RESUMO
BACKGROUND: Pediatric multiple sclerosis (MS) is a rare disorder with significant consequences. Quantitative MRI measurements may provide significant insights, however multicenter collaborative studies are needed given the small numbers of subjects. The goal of this study is to demonstrate feasibility and evaluate lesion volume (LV) characteristics in a multicenter cohort of children with MS. METHODS: A common MRI-scanning guideline was implemented at six member sites of the U.S. Network of Pediatric MS Centers of Excellence. We included in this study the first ten scans performed at each site on patients meeting the following inclusion criteria: pediatric RRMS within 3 years of disease onset, examination within 1 month of MRI and no steroids 1 month prior to MRI. We quantified T2 number, T2-LV and individual lesion size in a total of 53 MRIs passing quality control procedures and assessed gadolinium-enhancing lesion number and LV in 55 scans. We studied MRI measures according to demographic features including age, race, ethnicity and disability scores, controlling for disease duration and treatment duration using negative binomial regression and linear regression. RESULTS: The mean number of T2 lesions was 24.30 ± 19.68 (range:1-113) and mean gadolinium-enhancing lesion count was 1.85 ± 5.84, (range:0-32). Individual lesion size ranged from 14.31 to 55750.60 mm3. Non-white subjects had higher T2-LV (unadjusted pT2-LV = 0.028; adjusted pT2-LV = 0.044), and maximal individual T2-LV (unadjusted pMax = 0.007; adjusted pMax = 0.011) than white patients. We also found a trend toward larger mean lesion size in males than females (p = 0.07). CONCLUSION: Assessment of MRI lesion LV characteristics is feasible in a multicenter cohort of children with MS.
Assuntos
Pessoas com Deficiência , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico , Adolescente , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Masculino , Projetos Piloto , Estados UnidosRESUMO
OBJECTIVE: We sought to determine if vitamin D status, a risk factor for multiple sclerosis, is associated with the rate of subsequent clinical relapses in pediatric-onset multiple sclerosis. METHODS: This is a retrospective study of patients with pediatric-onset multiple sclerosis or clinically isolated syndrome who were consecutively recruited into a prospective cohort at their clinical visit at the pediatric multiple sclerosis center of University of California, San Francisco or State University of New York at Stony Brook. Of 171 eligible patients, 134 (78%) with multiple sclerosis/clinically isolated syndrome were included in the cohort; a further 24 were excluded from this analysis due to lack of available serum (n = 7) or lack of follow-up (n = 17). Serum 25-hydroxyvitamin D(3) levels were measured and were adjusted to reflect a deseasonalized value. The adjusted serum 25-hydroxyvitamin D(3) level was the primary predictor in a multivariate negative binomial regression model in which the main outcome measure was the number of subsequent relapses. RESULTS: Among the 110 subjects, the mean unadjusted 25-hydroxyvitamin D(3) level was 22 +/- 9 ng/ml. After adjustment for age, gender, race, ethnicity, disease duration, disease-modifying therapy, and length of follow-up, every 10 ng/ml increase in the adjusted 25-hydroxyvitamin D(3) level was associated with a 34% decrease in the rate of subsequent relapses (incidence rate ratio, 0.66; 95% confidence interval, 0.46-0.95; p = 0.024). INTERPRETATION: Lower serum 25-hydroxyvitamin D(3) levels are associated with a substantially increased subsequent relapse rate in pediatric-onset multiple sclerosis or clinically isolated syndrome, providing rationale for a randomized controlled trial of vitamin D supplementation.
Assuntos
Calcifediol/sangue , Esclerose Múltipla/sangue , Adolescente , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pediatria , Recidiva , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
An expanded polyglutamine domain in huntingtin underlies the pathogenic events in Huntington disease (HD), characterized by chorea, dementia and severe weight loss, culminating in death. Transglutaminase (TGase) may be critical in the pathogenesis, via cross-linking huntingtin. Administration of the TGase competitive inhibitor, cystamine, to transgenic mice expressing exon 1 of huntingtin containing an expanded polyglutamine repeat, altered the course of their HD-like disease. Cystamine given intraperitoneally entered brain where it inhibited TGase activity. When treatment began after the appearance of abnormal movements, cystamine extended survival, reduced associated tremor and abnormal movements and ameliorated weight loss. Treatment did not influence the appearance or frequency of neuronal nuclear inclusions. Unexpectedly, cystamine treatment increased transcription of one of the two genes shown to be neuroprotective for polyglutamine toxicity in Drosophila, dnaj (also known as HDJ1 and Hsp40 in humans and mice, respectively). Inhibition of TGase provides a new treatment strategy for HD and other polyglutamine diseases.
