The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.

Pineal gland ADC values in children aged 0 to 4 years: normative data and usefulness in the differential diagnosis with trilateral retinoblastoma.

PURPOSE: Normative ADC values of the pineal gland in young children are currently lacking, however, these are potentially useful in the differential diagnosis of pineal involvement in trilateral retinoblastoma, which is challenging when the size of the tumor is less than 10-15 mm. The main objective of this study was to establish ADC reference values of the normal pineal gland in a large cohort of children between 0 and 4 years. METHODS: This retrospective study was conducted in a tertiary pediatric hospital. We collected 64 patients with normal MRI examination (between 2017 and 2024) and clinical indication unrelated to the pineal gland, and divided them into 5 age groups (0 to 4 years). Gland size and mean ADC values were calculated, using the ellipsoid formula and ROI/histogram analysis, respectively. The established values were tested in three cases of trilateral retinoblastoma (10 to 20 months). RESULTS: Mean ADC values were always above 1000 × 10- 6 mm2/s, while in patients with trilateral retinoblastoma they were around 800 × 10- 6 mm2/s. Pineal ADC values were identical in both genders. The volume of the pineal gland showed a tendency to increase with age. CONCLUSIONS: We present ADC reference data for the pineal gland in children under 4 years of age. The distribution of mean ADC values of trilateral retinoblastoma was significantly different from the normative values, hence, the use DWI/ADC may help to identify small trilateral retinoblastoma in children with ocular pathology.

Pediatric nasal chondromesenchymal hamartomas: a case series.

PURPOSE: Nasal chondromesenchymal hamartomas (NCMH) are rare, predominantly benign tumors of the sinonasal tract. The distinction from higher grade malignancy may be challenging based on imaging features alone. To increase the awareness of this entity among radiologists, we present a multi-institutional case series of pediatric NCMH patients showing the varied imaging presentation. METHODS: Descriptive assessment of imaging appearances of the lesions on computed tomography (CT) and magnetic resonance imaging (MRI) was performed. In addition, we reviewed demographic information, clinical data, results of genetic testing, management, and follow-up data. RESULTS: Our case series consisted of 10 patients, with a median age of 0.5 months. Intraorbital and intracranial extensions were both observed in two cases. Common CT findings included bony remodeling, calcifications, and bony erosions. MRI showed heterogeneous expansile lesion with predominantly hyperintense T2 signal and heterogenous post-contrast enhancement in the majority of cases. Most lesions exhibited increased diffusivity on diffusion weighted imaging and showed signal drop-out on susceptibility weighted images in the areas of calcifications. Genetic testing was conducted in 4 patients, revealing the presence of DICER1 pathogenic variant in three cases. Surgery was performed in all cases, with one recurrence in two cases and two recurrences in one case on follow-up. CONCLUSION: NCMHs are predominantly benign tumors of the sinonasal tract, typically associated with DICER1 pathogenic variants and most commonly affecting pediatric population. They may mimic aggressive behavior on imaging; therefore, awareness of this pathology is important. MRI and CT have complementary roles in the diagnosis of this entity.

Integrating standard epilepsy protocol, ASL-perfusion, MP2RAGE/EDGE and the MELD-FCD classifier in the detection of subtle epileptogenic lesions: a 3 Tesla MRI pilot study.

