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This article presents an overview of evolving diagnostic criteria of pediatric multiple sclerosis and related disorders, emphasizing distinguishing clinical and neuroimaging features that should be considered for differential diagnosis in childhood and adolescence. New data on the integrity of brain tissue in children with MS provided by advanced MR imaging techniques are addressed as well.

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Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI) scans of patients with neuromyelitis optica (NMO) spectrum disorder, but the specific morphological and temporal patterns distinguishing them unequivocally from lesions caused by other disorders have not been identified. This literature review summarizes the literature on advanced quantitative imaging measures reported for patients with NMO spectrum disorder, including proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MR volumetry, and ultrahigh-field strength MRI. It was undertaken to consider the advanced MRI techniques used for patients with NMO by different specialists in the field. Although quantitative measures such as proton MR spectroscopy or magnetization transfer imaging have not reproducibly revealed diffuse brain injury, preliminary data from diffusion-weighted imaging and brain tissue volumetry indicate greater white matter than gray matter degradation. These findings could be confirmed by ultrahigh-field MRI. The use of nonconventional MRI techniques may further our understanding of the pathogenic processes in NMO spectrum disorders and may help us identify the distinct radiographic features corresponding to specific phenotypic manifestations of this disease.

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Paediatric multiple sclerosis (MS) accounts for up to 5% of all MS cases. No therapies have been formally approved for paediatric patients with MS. However, there is published experience on the use of disease modifying therapies in children and adolescents with MS. Neuromyelitis optica (NMO) is an autoimmune inflammatory disease preferentially targeting the optic nerves and spinal cord. This devastating disease usually requires preventive therapy with a range of immunosuppressive medications. There are limited studies informing the use of these medications in children with NMO. This review provides a comprehensive analysis of the published literature on therapeutic interventions in children and adolescents with MS and NMO.

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To expand current knowledge, we examined the safety and tolerability of subcutaneous interferon ß-1a in patients with pediatric-onset multiple sclerosis. Records from 307 patients who had received at least 1 injection of subcutaneous interferon ß-1a for demyelinating events when aged younger than 18 years were reviewed. Overall, 168 (54.7%) patients had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon ß-1a or specific to pediatric patients, 184 (59.9%) had nonserious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment. In conclusion, adult doses of subcutaneous interferon ß-1a (44 and 22 µg, 3 times weekly) were well tolerated in pediatric patients and were associated with reduced relapse rates.

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The advent of magnetic resonance imaging (MRI) has contributed to increase the interest and awareness in childhood white matter disorders. Pediatric inflammatory demyelinating diseases of the central nervous system (CNS) are clinically heterogeneous with respect to their mode of presentation, clinical severity, rate of progression, and prognosis. Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the CNS, typically transitory and self-limiting. The highest incidence of ADEM is observed during childhood. It is characterized by an acute encephalopathy with polyfocal neurological deficits. In the absence of specific biological markers the diagnosis of ADEM is still based on clinical features and MRI evidence of widespread demyelination, after ruling out other possible explanations for an acute encephalopathy. Over the past decade, many retrospective patient studies have focused on clinical and neuroimaging features, in an attempt to define specific diagnostic criteria. The occurrence of relapses in children with ADEM poses diagnostic difficulties in its differentiation from multiple sclerosis (MS) and neuromyelitis optica (NMO). With the widespread use of high-dose steroids, the long-term prognosis of ADEM with regard to functional and cognitive recovery is favorable. This chapter summarizes the available literature on ADEM in children, including the proposed consensus definitions for its monophasic and relapsing variants.

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BACKGROUND AND OBJECTIVE: Acute disseminated encephalomyelitis (ADEM) and relapsing-remitting multiple sclerosis (RRMS) share overlapping clinical, radiologic and laboratory features at onset. Because autoantibodies may contribute to the pathogenesis of both diseases, we sought to identify autoantibody biomarkers that are capable of distinguishing them. METHODS: We used custom antigen arrays to profile anti-myelin-peptide autoantibodies in sera derived from individuals with pediatric ADEM (n = 15), pediatric multiple sclerosis (Ped MS; n = 11) and adult MS (n = 15). Using isotype-specific secondary antibodies, we profiled both IgG and IgM reactivities. We used Statistical Analysis of Microarrays software to confirm the differences in autoantibody reactivity profiles between ADEM and MS samples. We used Prediction Analysis of Microarrays software to generate and validate prediction algorithms, based on the autoantibody reactivity profiles. RESULTS: ADEM was characterized by IgG autoantibodies targeting epitopes derived from myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein, and alpha-B-crystallin. In contrast, MS was characterized by IgM autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein and oligodendrocyte-specific protein. We generated and validated prediction algorithms that distinguish ADEM serum (sensitivity 62-86%; specificity 56-79%) from MS serum (sensitivity 40-87%; specificity 62-86%) on the basis of combined IgG and IgM anti-myelin autoantibody reactivity to a small number of myelin peptides. CONCLUSIONS: Combined profiles of serum IgG and IgM autoantibodies identified myelin antigens that may be useful for distinguishing MS from ADEM. Further studies are required to establish clinical utility. Further biological assays are required to delineate the pathogenic potential of these antibodies.

