Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.

BACKGROUND: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. METHODS: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. FINDINGS: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. INTERPRETATION: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. FUNDING: The Wellcome Trust, the MRC.

Distinguishing multicystic from focal encephalomalacia on delayed MRI in children with term hypoxic ischemic injury.

BACKGROUND AND PURPOSE: To define cystic patterns resulting from term hypoxic ischemic injury (HII) on delayed Magnetic Resonance Imaging (MRI) and determine associated HII patterns and lesions that reflect the severity of injury, from a database of African children with cerebral palsy. METHODS: Retrospective review of 1175 children with cerebral palsy due to term HII diagnosed on late MRI, identifying those with cystic changes. These were classified as multicystic or (multi-) focal-cystic, and were evaluated for associated injuries-thalami, basal ganglia, hippocampi, cerebellum, and presence of ulegyria. RESULTS: Three hundred and eighty-eight of 1175 (33%) children had cystic encephalomalacia. Two hundred and seven of 388 (53.3%) had focal-cystic and 181/388 (46.6%) had multicystic injury. The focal-cystic group comprised 87.9% (182/207) with thalamic injury, 25.6% (53/207) with basal ganglia injury, and 15% (31/207) with cerebellar involvement. Basal-ganglia-thalamus (BGT) pattern was present in 43.9% (91/207) and ulegyria in 69.6% (144/207). In the multicystic group, 88.9% (161/181) had thalamic injury, 30.9% (56/181) had basal ganglia injury, and 21% (38/181) had cerebellar involvement. BGT pattern was observed in 29.8% (54/181) and ulegyria in 28.7%. (52/181). Significant associations (p<.05) were found between multicystic injury and caudate/globus pallidus involvement, and between focal-cystic pattern of injury and ulegyria. CONCLUSIONS: Cystic encephalomalacia was seen in almost one-third of patients with term HII imaged with delayed MRI, with a similar prevalence of focal-cystic and multicystic injury. Multicystic injury was associated with caudate and globus pallidi involvement, typical of the BGT pattern of HII, whereas the focal-cystic pattern was associated with ulegyria, typical of watershed injury.

Acquired hump of the corpus callosum: a rare morphologic complication after CSF shunting.

PURPOSE: To present the longitudinal MR imaging of 4 children with an acquired corpus callosum hump, in order to demonstrate graphically that this represents a dysmorphology caused through a constellation of pre-existing pathology, timing, and complications of treatment. MATERIALS AND METHODS: Four cases with a corpus callosum hump were evaluated for common findings in the clinical history and on MRI scans. Those patients with available follow-up imaging were specifically evaluated for the presence of the hump on initial neonatal imaging and for evidence of development and progression of the deformity over time. Corpus callosum length was measured and compared against normal standards. RESULTS AND CONCLUSION: Congenital hydrocephalus, chronic ventricular over-shunting, white matter volume loss, and lateral ventricle communication were common to all cases. Corpus callosum length was above normal values. The corpus callosum hump term was previously described as dysplasia but was not present on initial scans in our cases. We conclude that the corpus callosum hump can be acquired as a complication of over-shunting in children with congenital hydrocephalus. Thus, we present our examples as "acquired hump of the corpus callosum," which differs from the prior example. We postulate that the lengthening of the stretched corpus callosum due to chronic hydrocephalus in the pre-myelinated state renders it unable to return to its normal shape when the ventricles are drained. Over-shunting of both lateral ventricles simultaneously in the absence of a septum pellucidum results in collapse and folding in of the corpus callosum on itself, resulting in the hump.

Arteriopathy in pediatric stroke: an underestimated clinical entity.

BACKGROUND: Pediatric arterial ischemic stroke (AIS), which was thought to be a rare disorder, is being increasingly recognized as an important cause of neurological morbidity, thanks to new advances in neuroimaging. OBJECTIVE: The aim of this study was to review the main etiologies of stroke due to arteriopathy in children. METHODS: Using a series of cases from our institution, we addressed its epidemiological aspects, physiopathology, imaging findings from CT, MR angiography, MR conventional sequences and MR DWI, and nuclear medicine findings. RESULTS: Through discussion of the most recent classification for childhood AIS (Childhood AIS Standardized Classification and Diagnostic Evaluation, CASCADE), we propose a modified classification based on the anatomical site of disease, which includes vasculitis, varicella, arterial dissection, moyamoya, fibromuscular dysplasia, Takayasu's arteritis and genetic causes (such as ACTA-2 mutation, PHACE syndrome and ADA-2 deficiency). We have detailed each of these separately. Conclusions: Prompt recognition of AIS and thorough investigation for potential risk factors are crucial for a better outcome. In this scenario, neurovascular imaging plays an important role in diagnosing AIS and identifying children at high risk of recurrent stroke.