Assuntos
Cistamina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Doença de Huntington/tratamento farmacológico , Transtornos dos Movimentos/prevenção & controle , Transglutaminases/antagonistas & inibidores , Animais , Encéfalo/enzimologia , Humanos , Camundongos , Camundongos Transgênicos , Sobrevida , Transglutaminases/genética , Redução de Peso/efeitos dos fármacosRESUMO
To address urgent need for strategies to limit mortality from coronavirus disease 2019 (COVID-19), this review describes experimental, clinical and epidemiological evidence that suggests that chronic sub-optimal hydration in the weeks before infection might increase risk of COVID-19 mortality in multiple ways. Sub-optimal hydration is associated with key risk factors for COVID-19 mortality, including older age, male sex, race-ethnicity and chronic disease. Chronic hypertonicity, total body water deficit and/or hypovolemia cause multiple intracellular and/or physiologic adaptations that preferentially retain body water and favor positive total body water balance when challenged by infection. Via effects on serum/glucocorticoid-regulated kinase 1 (SGK1) signaling, aldosterone, tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), aquaporin 5 (AQP5) and/or Na+/K+-ATPase, chronic sub-optimal hydration in the weeks before exposure to COVID-19 may conceivably result in: greater abundance of angiotensin converting enzyme 2 (ACE2) receptors in the lung, which increases likelihood of COVID-19 infection, lung epithelial cells which are pre-set for exaggerated immune response, increased capacity for capillary leakage of fluid into the airway space, and/or reduced capacity for both passive and active transport of fluid out of the airways. The hypothesized hydration effects suggest hypotheses regarding strategies for COVID-19 risk reduction, such as public health recommendations to increase intake of drinking water, hydration screening alongside COVID-19 testing, and treatment tailored to the pre-infection hydration condition. Hydration may link risk factors and pathways in a unified mechanism for COVID-19 mortality. Attention to hydration holds potential to reduce COVID-19 mortality and disparities via at least 5 pathways simultaneously.
Assuntos
COVID-19/complicações , COVID-19/mortalidade , Desidratação/complicações , Saliva/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Aquaporina 5/metabolismo , Água Corporal , COVID-19/genética , COVID-19/fisiopatologia , Citocinas/metabolismo , Ingestão de Líquidos , Predisposição Genética para Doença , Humanos , Proteínas Imediatamente Precoces/metabolismo , Sistema Imunitário , Pulmão/metabolismo , Programas de Rastreamento , Modelos Teóricos , Concentração Osmolar , Proteínas Serina-Treonina Quinases/metabolismo , Sistema Renina-Angiotensina , Fatores de Risco , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Diagnosing multiple sclerosis (MS) in a child is challenging because of the limited diagnostic criteria and their overlap with acute disseminated encephalomyelitis. Pediatric-onset MS patients are more likely to be male, have seizures, and have brainstem and cerebellar symptoms than adults, and are less likely to have spinal cord symptoms than adults. They mostly experience a relapsing-remitting course. Their initial brain MRI shows more frequent involvement of the posterior fossa, less well-defined ovoid lesions, and more confluent lesions that decrease over time in patients with prepubertal onset, making early diagnosis even more difficult. Although disability progression is slower than in adults, pediatric onset MS leads to significant disability at a younger age and may be worse in non-white patients (up to 50% in North America). The rareness of pediatric-onset MS has precluded enrollment in clinical trials. Thus, children are receiving off-label adult therapies without clear evidence of their effectiveness and limited knowledge of their tolerability.