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Children and adolescents with multiple sclerosis (MS) are reported to show high rates of relapse early in the course of the disease as well as cognitive deterioration over time. Immunomodulatory therapies developed for adult MS patients are currently the standard first-line agents for most paediatric MS patients. Available data indicate that the three interferon-beta preparations and glatiramer acetate are safe and well tolerated in children and adolescents with MS, and provide preliminary indications of efficacy in terms of relapse rate reduction. However, these treatments are only partly effective and their routes of administration can be bothersome, particularly for children. Emerging therapies for MS offer promise for improved disease control and long-term clinical outcome, with the advantage of an oral administration for some of them. The future approval of these new medications requires clinical trial consideration of such therapies in the paediatric population. Many of these new agents carry a higher risk for serious adverse events with increased toxicity and still undefined long-term side effects. There are ethical issues as well as issues related to feasibility that must be borne in mind when planning investigation trials for new pharmacological agents in the paediatric population, including immunological maturity, key period of exposure to numerous community-acquired infections, neurodevelopmental factors, in addition to short-term and long-term age-related toxicities. Furthermore, the lack of a large enough paediatric MS population worldwide limits some designs and the feasibility of participation in all the studies. Emerging new therapies have the potential to optimize the care of both paediatric and adult patients with MS. Future treatment trials in children and adolescents with MS will require a multicentre design, definition and selection of key outcome measures, and identification of the most promising therapies. Risks versus benefits of each specific treatment should be weighed and comprehensively discussed.

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Neuromyelitis optica (NMO) is an autoimmune demyelinating disease preferentially targeting the optic nerves and spinal cord. Once regarded as a variant of multiple sclerosis (MS), NMO is now recognized to be a different disease with unique pathology and immunopathogenesis that does not respond to traditional MS immunomodulators such as interferons. Preventive therapy in NMO has focused on a range of immunosuppressive medications, none of which have been validated in a rigorous randomized trial. However, multiple retrospective and a few recent prospective studies have provided evidence for the use of six medications for the prevention of NMO exacerbations: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate and mitoxantrone. This review provides a comprehensive analysis of each of these medications in NMO and concludes with a set of recommended consensus practices.

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PURPOSE OF REVIEW: Pediatric-onset multiple sclerosis (MS) is increasingly recognized. Conversely, MS diagnosis in the pediatric population continues to be challenging, particularly in the youngest group of patients. An interesting amount of data has been recently published concerning immunopathogenesis, environmental factors, diagnosis, and treatment of MS in pediatric patients. RECENT FINDINGS: Recent studies have demonstrated that brain MRI criteria may distinguish MS from acute disseminated encephalomyelitis, and from nondemyelinating disorders in children. The presence of native myelin oligodendrocyte glycoprotein antibodies strongly correlates with a particular pediatric MS phenotype. Vitamin D, Epstein-Barr virus infection, and cigarette smoke are risk factors likely to act at specific stages during life. Diffuse tissue damage was confirmed in normal-appearing white matter at early stages of disease in children with MS, pointing to the need for early treatment interventions. The cognitive involvement of MS in children is progressive. SUMMARY: Pediatric-onset MS needs a prompt identification and early treatment. Further multinational research studies are still necessary to advance on genetic, immunologic, and imaging features on the initial and ongoing aspects of this disorder in the pediatric population.