BACKGROUND: Malformations of cortical development (MCDs) in children with focal epilepsy pose significant diagnostic challenges, and a precise radiological diagnosis is crucial for surgical planning. New MRI sequences and the use of artificial intelligence (AI) algorithms are considered very promising in this regard, yet studies evaluating the relative contribution of each diagnostic technique are lacking. METHODS: The study was conducted using a dedicated "EPI-MCD MR protocol" with a 3 Tesla MRI scanner in patients with focal epilepsy and previously negative MRI. MRI sequences evaluated included 3D FLAIR, 3D T1 MPRAGE, T2 Turbo Spin Echo (TSE), 3D T1 MP2RAGE, and Arterial Spin Labelling (ASL). Two paediatric neuroradiologists scored each sequence for localisation and extension of the lesion. The MELD-FCD AI classifier's performance in identifying pathological findings was also assessed. We only included patients where a diagnosis of MCD was subsequently confirmed on histology and/or sEEG. RESULTS: The 3D FLAIR sequence showed the highest yield in detecting epileptogenic lesions, with 3D T1 MPRAGE, T2 TSE, and 3D T1 MP2RAGE sequences showing moderate to low yield. ASL was the least useful. The MELD-FCD classifier achieved a 69.2% true positive rate. In one case, MELD identified a subtle area of cortical dysplasia overlooked by the neuroradiologists, changing the management of the patient. CONCLUSIONS: The 3D FLAIR sequence is the most effective in the MRI-based diagnosis of subtle epileptogenic lesions, outperforming other sequences in localisation and extension. This pilot study emphasizes the importance of careful assessment of the value of additional sequences.

Pediatric-type diffuse low-grade gliomas.

The World Health Organization's 5th edition classification of Central Nervous System (CNS) tumors differentiates diffuse gliomas into adult and pediatric variants. Pediatric-type diffuse low-grade gliomas (pDLGGs) are distinct from adult gliomas in their molecular characteristics, biological behavior, clinical progression, and prognosis. Various molecular alterations identified in pDLGGs are crucial for treatment. There are four distinct entities of pDLGGs. All four of these tumor subtypes exhibit diffuse growth and share overlapping histopathological and imaging characteristics. Molecular analysis is essential for differentiating these lesions.

Os odontoideum and craniovertebral junction instability secondary to dystonia: case series and review of the literature.

INTRODUCTION: Os odontoideum refers to a rounded ossicle detached from a hypoplastic odontoid process at the body of the axis. The aetiology has been debated and believed to be either congenital or acquired (resulting from trauma). Os odontoideum results in incompetence of the transverse ligament and thus predisposes to atlantoaxial instability and spinal cord injury. METHODS/RESULTS: Three cases of children with severe dystonic cerebral palsy presenting with myelopathic deterioration secondary to atlantoaxial instability due to os odontoideum are presented. This observation supports the hypothesis of os odontoideum being an acquired phenomenon, secondary to chronic excessive movement with damage to the developing odontoid process. CONCLUSION: In children with cerebral palsy and dystonia, pre-existing motor deficits may conceal an evolving myelopathy and result in delayed diagnosis of clinically significant atlantoaxial subluxation.

Cochlear Implantation: Systematic Approach to Preoperative Radiologic Evaluation.

Sensorineural hearing loss results from abnormalities that affect the hair cells of the membranous labyrinth, inner ear malformations, and conditions affecting the auditory pathway from the cochlear nerve to the processing centers of the brain. Cochlear implantation is increasingly being performed for hearing rehabilitation owing to expanding indications and a growing number of children and adults with sensorineural hearing loss. An adequate understanding of the temporal bone anatomy and diseases that affect the inner ear is paramount for alerting the operating surgeon about variants and imaging findings that can influence the surgical technique, affect the choice of cochlear implant and electrode type, and help avoid inadvertent complications. In this article, imaging protocols for sensorineural hearing loss and the normal inner ear anatomy are reviewed, with a brief description of cochlear implant devices and surgical techniques. In addition, congenital inner ear malformations and acquired causes of sensorineural hearing loss are discussed, with a focus on imaging findings that may affect surgical planning and outcomes. The anatomic factors and variations that are associated with surgical challenges and may predispose patients to periprocedural complications also are highlighted. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center. Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.

Congenital melanocytic naevus syndrome and Dandy-Walker malformation - a mistaken association: case report and literature review.

