Paediatric multiple sclerosis and antibody-associated demyelination: clinical, imaging, and biological considerations for diagnosis and care

Fadda, Giulia; Armangué, Thaís; Hacohen, Yael; Chitnis, Tanuja; Banwell, Brenda

doi:10.1016/s1474-4422(20)30432-4

Cited by 75 publications

(72 citation statements)

References 116 publications

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“…An event of acquired CNS demyelination in children younger than 18 years old, also known as acquired demyelinating syndrome (ADS), could represent one of many neuroinflammatory diseases including AQP4-NMOSD, MOGSD, acute disseminated encephalomyelitis (ADEM) with encephalopathy, or a monophasic disease [ 14 ]. In fact, only 20% of pediatric ADS cases are ultimately diagnosed with POMS [ 15 ].…”

Section: Diagnosis Of Poms and Differential Diagnosismentioning

confidence: 99%

“… Table modified from Fadda et al [ 14 ] ADEM acute disseminated encephalomyelitis, AQP4-NMOSD aquaporin-4 neuromyelitis optica spectrum disorder, CSF cerebrospinal fluid, F:M female:male, LETM longitudinal extensive transverse myelitis, MOGSD myelin oligodendrocyte glycoprotein antibody spectrum disorder, MS multiple sclerosis, OCB oligoclonal bands, ON optic neuritis, POMS pediatric-onset multiple sclerosis …”

Section: Diagnosis Of Poms and Differential Diagnosismentioning

confidence: 99%

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Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

et al. 2021

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Pediatric-onset multiple sclerosis (POMS) is a rare neuroinflammatory and neurodegenerative disease that has a significant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good specificity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions significantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been significantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (fingolimod and teriflunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-β and glatiramer acetate) are also commonly used and result in a significant reduction in inflammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efficacy therapies such as dimethyl fumarate and high-efficacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efficacy DMTs generally provide additional reduction in inflammatory activity when compared with the first-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efficacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials.

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Section: Diagnosis Of Poms and Differential Diagnosismentioning

confidence: 99%

Section: Diagnosis Of Poms and Differential Diagnosismentioning

confidence: 99%

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

et al. 2021

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“…Compared with individual factors, this risk score model exhibited better performance to differentiate the children with relapse in the cohort. Actually, several of these 4 factors have been reported to be associated with clinical relapse; for example, maintenance therapies like AZA, MMF, and rituximab treatment have been demonstrated to decrease the risk of relapse and disability for pediatric patients with NMOSDs (6,12,19,33), and the increase in the risk of relapse was observed frequently in the patients starting with ADEM plus ON/TM (mixed lesion) (34).…”

Section: Discussionmentioning

confidence: 99%

“…Pediatric NMOSDs commonly manifest as recurrent attacks of variable symptoms if untreated and have a high risk of permanent visual and motor deficit due to the stepwise accumulation of disability (12). Hence, the accurate prediction of relapse and the early attack-preventing treatment are crucial for clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

Risk Factors and Nomogram for Predicting Relapse Risk in Pediatric Neuromyelitis Optica Spectrum Disorders

Zhang

Qiao

et al. 2022

Front. Immunol.