Assuntos
Esclerose Múltipla/epidemiologia , Adolescente , Idade de Início , Encéfalo/patologia , Criança , Diagnóstico Diferencial , Progressão da Doença , Encefalomielite Aguda Disseminada/diagnóstico , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Esclerose Múltipla/psicologia , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Neuromielite Óptica/diagnóstico , Fenótipo , Qualidade de Vida , Fatores de RiscoRESUMO
STUDY OBJECTIVE: To identify the neural structures and pathways underlying cataplexy during status cataplecticus in a narcoleptic patient, using brain perfusion single photon emission computed tomography (SPECT). METHODS: A 68-year-old woman with hypocretin-deficient narcolepsy-cataplexy suffered status cataplecticus after having stopped clomipramine. She underwent a 99mTc-ethylcysteinate dimer brain SPECT during an episode of cataplexy; this image was compared with her brain SPECT during an intervening asymptomatic period. Subtraction SPECT coregistered to magnetic resonance imaging (MRI)(SISCOM)-determined anatomic areas differentially perfused during cataplexy and basal wakefulness state. RESULTS: The areas hyperactivated during cataplexy corresponded on brain MRI with the cingular area, the left and right orbitofrontal cortex, the right temporal cortex, and the right putamen. No significant hypoperfused region was observed during the cataplectic episode. DISCUSSION: Cataplexy during status cataplecticus partially resembles normal rapid eye movement sleep (with high cingular, orbitofrontal, and putamen activity) but without the other imaging characteristics of this state (no hyperactivation of the pons, amygdale, or occipital cortex).
Assuntos
Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Cataplexia/classificação , Cataplexia/diagnóstico , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Encéfalo/diagnóstico por imagem , Cataplexia/diagnóstico por imagem , Eletroencefalografia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Imageamento por Ressonância Magnética , Neuropeptídeos/deficiência , Orexinas , Índice de Gravidade de Doença , Sono REM/fisiologia , Técnica de SubtraçãoRESUMO
STUDY OBJECTIVE: To evaluate eating behavior and energy balance as a cause of increased body mass index (BMI) in narcolepsy. DESIGN: Case controlled pilot study. SETTINGS: University hospital. PARTICIPANTS: 13 patients with narcolepsy (7 "typical" patients, with HLA DQB1*0602 and clear cut cataplexy, with suspected hypocretin deficiency; and 6 "atypical" narcoleptics, i.e., HLA negative or without cataplexy), and 9 healthy controls matched for age, gender, and ethnicity. INTERVENTION: Energy balance was evaluated by measuring BMI, rest energy expenditure with calorimetry, daily food and water intake, and plasma hormone levels. Eating behavior was evaluated using psychometric tests (EAT-40, EDI2, CIDI-2, MADRS). RESULTS: Patients with narcolepsy (whether typical or not) tended to be overweight and to have a lower basal metabolism than controls. Only patients with typical narcolepsy tended to eat less than controls. Narcoleptic patients who were overweight ate half as much as others, indicating caloric restriction. Plasma glucose, cortisol, thyroid, and sex hormones levels did not differ between groups, while prolactin levels were twice as high in patients with narcolepsy as in controls. Narcoleptic patients had higher EAT-40 scores and more frequent features of bulimia nervosa (independent of depressive mood) than controls, suggesting a mild eating disorder, classified as "Eating Disorder Not Other Specified." DISCUSSION: Both lower basal metabolism and subtle changes in eating behavior (rather than in calorie intake) could explain the positive energy balance leading to overweight in narcolepsy. Eating behavior changes may be a strategy to control weight or to avoid daytime sleepiness.
Assuntos
Metabolismo Energético , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Preferências Alimentares , Narcolepsia/metabolismo , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Calorimetria , Estudos de Casos e Controles , Ingestão de Energia , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Feminino , Hormônios Esteroides Gonadais/sangue , Humanos , Hidrocortisona/sangue , Masculino , Narcolepsia/complicações , Obesidade/metabolismo , Projetos Piloto , Psicometria , Hormônios Tireóideos/sangueRESUMO
Osteopontin (OPN) was initially isolated from bovine bone cortex, as a complex syalilated phospho-glyco-protein of around 60 kDa, with many postranslational modifications. It has been long considered a structural bone protein linking bone cells to the bone extracellular matrix (osteo : bone, pontin : bridge). It has been cloned for the first time in 1986. Since then, it was established that it is part of a protein family called SIBLINGs, which genes share common expression in bone and tooth, and encode among others a RGD motif. OPN is an intracellular as well as secreted protein, which binds to multiple organic or mineral ligands, like the integrin receptor alphaVbeta3, CD44, factor H and hydroxyapatite, depending on its final configuration (phosphorylation state). Pleiotropic functions of osteopontin have been demonstrated, and the osteopontin knock out phenotype in mice gave some new insight on the implication of the molecule in vivo. Osteopontin inhibits mineralization in bone and urine. Besides, it is a strong chemoattractive and proinflammatory molecule, implicated in tumors, like breast or prostate cancers, and in the defense against various infectious agents like tuberculosis, listeria or herpes. More recently, its key implication in TH1 mediated autoimmune diseases like multiple sclerosis and its animal model experimental autoimmune encephalomyelitis has been demonstrated. Osteopontin is a valuable therapeutic target in the animal model, and a biological tool correlating with clinical disease activity in humans. Structural, functional and pathological aspects of osteopontin are reviewed, as well as the osteopontin deficient phenotype in mouse.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Sialoglicoproteínas/genética , Sialoglicoproteínas/fisiologia , Animais , Fatores Quimiotáticos/fisiologia , Modelos Animais de Doenças , Humanos , Imunidade/fisiologia , Ligantes , Camundongos , Estrutura Molecular , Osteopontina , Fenótipo , Sialoglicoproteínas/químicaRESUMO
In the past 5 years, there has been an exponential growth in the knowledge about multiple sclerosis (MS) in children and adolescents. Recent publications have shed light on its diagnosis, pathogenesis, clinical course, and treatment. However, there remain several key areas that require further exploration. This article summarizes the current state of knowledge on pediatric MS and discusses future avenues of investigation.