Congenital melanocytic naevus (CMN) syndrome, previously termed neurocutaneous melanosis, is a rare disease caused by postzygotic mosaic mutations occurring during embryogenesis in precursors of melanocytes. The severity of neurological manifestations in CMN patients is related to central nervous system abnormalities found at magnetic resonance imaging. The association between CMN and Dandy-Walker malformation (DWM) has been described in the literature, but recent advances in imaging and genetics lead to diagnostic criteria revision. In this paper, we aim to re-evaluate the proposed association by reviewing the available literature and present a patient with CMN and a large posterior fossa cyst.

Data governance functions to support responsible data stewardship in pediatric radiology research studies using artificial intelligence.

The integration of human and machine intelligence promises to profoundly change the practice of medicine. The rapidly increasing adoption of artificial intelligence (AI) solutions highlights its potential to streamline physician work and optimize clinical decision-making, also in the field of pediatric radiology. Large imaging databases are necessary for training, validating and testing these algorithms. To better promote data accessibility in multi-institutional AI-enabled radiologic research, these databases centralize the large volumes of data required to effect accurate models and outcome predictions. However, such undertakings must consider the sensitivity of patient information and therefore utilize requisite data governance measures to safeguard data privacy and security, to recognize and mitigate the effects of bias and to promote ethical use. In this article we define data stewardship and data governance, review their key considerations and applicability to radiologic research in the pediatric context, and consider the associated best practices along with the ramifications of poorly executed data governance. We summarize several adaptable data governance frameworks and describe strategies for their implementation in the form of distributed and centralized approaches to data management.

Radiomics, machine learning, and artificial intelligence-what the neuroradiologist needs to know.

PURPOSE: Artificial intelligence (AI) is playing an ever-increasing role in Neuroradiology. METHODS: When designing AI-based research in neuroradiology and appreciating the literature, it is important to understand the fundamental principles of AI. Training, validation, and test datasets must be defined and set apart as priorities. External validation and testing datasets are preferable, when feasible. The specific type of learning process (supervised vs. unsupervised) and the machine learning model also require definition. Deep learning (DL) is an AI-based approach that is modelled on the structure of neurons of the brain; convolutional neural networks (CNN) are a commonly used example in neuroradiology. RESULTS: Radiomics is a frequently used approach in which a multitude of imaging features are extracted from a region of interest and subsequently reduced and selected to convey diagnostic or prognostic information. Deep radiomics uses CNNs to directly extract features and obviate the need for predefined features. CONCLUSION: Common limitations and pitfalls in AI-based research in neuroradiology are limited sample sizes ("small-n-large-p problem"), selection bias, as well as overfitting and underfitting.

Abusive head trauma: Canadian and global perspectives.

Canada has come a long way since Dr. C. Henry Kempe first described battered-child syndrome in 1962. The year 1999 was crucial in Canada's battle against shaken baby syndrome/abusive head trauma (SBS/AHT), when the first national conference on the topic was held in Saskatoon. This was followed by the issuance of a national statement and multidisciplinary guidelines, recently updated in 2020. Incidence of AHT in Canada is similar to that found in population-based studies from Switzerland and New Zealand. The mainstay of prevention of AHT in Canada is education of parents and caregivers with respect to their response to infant crying. Population-based data for global incidence of AHT are lacking, largely because of social and cultural differences contributing to poor understanding of AHT as a medico-legal entity. India faces a distinct challenge in the battle against female feticide and infanticide.

Venous pathologies in paediatric neuroradiology: from foetal to adolescent life.

The interpretation of cerebral venous pathologies in paediatric practice is challenging as there are several normal anatomical variants, and the pathologies are diverse, involving the venous system through direct and indirect mechanisms. This paper aims to provide a comprehensive review of these entities, as their awareness can avoid potential diagnostic pitfalls. We also propose a practical classification system of paediatric cerebral venous pathologies, which will enable more accurate reporting of the neuroimaging findings, as relevant to the underlying pathogenesis of these conditions. The proposed classification system comprises of the following main groups: arterio-venous shunting-related disorders, primary venous malformations and veno-occlusive disorders. A multimodal imaging approach has been included in the relevant subsections, with a brief overview of the modality-specific pitfalls that can also limit interpretation of the neuroimaging. The article also summarises the current literature and international practices in terms of management options and outcomes in specific disease entities.

