamin D association in MS. Acta Neurol Scand 2015; 131:231–239. The article explores the role of genes coding for enzymes involved in vitamin D metabolism on MS risk, noting that WT1 variants may play a role in altering the effects of interferon-b on vitamin D in MS.

17. Ramasamy A, Trabzuni D, Forabosco P, et al., North American Brain Expression Consortium (NABEC), UK Brain Expression Consortium (UKBEC). Genetic evidence for a pathogenic role for the vitamin D3 metabolizing enzyme CYP24A1 in multiple sclerosis. Mult Scler Relat Disord 2014; 3:211–219.

18. Ascherio A, Munch M. Epstein-Barr virus and multiple sclerosis. Epidemiology 2000; 11:220–224.

19. Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011; 76:1989–1995.

20. & Makhani N, Banwell B, Tellier R, et al. Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult Scler 2016; 22:385–388. The article explores the role of prior viral exposures on MS risk, noting that patients with remote EBV infection without remote CMV infection were at highest risk of subsequent MS diagnosis.

21. Sundstrom P, Nystrom L, Hallmans G. Smoke exposure increase the risk for multiple sclerosis. Eur J Neurol 2008; 15:579–583.

22. & Hedstrom AK, Olsson T, Alfredsson L. Smoking is a major preventable risk factor for multiple sclerosis. Mult Scler 2016; 22:1021–1026. The article explores the role of smoke exposure on MS risk, noting that smoking and exposure to passive smoking contribute to MS risk in a dose-dependent manner.

23. Hedstrom AK, Hillert J, Olsson T, Alfredsson L. Smoking and multiple sclerosis susceptibility. Eur J Epidemiol 2013; 28:867–874.

24. Mikaeloff Y, Caridade G, Tardieu M, et al. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 2007; 130:2589– 2595.

25. & McDonald J, Graves J, Waldman A, et al. A case-control study of dietary salt intake in pediatric-onset multiple sclerosis. Mult Scler Relat Disord 2016; 6:87–92. The article explores the role of salt intake on MS risk, noting no strong association.

26. Mowry EM, Carey RF, Blasco MR, et al. Multiple sclerosis susceptibility genes: associations with relapse severity and recovery. PLoS One 2013; 8:e75416.

27. van Pelt ED, Mescheriakova JY, Makhani N, et al. Risk genes associated with pediatric-onset MS but no with monophasic acquired CNS demyelination. Neurology 2013; 81:1996–2001.

28. Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 1997; 3:43–46.

29. Ruggieri M, Iannetti P, Polizzi A, et al. Multiple scle- rosis in children under 10 years of age. Neurol Sci 2004; 25:S326–S335.

30. Ghezzi A, Pozzilli C, Liguori M, et al. Prospective study of multiple sclerosis with early onset. Mult Scler 2002; 8:115–118.

31. Mikaeloff Y, Suissa S, Vallee L, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J Pediatr 2004; 144:246–252.

32. Trojano M, Liguori M, Bosco ZG, et al. Age-related disability in multiple sclerosis. Ann Neurol 2002; 51:475–480.

33. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69:292–302.

34. Mikaeloff Y, Adamsbaum C, Husson B, et al. MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain 2004; 127:1942–1947.

35. Wilejto M, Shroff M, Buncic JR, et al. The clinical features, MRI findings, and outcome of optic neuritis in children. Neurology 2006; 67:258–262.

36. Dale RC, de Sousa C, Chong WK, et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 2000; 123:2407–2422.

37. Pohl D, Rostasy K, Reiber H, Hanefeld F. CSF characteristics in early-onset multiple sclerosis. Neurology 2004; 63:1966–1967.

38. Riikonen R, Ketonen L, Sipponen J. Magnetic resonance imaging, evoked responses and cerebrospinal fluid findings in a follow-up study of children with optic neuritis. Acta Neurol Scand 1988; 77:44–49.

39. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology 2002; 59:1224–1231.

40. Kolodny EH. Dysmyelinating and demyelinating conditions in infancy. Curr Opin Neurol Neurosurg 1993; 6:379–386.

41. Wilson CJ, Pronk JC, Van der Knaap MS. Vanishing white matter disease in a child presenting with ataxia. J Paediatr Child Health 2005; 41:65–67.

42. Lanthier S. Primary angiitis of the central nervous system in children: 10 cases proven by biopsy. J Rheumatol 2002; 29:1575–1576.

43. Yaari R, Anselm IA, Szer IS, et al. Childhood primary angiitis of the central nervous system: two biopsy-proven cases. J Pediatr 2004; 145:693– 697.

44. Rafay MF, Sutcliffe TL, Shroff M, et al. Primary central nervous system angiitis in a 10-year-old girl. Can J Neurol Sci 2005; 32:243–245.

45. Barkhof F, Hommes OR, Scheltens P, et al. Quantitative MRI changes in gadolinium-DTPA enhancement after high-dose intravenous methylprednisolone in multiple sclerosis. Neurology 1991; 41:1219–1222.

46. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev 2000; 4:CD001331.

47. Spalice A, Properzi E, Lo Faro V, et al. Intravenous immunoglobulin and interferon: successful treatment of optic neuritis in pediatric multiple sclerosis. J Child Neurol 2004; 19:623–626.

48. Weinshenker BG, O’Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; 46:878–886.

49. Mikaeloff Y, Caridade G, Assi S, et al. Prognostic factors for early severity in a childhood multiple sclerosis cohort. Pediatrics 2006; 118:1133–1139.

50. Gusev E, Boiko A, Bikova O, et al. The natural history of early onset multiple sclerosis: comparison of data from Moscow and Vancouver. Clin Neurol Neurosurg 2002; 104:203–207.

51. Boiko A, Vorobeychik G, Paty D, et al. Early onset multiple sclerosis: a longitudinal study. Neurology 2002; 59:1006–1010.

52. & Till C, Noguera A, Verhey LH, et al. Cognitive and behavioral functioning in childhood acquired demyelinating syndromes. J Int Neuropsychol Soc 2016; 22:1050–1060. The article examines neurocognition in children with acute demyelinating syndrome, noting favorable short-term outcome, even in those confirmed to have MS.

53. Amato MP, Goretti B, Ghezzi A, et al., MS Study Group of the Italian Neurological Society. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology 2014; 83:1432–1438.

54. Banwell BL, Anderson PE. The cognitive burden of multiple sclerosis in children. Neurology 2005; 64:891–894.

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