A prediction rule for polyarticular extension in oligoarticular-onset juvenile idiopathic arthritis.

OBJECTIVES: To search for predictors of polyarticular extension in children with oligoarticular-onset juvenile idiopathic arthritis (JIA) and to develop a prediction model for an extended course. METHODS: The clinical charts of consecutive patients with oligoarticular-onset JIA and ≥2 years of disease duration were reviewed. Predictor variables included demographic data, number and type of affected joints, presence of iridocyclitis, laboratory tests including antinuclear antibodies, and therapeutic interventions in the first 6 months. Joint examinations were evaluated to establish whether after the first 6 months of disease patients had persistent or extended course (i.e. involvement of 4 or less, or 5 or more joints). Statistics included univariable and multivariable analyses. Regression coefficients (ß) of variables that entered the best-fitting logistic regression model were converted and summed to obtain a "prediction score" for an extended course. RESULTS: A total of 480 patients with a median disease duration of 7.4 years were included. 61.2% had persistent oligoarthritis, whereas 38.8% experienced polyarticular extension. On multivariable analysis, independent correlations with extended course were identified for the presence of ≥2 involved joints and a CRP >0.8 mg/dl in the first 6 months. The prediction score ranged from 0 to 6 and its cut-off that discriminated best between patients who had or did not have polyarticular extension was >1. Sensitivity and specificity were 59.6 and 79.8, respectively. CONCLUSIONS: The number of affected joints and the CRP level in the first 6 months were the strongest predictors of polyarticular extension in our children with oligoarticular-onset JIA.

Analysis of arthritis flares after achievement of inactive disease with methotrexate monotherapy in juvenile idiopathic arthritis.

OBJECTIVES: To investigate the frequency of arthritis flare and factors affecting occurrence of flare in children with juvenile idiopathic arthritis (JIA) who achieved inactive disease (ID) with methotrexate (MTX) monotherapy. METHODS: A total of 217 patients were included. The modality of treatment discontinuation, time of MTX withdrawal, and disease course were examined retrospectively. For each patient, the first episode of ID after MTX start was evaluated. Patient follow-up was censored at occurrence of flare or at last visit with persistent ID. RESULTS: 170 patients (78.3%) had arthritis flare after a median of 1.6 years, whereas 47 (21.7%) maintained ID until last visit, after a median of 3 years. 54.2% of patients had discontinued MTX after ID, whereas 45.8% were still receiving MTX at the time of study censoring. Among patients who had MTX withdrawn, the median interval between ID and MTX stop was 1.5 years. Occurrence of flare was more common in patients who were still receiving MTX at study censoring than in those who had discontinued MTX (p<0.001). Most patients (78.8%) had MTX tapered over time by increasing the interval between doses. Tapering modality was comparable between patients with flare and persistent ID. Only 7.7% of the patients had a biologic DMARD started at the time of flare. CONCLUSIONS: Our results confirm that children with JIA who achieve ID with MTX monotherapy have a high risk of arthritis flare. The risk of flare was independent of withdrawal strategy. Most flare episodes were not treated with biologic therapy.

Spatial coefficient of variation applied to arterial spin labeling MRI may contribute to predict surgical revascularization outcomes in pediatric moyamoya vasculopathy.

PURPOSE: In moyamoya vasculopathy, prolonged arterial transit time may increase the arterial spin labeling (ASL) signal heterogeneity, which can be quantitatively expressed by the spatial coefficient of variation of ASL-CBF (ASL-sCoV). The aim was to compare the accuracy of ASL-sCoV and ASL-CBF with dynamic susceptibility contrast (DSC)-CBF and time-to-peak (DSC-TTP) in the evaluation of perfusion changes and clinical outcome after encephalo-duro-arterio-myo-synangiosis (EDAMS) in pediatric moyamoya patients. METHODS: A total of 37 children with moyamoya vasculopathy (mean age 6.31 years (1.12-15.42)) underwent ASL and DSC perfusion imaging at 3T before and up to 24 months after EDAMS. Mean DSC-CBF, mean DSC-TTP, mean ASL-CBF, and ASL-sCoV were calculated in middle cerebral artery territories. Generalized linear model analyses were used to evaluate temporal variations of postoperative perfusion changes and to compare these variations between patients developing valid pial collateralization and those without angiographic improvement. Relationship between perfusion parameters and clinical outcome after surgery was tested using multivariate regression analysis. RESULTS: Significant reduction was observed after EDAMS for ASL-sCoV (P = .002; eta-squared (η2) = 0.247) and DSC-TTP (P < .001; η2 = 0.415), whereas only a trend of increase was observed for DSC-CBF and ASL-CBF, with larger discrepancy before and 6 months after surgery. At last follow-up, children developing pial collateralization showed lower absolute ASL-sCoV (P = .002 Cohen's d = 0.84) and DSC-TTP (P = .027; Cohen's d = 0.64) and higher DSC-CBF (P = .002; Cohen's d = - 0.55) compared with those without vascular improvement. Low preoperative and early post-surgical ASL-sCoV predicted better long-term neurological outcome (P < .001; ß = - 0.631). CONCLUSIONS: ASL-sCoV may contribute to predict surgical outcomes in pediatric moyamoya patients undergoing EDAMS.

