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Purpose This study assessed the position of the termination of the conus medullaris (the point where the spinal cord tapers to an end) and thecal sac (the sheath of dura mater that surrounds the spinal cord and caudal nerve roots) in a large pediatric population, to characterise the nature of the pediatric Gaussian distribution and assess whether age affected the distribution. The study further aimed to assess the effect of gender on termination positions. Methods A total of 520 MRI spine studies of children aged between 1 month and 19 years old were collected from two pediatric tertiary referral centres in the UK and Italy. Studies with pathological findings were excluded, and normal scans were found using keyword search algorithms on a database of radiologists’ reports. The reported scans were individually assessed and reviewed by two experienced neuroradiologists. The termination points of the conus medullaris and thecal sac were determined for each study. Local IRB approvals were sought. Results The results showcased a Gaussian distribution in both conus medullaris (r=0.8997) and thecal sac termination levels (r=0.9639). No statistically significant results were noted with increasing age for the termination positions of the conus medullaris or thecal sac (p = 0.154, 0.063). No statistical significance was observed with gender variation with either anatomical landmark. A weak positive correlation was observed between the termination levels of the conus medullaris and the thecal sac (r=0.2567) Conclusion Termination levels across all pediatric age range followed a Gaussian distribution. Knowledge of normal termination levels has relevant clinical implications, including the assessment of patients with suspected spinal dysraphism.

Introduction Most coronavirus disease 2019 (COVID-19) pediatric patients are asymptomatic; however, several neurological manifestations associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been reported. Demyelinating events such as acute disseminated encephalomyelitis have been recently included among potential complications of COVID-19. Case Report We describe the case of a 12-year-old boy who developed central nervous system demyelinating lesions following SARS-CoV-2 infection. Two months prior he had been diagnosed with panuveitis but was otherwise healthy. Three weeks after testing positive for SARS-CoV-2, he started to complain of right temporal headache associated with right orbital pain without vision impairment. Brain magnetic resonance imaging showed large leukodystrophy-like demyelinating lesions. Standard electroencephalogram revealed a slow activity on the right hemisphere. His clinical and electroencephalographic course was favorable, with a good response to corticosteroid therapy and infusions of intravenous immunoglobulins. Delayed but complete resolution of brain lesions was noted on imaging. Conclusion Our case contributes to broaden the knowledge regarding the spectrum of possible complications of SARS-CoV-2 infection. The relative lack of clinical manifestations in our patient can be seen as a warning not to underestimate even mild neurological symptoms correlated with COVID-19.

In a previous study of classifying fetuses with cortical formation abnormalities (CFA) with fetal MR, we noticed a cluster of cases with unilateral CFA and complete agenesis of the corpus callosum (ACC). In this study, we provide a detailed morphological analysis of such fetuses using fetal MR to determine if there are indicators (such as the gender of the fetus) that could be used to delineate a genetic substrate of the phenotype in order to inform future studies.We have studied 45 fetuses with the unilateral CFA/ACC phenotype and analysed through an expert consensus panel the location and fine detail of the CFA and the associated findings such as associated anomalies, head size, and sex of the fetus.The frontal lobe was significantly more frequently involved by CFA when compared with other lobes (p0.001) but no preference for the left or right hemisphere. CFA most often consisted of excessive/dysmorphic sulcation. The CFA/ACC phenotype was overwhelmingly more frequent in male fetuses (M:F 4.5:1-p0.0001). The most frequent associated findings were: ventriculomegaly (16/45 fetuses) and interhemispheric cysts (12/45 cases).This report highlights the specific phenotype of unilateral CFA/ACC that is much more common in male fetuses. This finding provides a starting point to study possible sex-linked genetic abnormalities that underpin the unilateral CFA/ACC phenotype.• We collected fetuses with unilateral cortical formation abnormality and callosal agenesis. • That distinctive neuroimaging phenotype has a strong male gender prevalence (over 80%). • This observation forms the basis of studies about outcomes and genetic substrates.

