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BackgroundSyringomyelia and Chiari malformation are classified as rare diseases on Orphanet, but international guidelines on diagnostic criteria and case definition are missing. Aim of the study: to reach a consensus among international experts on controversial issues in diagnosis and treatment of Chiari 1 malformation and syringomyelia in adults.MethodsA multidisciplinary panel of the Chiari and Syringomyelia Consortium (4 neurosurgeons, 2 neurologists, 1 neuroradiologist, 1 pediatric neurologist) appointed an international Jury of experts to elaborate a consensus document. After an evidence-based review and further discussions, 63 draft statements grouped in 4 domains (definition and classification/planning/surgery/isolated syringomyelia) were formulated. A Jury of 32 experts in the field of diagnosis and treatment of Chiari and syringomyelia and patient representatives were invited to take part in a three-round Delphi process. The Jury received a structured questionnaire containing the 63 statements, each to be voted on a 4-point Likert-type scale and commented. Statements with agreement <75% were revised and entered round 2. Round 3 was face-to-face, during the Chiari Consensus Conference (Milan, November 2019).ResultsThirty-one out of 32 Jury members (6 neurologists, 4 neuroradiologists, 19 neurosurgeons, and 2 patient association representatives) participated in the consensus. After round 2, a consensus was reached on 57/63 statements (90.5%). The six difficult statements were revised and voted in round 3, and the whole set of statements was further discussed and approved.ConclusionsThe consensus document consists of 63 statements which benefited from expert discussion and fine-tuning, serving clinicians and researchers following adults with Chiari and syringomyelia.

BackgroundChiari malformation type 1 (CM1) is a rare condition where agreed classification and treatment are still missing. The goal of this study is to achieve a consensus on the diagnosis and treatment of CM1 in children.MethodsA multidisciplinary panel formulated 57 provisional statements based on a review of the literature. Thirty-four international experts (IE) participated in a Delphi study by independently rating each statement on a 4-point Likert scale (“strongly disagree,” “disagree,” “agree,” “strongly agree”). Statements that were endorsed (“agree” or “strongly agree”) by < 75% of raters were re-formulated, or new statements were added, and another Delphi round followed (up to a maximum of three).ResultsThirty-five IE were contacted and 34 agreed to participate. A consensus was reached on 30/57 statements (52.6%) after round 1. Three statements were added, and one removed. After round 2, agreement was reached on 56/59 statements (94.9%). Finally, after round 3, which took place during the 2019 Chiari Consensus Conference (Milan, Italy), agreement was reached on 58/59 statements (98.3%) about four main sections (Definition and Classification, Planning, Surgery, Isolated Syringomyelia). Only one statement did not gain a consensus, which is the “definition of radiological failure 24 month post-surgery.”ConclusionsThe consensus document consists of 58 statements (24 on diagnosis, 34 on treatment), serving clinicians and researchers following children with CM1. There is a clear need for establishing an international network and registry and to promote collaborative studies to increase the evidence base and optimize the long-term care of this patient population.

Background Tuberous Sclerosis Complex (TSC) and Neurofibromatosis type 1 (NF1) are neurocutaneous disorders commonly characterized by neuropsychiatric comorbidities. The TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist is currently used to quickly screen for behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations in patients with TSC. We administered the authorized Italian version of the TAND Checklist to the parents of 42 TSC patients and 42 age- and sex-matched NF1 patients, for a total of 84 individuals, aged 4–20 years. Aims of this study: - to test the overall usability of the TAND Checklist in NF1, −to compare the results between children and adolescents with TSC and NF1, and -to examine the association between neuropsychiatric manifestations and severity of the phenotype in terms of epilepsy severity in the TSC cohort and disease severity according to the modified version of the Riccardi severity scale in the NF1 cohort. Results TSC cohort: 35.6% had Intellectual Disability (ID), 11.9% Specific Learning Disorders (SLD), 50.0% Attention Deficit Hyperactivity Disorder (ADHD) and 16.6% anxious/mood disorder. 33.3% had a formal diagnosis of Autism Spectrum Disorder (ASD). Paying attention and concentrating (61.9%), impulsivity (54.8%), temper tantrums (54.8%), anxiety (45.2%), overactivity/hyperactivity (40.5%), aggressive outburst (40.5%), absent or delayed onset of language (40.5%), repetitive behaviors (35.7%), academic difficulties (> 40%), deficits in attention (61.9%) and executive skills (50.0%) were the most commonly reported problems. NF1 cohort: 9.5% had ID, 21.4% SLD, 46.6% ADHD, and 33.3% anxious/mood disorder. No one had a diagnosis of ASD. Commonly reported issues were paying attention and concentrating (59.5%), impulsivity (52.4%), anxiety (50.0%), overactivity/hyperactivity (38.1%), temper tantrums (38.1%), academic difficulties (> 40%), deficits in attention (59.5%), and executive skills (38.1%). Neuropsychiatric features in TSC vs NF1: Aggressive outburst and ASD features were reported significantly more frequently in TSC than in NF1. Neuropsychiatric manifestations and phenotype severity: Depressed mood, absent or delayed onset of language, repetitive language, difficulties in relationship with peers, repetitive behaviors, spelling, mathematics, dual-tasking, visuo-spatial tasks, executive skills, and getting disoriented were significantly different among TSC patients with different epilepsy severity. No statistically significant differences in the NF1 subgroups were noted for any of the items in the checklist. Conclusion The TAND Checklist used for TSC is acceptable and feasible to complete in a clinical setting, and is able to detect the complexity of neuropsychiatric involvement in NF1 as well. NF1 is mainly characterized by an ADHD profile, anxiety problems and SLD, while ASD features are strongly associated with TSC. In conclusion, the TAND Checklist is a useful and feasible screening tool, in both TSC and NF1.

