The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex.

BACKGROUND: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. METHODS: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

Neuroimaging characterization of multiple sclerosis lesions in pediatric patients: an exploratory radiomics approach.

Introduction: Multiple sclerosis (MS), a chronic inflammatory immune-mediated disease of the central nervous system (CNS), is a common condition in young adults, but it can also affect children. The aim of this study was to construct radiomic models of lesions based on magnetic resonance imaging (MRI, T2-weighted-Fluid-Attenuated Inversion Recovery), to understand the correlation between extracted radiomic features, brain and lesion volumetry, demographic, clinical and laboratorial data. Methods: The neuroimaging data extracted from eleven scans of pediatric MS patients were analyzed. A total of 60 radiomic features based on MR T2-FLAIR images were extracted and used to calculate gray level co-occurrence matrix (GLCM). The principal component analysis and ROC analysis were performed to select the radiomic features, respectively. The realized classification task by the logistic regression models was performed according to these radiomic features. Results: Ten most relevant features were selected from data extracted. The logistic regression applied to T2-FLAIR radiomic features revealed significant predictor for multiple sclerosis (MS) lesion detection. Only the variable "contrast" was statistically significant, indicating that only this variable played a significant role in the model. This approach enhances the classification of lesions from normal tissue. Discussion and conclusion: Our exploratory results suggest that the radiomic models based on MR imaging (T2-FLAIR) may have a potential contribution to characterization of brain tissues and classification of lesions in pediatric MS.

Clinical predictors of NEDA-3 one year after diagnosis of pediatric multiple sclerosis: an exploratory single-center study.

Introduction: Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of central nervous system that can be diagnosed in pediatric age (<18 years) in 3-5% of the cases. This early onset is associated with higher relapse rates and earlier progression to neurological disability. By using NEDA-3 (No Evidence of Disease Activity-3) criteria, we aimed to identify clinical predictors associated with absence of disease activity and control of disease progression 12 months after the diagnosis, in a cohort of pediatric-onset MS (POMS) patients regularly followed-up in our center. Methods: We analyzed demographic, clinical, laboratorial and imaging variables of patients with POMS identified in our center, between 2010 and 2021, in two moments: at the diagnosis and 12 months after it. Statistical tests were applied to compare the distribution of those variables between groups defined by NEDA-3 status and by each one of its three variable components. Results: We included 27 patients in the study (18 female), with a mean age of 14.8 years (± 2.8), being all diagnosed with relapsing-remitting MS and with a median score of 1.5 at the Expanded Disability Status Scale (EDSS). The use of natalizumab (p = 0.017) and the negativity for anti-EBV IgG antibodies (p = 0.018) at diagnosis were associated with a higher achievement of NEDA-3 status 12 months after, in our cohort. Prescribed treatment was also associated with statistically significant differences in the "absence of MRI activity" component of NEDA-3 (p = 0.006): patients under treatment with natalizumab had a higher probability of achieving this status, and the opposite was observed in glatiramer acetate-treated children. Discussion and conclusion: Our exploratory results underline the pivotal importance that an early and more effective therapeutical approach may have in the control of disease activity, in POMS. Additionally, they also seem to suggest that the presence of anti-EBV antibodies is not innocent, as it can be related to a less favorable evolution of the disease, even at a very early stage. Further studies are needed to confirm the applicability of these variables as prognostic and personalized tools in this clinical setting.

An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene ( LMNB1 ) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR modified cell lines and mouse models, we have identified a novel silencer element that is lost in ADLD patients and that specifically targets overexpression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving the LMNB1 and the recruitment of the PRC2 repressor complex. Loss of the silencer element in ADLD identifies a previously unknown role for silencer elements in tissue specificity and disease causation.

Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.

Multiple sclerosis under the age of ten: the challenge of a rare diagnosis in a special population - a case series.

Introduction: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disease of the central nervous system which, when it begins before the age of 18, is defined as paediatric MS. Most common clinical presentations include long tract involvement, brainstem/cerebellum syndromes, optic neuritis and acute disseminated encephalomyelitis. Paediatric-onset MS typically has a more inflammatory-active course and a higher lesion burden in imaging studies, but an extensive post-relapse recovery, with a slower long-term disability progression. The first demyelinating clinical attack occurs before 10 years old in less than 1% of patients, and, in this special population, the condition has particularities in clinical presentation, differential diagnosis, diagnostic assessment, current treatment options and outcome. Clinical cases: We present the cases of four Caucasian children (2 girls) diagnosed with relapsing-remitting MS before the age of ten, with a mean age at the time of the first relapse of 7.4 ± 2.4 years. Clinical presentation included optic neuritis, myelitis, brainstem syndrome, and acute disseminated encephalomyelitis. Baseline MRI identified several lesions, frequently large and ill-defined. Two patients were included in clinical trials and two patients remain in clinical and imaging surveillance. Conclusion: Diagnosis of MS before the age of 10 years is rare, but it has significant long-term physical and cognitive consequences, as well as a substantial impact on the current and future quality of life of the child and family. Early and correct diagnosis is essential. Prospective, randomized, large cohort studies are needed to assess the efficacy and safety of disease-modifying treatments in children under the age of ten.