Correction to: Venous pathologies in paediatric neuroradiology: from foetal to adolescent life.

The original version of this article unfortunately contained a referencing omission. Figure 11 is reused from the original publication of Figure 10 of Gunny and Lin [1].

Advances in magnetic resonance imaging for the assessment of paediatric focal epilepsy: a narrative review.

Background and Objective: Epilepsy affects approximately 50 million people worldwide, with 30-40% of patients not responding to medication, necessitating alternative therapies such as surgical intervention. However, the accurate localization of epileptogenic lesions, particularly in pediatric magnetic resonance imaging (MRI)-negative drug-resistant epilepsy, remains a challenge. This paper reviews advanced neuroimaging techniques aimed at improving the detection of such lesions to enhance surgical outcomes. Methods: A comprehensive literature search was conducted using PubMed, focusing on advanced MRI sequences, focal epilepsy, and the integration of artificial intelligence (AI) in the diagnostic process. Key Content and Findings: New MRI sequences, including magnetization prepared 2 rapid gradient echo (MP2RAGE), edge-enhancing gradient echo (EDGE), and fluid and white matter suppression (FLAWS), have demonstrated enhanced capabilities in detecting subtle epileptogenic lesions. Quantitative MRI techniques, notably magnetic resonance fingerprinting (MRF), alongside innovative post-processing methods, are emphasized for their effectiveness in delineating cortical malformations, whether used alone or in combination with ultra-high field MRI systems. Furthermore, the integration of AI in radiology is progressing, providing significant support in accurately localizing lesions, and potentially optimizing pre-surgical planning. Conclusions: While advanced neuroimaging and AI offer significant improvements in the diagnostic process for epilepsy, some challenges remain. These include long acquisition times, the need for extensive data analysis, and a lack of large, standardized datasets for AI validation. However, the future holds promise as research continues to integrate these technologies into clinical practice. These efforts will improve the clinical applicability and effectiveness of these advanced techniques in epilepsy management, paving the way for more accurate diagnoses and better patient outcomes.

Enzyme Replacement Therapy for CLN2 Disease: MRI Volumetry Shows Significantly Slower Volume Loss Compared with a Natural History Cohort.

BACKGROUND AND PURPOSE: Neuronal ceroid lipofuscinoses are a group of neurodegenerative disorders. Recently, enzyme replacement therapy (ERT) was approved for neuronal ceroid lipofuscinosis type 2 (CLN2), a subtype of neuronal ceroid lipofuscinoses. The aim of this study was to quantify brain volume loss in CLN2 disease in patients on ERT in comparison with a natural history cohort using MRI. MATERIALS AND METHODS: Nineteen (14 female, 5 male) patients with CLN2 disease at 1 UK center were studied using serial 3D T1-weighted MRI (follow-up time, 1-9 years). Brain segmentation was performed using FreeSurfer. Volume measurements for supratentorial gray and white matter, deep gray matter (basal ganglia/thalami), the lateral ventricles, and cerebellar gray and white matter were recorded. The volume change with time was analyzed using a linear mixed-effects model excluding scans before treatment onset. Comparison was made with a published natural history cohort of 12 patients (8 female, 4 male), which was re-analyzed using the same method. RESULTS: Brain volume loss of all segmented brain regions was much slower in treated patients compared with the natural history cohort. For example, supratentorial gray matter volume in treated patients decreased by a mean of 3% (SD, 0.74%) (P < .001) annually compared with an annual volume loss of a mean of 16.8% (SD, 1.5%) (P < .001) in the natural history cohort. CONCLUSIONS: Our treatment cohort showed a significantly slower rate of brain parenchymal volume loss compared with a natural history cohort in several anatomic regions. Our results complement prior clinical data that found a positive response to ERT. We demonstrate that automated MRI volumetry is a sensitive tool to monitor treatment response in children with CLN2 disease.