Correction to: Spatial coefficient of variation applied to arterial spin labeling MRI may contribute to predict surgical revascularization outcomes in pediatric moyamoya vasculopathy.

This article was published online with incorrect alignment in Table 4. Column and rows are out of order. The correct Table 4 is presented here. The original article has been corrected.

Novel asymptomatic CNS findings in patients with ACVR1/ALK2 mutations causing fibrodysplasia ossificans progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva is an autosomal dominant disorder due to germline mutations of ACVR1/ALK2 causing progressive heterotopic endochondral ossifications. Evidence of central nervous system involvement has emerged only recently. METHODS: We performed an observational cross-sectional brain MRI study in 13 patients (8 females, mean age 20 years), examining the relationship of clinical and neuroradiological findings. RESULTS: All patients presented small asymptomatic lesions similar to hamartomas at the level of the dorsal medulla and ventral pons, associated with minor brainstem dysmorphisms and abnormal origin of the vestibulocochlear and facial nerves. The size of the brainstem lesions did not correlate with patient's age (p=0.061), age at first flare-up (p=0.733), severity of disability (p=0.194), history of head trauma (p=0.415) or hearing loss (p=0.237). The radiologic features and the absence of neurological symptoms were consistent with a benign process. Variable signal abnormalities and/or calcifications of the dentate nuclei were noted in all patients, while basal ganglia abnormalities were present in nine subjects. Brain calcifications positively correlated with patient's age (p<0.001) and severity of disability (p=0.002). CONCLUSIONS: Our data support the hypothesis that the effects of mutation of the ACVR1/ALK2 gene are extended to the central nervous system. Brainstem hamartomatous lesions and dysmorphisms, variably associated with dentate nucleus and basal ganglia signal abnormalities and/or calcifications, may represent useful disease hallmarks.

New insights into central nervous system involvement in FOP: Case report and review of the literature.

Fibrodyspasia ossificans progressiva is an autosomal dominant disease due to activating mutations in activin receptor type IA and characterized by progressive heterotopic ossification. Recently, the same non-synonymous heterozygous somatic mutations of ACVR1 have been identified in brain biopsies or autopsy of 24-27% of patients with a rare cerebral tumor, the diffuse intrinsic pontine glioma. We report the first case of a patient with FOP with incidental findings of an abnormal soft tissue mass surrounding the brainstem and causing obstructive hydrocephalus, associated with bilateral dentate lesions. Clinico-radiological course during 10 years of follow-up was consistent with a benign lesion, excluding an oncogenic role of ACVR1 mutations.

A practical approach to the use of low molecular weight heparins in VTE treatment and prophylaxis in children and newborns.

Low-molecular weight heparins are currently the most commonly used anticoagulants in children and newborns. However, since thrombotic complications rarely occur outside large children's hospitals, physicians often encounter some practical problems in managing these treatments when a pediatric thrombosis specialist is not available. The drug of choice is enoxaparin, due to its favorable FXa/FIIa ratio and the availability of pharmacokinetic and pharmacodynamic data. The treatment of acute thrombosis should be started with two daily injections but when compliance is an issue, a single daily administration schedule could be chosen for secondary prophylaxis ensuring careful measurement of the post 24-hour anti-FXa activity. Furthermore, a subcutaneous device may be a useful tool and a topical dermal anesthetic could be effective in controlling pain without affecting anti-FXa levels. In neonate and toddlers, where mini doses are frequently needed, the dead space of syringes and needles could represent an issue and therefore the use of insulin syringes without dead space is advisable, while a dilution of the drug is useful with other syringes. This article derives from a nonsystematic review of the available literature, with special attention to recent international guidelines and expert recommendations, combined to authors' clinical practice in large tertiary pediatric hospitals and will provide concise and practical information for the use of low-molecular weight heparin in childhood and infancy in a sort of "answering frequently asked questions."