Neutrophil/lymphocyte and monocyte/lymphocyte indexes as potential predictors of relapse at 1 year after diagnosis of pediatric multiple sclerosis: a single-center, exploratory and proof-of-concept study.

Introduction: Early identification of patients with a more unfavorable outcome in Multiple Sclerosis (MS) is crucial to optimize individualized treatment. Neutrophil-lymphocyte index (NLI) and monocyte-lymphocyte index (MLI) have been considered as potential biomarkers for disease prognosis. Our study aims to investigate the usefulness of NLI and MLI as predictors of relapse, disability progression, and lesion accumulation on magnetic resonance imaging (MRI) 1 year after diagnosis and treatment initiation, in pediatric-onset MS. Methods: A retrospective single-center study was conducted, including patients with diagnosis of MS established in pediatric age (<18 years old), at least 1-year of follow-up, and a complete blood count (CBC) performed at diagnosis. We collected the nearest-to-diagnosis NLI and MLI, as well as clinical and imaging variables, at diagnosis and 12 months later. Our cohort was further dichotomized into two groups, based on the presence of relapses. Statistical significance was considered for p < 0.05. Results: Eighteen patients (n = 18) were included. The relapsing group had higher mean, minimum, and maximum values for both NLI (5.17 ± 5.85, range: 1.57-11.92) and MLI (0.35 ± 0.22, range: 0.19-0.59), compared to the non-relapsing group (2.19 ± 1.63, range: 1.12-7.32 for NLI, and 0.24 ± 0.09, range: 0.14-0.44 for MLI). A higher percentage of patients in the relapsing group had increased NLI (>1.89, 66.7%) and MLI (>0.21, 66.7%) values than those in the non-relapsing group (46.7%). Patients who presented new T2-hyperintense lesions on MRI after 1 year of follow-up also had higher mean, minimum, and maximum values of both biomarkers. Patients who did not achieve No Evidence of Disease Activity-3 (NEDA-3) state exhibited higher values for both ratios. However, in our sample, no statistically significant correlations were found between MLI and NLI values and the clinical and imaging variables considered. Conclusion: The ease of obtaining NLI and MLI from routine blood tests renders them useful biomarkers as a screening tool in longitudinal follow-up. Our study was based on a very small sample size, but it allowed us to verify the feasibility of the protocol used. It is intended to involve other centers in the next phase of this work, testing the possible usefulness of the indices under analysis on a larger sample.

Monitoring and Managing Patients with Tuberous Sclerosis Complex: Current State of Knowledge.

Tuberous sclerosis complex (TSC) is a rare genetic disease of autosomal dominant transmission that, in most cases, results from the presence of pathogenic variants of the TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively. It is a multisystemic disease, affecting most frequently the brain, skin, kidney, and heart. The wide variety of possible clinical manifestations, given this multisystem dimension, makes the follow-up of patients with TSC an exercise of multidisciplinarity. In fact, these patients may require the intervention of various medical specialties, which thus have to combine their efforts to practice a medicine that is truly holistic. The past few years have witnessed a dramatic leap not only in the diagnosis and management of TSC patients, with standard monitoring recommendations, but also in the therapeutic field, with the use of mTORC1 inhibitors. In this article, we review the clinical manifestations associated with TSC, as well as the treatment and follow-up strategies that should be implemented, from a multidisciplinary perspective.

Defining milestones for the study of remyelination using the cuprizone mouse model: How early is early?

BACKGROUND: Cuprizone (CPZ) is a copper chelator used to produce a reversible oligodendrocytopathy in animals, which has some similarities to the pathology found in human multiple sclerosis (MS). This model is attractive to study remyelination. AIMS: To demonstrate that a two-week period after cessation of CPZ exposure is sufficient to establish changes compatible with remyelination, without accompanying behavior or brain magnetic resonance imaging (MRI) disturbances. METHODS: Two groups of male C57BL/6 mice were fed an oral solution of CPZ (0.2%) for 5 weeks (W5); half of the animals were kept under the vehicle for another 2 weeks (W7). After 5 and 7 weeks, animals were subjected to a battery of behavioural tests and 18 animals to brain MRI. Animals' cerebellar samples were studied for gene expression and/or protein levels of GFAP, myelin proteolipid protein (PLP), TNF-α and IL-1ß. RESULTS: No differences were observed between CPZ-exposed and control animals, regarding behavior and MRI, both at W5 and W7. However, myelin PLP levels decreased in CPZ (W5) treated animals, and these changes reverted at W7. GFAP levels varied in the opposite direction. CONCLUSIONS: Observed changes validate the use of W5 and W7 temporal moments for the study of demyelination and early remyelination in this model.