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BackgroundNeuromyelitis optica spectrum disorders (NMOSDs) are attack-relapsing autoimmune inflammatory diseases of the central nervous system, which are characterized by the presence of serological aquaporin-4 (AQP4) antibody. However, this disorder is uncommon in children, and AQP4 antibody was often found to be seronegative. However, some pediatric patients diagnosed with NMOSDs were tested to be positive for myelin oligodendrocyte glycoprotein (MOG) antibody. The previous investigations of pediatric NMOSDs were usually focused on the clinical presentation, treatment responses, and long-term prognoses, but little is known about the risk factors predicting NMOSD relapse attacks in a shorter time, especially, for Chinese children.MethodsWe retrospectively identified 64 Chinese pediatric patients, including 39 positive for AQP4 antibody, 12 positive for MOG antibody, and the rest negative for AQP4 and MOG antibodies. Independent risk factors predicting relapse in 1-year follow-up were extracted by multivariate regression analysis to establish a risk score model, its performance evaluation was analyzed using receiver operating characteristic (ROC) curve, and the independent risk factors related to relapse manifestation were also explored through multivariate logistic analysis. A nomogram was generated to assess relapse attacks in 1-year follow-up. Thirty-five patients from 3 other centers formed an external cohort to validate this nomogram.ResultsFour independent relapsed factors included discharge Expanded Disability Status Scale (EDSS) (p = 0.017), mixed-lesion onset (p = 0.010), counts (≧1) of concomitant autoantibodies (p = 0.015), and maintenance therapy (tapering steroid with mycophenolate mofetil (MMF), p = 0.009; tapering steroid with acetazolamide (AZA), p = 0.045; and tapering steroid only, p = 0.025). The risk score modeled with these four factors was correlated with the likelihood of relapse in the primary cohort (AUC of 0.912) and the validation cohort (AUC of 0.846). Also, our nomogram exhibited accurate relapse estimate in the primary cohort, the validation cohort, and the whole cohort, but also in the cohorts with positive/negative AQP4 antibody, and noticeably, it performed predictive risk improvement better than other factors in the concordance index (C-index), net reclassification improvement (NRI), and integrated discrimination improvement (IDI).ConclusionsThe risk score and nomogram could facilitate accurate prognosis of relapse risk in 1-year follow-up for pediatric NMOSDs and help clinicians provide personalized treatment to decrease the chance of relapse.

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“…The results substantiated that mice exposed to BCAS plus CRS exhibited severe anxiety and depression-like behavior due to myelin loss in vHIP, that could be partially mitigated with application of Quercetin, indicating that Quercetin turnovers the loss of mature oligodendrocytes and might potentiate the regenerative ability of OPCs, in a degree. Previous studies have demonstrated that cerebral hypoperfusion is one of the most common pathophysiological mechanism, which is a main cause to cognitive decline and neuropsychiatric symptoms progression in AD and VaD [43][44][45]42]. However, unlike AD, there are no pharmacological treatments for VaD-associated neuropsychiatric symptoms.…”

Section: Discussionmentioning

confidence: 99%

Quercetin Alleviates Demyelination to Mitigate Neuropsychiatric Symptoms Through Promoting Microglia M2 Polarization in Mice with Vascular Dementia

Tan

Yang

Qiu

et al. 2021

Preprint

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Cerebral hypoperfusion plays a pivotal role in the ictus and development of vascular dementia (VaD) with neuropsychiatric symptoms. To date, few pharmacological interventions for neuropsychiatric symptoms are available in the VaD patients with neuropsychiatric impairments. Here, our results demonstrated that the extent of demyelination was dramatically deteriorated and the thickness of myelin sheath were evidently decreased in the presence of cerebral hypoperfusion, whereas Quercetin possessed the potential of abrogating these effects at least in part, then relieving anxiety and depression-like behavior when mice exposed to bilateral carotid artery stenosis (BCAS)/chronic restraint stress (CRS). The underlying mechanism was that Quercetin facilitated microglia transformation into M2 phenotype, which expedited secretion of anti-inflammatory cytokines (IL-4 and IL-10), and in turn decreased production of pro-inflammatory factors (TNF-α and IL-1β), thereafter enhancing the microglial engulfment ability of myelin fragments in vitro and in vivo. Collectively, the results demonstrated that that Quercetin facilitated microglia transition into M2 phenotype to reduce demyelination in ventral hippocampus (vHIP), thereafter mitigating neuropsychiatric deficits (including anxiety and depression). The present research broadens the therapeutic scope of Quercetin in central nervous system (CNS) disorders with presence of white matter damage and/or the insufficient activation of M2 microglia, particularly for vascular dementia with/without neuropsychiatric symptoms.

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Paediatric multiple sclerosis and antibody-associated demyelination: clinical, imaging, and biological considerations for diagnosis and care

Cited by 75 publications

References 116 publications

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

Risk Factors and Nomogram for Predicting Relapse Risk in Pediatric Neuromyelitis Optica Spectrum Disorders

Quercetin Alleviates Demyelination to Mitigate Neuropsychiatric Symptoms Through Promoting Microglia M2 Polarization in Mice with Vascular Dementia

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