Arterial Ischemic Stroke in Children.

Arterial ischemic stroke (AIS) in children has a high mortality and life-long disability rate in surviving patients. Diagnostic delays are longer and risk factors are different compared with AIS in the adult population. Congenital heart disease, cervical arterial dissection, and intracranial arteriopathies are the main causes of AIS in children. New revascularization time windows in children require the definition of diagnostic protocols for stroke in each referral center. In this article, we discuss the neuroimaging techniques and protocols, describe the main underlying causes, and review the current treatment options for pediatric and perinatal AIS.

Pediatric intensive bowel continence rehabilitation training: a retrospective study to evaluate feasibility, tolerance and effectiveness.

BACKGROUND: Pediatric continence dysfunction is not uncommon. It causes long-term disability, impairing quality of life, activities and relationships with pears and can affect until adulthood. A high-risk population are children with Hirschsprung's disease and congenital anorectal malformation. Conservative medical and surgical management of continence dysfunction in this population is deeply described, while the rehabilitation issues are still unexplored. Aim of this study is to preliminary verify the feasibility, tolerance and effectiveness of an intensive technological aided and individualized pelvic floor rehabilitation program for pediatric patients. METHODS: This is a single-center, retrospective observational study. The assessment was performed by collecting demographic data, general and local physical examination and scoring assessment tools (Rintala Continence Score and Wexner Score). The study was conducted in the Rehabilitation Unit of the pediatric Giannina Gaslini Institute, a tertiary care pediatric hospital in Genoa (Italy) between September 2015 to August 2019. We enrolled 31 children; 25 male (80.6%) and six females (19%), aged between 5 and 14 years (mean age 9 years) at the beginning of the training. Twenty children (65.5%) had Hirschsprung's disease, and 11 children (34.5%) had a congenital anorectal malformation. The rehabilitation training program was customized on the compromised function, the anatomic characteristics, the child's age and compliance. The training was aimed at improving tone, strength, endurance of the pelvic floor, compliance and rectal sensitivity, and also the frequency of the bowel movements. All patients enrolled in the study underwent an intensive outpatient treatment lasted 5 days for children older than 7 years; 10 days for younger. The intensive rehabilitation treatment was followed by a continuous home training program. RESULTS: Twenty-nine children (96.8%) completed the training. A global improvement is observed in continence functioning in all the cohort at T1 (P<0.0001), maintained at T3 (P<0.0001) at both Rintala Continence Score and Wexner Score. No adverse effects have been referred. CONCLUSIONS: Our specific pediatric training program for pelvic floor rehabilitation is effective and safe for children with continence dysfunctions after pelvic surgery due to Hirschsprung's disease and anorectal malformations. The continence rehabilitation multimodal program should be integrated in the care of children with continence dysfunctions. It cooperates in the prevention of the long-term health global impairment and also in the reduction of social economic effort.

The wide world of technological telerehabilitation for pediatric neurologic and neurodevelopmental disorders - a systematic review.

Introduction: The use of Information and Communication Technology (ICT) for assessing and treating cognitive and motor disorders is promoting home-based telerehabilitation. This approach involves ongoing monitoring within a motivating context to help patients generalize their skills. It can also reduce healthcare costs and geographic barriers by minimizing hospitalization. This systematic review focuses on investigating key aspects of telerehabilitation protocols for children with neurodevelopmental or neurological disorders, including technology used, outcomes, caregiver involvement, and dosage, to guide clinical practice and future research. Method: This systematic review adhered to PRISMA guidelines and was registered in PROSPERO. The PICO framework was followed to define the search strategy for technology-based telerehabilitation interventions targeting the pediatric population (aged 0-18) with neurological or neurodevelopmental disorders. The search encompassed Medline/PubMed, EMBASE, and Web of Science databases. Independent reviewers were responsible for selecting relevant papers and extracting data, while data harmonization and analysis were conducted centrally. Results: A heterogeneous and evolving situation emerged from our data. Our findings reported that most of the technologies adopted for telerehabilitation are commercial devices; however, research prototypes and clinical software were also employed with a high potential for personalization and treatment efficacy. The efficacy of these protocols on health or health-related domains was also explored by categorizing the outcome measures according to the International Classification of Functioning, Disability, and Health (ICF). Most studies targeted motor and neuropsychological functions, while only a minority of papers explored language or multi-domain protocols. Finally, although caregivers were rarely the direct target of intervention, their role was diffusely highlighted as a critical element of the home-based rehabilitation setting. Discussion: This systematic review offers insights into the integration of technological devices into telerehabilitation programs for pediatric neurologic and neurodevelopmental disorders. It highlights factors contributing to the effectiveness of these interventions and suggests the need for further development, particularly in creating dynamic and multi-domain rehabilitation protocols. Additionally, it emphasizes the importance of promoting home-based and family-centered care, which could involve caregivers more actively in the treatment, potentially leading to improved clinical outcomes for children with neurological or neurodevelopmental conditions. Systematic review registration: PROSPERO (CRD42020210663).