Sotos Syndrome: Deep Neuroimaging Phenotyping Reveals a High Prevalence of Malformations of Cortical Development.

BACKGROUND AND PURPOSE: Sotos syndrome is a rare autosomal dominant condition caused by pathogenic mutations in the NSD1 gene that presents with craniofacial dysmorphism, overgrowth, seizures, and neurodevelopmental delay. Macrocephaly, ventriculomegaly, and corpus callosal dysmorphism are typical neuroimaging features that have been described in the medical literature. The purpose of this study was to expand on the neuroimaging phenotype by detailed analysis of a large cohort of patients with genetically proved Sotos syndrome. MATERIALS AND METHODS: This multicenter, multinational, retrospective observational cohort study systematically analyzed the clinical characteristics and neuroimaging features of 77 individuals with genetically diagnosed Sotos syndrome, via central consensus review with 3 pediatric neuroradiologists. RESULTS: In addition to previously described features, malformations of cortical development were identified in most patients (95.0%), typically dysgyria (92.2%) and polymicrogyria (22.1%), varying in location and distribution. Incomplete rotation of the hippocampus was observed in 50.6% of patients and was associated with other imaging findings, in particular with dysgyria (100% versus 84.2%, P = .012). CONCLUSIONS: Our findings show a link between the genetic-biochemical basis and the neuroimaging features and aid in better understanding the underlying clinical manifestations and possible treatment options. These findings have yet to be described to this extent and correspond with recent studies that show that NSD1 participates in brain development and has interactions with other known relevant genetic pathways.

Pediatric MOG-Ab-Associated Encephalitis: Supporting Early Recognition and Treatment.

BACKGROUND AND OBJECTIVES: Antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab) have recently been reported in patients with encephalitis who do not fulfill criteria for acute disseminated encephalomyelitis (ADEM). We evaluated a cohort of these children and compared them with children with ADEM. METHODS: This retrospective, multicenter cohort study comprised consecutive patients <18 years of age with MOG-Ab who fulfilled criteria for autoimmune encephalitis. These patients were stratified into (1) children not fulfilling criteria for ADEM (encephalitis phenotype) and (2) children with ADEM. Clinical/paraclinical data were extracted from the electronic records. Comparisons were made using the Mann-Whitney U test and χ2 Fisher exact test for statistical analysis. RESULTS: From 235 patients with positive MOG-Ab, we identified 33 (14%) with encephalitis and 74 (31%) with ADEM. The most common presenting symptoms in children with encephalitis were headache (88%), seizures (73%), and fever (67%). Infective meningoencephalitis was the initial diagnosis in 67%. CSF pleocytosis was seen in 79%. Initial MRI brain was normal in 8/33 (24%) patients. When abnormal, multifocal cortical changes were seen in 66% and unilateral cortical changes in 18%. Restricted diffusion was demonstrated in 43%. Intra-attack new lesions were seen in 7/13 (54%). When comparing with children with ADEM, children with encephalitis were older (median 8.9 vs 5.7 years, p = 0.005), were more likely to be admitted to intensive care (14/34 vs 4/74, p < 0.0001), were given steroid later (median 16.6 vs 9.6 days, p = 0.04), and were more likely to be diagnosed with epilepsy at last follow-up (6/33 vs 1/74, p = 0.003). DISCUSSION: MOG-Ab should be tested in all patients with suspected encephalitis even in the context of initially normal brain MRI. Although exclusion of infections should be part of the diagnostic process of any child with encephalitis, in immunocompetent children, when herpes simplex virus CSF PCR and gram stains are negative, these features do not preclude the diagnosis of immune mediated disease and should not delay initiation of first-line immunosuppression (steroids, IVIG, plasma exchange), even while awaiting the antibody results.