Elsevier

The Lancet Neurology

Volume 6, Issue 10, October 2007, Pages 887-902
The Lancet Neurology

Review
Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions

https://doi.org/10.1016/S1474-4422(07)70242-9Get rights and content

Summary

The onset of multiple sclerosis (MS) in childhood poses diagnostic and therapeutic challenges, particularly if the symptoms of the first demyelinating event resemble acute disseminated encephalomyelitis (ADEM). MRI is an invaluable diagnostic tool but it lacks the specificity to distinguish ADEM from the first attack of MS. Advanced MRI techniques might have the required specificity to reveal whether the loss of integrity in non-lesional tissue occurs as a fundamental feature of MS. Although the onset of MS in childhood typically predicts a favourable short-term prognosis, some children are severely disabled, either physically or cognitively, and more than 50% are predicted to enter the secondary-progressive phase of the disease by the age of 30 years. Immunomodulatory therapies for MS and their safe application in children can improve long-term prognosis. Genetic and environmental factors, such as viral infection, might be uniquely amenable to study in paediatric patients with MS. Understanding the immunological consequences of these putative exposures will shed light on the early pathological changes in MS.

Introduction

Multiple sclerosis (MS) in children and adolescents is increasingly recognised worldwide. The disorder presents almost exclusively as a relapsing-remitting disease in children, and most recover from the initial attacks. The accumulation of disabilities and the development of secondary-progressive MS most commonly occur more than 15 years after the first attack. MRI has contributed substantially to the increasing recognition of and certainty in the diagnosis of MS in children. The potential for advanced MRI techniques to visualise fundamental features of myelin integrity and repair provides exciting opportunities for future research. Treatment is currently based on strategies optimised for adult-onset MS and seems to be safe and well tolerated, although prospective therapeutic trials in paediatric MS have not been done.

We describe the clinical, radiographic, and biological characteristics of MS and the other disorders considered in the differential diagnosis in children. We also describe current therapeutic practice and discuss avenues of future research.

Section snippets

Acute demyelination of the CNS

The first acute demyelinating event, termed a clinically isolated syndrome, can manifest with signs and symptoms caused by a single lesion (monofocal clinically isolated syndrome) or with polyfocal features, implicating multiple lesions. There are published clinical definitions for these various clinical demyelinating presentations (figure 1).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23

In a prospective study of 296 children with acute demyelination, 81

Differential diagnosis

A cornerstone of the diagnosis of MS in adults and children rests on showing lesion dissemination in space and time and the exclusion of other disorders.7 One approach to discount disorders in the differential diagnosis of acute CNS demyelination was set out in a recent consensus article (figure 2 and webfigure).50 CNS infection and intracerebral malignancy must always be considered. Although CNS lymphoma is rare in children, intracallosal involvement can be similar to the white-matter lesions

Characteristics of child-onset MS

An estimated 3–10% of all patients with MS have onset before the age of 18 years.71, 94, 95, 96, 97 The true frequency of paediatric MS will be determined only from prospective studies from both paediatric and adult clinical centres.

Disability and outcome

Kurtzke's expanded disability status scale (EDSS) is the most common measure of physical neurological sequelae in adults and children with MS (table 3),68, 73, 94, 96, 105 although the measure has several key limitations (non-linear ordinals, wide intraobserver and interobserver variability, and, essentially, exclusive weighting of motor dysfunction at the higher range of the scale).

In a prospective study of 54 children or adolescents with MS disease duration of 8 years or longer, 36 had an

Management

The care of children with MS needs a multidisciplinary team comprising paediatric and adult neurologists, nurses, physiotherapists, occupational therapists, social workers, psychologists, and psychiatrists.130 The diagnosis of chronic illness has substantial emotional effects on children with MS and their families. Compliance with medication, particularly in adolescents, rests on a strong relationship between medical teams, patients, and parents.

Genetic studies

HLA-DR2 was more common in 47 children154 and adults155 with MS from Russia than in the general population. Unlike in adults from the same region with MS, a high prevalence of the TNFα 7 allele was also found, and this was proposed as a potential biomarker for paediatric MS.156 By contrast, a study of 24 children with MS in Turkey did not detect MS-specific TNFα mutations.157 Genetic studies of MOG, the gene encoding myelin oligodendrocyte glycoprotein, located in close proximity to the HLA

Conclusions

The diagnosis and care of children with MS will be helped by the recognition of the presenting features of the disease, the use of MRI, and the laboratory exclusion of the other disorders considered in the differential. Consensus criteria for the diagnosis of paediatric MS now exist, and the development of evidence-based radiographic criteria will promote even greater diagnostic certainty. Immunomodulatory therapies are well tolerated and efficacious, although prospective studies are required

Search strategy and selection criteria

Publications in English were identified by MEDLINE searches (1975 to March, 2007), and the respective bibliographies. Search terms included “multiple sclerosis”, “acute disseminated encephalomyelitis”, “encephalomyelitis”, “transverse myelitis”, “optic neuritis”, “neuromyelitis optica”, “Devic's disease”, and the more general term “demyelination”, combined with either “child(ren)(hood)”, “pediatric(s)”, “adolescen(t)ce”, “early onset”, or “very early onset”. Single case reports or case

References (180)

  • R Yaari et al.

    Childhood primary angiitis of the central nervous system: two biopsy-proven cases

    J Pediatr

    (2004)
  • E Haddad et al.

    Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis

    Blood

    (1997)
  • J Feldmann et al.

    Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity

    Blood

    (2005)
  • M Tardieu et al.

    What is acute disseminated encephalomyelitis (ADEM)?

    Eur J Paediatr Neurol

    (2004)
  • M Tardieu et al.

    Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome

    Blood

    (2005)
  • S Ozakbas et al.

    Childhood and juvenile onset multiple sclerosis: clinical and paraclinical features

    Brain Dev

    (2003)
  • VA Lennon et al.

    A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis

    Lancet

    (2004)
  • LA Hudson et al.

    Neuromyelitis optica immunoglobulin G in a child

    Pediatr Neurol

    (2006)
  • D Pohl et al.

    Pediatric multiple sclerosis: detection of clinically silent lesions by multimodal evoked potentials

    J Pediatr

    (2006)
  • P Duquette et al.

    Multiple sclerosis in childhood: clinical profile in 125 patients

    J Pediatr

    (1987)
  • L Krupp et al.

    Consensus definitions proposed for pediatric multiple sclerosis

    Neurology

    (2007)
  • DM Wingerchuk et al.

    Revised diagnostic criteria for neuromyelitis optica

    Neurology

    (2006)
  • SJ Pittock et al.

    Brain abnormalities in neuromyelitis optica

    Arch Neurol

    (2006)
  • J Kesselring et al.

    Acute disseminated encephalomyelitis. MRI findings and the distinction from multiple sclerosis

    Brain

    (1990)
  • DM Wingerchuk et al.

    Neuromyelitis optica: clinical predictors of a relapsing course and survival

    Neurology

    (2003)
  • WI McDonald et al.

    Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis

    Ann Neurol

    (2001)
  • CM Poser et al.

    New diagnostic criteria for multiple sclerosis: guidelines for research protocols

    Ann Neurol

    (1983)
  • BG Weinshenker et al.

    Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis

    Ann Neurol

    (2006)
  • CF Lucchinetti et al.

    Risk factors for developing multiple sclerosis after childhood optic neuritis

    Neurology

    (1997)
  • Proposed diagnostic criteria and nosology of acute transverse myelitis

    Neurology

    (2002)
  • A Ghezzi et al.

    Clinical characteristics, course and prognosis of relapsing Devic's neuromyelitis optica

    J Neurol

    (2004)
  • DM Wingerchuk et al.

    The clinical course of neuromyelitis optica (Devic's syndrome)

    Neurology

    (1999)
  • DM Wingerchuk et al.

    Neuromyelitis optica: current treatment options

    Neurology

    (2005)
  • G Alper et al.

    Toward the definition of acute disseminated encephalitis of childhood

    Curr Opin Pediatr

    (2004)
  • JA Leake et al.

    Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features

    Pediatr Infect Dis J

    (2004)
  • SN Murthy et al.

    Acute disseminated encephalomyelitis in children

    Pediatrics

    (2002)
  • JL Hynson et al.

    Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children

    Neurology

    (2001)
  • S Tenembaum et al.

    Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients

    Neurology

    (2002)
  • RK Garg

    Acute disseminated encephalomyelitis

    Postgrad Med J

    (2003)
  • RC Dale et al.

    Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children

    Brain

    (2000)
  • M Stonehouse et al.

    Acute disseminated encephalomyelitis: recognition in the hands of general paediatricians

    Arch Dis Child

    (2003)
  • M Wilejto et al.

    The clinical features, MRI findings, and outcome of optic neuritis in children

    Neurology

    (2006)
  • A Kriss et al.

    Recovery after optic neuritis in childhood

    J Neurol Neurosurg Psychiatry

    (1988)
  • M Knebusch et al.

    Acute transverse myelitis in childhood: nine cases and review of the literature

    Dev Med Child Neurol

    (1998)
  • P Defresne et al.

    Efficacy of high dose steroid therapy in children with severe acute transverse myelitis

    J Neurol Neurosurg Psychiatry

    (2001)
  • K Dunne et al.

    Acute transverse myelopathy in childhood

    Dev Med Child Neurol

    (1986)
  • G Sebire et al.

    High dose methylprednisolone in severe acute transverse myelopathy

    Arch Dis Child

    (1997)
  • CM Chang et al.

    Postinfectious myelitis, encephalitis and encephalomyelitis

    Clin Exp Neurol

    (1992)
  • JM Wilmshurst et al.

    Rapid onset transverse myelitis in adolescence: implications for pathogenesis and prognosis

    Arch Dis Child

    (1999)
  • P Defresne et al.

    Acute transverse myelitis in children: clinical course and prognostic factors

    J Child Neurol

    (2003)
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