Imaging of brain tumors in children: the basics-a narrative review.

Primary pediatric brain tumors comprise a broad group of neoplasm subtypes that can be categorized based on their histological and molecular features according to the 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The majority of the pediatric brain tumors demonstrate a singular preference for this age group and have a unique molecular profile. The separation of certain tumor entities, including different types of embryonal tumors, low-grade gliomas, and high-grade gliomas, may have a significant impact by guiding appropriate treatment for these children and potentially changing their outcomes. Currently, the focus of the imaging diagnostic studies is to follow the molecular updates, searching for potential imaging patterns that translate this information in molecular profile results, therefore helping the final diagnosis. Due to the high impact of accurate diagnosis in this context, the scientific community has presented extensive research on imaging pediatric tumors in recent years. This article summarizes the key characteristics of the imaging features of the most common primary childhood brain tumors, categorizing them according to the recent WHO classification update, which is based on each of their molecular profiles. The purpose of this review article is to familiarize radiologists with their key imaging features and thereby improve diagnostic accuracy.

Arteriopathy in pediatric stroke: an underestimated clinical entity / Arteriopatia em crianças com acidente vascular cerebral: uma entidade clínica subestimada

ABSTRACT Background: Pediatric arterial ischemic stroke (AIS), which was thought to be a rare disorder, is being increasingly recognized as an important cause of neurological morbidity, thanks to new advances in neuroimaging. Objective: The aim of this study was to review the main etiologies of stroke due to arteriopathy in children. Methods: Using a series of cases from our institution, we addressed its epidemiological aspects, physiopathology, imaging findings from CT, MR angiography, MR conventional sequences and MR DWI, and nuclear medicine findings. Results: Through discussion of the most recent classification for childhood AIS (Childhood AIS Standardized Classification and Diagnostic Evaluation, CASCADE), we propose a modified classification based on the anatomical site of disease, which includes vasculitis, varicella, arterial dissection, moyamoya, fibromuscular dysplasia, Takayasu's arteritis and genetic causes (such as ACTA-2 mutation, PHACE syndrome and ADA-2 deficiency). We have detailed each of these separately. Conclusions: Prompt recognition of AIS and thorough investigation for potential risk factors are crucial for a better outcome. In this scenario, neurovascular imaging plays an important role in diagnosing AIS and identifying children at high risk of recurrent stroke.

RESUMO Introdução: O acidente vascular cerebral (AVC) pediátrico, considerado um distúrbio raro, está sendo cada vez mais reconhecido como importante causa de morbidade neurológica, graças aos novos avanços na neuroimagem. Objetivo: Revisar as principais etiologias do AVC por arteriopatia em crianças. Métodos: Utilizando-se de uma série de casos de nossa instituição, abordamos seus aspectos epidemiológicos, fisiopatológicos e de imagem na angiotomografia computadorizada e angiorressonância magnética, sequências convencionais e avançadas de ressonância magnética e medicina nuclear. Resultados: Com base na classificação mais recente de AVC na infância (Classificação Padronizada e Avaliação Diagnóstica do AVC na Infância - CASCADE) propusemos uma classificação modificada com base no local anatômico da doença, que inclui vasculite, varicela, dissecção arterial, Moyamoya, displasia fibromuscular, arterite de Takayasu e causas genéticas (como mutação ACTA-2, síndrome PHACE e deficiência de ADA-2), detalhando cada uma separadamente. Conclusões: O reconhecimento imediato do AVC na infância e a investigação minuciosa de possíveis fatores de risco são cruciais para um melhor resultado. Nesse cenário, a imagem neurovascular desempenha papel importante no diagnóstico de AVC e na identificação de crianças com alto risco de recorrência.

Intracranial calcifications in childhood: Part 1.