In anticipation of the “Chiari and Syringomyelia Consensus Conference” held in Milan in 2019, we performed a systematic literature review on the management of Chiari malformation type 1 (CM1) and syringomyelia (Syr) in children.We aimed to summarize the available evidence and identify areas where consensus has not been reached and further research is needed.In accordance with PRISMA guidelines, we formulated seven questions in Patients-Interventions-Comparators-Outcomes (PICO) format. Six PICOs concerned CM1 children with/without additional structural anomalies (Syr, craniosynostosis, hydrocephalus, tethered cord, and cranio-vertebral junction anomalies), and one PICO Syr without CM1. We searched Medline, Embase, Cochrane, and NICE databases from January 1, 1999, to May 29, 2019. Cohort studies, controlled and randomized clinical trials (CCTs, RCTs), and systematic reviews were included, all pertinent only to patients ≤ 18 years of age.For CM1, 3787 records were found, 460 full texts were assessed and 49 studies (46 cohort studies, one RCT, and two systematic reviews) were finally included. For Syr, 376 records were found, 59 full texts were assessed, and five studies (one RCT and four cohort studies) were included. Data on each PICO were synthetized narratively due to heterogeneity in the inclusion criteria, outcome measures, and length of follow-up of the included studies.Despite decades of experience on CM1 and Syr management in children, the available evidence remains limited. Specifically, there is an urgent need for collaborative initiatives focusing on the adoption of shared inclusion criteria and outcome measures, as well as rigorous prospective designs, particularly RCTs.

We report the clinical and EEG data of two patients harboring heterozygous SLC6A1 mutations, who presented with typical absence seizures at 3 Hz spike and wave as well as with mild cognitive disability. Neuroradiological and other laboratory investigations were normal. Our observations suggest that SLC6A1 mutations can be suspected in children with typical absences as the only seizure type, especially if associated with, even mild, cognitive deficits.

Visual-spatial impairment has long been considered a hallmark feature of neurofibromatosis type 1 (NF1). No study investigating the cognitive and neuropsychological profile of NF1 used the Rey Complex Figure Test (RCFT) task as the primary measure of visual-perceptual abilities taking into consideration all functions involved including the strategic processing style. We compared 18 children with NF1, 17 siblings (S), and 18 typically developing children (TD) at intelligence scale and RCFT copy, recall, and recognition trials; we also evaluated the copy strategy as a measure of a visual-processing style. Children with NF1 had normal total IQ, with cognitive weaknesses in the perceptual organization and working memory in line with the existing literature. At the RCFT copy, immediate and delay recall scores are significantly lower in NF1 than S and TD, while recognition is in the normal range in all groups. Copy style was poor and less efficient in children with NF1 and correlated to copy and recall ability, but the effect of the group in the RCFT copy and recall remained significantly controlling for strategic approach. The present study confirms visuospatial impairment in children with NF1, due to a deficit in perceptual analysis of shape and their spatial features, in visuomotor integration efficiency and strategies, in recall memory, while recognition memory is preserved. A more configural/holistic style may facilitate both the visual-perceptual and visuomotor ability and the recall process. Visuoperceptual impairment in NF1 seems to be a unified process from early visual processing to higher order functions (planning, strategy, and executive functioning).

PurposeVisual impairment (VI) is a leading cause of disability in young people and profoundly affects their psychological well-being and that of their families. In Italy, Legislative Decree No. 62/2024 redefined disability according to the biopsychosocial model and focused on the individualised life project. Given the limited research in this field, this study explores the subjective experiences of disability among young people with VI and their close networks, within their social context.Method36 semistructured interviews with 12 young people with VI (8–18 years old), 14 parents and 10 health professionals were conducted in four Italian centres participating in the EU project SeeMyLife. Data were analysed using a thematic approach aided by NVivo V.14 software. Representative quotations and emerging themes were identified and reported.ResultsFour major themes emerged from the analysis: (1) Understanding disability: medical vs social definitions; (2) Personal experiences and biopsychosocial perspectives; (3) Disability in social context: barriers and facilitators and (4) Interpersonal relationships and social dynamics. Although participants were familiar with the term ‘disability’, it was not always framed within a biopsychosocial perspective. Young people with VI described living similarly to their peers but with more limitations in autonomy and social participation. These limitations reflect individual functioning but also environmental and social barriers, consistent with the International Classification of Functioning, Disability and Health (ICF) framework.DiscussionThe findings, within the framework of the updated Italian legislative context, have significant implications for clinical practice, offering insights for practitioners and policymakers and supporting multidimensional decision-making in care planning and service delivery. These insights should be interpreted through the ICF lens to ensure person-centred and integrated care.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45dimCD34+CD133+ mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.

BackgroundLombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced.MethodsAt the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children.ResultsAfter a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March–September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high.ConclusionsDuring the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes (TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1) have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in RNASEH2B, SAMHD1 and IFIH1 gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in RNASEH2B and a lower frequency of mutations in TREX1 than those seen in international series. RNASEH2B mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.