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BACKGROUND: Paediatric multiple sclerosis accounts for up to 10% of all MS cases. The initial course of the disease is relapsing-remitting in most children, with a relapse rate generally higher than that observed in adult patients. There is published experience on the use of first-line disease modifying therapies in children with MS. However, about 1/3 of paediatric MS cases do not respond to IFN-beta or glatiramer acetate and continue to develop relapses and disease progression. These patients could be proposed to a second-line treatment. METHODS: A comprehensive review of the published literature related to pharmacologic treatment of MS in adults and paediatric patients was performed. The recent literature has been extracted for new evidence from controlled trials in adult patients, and open treatment studies and reported expert opinion in paediatric patients. RESULTS: No disease modifying drug has been approved for the treatment of children and adolescents with MS, although the currently available first-line therapies for adults seem to be safe and well tolerated in this population. Further studies are required to assess the safety and efficacy of second-line treatments in children with MS. CONCLUSION: The present article constitutes an update of the existing publications regarding treatment of acute events of CNS demyelination in children and adolescents as well as considerations for the use of immunomodulatory therapies.

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The advent of MRI has contributed to increase the interest and awareness in childhood white matter disorders. A major priority is to distinguish transient and self-limited demyelinating syndromes like disseminated encephalomyelitis (DEM), from life-long diseases like multiple sclerosis (MS). However, the term DEM has been inconsistently applied across studies due to the lack of clear clinical and neuroimaging diagnostic criteria. The present review summarizes the available literature on DEM in children, outlines the main clinical and neuroimaging features at presentation, pathogenesis and outcome, and its differentiation from other conditions with acute impact in the CNS. The recently proposed clinical definitions for monophasic disseminated encephalomyelitis and its relapsing variants are discussed, and controversies surrounding the diagnosis of MS in children are addressed.

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Multiple sclerosis (MS) is usually a disease of young adulthood, its clinical onset occurring between 20 and 40 years of age; however, today there is general consensus that MS can also occur in children, adolescents and even in infants. In order to gain further insight into the T-cell repertoire present in this particular group of patients myelin basic protein (MBP)-, MBP exon-2- and myelin oligodendrocyte glycoprotein (MOG)Igd-specific T-cell lines (TCLs) were isolated from 18 patients whose symptoms had started before the age of 16. Epitope specificity was established by measuring proliferative responses, and interferon-y (IFN-y) secretion by using a panel of overlapping synthetic peptides. For MOGIgd, the T-cell response was focused on three main immunodominant epitopes comprising residues 1-26, 36-60 and 63-87. For MBP the predominant immune responses were directed against peptides 83-102, 139-153 and 146-162. When compared to those observed in adult-onset MS patients, anti-MOGIgd specificity and anti-MBP responses showed similar results. Moreover, the number of MBP exon-2 TCLs isolated, and the magnitude of the specific IFN-gamma secretion induced were similar, both in childhood/juvenile-onset and adult-onset MS patients. Thus, despite differences in the clinical and neuroimaging manifestations of MS, these results would seem to indicate that both the spectrum of MBP found, as well as the MOGIgd epitopes recognized by peripheral blood T cells in MS, appear to be similar for childhood/juvenile-onset and adult-onset patients.

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The authors studied the safety and tolerability of subcutaneous interferon beta-1a at different doses in 24 children with clinically definite multiple sclerosis. After a mean treatment period of 44 months, interferon beta-1a was well tolerated in 22 patients, although two experienced possible serious adverse events. Although effectiveness cannot be inferred from this study, the authors did observe a significant reduction in the relapse rate at 22 mug, three times weekly, in the relapsing-remitting subgroup.

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La encefalomielitis aguda diseminada, la esclerosis múltiple, la neuritis óptica, la mielitis transversa y la neuromielitis óptica son algunos ejemplos de trastornos desmielinizantes, cuyos criterios diagnósticos en adultos son objeto de revisión permanente. Se actualizarán los aspectos importantes de las dos enfermedades desmielinizantes más frecuentes en pediatría. La encefalomielitis aguda diseminada puede ocurrir a cualquier edad, es más frecuente en niños y presenta curso monofásico. Sin embargo, se han descrito algunas formas con recaídas, haciendo difícil su distinción de la esclerosis múltiple. Los pacientes con encefalomielitis aguda diseminada inicial que evolucionan a la esclerosis múltiple varían entre 9.5-27 por ciento. No existe tratamiento estandarizado más allá de las medidas iniciales de sostén. No se ha realizado hasta el momento un ensayo controlado y asignado al azar para su tratamiento en niños o en adultos. El tratamiento con corticoides constituye la terapia más utilizada y mejor tolerada en pacientes pediátricos. El diagnóstico de esclerosis múltiple en pacientes menores de diez años es excepcional. Las características de las neuroimágenes en niños difieren del patrón usual del adulto. La esclerosis múltiple se define como una enfermedad del sistema nervioso central caracterizada por desmielinización, inflamación y daño axonal. La forma evolutiva más frecuente, en niños, es la esclerosis múltiple con recaídas y remisiones (80 por ciento a los diez años), seguida por las formas: secundaria progresiva (26 por ciento) y primaria progresiva (6-14 por ciento). Es necesario reconsiderar el límite inferior de edad para el diagnóstico de esclerosis múltiple, o bien, desarrollar criterios diagnósticos clínicos y radiológicos específicos para pacientes pediátricos. Debe considerarse la particular forma de presentación en los niños menores de diez años y establecer claramente el diagnóstico diferencial con las formas recurrentes y multifásicas ...