Assuntos
Esclerose Múltipla/diagnóstico , Pediatria , Transtornos Cognitivos/etiologia , Diagnóstico Diferencial , Avaliação da Deficiência , Suscetibilidade a Doenças , Fadiga/etiologia , Humanos , Transtornos Mentais/etiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/genética , Esclerose Múltipla/terapia , Qualidade de VidaRESUMO
BACKGROUND: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown. METHODS: This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch. RESULTS: In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p =â 0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004). CONCLUSIONS: Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies.
Assuntos
Substituição de Medicamentos , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Algoritmos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Quimioterapia Adjuvante , Estudos de Coortes , Progressão da Doença , Substituição de Medicamentos/métodos , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/patologia , Natalizumab , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND: Currently available disease-modifying therapies (DMTs) are known to be only partially effective in adults with multiple sclerosis (MS). Little is known about pediatric patients with MS who experience refractory disease while receiving first-line DMTs. OBJECTIVE: To assess the occurrence and management of refractory disease in a group of pediatric patients with MS treated with first-line DMTs approved for adult patients within a network of pediatric MS centers in the United States. DESIGN, SETTING, AND PATIENTS: A multicenter, retrospective, longitudinal, open-label study design involving record review of 258 patients with pediatric-onset MS (68.6% female; mean [SD] age at disease onset, 13.2 [3.5] years; range of age at onset, 2.0-17.9 years) who were seen at 6 pediatric MS centers in the United States. INTERVENTION: We evaluated medication changes owing to refractory disease in cases of pediatric-onset MS. MAIN OUTCOME MEASURE: Disease stability as represented by lack of medication change for breakthrough disease. RESULTS: Records of 258 children with a confirmed diagnosis of MS and exposure to DMTs were reviewed. Interferon beta (prescribed to 200 of 258 children [77.5%]) and glatiramer acetate (prescribed to 53 of 258 children [20.5%]) were the 2 most frequently used first-line DMTs. Overall, 144 children (55.8%) continued receiving 1 therapy, while 65 (25.2%), 29 (11.2%), and 20 (7.8%) received 2, 3, or 4 or more sequential therapies, respectively, during a mean (SD) observation period of 3.9 (2.8) years. Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%). Hispanic children were more likely to experience breakthrough disease while receiving first-line DMTs than non-Hispanic children. CONCLUSION: Although switching between first-line DMTs may be effective in pediatric patients with disease that is refractory to initial treatment, a subset of patients may require second-line therapeutic interventions.
Assuntos
Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Imunoglobulinas/uso terapêutico , Interferon beta/uso terapêutico , Estudos Longitudinais , Masculino , Natalizumab , Estudos RetrospectivosRESUMO
The health-related quality of life of children with multiple sclerosis was compared with that of healthy children and of those with other neurologic diseases. The Pediatric Quality of Life Inventory Version 4.0 was administered to children with multiple sclerosis and clinically isolated syndrome and their parents (proxy reporters) at the University of California, San Francisco (UCSF), Regional Pediatric Multiple Sclerosis Center. Scores were compared with those of siblings and to those of children seen at the UCSF Pediatric Muscular Dystrophy Association Center. After adjustment for age and sex, children with multiple sclerosis or clinically isolated syndrome (P = 0.003) and their parents (P = 0.001) reported worse overall health-related quality of life than their siblings. Although overall scores for those with early multiple sclerosis or clinically isolated syndrome were better than for children with neuromuscular disease, their self-reported psychosocial scores were similar. The main predictor of reduced self-reported health-related quality of life among children with multiple sclerosis or clinically isolated syndrome was greater neurologic disability, whereas parents reported worse scores for girls, older children, and those with longer disease duration. Although it is better than for children with chronic neuromuscular diseases, children with multiple sclerosis or clinically isolated syndrome have substantial reductions in health-related quality of life.