Systematic review and meta-analysis of the prevalence of coronavirus: One health approach for a global strategy.

Coronaviruses have been responsible for major epidemic crises in 2003 with SARS-CoV-1, in 2012 with MERS-CoV and in 2019 with SARS-CoV-2 (COVID-19), causing serious atypical pneumonia in humans. We intend, with this systematic analysis and meta-analysis, to clarify the prevalence of the various strains of coronavirus in different animal species. For this purpose, we carried out an electronic survey using Pubmed's Veterinary Science search tool to conduct a systematic assessment of published studies reporting the prevalence of different strains of coronavirus in different animal species between 2015 and 2020. We conducted different analysis to assess sensitivity, publication bias, and heterogeneity, using random effect. The final meta-analysis included 42 studies for systematic review and 29 in the meta-analysis. For the geographic regions with a prevalence greater than or equal to 0.20 (Forest plot overall; prevalence = 0.20, p < 0.01, Q = 10,476.22 and I2 = 100%), the most commonly detected viruses were: enteric coronavirus (ECoV), pigeon-dominant coronavirus, (PdCoV), Avian coronavirus M41, Avian coronavirus C46, Avian coronavirus A99, Avian coronavirus JMK, MERS-CoV, Bovine coronavirus, Ro-BatCoV GCCDC1, Alphacoronavirus, Betacoronavirus, Deltacoronavirus, Gamacoronavirus and human coronaviruses (HCoVs). The wide presence of different strains of coronavirus in different animal species on all continents demonstrates the great biodiversity and ubiquity of these viruses. The most recent epidemiological crises caused by coronavirus demonstrates our unpreparedness to anticipate and mitigate emerging risks, as well as the need to implement new epidemiological surveillance programs for viruses. Combined with the need to create advanced training courses in One Health, this is paramount in order to ensure greater effectiveness in fighting the next pandemics.

Pediatric neuromyelitis optica spectrum disorders in Portugal: A multicentre retrospective study.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) are more prevalent in adulthood, with few cases reported in pediatric age (<18 years). In this group, anti-aquaporin 4 (AQP4) antibodies are less frequent, while antibodies against myelin oligodendrocyte glycoprotein (MOG) are more commonly detectable than in adults. OBJECTIVE AND METHODS: Description of pediatric NMOSD cases identified in a national multicentric NMOSD Portuguese registry. RESULTS: Twenty (11.1%) NMOSD cases were diagnosed in pediatric age. Twelve (60%) were female, with a median age of onset of 12.5 (6.8-16.5) years. The presenting feature was transverse myelitis in 10 (50%), 4 of which with simultaneous optic neuritis and 2 with concomitant brainstem syndrome. Nine patients (45%) had pleocytosis in the CSF. Six (30.0%) exhibited anti-AQP4 antibodies, 13 (65.0%) anti-MOG antibodies, and one was seronegative for both. Four anti-AQP4 antibodies-positive patients had ≥1 relapse. Most anti-MOG-positive cases were monophasic (53.8%). In the acute phase, all patients received IV methylprednisolone, nine received IVIg and four plasma exchange. One anti-AQP4-positive patient died. Ten patients (5 anti-AQP4-positive/5 anti-MOG-positive) were on maintenance immunosuppressive therapy at the time of data collection. CONCLUSION: NMOSD may present in pediatric age. It is essential to establish the diagnosis and promptly start therapy to improve the prognosis.

Pediatric cerebral sinus venous thrombosis: clinical characterization of a Portuguese cohort.

INTRODUCTION: Pediatric cerebral sinus venous thrombosis (CSVT) is a rare entity. Risk factors differ from the adults, and treatment is not consensual. With this work, we aimed to characterize a pediatric cohort from two Portuguese tertiary centers. METHODS: All patients under 18 years old with confirmed CSVT admitted between 2006 and 2019 were retrospectively included. Demographics, clinical presentation, workup, and follow-up were evaluated. RESULTS: Fifty-three patients were included, 29 were male (54.7%). Median age was 5 years (IQR 11.08, range 0-17 years old). Headache, seizures and impairment of consciousness were the most frequent manifestations. A risk factor was identified in 90.6% (n = 48), mostly infections (43.8%; n = 21). CNS complications were comprised of hemorrhage, venous infarction, hydrocephalus and edema. Treatment included anticoagulation in 36 patients (67.9%), and there were no recurrences on follow-up. Prognosis was favorable, with most patients presenting no or only slight disability comparing to same age and sex children, on the follow-up. DISCUSSION: In this cohort, impairment of consciousness was the most frequent clinical presentation and infections were the most frequent risk factors. The outcome was mainly favorable, with most patients presenting none or mild disability and without recurrences on follow-up. Studies are needed to define the criteria for anticoagulation and its recommended duration in children.

Neuromyelitis optica spectrum disorders: A nationwide Portuguese clinical epidemiological study.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits. OBJECTIVE: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics. METHODS: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included. RESULTS: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome. CONCLUSION: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries.