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The glymphatic system allows cerebrospinal fluid (CSF) flow along the brain’s perivascular spaces (PVS), aiding in the removal of harmful substances into the venous system. Previous studies have suggested that younger males with severe autism spectrum disorder (ASD) exhibit enlarged PVS (ePVS), although the specific regions or extent of PVS enlargement remain unclear. Additionally, it is still unknown whether the localization of ePVS correlates with specific ASD symptoms. Using automated MRI-based PVS quantification, we conducted a descriptive observational study to map the number, diameter, and volume of PVS across 72 brain areas, correlating these features with the clinical severity of autism and the presence or absence of three distinct ASD symptoms: language impairment, stereotypies, and hypersensoriality. The study involved 36 children with ASD (ages 1–9 years). A thorough analysis of ePVS in the white matter underlying 72 cortical areas revealed that different ASD symptoms exhibit specific ePVS localizations. Moreover, ePVS in the white matter beneath the two rostral middle frontal regions were associated with the overall clinical severity of ASD as well as specific symptoms (verbal dysfunction, stereotypies, and hypersensoriality). When these prefrontal subregions experience excessive PVS enlargement, it may lead to hypoactivity in the dorsolateral prefrontal cortex (DLPFC), contributing to the manifestation of ASD symptoms.

Our single-center case-control study aimed to evaluate the unclear glymphatic system alteration in autism spectrum disorder (ASD) through an innovative neuroimaging tool which allows to segment and quantify perivascular spaces in the white matter (WM-PVS) with filtering of non-structured noise and increase of the contrast-ratio between perivascular spaces and the surrounding parenchyma. Briefly, files of 65 ASD and 71 control patients were studied. We considered: ASD type, diagnosis and severity level and comorbidities (i.e., intellectual disability, attention-deficit hyperactivity disorder, epilepsy, sleep disturbances). We also examined diagnoses other than ASD and their associated comorbidities in the control group. When males and females with ASD are included together, WM-PVS grade and WM-PVS volume do not significantly differ between the ASD group and the control group overall. We found, instead, that WM-PVS volume is significantly associated with male sex: males had higher WM-PVS volume compared to females (p = 0.01). WM-PVS dilation is also non-significantly associated with ASD severity and younger age (< 4 years). In ASD patients, higher WM-PVS volume was related with insomnia whereas no relation was found with epilepsy or IQ. We concluded that WM-PVS dilation can be a neuroimaging feature of male ASD patients, particularly the youngest and most severe ones, which may rely on male-specific risk factors acting early during neurodevelopment, such as a transient excess of extra-axial CSF volume. Our findings can corroborate the well-known strong male epidemiological preponderance of autism worldwide.

Pediatric acute-onset neuropsychiatric syndrome (PANS) features a heterogeneous constellation of acute obsessive-compulsive disorder (OCD), eating restriction, cognitive, behavioral and/or affective symptoms, often followed by a chronic course with cognitive deterioration. An immune-mediated etiology is advocated in which the CNS is hit by different pathogen-driven (auto)immune responses. This narrative review focused on recent clinical (ie, diagnostic criteria, pre-existing neurodevelopmental disorders, neuroimaging) and pathophysiological (ie, CSF, serum, genetic and autoimmune findings) aspects of PANS. We also summarized recent points to facilitate practitioners with the disease management. Relevant literature was obtained from PubMed database which included only English-written, full-text clinical studies, case reports, and reviews. Among a total of 1005 articles, 205 were pertinent to study inclusion. Expert opinions are converging on PANS as the effect of post-infectious events or stressors leading to \"brain inflammation\", as it is well-established for anti-neuronal psychosis. Interestingly, differentiating PANS from either autoimmune encephalitides and Sydenham's chorea or from alleged \"pure\" psychiatric disorders (OCD, tics, Tourette's syndrome), reveals several overlaps and more analogies than differences. Our review highlights the need for a comprehensive algorithm to help both patients during their acute distressing phase and physicians during their treatment decision. A full agreement on the hierarchy of each therapeutical intervention is missing owing to the limited number of randomized controlled trials. The current approach to PANS treatment emphasizes immunomodulation/anti-inflammatory treatments in association with both psychotropic and cognitive-behavioral therapies, while antibiotics are suggested when an active bacterial infection is established. A dimensional view, taking into account the multifactorial origin of psychiatric disorders, should suggest neuro-inflammation as a possible shared substrate of different psychiatric phenotypes. Hence, PANS and PANS-related disorders should be considered as a conceptual framework describing the etiological and phenotypical complexity of many psychiatric disorders.

Proposed co-factors triggering the pathogenesis of multiple sclerosis (MS) are the Epstein Barr virus (EBV), and the potentially neuropathogenic MSRV (MS-associated retrovirus) and syncytin-1, of the W family of human endogenous retroviruses. In search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350), was studied on peripheral blood mononuclear cells (PBMC) from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT-PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV-W/MSRV/syncytin-1, with requirement of the NF-κB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines. In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as initial trigger of future MS, years later, and HERV-W/MSRV/syncytin-1 as actual contributor to MS pathogenicity, in striking parallelism with disease behaviour.

A significant proportion of children with Autism spectrum disorder (ASD) experience sleep issues, such as insomnia and other disorders, as assessed by the Sleep Disturbance Scale for Children. Our study investigated the link between six single nucleotide polymorphisms (SNPs) in the melatonin receptor genes MT1 and MT2 and ASD susceptibility, clinical severity and associated sleep problems. A total of 139 ASD children, 82 siblings, and 53 unrelated healthy controls, all of Sardinian ancestry, were studied; among them, 38 children with co-occurring sleep issues were assessed for the outcomes of a rehabilitative program, including behavioral therapy and sleep hygiene. The MT2 rs10830963 G allele is more prevalent in ASD children and their siblings compared to the healthy controls, while rs2119882 (MT1) and rs1562444 (MT2) are associated with DIMS, DA, and SHY. ASD Children carrying the rs2119882 T allele have higher scores for DIMS and DA compared to C allele carriers, and those carrying rs1562444 A allele have higher scores for SHY than G allele carriers. After rehabilitative treatment, homozygous TT carriers of rs2119882 showed less improvement in DIMS symptoms compared to CT and CC carriers. A similar result was observed for AA carriers of SNP rs1562444 about SHY. We may suggest that the MT1 and MT2 variants may serve as useful predictive genetic markers for the severity of sleep disorders in children with ASD, potentially informing the design of more targeted rehabilitative treatments.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by persistent social communication difficulties, restricted interests, repetitive behaviors, and frequent medical comorbidities. Although early brain development in ASD has been extensively investigated, its biological progression across adulthood and aging remains largely unexplored. Growing evidence suggests that perivascular space (PVS) abnormalities may indicate impaired neurovascular integrity and reduced glymphatic clearance in ASD. Enlarged perivascular spaces (ePVS) in children commonly present alongside increased extra-axial CSF accumulation and more severe clinical manifestations, consistent with early alterations in CSF homeostasis and neuroimmune signaling. However, whether these abnormalities persist or evolve with aging remains unknown. Given that glymphatic and vascular integrity decline with age, and adults with ASD show elevated rates of sleep, metabolic, and cardiovascular disorders, PVS alterations may represent a unifying mechanism linking early neurodevelopmental divergence with later neurovascular vulnerability and cognitive aging. Advances in ultra-high-field MRI and automated segmentation now enable precise in vivo quantification of PVS burden, offering new opportunities for lifespan studies. By combining structural and functional methodologies, researchers may determine whether PVS constitute enduring traits, dynamic indicators of disease, or actionable therapeutic targets. Understanding their trajectories could provide critical insights into the continuum between neurodevelopmental and neurodegenerative phenomena in autism.

Background/Objectives: The severity of autism spectrum disorder (ASD) is clinically assessed through a comprehensive evaluation of social communication deficits, restricted interests, repetitive behaviors, and the level of support required (ranging from level 1 to level 3) according to DSM-5 criteria. Along with its varied clinical manifestations, the neuroanatomy of ASD is characterized by heterogeneous abnormalities. Notably, brain MRI of children with ASD often reveals an increased number of perivascular spaces (PVSs) compared to typically developing children. Our recent findings indicate that enlarged PVSs (ePVSs) are more common in younger male patients with severe ASD and that specific ePVS locations are significantly associated with ASD symptoms. Methods: In this study, we mapped ePVSs across key regions of three major cognitive networks—the Default Mode Network (DMN), the combined Central Executive/Frontoparietal Network (CEN/FPN), and the Salience Network (SN)—in 36 individuals with different symptom severities and rehabilitation needs due to ASD. We explored how the number, size, and location of PVSs in these networks are related to specific ASD symptoms and the overall need for rehabilitation and support. Results: Our results suggest that ePVSs in the DMN, CEN/FPN, and SN are strongly correlated with the severity of certain ASD symptoms, including verbal deficits, stereotypies, and sensory disturbances. We found a mild association between ePVSs and the level of support needed for daily living and quality of life. Conclusions: Dysfunction in cognitive networks associated with the presence of ePVSs has a significant impact on the severity of ASD symptoms. However, the need for assistance may also be influenced by other comorbid conditions and dysfunctions in smaller, overlapping brain networks.

Parry-Romberg syndrome (PRS) is a progressive facial hemiatrophy often associated with severe epilepsy. Although an immune-mediated vasculitic pathogenesis is widely assumed, no CNS-specific autoantibody has been described so far. A 2-year-old boy was admitted for a status epilepticus preceded by fever, restlessness, insomnia, and left facial rash. Cerebrospinal fluid was positive for glutamic acid decarboxylase (GAD)-antibodies. Brain MRI revealed FLAIR hyperintensities on left mediotemporal areas. He was successfully treated with intravenous methylprednisolone. One month later, seizures and facial rash reappeared and steroids were satisfactorily repeated. However, left hemifacial rash reappeared 5 months later, slowly followed by sclerotic skin lesions on frontal scalp and hemifacial sub-atrophy, leading to a diagnosis of PRS. Three years later, and despite chronic immunosuppression, new MRI lesions on left white matter are seen and left hemifacial atrophy has progressed. For the first time, we describe GAD autoantibodies in a PRS patient with epileptic encephalopathy. Epileptic syndromes with GAD autoantibodies are frequently described though with a questionable pathogenic significance. Given the clinical and MRI similarities of PRS with both Morphea and Rasmussen’s encephalitis, we suggest that, in our patient, the initial facial skin vasculitis spread into CNS vessels through perforating arteries, inducing neuronal MHC-class I presentation of GAD epitopes, ultimately causing CD8-mediated neuronal cytotoxicity and the epileptic encephalopathy. GAD autoantibodies might represent the missing pathophysiological link between PRS and neuropsychiatric manifestations.

In its typical presentation, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) occurs more often in old males as a progressive/recurrent motor and sensory nerve dysfunction with tendon areflexia. However, CIDP has also atypical clinical presentations, including pure sensory neuropathies, among which chronic immune sensory polyradiculopathy (CISP) accounts for only 0.5% of all CIDP, with no juvenile cases reported as yet. A 17-year-old girl presented for a progressive sensory ataxia and hands clumsiness. Diffuse tendon areflexia and hypokinaesthesia were observed. Motor and sensory nerve conduction studies were normal. F-waves were normal in median nerves and elongated in tibial nerves. H-reflex and somatosensory evoked potentials (SSEP) were absent. CSF normal cellularity with hyperproteinorrachia was found. Paraneoplastic, metabolic, and paraproteinemic neuropathies were excluded. A diagnosis of CISP has been made based on the presence of pure sensory symptoms in a polyneuropathic distribution, normal peripheral nerve conduction studies, and two supportive criteria (SSEP and CSF). Our paper describes the first CISP case in the pediatric age. We confirm SSEP and CSF as useful complementary tests for this diagnosis also at this age and suggest that clinicians should consider CISP in the spectrum of sporadic sensory ataxias of the pediatric age. We also suggest that in the presence of normal F-wave and peripheral motor nerve conduction, an absent H-reflex can further substantiate SSEPs in the diagnosis of CISP. Intravenous immunoglobulins were rapidly effective and safe.

Study Objectives: PANS (pediatric acute onset neuropsychiatric syndrome) is thought to be the result of several mechanisms and multiple etiologies, ranging from endocrine/metabolic causes to postinfectious autoimmune and neuroinflammatory disorders. Sleep disorders represent one of the most frequent manifestations of PANS, involving around 80% of patients. The present study describes the clinical and polysomnographic features in a group of PANS children identifying the relationships between sleep disorders and other PANS symptoms. Methods: All participants underwent a clinical evaluation including comprehensive sleep history, polysomnography, cognitive assessment and blood chemistry examination. A data mining approach with fourth-generation artificial neural networks has been used in order to discover subtle trends and associations among variables. Results: Polysomnography showed abnormality in 17 out of 23 recruited subjects (73.9%). In particular, 8/17 children (47%) had ineffective sleep, 10/17 (58.8%) fragmented sleep, 8/17 (47.1%) periodic limb movement disorder (PLMD) and 11/17 (64.7%) REM-sleep without atonia (RSWA). Most subjects presented more than one sleep disturbances. Notably, among the 19/23 patients diagnosed with Tic/Tourette disorder, 8/19 (42.1%) show PLMD and 10/19 (52.6%) RSWA. Artificial neural network methodology and the auto-contractive map exploited the links among the full spectrum of variables revealing the simultaneous connections among them, facing the complexity of PANS phenotype. Conclusion: Disordered sleep represents, for prevalence and impact on quality of life, a cardinal symptom in patients with PANS. Thus, considering the weight of sleep disturbances on diagnosis and prognosis of PANS, we could consider the possibility of including them among the major diagnostic criteria. Keywords: PANS, pediatric acute onset neuropsychiatric syndrome, sleep disorders, Tourette disorder, polysomnography, auto-contractive map