Assuntos
Adaptação Psicológica/fisiologia , Nível de Saúde , Esclerose Múltipla/psicologia , Pediatria , Qualidade de Vida/psicologia , Adolescente , Criança , Pré-Escolar , Feminino , Indicadores Básicos de Saúde , Humanos , Masculino , Doenças Neuromusculares/psicologia , Valor Preditivo dos Testes , Autoimagem , Índice de Gravidade de Doença , Irmãos , Inquéritos e QuestionáriosRESUMO
IMPORTANCE OF THE FIELD: Pediatric multiple sclerosis is an acquired inflammatory, demyelinating CNS disorder associated with recurrent episodes of neurologic dysfunction. Precise diagnosis is increasingly important as disease modifying therapies have been developed in adults and introduced into pediatric practice. AREAS COVERED IN THIS REVIEW: Literature published over the past two decades relating to pharmacologic treatment of multiple sclerosis (MS) in adults and children is reviewed, with emphasis on current publications. WHAT THE READER WILL GAIN: This article reviews available research and clinical experience regarding treatment of acute episodes of CNS demyelination in children and adolescents, strategies for introduction and modification of disease-modifying therapies depending on disease course, and use of medication for symptomatic improvement in quality of life. TAKE HOME MESSAGE: Pharmacotherapy for MS has been studied in adults but to a significantly lesser extent in children or adolescents. However, children and adolescents have different biology than adults in terms of drug metabolism, immune mechanisms and incomplete maturity of CNS myelin. Effectiveness as well as long-term safety needs to be studied in children and adolescents.
Assuntos
Glucocorticoides/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Peptídeos/uso terapêutico , Troca Plasmática/métodos , Adolescente , Adulto , Criança , Acetato de Glatiramer , Humanos , Esclerose Múltipla/imunologiaRESUMO
Distinguishing between a first episode of multiple sclerosis and acute disseminated encephalomyelitis in children who present with an initial demyelinating event can be a clinical challenge. New brain MRI criteria that aim to differentiate these clinical presentations, and revised McDonald MRI criteria specific for the pediatric population, are both worthy of note.
Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico , Pré-Escolar , Feminino , HumanosRESUMO
The diagnosis of multiple sclerosis (MS) in a child remains challenging, given the limited diagnostic criteria and the somewhat poorly defined overlap with acute disseminated encephalomyelitis. Although there are many similarities between pediatric-onset and adult-onset MS, an earlier age at disease presentation seems to be associated with specific features such as more frequent encephalopathy, seizures, and brainstem and cerebellar symptoms during the first event. In addition, the initial brain MRI scan of younger patients shows more frequent involvement of the posterior fossa and higher numbers of ovoid, ill-defined T2-bright foci that often partially resolve on the follow-up scan, thereby challenging early diagnosis. Finally, the spinal fluid in younger patients may fail to reveal oligoclonal bands or elevated IgG index at disease onset. No therapy for MS in children has been approved by the US Food and Drug Administration. As a result, physicians have started to use off-label drugs approved for adults. Recent data suggest that some children experience a disease breakthrough on first-line therapies approved for adult MS, and thus second-line therapies must be considered.
RESUMO
Pediatric multiple sclerosis (MS) accounts for up to 5% of all MS cases. Work conducted over the past 5 years has provided new information about the treatment, pathogenesis, demographics, and natural history of this disorder. Genetic and environmental factors seem to exert critical influences on its development. Clinical, MRI and laboratory data from prepubertal and postpubertal children suggest differences between the immune response and/or CNS environment in younger compared with older children and adults with MS. Randomized, controlled treatment trials for pediatric MS have not yet been performed, but therapies used in adult MS have been evaluated in this population, and their use seems to be safe. This article provides a comprehensive review of current knowledge regarding pediatric MS, highlighting new advances in the field.