Background: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2. Methods: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients Results: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P P =0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P =0.14. Conclusions: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

Background and objective: Choosing the most appropriate denoising method to improve the quality of diagnostic images maximally is key in pre-processing of diffusion MRI images. Recent advancements in acquisition and reconstruction techniques have questioned traditional noise estimation methods favoring adaptive denoising frameworks, circumventing the need to know a priori information that is hardly avail-able in a clinical setting. In this observational study, we compared two innovative adaptive techniques sharing some features, Patch2Self and Nlsam, through application on reference adult data at 3T and 7T. The primary aim was identifying the most effective method in case of Diffusion Kurtosis Imaging (DKI) data -particularly susceptible to noise and signal fluctuations -at 3T and 7T fields. A side goal consisted of investigating the dependence of kurtosis metrics' variability with respect to the magnetic field on the adopted denoising methodology.Methods: For comparison purposes, we focused on qualitative and quantitative analysis of DKI data and related microstructural maps before and after applying the two denoising approaches. Specifically, we assessed computational efficiency, preservation of anatomical details via perceptual metrics, consistency of microstructure model fitting, alleviation of degeneracies in model estimation, and joint variability with varying field strength and denoising method.Results: Accounting for all these factors, Patch2Self framework has turned out to be specifically suitable for DKI data, with improving performance at 7T. Nlsam method is more robust in alleviating degenerate black voxels while introducing some blurring, which in turn is reflected in an overall loss of image sharp-ness. Regarding the impact of denoising on field-dependent variability, both methods have been shown to make variations from standard to Ultra-High Field more concordant with theoretical evidence, claiming that kurtosis metrics are sensitive to susceptibility-induced background gradients, directly proportional to the magnetic field strength and sensitive to the microscopic distribution of iron and myelin.Conclusions: This study serves as a proof-of-concept stressing the need for an accurate choice of a denois-ing methodology, specifically tailored for the data under analysis and allowing higher spatial resolution acquisition within clinically compatible timings, with all the potential benefits that improving suboptimal quality of diagnostic images entails.(c) 2023 Published by Elsevier B.V.

Objectives: To evaluate compliance with the available recommendations, we assessed the current clinical practice of imaging in the evaluation of multiple sclerosis (MS). Methods: An online questionnaire was emailed to all members and affiliates. Information was gathered on applied MR imaging protocols, gadolinium-based contrast agents (GBCA) use and image analysis. We compared the survey results with the Magnetic Resonance Imaging in MS (MAGNIMS) recommendations considered as the reference standard. Results: A total of 428 entries were received from 44 countries. Of these, 82% of responders were neuroradiologists. 55% performed more than ten scans per week for MS imaging. The systematic use of 3 T is rare (18%). Over 90% follow specific protocol recommendations with 3D FLAIR, T2-weighted and DWI being the most frequently used sequences. Over 50% use SWI at initial diagnosis and 3D gradient-echo T1-weighted imaging is the most used MRI sequence for pre- and post-contrast imaging. Mismatches with recommendations were identified including the use of only one sagittal T2-weighted sequence for spinal cord imaging, the systematic use of GBCA at follow-up (over 30% of institutions), a delay time shorter than 5 min after GBCA administration (25%) and an inadequate follow-up duration in pediatric acute disseminated encephalomyelitis (80%). There is scarce use of automated software to compare images or to assess atrophy (13% and 7%). The proportions do not differ significantly between academic and non-academic institutions. Conclusions: While current practice in MS imaging is rather homogeneous across Europe, our survey suggests that recommendations are only partially followed. Clinical relevance statement: Hurdles were identified, mainly in the areas of GBCA use, spinal cord imaging, underuse of specific MRI sequences and monitoring strategies. This work will help radiologists to identify the mismatches between their own practices and the recommendations and act upon them. Key Points: • While current practice in MS imaging is rather homogeneous across Europe, our survey suggests that available recommendations are only partially followed. • Several hurdles have been identified through the survey that mainly lies in the areas of GBCA use, spinal cord imaging, underuse of specific MRI sequences and monitoring strategies.

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p p p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.

PURPOSECoffin-Siris and Nicolaides-Baraitser syndromes, are recognisable neurodevelopmental disorders caused by germline variants in BAF complex subunits. TheSMARCC2BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.METHODSClinical symptoms for 41 novel and 24 previously published cases were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlation, molecular data were standardized and grouped into non-truncating and likely gene-disrupting variants (LGD). Missense variant protein expression and BAF subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.RESULTSNeurodevelopmental delay with intellectual disability, muscular hypotonia and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, while non-truncating variants were mostlyde novoand presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms.In vitrotesting showed decreased protein expression for N-terminal missense variants similar to LGD.CONCLUSIONThis study improvedSMARCC2variant classification and identified discernibleSMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.

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.

Data de publicació electrònica: 04-04-2022 Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Funding: most families were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This study was also supported by JSPS/MEXT KAKENHI (Grants 19H03331, 19K22439 and 21K19390 to Y.F., Grant 19K16269 to Y.M., and Grants 20H00459 and 20H04915 to M.F.) and Japan Agency for Medical Research and Development (21wm0525022h0001 to Y.F.); intramural funding (fortüne) from the University of Tübingen (Grant 2545-1-0) and the Ministry of Science, Research and Art Baden-Württemberg to B.V. P.S. contributed to this work within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). T.B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 418081722, 433158657. I.S.P., V.Y.V. are supported by the Government Assignment of the Russian Ministry of Health (#121061500066-2). HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). S.H. is funded by TUBITAK (Turkish Scientific and Technological Research Council) Project number 216S771. R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who received support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)

Background: During the last decades, severe brain lesions affecting very low birth weight ( Objective: The objective of this study is to define type, frequency and 3 years of neurodevelopmental outcome of prematurity-related brain lesions in a modern cohort of VLBW infants. Method: VLBW infants admitted to our NICU in 5 years period with brain MRI at term-equivalent age were included. MRI scans were reviewed to identify and grade white matter lesions (WML), intraventricular hemorrhage (IVH), and cerebellar hemorrhage (CBH). Linear measurements of brain size, biparietal width (BPW) and trans-cerebellar diameter (TCD) were carried out. Total maturation score (TMS) was calculated. Developmental Coefficients (DQ) on Griffiths Scale at 3 years of age were compared between patients with different types and grades of lesions and patients without lesions; possible correlations between linear brain measurements, brain maturation and outcome were explored. Result: Study included 407 patients. Of them, 187 (46%) had at least one brain lesion on MRI, while 37 (9%) had severe lesions. The most frequent lesion was IVH (28%), followed by WML (21%) and CBH (17%). Mild and severe IVH, moderate and severe WML and all grades of CBH were related to worst outcome at 3 years. In patients without lesions, small BPW and small TCD were associated with worse outcomes. No correlations were observed between TMS and outcome. Conclusion: We have observed that even mild brain lesions have a negative influence on neurological outcome at 3 years of age.

Preterm birth still represents a concrete emergency to be managed and addressed globally. Since cerebral white matter injury is the major form of brain impairment in survivors of premature birth, the identification of reliable, non-invasive markers of altered white matter development is of utmost importance in diagnostics. Diffusion MRI has recently emerged as a valuable tool to investigate these kinds of alterations. In this work, rather than focusing on a single MRI modality, we worked on a compound of beyond-DTI High Angular Resolution Diffusion Imaging (HARDI) techniques in a group of 46 preterm babies studied on a 3T scanner at term equivalent age and in 23 control neonates born at term. After extracting relevant derived parameters, we examined discriminative patterns of preterm birth through (i) a traditional voxel-wise statistical method such as the Tract-Based Spatial Statistics approach (TBSS); (ii) an advanced Machine Learning approach such as the Support Vector Machine (SVM) classification; (iii) establishing the degree of association between the two methods in voting white matter most discriminating areas. Finally, we applied a multi-set Canonical Correlation Analysis (CCA) in search for sources of linked alterations across modalities. TBSS analysis showed significant differences between preterm and term cohorts in several white matter areas for multiple HARDI features. SVM classification performed on skeletonized HARDI measures produced satisfactory accuracy rates, especially as for highly informative parameters about fibers’ directionality. Assessment of the degree of overlap between the relevant measures identified by the two methods exhibited a good, though parameter-dependent rate of agreement. Finally, CCA analysis identified joint changes precisely for those features exhibiting less correspondence between TBSS and SVM. Our results suggest that a data-driven intramodal imaging approach is crucial to extract deep and complementary information that cannot be extracted from a single modality.

NAA20 is the catalytic subunit of the NatB complex, which is responsible for N-terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20-related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N-terminal acetylation.

OBJECTIVE The objective of this study was to describe the clinical and neuroradiological characteristics of a cohort of preterm infants who had undergone external ventricular drain insertion as a temporary measure to treat posthemorrhagic ventricular dilatation. In addition, the authors investigated the factors predicting permanent shunt dependency. METHODS The authors retrospectively reviewed the medical records of a cohort of preterm infants who had undergone external ventricular drain insertion at Gaslini Children’s Hospital (Genoa, Italy) between March 2012 and February 2018. They also analyzed clinical characteristics and magnetic resonance imaging data, including diffusion- and susceptibility-weighted imaging studies, which were obtained before both catheter insertion and removal. RESULTS Twenty-eight infants were included in the study. The mean gestational age was 28.2 ± 2.7 weeks, and the mean birth weight was 1209 ± 476 g. A permanent ventriculoperitoneal shunt was inserted in 15/28 (53.6%) infants because of the failure of external ventricular drainage as a temporary treatment option. Compared with the shunt-free group, the shunt-dependent group had a significantly lower gestational age (29.3 ± 2.3 vs 27.2 ± 2.7 weeks, p = 0.035) and tended toward a lower birth weight (p = 0.056). None of the clinical and neuroradiological characteristics significantly differed between the shunt-free and shunt-dependent groups at the time of catheter insertion. As expected, ventricular parameters as well as the intraventricular extension of intracerebral hemorrhage, as assessed using the intraventricular hemorrhage score, were reportedly higher in the shunt-dependent group than in the shunt-free group before catheter removal. CONCLUSIONS External ventricular drainage is a reliable first-line treatment for posthemorrhagic hydrocephalus. However, predicting its efficacy as a unique treatment remains challenging. A lower gestational age is associated with a higher risk of posthemorrhagic hydrocephalus progression, suggesting that the more undeveloped the mechanisms for the clearance of blood degradation products, the greater the risk of requiring permanent cerebrospinal fluid diversion, although sophisticated MRI investigations are currently unable to corroborate this hypothesis.

PathogenicACTBandACTG1gene variants, encoding the actin isoformsβCYA andγCYA, respectively, are frequently associated with theBaraitser-Winter-CerebroFrontoFacial syndrome (BWCFF-S) that includes malformations of cortical development. Here we explore whether cerebral organoids grown from BWCFF-S patient-derived induced pluripotent stem cells can provide insight into the pathogenesis underlying the cortical malformations of these patients. Cerebral organoids expressing either anACTBor anACTG1gene variant, each with a point mutation resulting in a single amino acid substitution, are reduced in size, showing smaller ventricle-like structures with a thinner ventricular zone (VZ). This decrease in VZ- progenitors is associated with a striking change in the orientation of their cleavage plane from predominantly vertical (control) to predominantly horizontal (BWCFF-S), which is incompatible with increasing VZ-progenitor abundance. The underlying cause appears to be an altered subcellular tubulin localization due to the actin mutations that affects mitotic spindle positioning of VZ-progenitors in BWCFF-S.

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., Purpose: There is limited data concerning neuroimaging findings and longitudinal evaluation of familial cerebral cavernous malformations (FCCM) in children. Our aim was to study the natural history of pediatric FCCM, with an emphasis on symptomatic hemorrhagic events and associated clinical and imaging risk factors. Methods: We retrospectively reviewed all children diagnosed with FCCM in four tertiary pediatric hospitals between January 2010 and March 2022. Subjects with first available brain MRI and [Formula: see text] 3 months of clinical follow-up were included. Neuroimaging studies were reviewed, and clinical data collected. Annual symptomatic hemorrhage risk rates and cumulative risks were calculated using survival analysis and predictors of symptomatic hemorrhagic identified using regression analysis. Results: Forty-one children (53.7% males) were included, of whom 15 (36.3%) presenting with symptomatic hemorrhage. Seven symptomatic hemorrhages occurred during 140.5 person-years of follow-up, yielding a 5-year annual hemorrhage rate of 5.0% per person-year. The 1-, 2-, and 5-year cumulative risks of symptomatic hemorrhage were 7.3%, 14.6%, and 17.1%, respectively. The latter was higher in children with prior symptomatic hemorrhage (33.3%), CCM2 genotype (33.3%), and positive family history (20.7%). Number of brainstem (adjusted hazard ratio [HR] = 1.37, P = 0.005) and posterior fossa (adjusted HR = 1.64, P = 0.004) CCM at first brain MRI were significant independent predictors of prospective symptomatic hemorrhage. Conclusion: The 5-year annual and cumulative symptomatic hemorrhagic risk in our pediatric FCCM cohort equals the overall risk described in children and adults with all types of CCM. Imaging features at first brain MRI may help to predict potential symptomatic hemorrhage at 5-year follow-up.

BACKGROUND AND PURPOSE: The ganglionic eminences are transient fetal brain structures that produce a range of neuron types. Ganglionic eminence anomalies have been recognized on fetal MR imaging and anecdotally found in association with a number of neurodevelopmental anomalies. The aim of this exploratory study was to describe and analyze the associations between ganglionic eminence anomalies and coexisting neurodevelopmental anomalies. MATERIALS AND METHODS: This retrospective study includes cases of ganglionic eminence anomalies diagnosed on fetal MR imaging during a 20-year period from 7 centers in Italy and England. Inclusion criteria were cavitation or increased volume of ganglionic eminences on fetal MR imaging. The studies were analyzed for associated cerebral developmental anomalies: abnormal head size and ventriculomegaly, reduced opercularization or gyration, and abnormal transient layering of the developing brain mantle. The results were analyzed using χ(2) and Fisher exact tests. RESULTS: Sixty fetuses met the inclusion criteria (21 females, 24 males, 15 sex unknown). Thirty-four had ganglionic eminence cavitations (29 bilateral and 5 unilateral), and 26 had increased volume of the ganglionic eminences (19 bilateral, 7 unilateral). Bilateral ganglionic eminence cavitations were associated with microcephaly (P = .01), reduced opercularization, (P < .001), reduced gyration (P < .001), and cerebellar anomalies (P = .01). Unilateral ganglionic eminence cavitations were not significantly associated with any particular feature. Bilateral increased volume of the ganglionic eminences showed an association with macrocephaly (P = .03). Unilateral increased volume was associated with macrocephaly (P = .002), abnormal transient layering (P = .001), unilateral polymicrogyria (P = .001), and hemimegalencephaly (P < .001). CONCLUSIONS: Ganglionic eminence anomalies are associated with specific neurodevelopmental anomalies with ganglionic eminence cavitations and increased ganglionic eminence volume apparently having different associated abnormalities.

SUMMARY: Adenosine deaminase 2 deficiency (OMIM #615688) is an autosomal recessive disorder characterized by a wide clinical spectrum, including small- and medium-sized vessel vasculopathies, but data focusing on the associated neuroimaging features are still scarce in the literature. Here, we describe the clinical neuroimaging features of 12 patients with genetically proven adenosine deaminase 2 deficiency (6 males; median age at disease onset, 1.3 years; median age at genetic diagnosis, 15.5 years). Our findings expand the neuroimaging phenotype of this condition demonstrating, in addition to multiple, recurrent brain lacunar ischemic and/or hemorrhagic strokes, spinal infarcts, and intracranial aneurysms, also cerebral microbleeds and a peculiar, likely inflammatory, perivascular tissue in the basal and peripontine cisterns. Together with early clinical onset, positive family history, inflammatory flares and systemic abnormalities, these findings should raise the suspicion of adenosine deaminase 2 deficiency, thus prompting genetic evaluation and institution of tumor necrosis factor inhibitors, with a potential great impact on neurologic outcome.

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. Comprehensive studies revealed no pathological impact on TREX1 enzymatic function for the p.A136V variant. The p.R174G variant modestly altered exonuclease activity consistently 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. Whilst Patient A’s manifestations are not related to p.A136V variant, Patient B’s phenotype is likely related to the p.R174G variant. Further functional investigations of TREX1 variants found in CADASIL-like patients are warranted to establish a causal link and interrogate the molecular disease mechanism.

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

To explore the relationships between clinical-radiological features and surgical outcomes in subjects with interhemispheric cysts (IHC) and corpus callosum anomalies.We reviewed the clinico-radiological and neurosurgical data of 38 patients surgically treated with endoscopic fenestration, shunting, or combined approaches from 2000 to 2018 (24 males, median age 9 years). Pre- and postoperative changes in IHC volume were calculated. Outcome assessment was based on clinico-radiological data. Group comparisons were performed using χMedian age at first surgery was 4 months (mean follow-up 8.3 years). Eighteen individuals (47.3%) required 1 intervention due to IHC regrowth and/or shunt malfunction. Larger preoperative IHC volume (P = .008) and younger age at surgery (P = .016) were associated with cyst regrowth. At last follow-up, mean cystic volume was 307.8 cmEndoscopic fenestration and shunting approaches are both effective but often require multiple procedures especially in younger patients. Larger IHC are more frequently complicated by cyst regrowth after surgery.

