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

Department of Paediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
The Lancet Neurology (Impact Factor: 21.82). 11/2007; 6(10):887-902. DOI: 10.1016/S1474-4422(07)70242-9
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: Objective: Axonal damage occurs early in multiple sclerosis (MS) and contributes to the degree of clinical disability. Children with MS more often show disabling and polyfocal neurological symptoms at disease onset than adults with MS. Thus, axonal damage may differ between pediatric and adult MS patients.Methods: We analyzed axonal pathology in archival brain biopsy and autopsy samples from 19 children with early MS. Lesions were classified according to demyelinating activity and presence of remyelination. Axonal density and extent of acute axonal damage were assessed using Bielschowsky's silver impregnation and immunohistochemistry for amyloid precursor protein (APP) respectively. Axonal injury was correlated with the inflammatory infiltrate as well as clinical characteristics. Results were compared with data from adult MS patients.Results: Acute axonal damage was most extensive in early active demyelinating (EA) lesions of pediatric patients and correlated positively with the Expanded Disability Status Scale at attack leading to biopsy/autopsy. Comparison with 12 adult patients showed a 50% increase in the extent of acute axonal damage in EA lesions from children compared to adults, with the highest number of APP-positive spheroids found prior to puberty. The extent of acute axonal damage correlated positively with the number of lesional macrophages. Axonal density was reduced in pediatric lesions irrespective of the demyelinating activity or the presence of remyelination. Axonal reduction was similar between children and adults.Interpretation: Our results provide evidence for more pronounced acute axonal damage in inflammatory demyelinating lesions from children compared to adults. This article is protected by copyright. All rights reserved.
    Annals of Neurology 01/2015; DOI:10.1002/ana.24364 · 11.91 Impact Factor
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    ABSTRACT: In multiple sclerosis (MS), cerebellar signs and symptoms as well as cognitive dysfunction are frequent and contribute to clinical disability with only poor response to symptomatic treatment. The current consensus paper highlights the broad range of clinical signs and symptoms of MS patients, which relate to cerebellar dysfunction. There is considerable evidence of cerebellar involvement in MS based on clinical, histopathological as well as structural and functional magnetic resonance imaging (MRI) studies. The review of the recent literature, however, also demonstrates a high variability of results. These discrepancies are, at least partially, caused by the use of different techniques and substantial heterogeneity among the patient cohorts in terms of disease duration, number of patients, and progressive vs. relapsing disease courses. Moreover, the majority of studies were crosssectional, providing little insight into the dynamics of cerebellar involvement in MS. Some links between the histopathological changes, the structural and functional abnormalities as captured by MRI, cerebellar dysfunction, and the clinical consequences are starting to emerge and warrant further study. A consensus is formed that this line of research will benefit from advances in neuroimaging techniques that allow to trace cerebellar involvement at higher resolution. Using a prospective study design, multimodal high-resolution cerebellar imaging is highly promising, particularly in patients who present with radiologically or clinically isolated syndromes or newly diagnosed MS.
    The Cerebellum 01/2015; DOI:10.1007/s12311-014-0634-8 · 2.60 Impact Factor
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    ABSTRACT: To identify early prognostic factors of relapse and disability in children presenting with an acute idiopathic transverse myelitis (TM). Ninety-five children with acute idiopathic TM from 2 national European cohorts (France and United Kingdom) of CNS demyelinating diseases in children were identified and studied for early factors that predict relapse and disability using logistic regression models. Sixteen (17%) relapsed, with a diagnosis of multiple sclerosis in 13 (14%) and neuromyelitis optica in 3 (3%). Logistic regression revealed 2 main criteria as risk factors for relapse: female sex (odds ratio [OR] 3.21, 95% confidence interval [CI] 0.88-11.78) and presence of associated brain lesions (OR 14.0, 95% CI 2.8-69.3). Twenty-eight (30%) children had a poor outcome defined by a Kurtzke Expanded Disability Status Scale score ≥4 or an American Spinal Injury Association impairment (ASIA) scale <D at last follow-up. Five factors were associated with poor outcome: female sex (OR 5.8, 95% CI 0.99-32.7), severe ASIA scale at onset (OR 33.5, 95% CI 1.8-618), gadolinium enhancement on spinal MRI (OR 24.1, 95% CI 3.78-153.88), absence of pleocytosis (OR 4.6, 95% CI 0.87-26.0), and absence of cervical or cervico-thoracic lesion on spinal MRI (OR 3.9, 95% CI 0.78-19.6). Early predictors of relapse and disability identified in this large childhood study of acute idiopathic TM have important utility for clinical management. Larger prospective collaborative studies are required to validate these findings, which may improve the design of clinical trials. © 2014 American Academy of Neurology.
    Neurology 12/2014; DOI:10.1212/WNL.0000000000001179 · 8.30 Impact Factor

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