Emotional and social functioning after stroke in childhood: a systematic review.

PURPOSE: To provide an overview of the effects of pediatric stroke on emotional and social functioning in childhood. METHODS: A literature review was completed in accordance with the Preferred Reporting Items for Systematic Reviews. A systematic search of studies on internalizing problems and social functioning after pediatric stroke in PsycInfo, PsycArticles, and PubMed databases was conducted from inception to November 2021. A total of 583 studies were identified, and 32 met the inclusion criteria. RESULTS: The review suggests that children after stroke are at risk of developing internalizing problems and a wide range of social difficulties. Internalizing problems are often associated with environmental factors such as family functioning and parents' mental health. In addition, a higher risk of developing psychosocial problems is associated with lower cognitive functioning and severe neurological impairment. CONCLUSIONS: The assessment of psychological well-being and social functioning after pediatric stroke is helpful to provide adequate support to children and their families. Future studies are needed to better investigate these domains and to develop adequate methodologies for specific interventions.Implication for rehabilitationThis paper reviews research concerning emotional and social functioning following pediatric stroke in order to provide helpful information to clinicians and families and to improve rehabilitation pathways.Emotional and social functioning should be addressed during post-stroke evaluation and follow-up, even when physical and cognitive recovery is progressing well.Care in pediatric stroke should include volitional treatment and address emotional and social issues.

[Formula: see text] Executive functions and psychosocial impairment in children following arterial ischemic stroke.

This study examined the executive function (EF) of children with a history of arterial ischemic stroke (AIS) and preserved intellectual abilities, with reference to age at stroke onset, lesion characteristics, language, and motor functioning. In addition, the associations between EF and emotional and behavioral functioning were investigated. A battery of standardized neuropsychological tests was administered to children with previous AIS aged 7-12 in order to assess EF, including inhibition, working memory, cognitive flexibility, and attention. Parents rated questionnaires regarding real-life emotional and behavioral functioning. Finally, clinical and neuroradiological data were also gathered. Thirty patients were enrolled. Eight children fall in the lower end of the normative range or below in more than half of the EF measures, with working memory, inhibition and cognitive flexibility equally impaired, and attention relatively better preserved. Larger lesion size and language deficits were significantly associated with higher EF impairment. Emotional and behavioral functioning was lower in children with weaker EF. Children with a history of AIS, even those with preserved intellectual functioning, have a high risk of showing poor EF, mostly regardless of clinical features or functional impairment. EF difficulties are in turn associated with emotional and behavioral problems. Therefore, a standardized evaluation of EF in this population is mandatory as part of the follow-up, in order to ensure an early intervention and prevent related difficulties.

Multicentric Carpo-Tarsal Osteolysis Syndrome (MCTO) and "Function Profile": a rehabilitative approach.

BACKGROUND: Multicentric Carpo-Tarsal Osteolysis Syndrome (MCTO) is an autosomal dominant disease with increased bone reabsorption in the carpus and tarsus and the elbows, knees and spine. The disease is extremely heterogeneous and secondary and tertiary injuries vary widely and can lead to progressive disability and severe functional limitations. In addition to the available and upcoming drug therapies, physical medicine and rehabilitation are important treatment options. Currently, the indication and plan are overlooked, nonspecific and reported only for one patient. METHODS: We describe a case series of MCTO patients diagnosed and followed by a centre to identify functional deficit as a potential clinical marker of disease progression for future etiological therapies. In addition, we define a symptomatic treatment approach and specific clinical management, including a patient-centred rehabilitation approach. Functional assessments are performed independently by a multidisciplinary group to establish the functional abilities of patients and the relationship between residual motor skills and their degree of autonomy and participation. We suggest a way to identify a rehabilitation plan based on a specific disease using the International Classification of Functioning, Disability and Health Children and Youth (ICF-CY). RESULTS: To define a reliable and reproducible "Function Profile", through age and over time, we used to value the disease status according to the ICF-CY domains. It could be used to determine the complexity of the illness, its overall impact on the complexity of the person and the burden on the caregiver, and an eventual short- and long-term rehabilitation plan for MCTO and other ultra-rare diseases. CONCLUSION: Based on the MCTO experience, we suggest a way to determine a rehabilitation plan based on a specific disease and patient needs, keeping in mind that often the final point is not recovering the full function but improving or maintaining the starting point. In all cases, each patient at the time of diagnosis requires a functional assessment that must be repeated over time to adjust the course of rehabilitation. The evaluations revealed the importance of early rehabilitation management in enhancing independence, participation and control of stress deconditioning, shrinking of muscle tendons and loss of movement to immobility.