This article is the first of a two-part series on intracranial calcification in childhood. Intracranial calcification can be either physiological or pathological. Physiological intracranial calcification is not an expected neuroimaging finding in the neonatal or infantile period but occurs, as children grow older, in the pineal gland, habenula, choroid plexus and occasionally the dura mater. Pathological intracranial calcification can be broadly divided into infectious, congenital, endocrine/metabolic, vascular and neoplastic. The main goals in Part 1 are to discuss the chief differences between physiological and pathological intracranial calcification, to discuss the histological characteristics of intracranial calcification and how intracranial calcification can be detected across neuroimaging modalities, to emphasize the importance of age at presentation and intracranial calcification location, and to propose a comprehensive neuroimaging approach toward the differential diagnosis of the causes of intracranial calcification. Finally, in Part 1 the authors discuss the most common causes of infectious intracranial calcification, especially in the neonatal period, and congenital causes of intracranial calcification. Various neuroimaging modalities have distinct utilities and sensitivities in the depiction of intracranial calcification. Age at presentation, intracranial calcification location, and associated neuroimaging findings are useful information to help narrow the differential diagnosis of intracranial calcification. Intracranial calcification can occur in isolation or in association with other neuroimaging features. Intracranial calcification in congenital infections has been associated with clastic changes, hydrocephalus, chorioretinitis, white matter abnormalities, skull changes and malformations of cortical development. Infections are common causes of intracranial calcification, especially neonatal TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus and herpes) infections.

Intracranial calcifications in childhood: Part 2.

This article is the second of a two-part series on intracranial calcification in childhood. In Part 1, the authors discussed the main differences between physiological and pathological intracranial calcification. They also outlined histological intracranial calcification characteristics and how these can be detected across different neuroimaging modalities. Part 1 emphasized the importance of age at presentation and intracranial calcification location and proposed a comprehensive neuroimaging approach toward the differential diagnosis of the causes of intracranial calcification. Pathological intracranial calcification can be divided into infectious, congenital, endocrine/metabolic, vascular, and neoplastic. In Part 2, the chief focus is on discussing endocrine/metabolic, vascular, and neoplastic intracranial calcification etiologies of intracranial calcification. Endocrine/metabolic diseases causing intracranial calcification are mainly from parathyroid and thyroid dysfunction and inborn errors of metabolism, such as mitochondrial disorders (MELAS, or mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; Kearns-Sayre; and Cockayne syndromes), interferonopathies (Aicardi-Goutières syndrome), and lysosomal disorders (Krabbe disease). Specific noninfectious causes of intracranial calcification that mimic TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus, and herpes) infections are known as pseudo-TORCH. Cavernous malformations, arteriovenous malformations, arteriovenous fistulas, and chronic venous hypertension are also known causes of intracranial calcification. Other vascular-related causes of intracranial calcification include early atherosclerosis presentation (children with risk factors such as hyperhomocysteinemia, familial hypercholesterolemia, and others), healed hematoma, radiotherapy treatment, old infarct, and disorders of the microvasculature such as COL4A1- and COL4A2-related diseases. Intracranial calcification is also seen in several pediatric brain tumors. Clinical and familial information such as age at presentation, maternal exposure to teratogens including viruses, and association with chromosomal abnormalities, pathogenic genes, and postnatal infections facilitates narrowing the differential diagnosis of the multiple causes of intracranial calcification.

Updates in Pediatric Malignant Gliomas.

Malignant gliomas constitute a smaller portion of brain tumors in children compared with adults. Nevertheless, they can be devastating tumors with poor prognosis. Recent advances and improved understanding of the genetic and molecular characterization of pediatric brain tumors, including those of malignant gliomas, have led to the reclassification of many pediatric brain tumors and new entities have been defined. In this paper, we will present some of the more recent characterization and pertinent changes in pediatric high-grade gliomas, along with the conventional and advanced imaging features associated with these entities. Implications of the recent changes in pediatric malignant glioma classifications will also be discussed.

Childhood Medulloblastoma Revisited.

Medulloblastoma is the most common malignant solid tumor in childhood and the most common embryonal neuroepithelial tumor of the central nervous system. Several morphological variants are recognized: classic medulloblastoma, large cell/anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity. Recent advances in transcriptome and methylome profiling of these tumors led to a molecular classification that includes 4 major genetically defined groups. Accordingly, the 2016 revision of the World Health Organization's Classification of Tumors of the Central Nervous System recognizes the following medulloblastoma entities: Wingless (WNT)-activated, Sonic hedgehog (SHH)-activated, Group 3, and Group 4. This transcriptionally driven classification constitutes the basis of new risk stratification schemes applied to current therapeutic clinical trials. Because additional layers of molecular tumor heterogeneities are being progressively unveiled, several clinically relevant subgroups within the 4 major groups have already been identified. The purpose of this article is to review the recent basic science and clinical advances in the understanding of "medulloblastomas," and their diagnostic imaging correlates and the implications of those on current neuroimaging practice.