We describe 64 foetuses with cortical formation abnormalities (CFA) who had two in utero magnetic resonance (iuMR) exams, paying particular detail to those in which the original classification of CFA category changed between the two studies. The goal was to attempt to quantify the value of third-trimester follow-up studies in CFA foetuses on second-trimester iuMR imaging. The 64 foetuses reviewed came from a CFA cohort of 374 foetuses reported in an earlier publication, which detailed a classification for foetal CFA. A consensus panel of senior paediatric neuroradiologists reviewed both studies, described any change in the category of CFA between them, and attempted to predict the possible clinical significance of any differences based on the combined clinical experience of the panel. In 40/64 (62%) foetuses, the CFA description was the same on both studies. In 24/64 (38%) cases, there was a category change which included three foetuses without CFA on first examination, six foetuses where the difference involved change in laterality/symmetry, and in 15 cases the re-classification involved categorical change within the same group. Brain abnormalities other than CFA were present in 30/64 (47%) foetuses on the first study and in 33/64 (52%) on the second. We predicted that prognosis would have changed on the basis of the second study in 8% of cases, all indicating worse prognosis. We have shown that the extra diagnostic and predicted prognostic yield justifies follow-up studies in the third trimester if a CFA is shown on the second-trimester iuMR imaging. • Sixty-four foetuses with cortical formation abnormalities had two iuMR studies, for the vast majority the baseline in the second trimester and the sequential in the third. • In three foetuses, the cortical formation abnormality (CFA) was not visible on the first study. In a further 21 foetuses, the categorical description of the CFA changed between the two studies. Prognosis changed in 8% of the cases following the second iuMR study, and in all cases, the prognosis was worse. • Multiple iuMR studies provide information about the natural history of CFA; the extra diagnostic and predicted prognostic yield justifies follow-up studies.

The long-term impact of low-grade germinal matrix-intraventricular hemorrhage (GMH-IVH) on brain perfusion has not been fully investigated. We aimed to compare cortical and deep gray matter (GM) cerebral blood flow (CBF) obtained with pseudo-continuous arterial spin labeling (pCASL), among preterm neonates with and without low-grade GMH-IVH and full-term controls. 3T-pCASL examinations of 9 healthy full-term neonates (mean gestational age 38.5 weeks, range 38–39) and 28 preterm neonates studied at term-equivalent age were analyzed. Eighteen preterm neonates presented normal brain MRI (mean gestational age 30.50 weeks, range 29–31) and 10 low-grade GMH-IVH according to Volpe’s grading system (mean gestational age 32 weeks, range 28–34). A ROI-based mean CBF quantification was performed in 5 cortical (frontal, parietal, temporal, insula, occipital), and 4 subcortical GM regions (caudate, putamen, pallidum, thalamus) for each cerebral hemisphere. CBF differences were explored using a nonparametric analysis of covariance. Low-grade GMH-IVH hemispheres showed consistently lower CBF in all GM regions when compared with healthy preterm neonates, after controlling the confounding effect of gestational age, postmenstrual age, and birth weight P

Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.

To formulate a classification system for foetal cortical formation abnormalities (CFAs) based on in utero magnetic resonance (iuMR) appearances and trial it in 356 cases. This retrospective study included all cases of foetal CFA diagnosed between 2000 and 2017 from seven centres in Italy and UK. All of the studies were reviewed by a panel of paediatric neuroradiologists experienced in iuMR with the aid of an algorithm designed to categorise the abnormalities. Consensus expert review confirmed 356 foetuses with CFA and the first level of classification distinguished bilateral CFA (229/356–64%) from unilateral CFA (127/356–36%) cases with sub-classification of the bilateral cases into asymmetric (65/356–18%) and symmetric (164/356–46%) involvement. There was a statistically significant excess of foetuses with small head size, e.g. 17% of the cohort had a bi-parietal diameter