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La encefalomielitis diseminada aguda (EMDA) es una enfermedad desmielinizante son retrospectivas, con seguimiento a corto plazo. El objetivo de este trabajo es describir una extensa cohorte pediátrica con EMDA, su pronóstico a largo plazo y establecer indicadores clínicos o neuroradiológicos pronósticos. Pacientes y método: estudio prospectivo y longitudinal (1989 2004) en 111 pacientes que cumplieron criterios diagnósticos para EMDA. Resultados: edad de inicio (media) 6 más o menos 3.9 años (rango, 0.4 menos16 años). Antecedente viral o vaccinal en el 79 por ciento. El cuadro de presentación incluyó compromiso de la conciencia (86 por ciento), signos piramidales (82 por ciento), hemi o cuadriparesia aguda (76 por ciento) y ataxia (53 por ciento). Se identificaron cuatro subgrupos por RMN. Los pacientes estudiados no presentaron bandas oligocionales intratecales. El tratamiento con altas dosis de corticoides se asoció con una buena recuperación neurológica y resolución de las lesiones. Seguimiento: media de 8.6 más o menos 3.8 años (rango, 1 a 17 años). El 94 por ciento tuvo una evolución monofásica, y el 6 por ciento restante bifásica. Noventa y ocho niños (88 por ciento) mostraron buena recuperación , con evaluaciones normales o hallazgos semiológicos sin discapacidad actual. No encontramos asociación significativa entre los subgrupos radiológicos y el pronóstico final. La discapacidad residual se asoció con compromiso inicial del nervio óptico. Conclusiones: la EMDA pediátrica puede considerarse una enfermedad de buen pronóstico. Su frecuencia real es mayor que la publicada. Las características de la RMN no tienen valor predictivo pronóstico. Aún en los casos con recaídas, es posible establecer la diferencia entre EMDA y esclorosis múltiple infantil(AU)

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La encefalomielitis diseminada aguda (EMDA) es una enfermedad desmielinizante son retrospectivas, con seguimiento a corto plazo. El objetivo de este trabajo es describir una extensa cohorte pediátrica con EMDA, su pronóstico a largo plazo y establecer indicadores clínicos o neuroradiológicos pronósticos. Pacientes y método: estudio prospectivo y longitudinal (1989 2004) en 111 pacientes que cumplieron criterios diagnósticos para EMDA. Resultados: edad de inicio (media) 6 más o menos 3.9 años (rango, 0.4 menos16 años). Antecedente viral o vaccinal en el 79 por ciento. El cuadro de presentación incluyó compromiso de la conciencia (86 por ciento), signos piramidales (82 por ciento), hemi o cuadriparesia aguda (76 por ciento) y ataxia (53 por ciento). Se identificaron cuatro subgrupos por RMN. Los pacientes estudiados no presentaron bandas oligocionales intratecales. El tratamiento con altas dosis de corticoides se asoció con una buena recuperación neurológica y resolución de las lesiones. Seguimiento: media de 8.6 más o menos 3.8 años (rango, 1 a 17 años). El 94 por ciento tuvo una evolución monofásica, y el 6 por ciento restante bifásica. Noventa y ocho niños (88 por ciento) mostraron buena recuperación , con evaluaciones normales o hallazgos semiológicos sin discapacidad actual. No encontramos asociación significativa entre los subgrupos radiológicos y el pronóstico final. La discapacidad residual se asoció con compromiso inicial del nervio óptico. Conclusiones: la EMDA pediátrica puede considerarse una enfermedad de buen pronóstico. Su frecuencia real es mayor que la publicada. Las características de la RMN no tienen valor predictivo pronóstico. Aún en los casos con recaídas, es posible establecer la diferencia entre EMDA y esclorosis múltiple infantil

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