An Atypical Case of Aphasia: Transitory Ischemic Attack in a 13-Year-Old Patient with Asymptomatic SARS-CoV-2 Infection.

We report the case of a 13-year-old patient, female, born in Northern Italy, who presented with an acute episode of aphasia, lasting about 15 min, accompanied by left arm dysesthesia. The state of consciousness remained preserved throughout the episode. After a first clinical evaluation at second-level hospital, the patient was sent to our institute for further investigations. Brain MRI performed at admission showed no noteworthy structural alterations. Electroencephalogram was not significant, as was the echocardiographic examination. ECG was normal, except for a corrected-QT at the upper limits of the normal range for age and gender. The neurological examination was substantially normal for the entire duration of the hospital stay. The symptomatology initially described has never reappeared. Blood tests were substantially negative, in particular thrombophilic screening excluded hereditary-familial thrombophilic diseases. Color doppler ultrasound of the supra-aortic trunks, splanchnic vessels and lower limbs were also normal. Only positivity to SARS-CoV-2 serology is reported. In the recent clinical history there were no symptoms attributable to symptomatic coronavirus infection.

The Genetic Landscape of Ischemic Stroke in Children - Current Knowledge and Future Perspectives.

Stroke in childhood has multiple etiologies, which are mostly distinct from those in adults. Genetic discoveries over the last decade pointed to monogenic disorders as a rare but significant cause of ischemic stroke in children and young adults, including small vessel and arterial ischemic stroke. These discoveries contributed to the understanding that stroke in children may be a sign of an underlying genetic disease. The identification of these diseases requires a detailed medical and family history collection, a careful clinical evaluation for the detection of systemic symptoms and signs, and neuroimaging assessment. Establishing an accurate etiological diagnosis and understanding the genetic risk factors for stroke are essential steps to decipher the underlying mechanisms, optimize the design of tailored prevention strategies, and facilitate the identification of novel therapeutic targets in some cases. Despite the increasing recognition of monogenic causes of stroke, genetic disorders remain understudied and therefore under-recognized in children with stroke. Increased awareness among healthcare providers is essential to facilitate accurate diagnosis in a timely manner. In this review, we provide a summary of the main single-gene disorders which may present as ischemic stroke in childhood and describe their clinical manifestations. We provide a set of practical suggestions for the diagnostic work up of these uncommon causes of stroke, based upon the stroke subtype and imaging characteristics that may suggest a monogenic diagnosis of ischemic stroke in children. Current hurdles in the genetic analyses of children with ischemic stroke as well as future prospectives are discussed.

Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core.

The TREX1 exonuclease degrades DNA to prevent aberrant nucleic-acid sensing through the cGAS-STING pathway, and dominant Aicardi-Goutières Syndrome type 1 (AGS1) represents one of numerous TREX1-related autoimmune diseases. Monoallelic TREX1 mutations were identified in patients showing early-onset cerebrovascular disease, ascribable to small vessel disease, and CADASIL-like neuroimaging. We report the clinical-neuroradiological features of two patients with AGS-like (Patient A) and CADASIL-like (Patient B) phenotypes carrying the heterozygous p.A136V and p.R174G TREX1 variants, respectively. Genetic findings, obtained by a customized panel including 183 genes associated with monogenic stroke, were combined with interferon signature testing and biochemical assays to determine the mutations' effects in vitro. Our results for the p.A136V variant are inconsistent with prior biochemistry-pathology correlates for dominant AGS-causing TREX1 mutants. The p.R174G variant modestly altered exonuclease activity in a manner consistent with perturbation of substrate interaction rather than catalysis, which represents the first robust enzymological data for a TREX1 variant identified in a CADASIL-like patient. In conclusion, functional analysis allowed us to interpret the impact of TREX1 variants on patients' phenotypes. While the p.A136V variant is unlikely to be causative for AGS in Patient A, Patient B's phenotype is potentially related to the p.R174G variant. Therefore, further functional investigations of TREX1 variants found in CADASIL-like patients are warranted to determine any causal link and interrogate the molecular disease mechanism(s).