Assuntos
Esclerose Múltipla/etiologia , Esclerose Múltipla/terapia , Pediatria , Adolescente , Adulto , Fatores Etários , Criança , Diagnóstico Diferencial , Progressão da Doença , Suscetibilidade a Doenças , Meio Ambiente , Feminino , Herpesvirus Humano 4/fisiologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/epidemiologia , América do Norte/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores SexuaisRESUMO
OBJECTIVE: To compare initial brain magnetic resonance imaging (MRI) characteristics of children and adults at multiple sclerosis (MS) onset. DESIGN: Retrospective analysis of features of first brain MRI available at MS onset in patients with pediatric-onset and adult-onset MS. SETTING: A pediatric and an adult MS center. PATIENTS: Patients with pediatric-onset <18 years) and adult-onset (> or =18 years) MS. MAIN OUTCOME MEASURES: We evaluated initial and second (when available) brain MRI scans obtained at the time of first MS symptoms for lesions that were T2-bright, ovoid and well defined, large (> or =1cm), or enhancing. RESULTS: We identified 41 patients with pediatric-onset MS and 35 patients with adult-onset MS. Children had a higher number of total T2- (median, 21 vs 6; P < .001) and large T2-bright areas (median, 4 vs 0; P < .001) than adults. Children more frequently had T2-bright foci in the posterior fossa (68.3% vs 31.4%; P = .001) and enhancing lesions (68.4% vs 21.2%; P < .001) than adults. On the second brain MRI, children had more new T2-bright (median, 2.5 vs 0; P < .001) and gadolinium-enhancing foci (P < .001) than adults. Except for corpus callosum involvement, race/ethnicity was not strongly associated with disease burden or lesion location on the first scan, although other associations cannot be excluded because of the width of the confidence intervals. CONCLUSION: While it is unknown whether the higher disease burden, posterior fossa involvement, and rate of new lesions in pediatric-onset MS are explained by age alone, these characteristics have been associated with worse disability progression in adults.
Assuntos
Encéfalo/patologia , Efeitos Psicossociais da Doença , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico , Idade de Início , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Estudos RetrospectivosRESUMO
Multiple sclerosis (MS) occurs at all ages of the pediatric population. Childhood MS may represent up to 10% of all MS cases. Establishing the diagnosis of MS in a child is complicated by the limited diagnostic criteria and the possibility of significant clinical and magnetic resonance imaging (MRI) overlap with acute disseminated encephalomyelitis and other pediatric diseases. Although the clinical profile of MS appears similar to that seen in adults, several features may differ and specific issues arise in children. Sex ratios are different between young children with MS and adolescents--implicating a role for sex hormones in disease pathogenesis and/or modification of disease expression. Younger patients with MS are more likely to have seizures, brainstem, and cerebellar symptoms than adults. Children with MS may have fewer T2 hyperintense areas on MRI scans, therefore not meeting MRI criteria established for adults. It is possible that the pediatric MS course is more indolent than in adult patients but the disease may lead to significant disability at a younger age, e.g., while patients are students, young professionals, or want to start a family. There has been no controlled clinical trial in children with disease modifying therapies approved for adult MS due to the limited number of patients under the age of 18 years compared with the adult contingent. As a result, children are receiving adult therapies in an arbitrary manner and our understanding of pediatric treatment effect and tolerability is limited. Available data on tolerability of approved drugs for adults is reviewed.
Assuntos
Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Criança , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/complicações , Esclerose Múltipla/fisiopatologiaRESUMO
Human narcolepsy is a genetically complex disorder. Family studies indicate a 20-40 times increased risk of narcolepsy in first-degree relatives and twin studies suggest that nongenetic factors also play a role. The tight association between narcolepsy-cataplexy and the HLA allele DQB1*0602 suggests that narcolepsy has an autoimmune etiology. In recent years, extensive genetic studies in animals, using positional cloning in dogs and gene knockouts in mice, have identified abnormalities in hypothalamic hypocretin (orexin) neurotransmission as key to narcolepsy pathophysiology. Though most patients with narcolepsy-cataplexy are hypocretin deficient, mutations or polymorphisms in hypocretin-related genes are extremely rare. It is anticipated that susceptibility genes that are independent of HLA and impinge on the hypocretin neurotransmitter system are isolated in human narcolepsy.