Publications by authors named "Kshitij Mankad"

164 Publications

Neuroimaging of paediatric pineal, sellar and suprasellar tumours: a guide to differential diagnosis.

Childs Nerv Syst 2021 Sep 16. Epub 2021 Sep 16.

Great Ormond Street Hospital for Children NHS Trust, Department of Radiology, London, UK.

Introduction: Pineal, sellar and suprasellar tumours in children comprise a wide range of diseases with different biological behaviours and clinical management. Neuroimaging plays a critical role in the diagnosis, treatment planning and follow up of these patients, but imaging interpretation can prove challenging due to the significant overlap in radiological features.

Materials And Method: A review of the literature was performed by undertaking a search of the MEDLINE and EMBASE databases for appropriate MeSH terminology. Identified abstracts were screened for inclusion and articles meeting the objectives of the review were included.

Results And Conclusion: In this article, we review radiological appearances of common and uncommon pineal, sellar and suprasellar tumours occurring in the paediatric population. We discuss the importance of anatomical localization, clinical information and cerebrospinal fluid tumour markers, and propose a practical approach to differential diagnosis. Lastly, we discuss future directions and prospective new imaging strategies to support state-of-the-art patient care.
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http://dx.doi.org/10.1007/s00381-021-05359-6DOI Listing
September 2021

L1CAM variants cause two distinct imaging phenotypes on fetal MRI.

Ann Clin Transl Neurol 2021 Sep 12. Epub 2021 Sep 12.

Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic-mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing.
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http://dx.doi.org/10.1002/acn3.51448DOI Listing
September 2021

Machine Assist for Pediatric Posterior Fossa Tumor Diagnosis: A Multinational Study.

Neurosurgery 2021 Aug 14. Epub 2021 Aug 14.

Department of Neurosurgery, Great Ormond Street Hospital, London, United Kingdom.

Background: Clinicians and machine classifiers reliably diagnose pilocytic astrocytoma (PA) on magnetic resonance imaging (MRI) but less accurately distinguish medulloblastoma (MB) from ependymoma (EP). One strategy is to first rule out the most identifiable diagnosis.

Objective: To hypothesize a sequential machine-learning classifier could improve diagnostic performance by mimicking a clinician's strategy of excluding PA before distinguishing MB from EP.

Methods: We extracted 1800 total Image Biomarker Standardization Initiative (IBSI)-based features from T2- and gadolinium-enhanced T1-weighted images in a multinational cohort of 274 MB, 156 PA, and 97 EP. We designed a 2-step sequential classifier - first ruling out PA, and next distinguishing MB from EP. For each step, we selected the best performing model from 6-candidate classifier using a reduced feature set, and measured performance on a holdout test set with the microaveraged F1 score.

Results: Optimal diagnostic performance was achieved using 2 decision steps, each with its own distinct imaging features and classifier method. A 3-way logistic regression classifier first distinguished PA from non-PA, with T2 uniformity and T1 contrast as the most relevant IBSI features (F1 score 0.8809). A 2-way neural net classifier next distinguished MB from EP, with T2 sphericity and T1 flatness as most relevant (F1 score 0.9189). The combined, sequential classifier was with F1 score 0.9179.

Conclusion: An MRI-based sequential machine-learning classifiers offer high-performance prediction of pediatric posterior fossa tumors across a large, multinational cohort. Optimization of this model with demographic, clinical, imaging, and molecular predictors could provide significant advantages for family counseling and surgical planning.
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http://dx.doi.org/10.1093/neuros/nyab311DOI Listing
August 2021

Giant pattern VEPs in children.

Eur J Paediatr Neurol 2021 Jul 30;34:33-42. Epub 2021 Jul 30.

Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London, WC1N 3JH, UK; Ulverscroft Vision Research Group, UCL Great Ormond Street Institute for Child Health, 30 Guilford Street, London, WC1N 1EH, UK.

Our aim is to elaborate the clinical significance of giant amplitude pattern reversal visual evoked potentials (VEPs) in children. 'Giant' amplitude VEPs exceed the upper 97.5 centile, 90% CI for age. We scrutinised 2750 pattern VEPs recorded to international standards between Jan 2015 and 2017 from children aged 16 years and under, attending a specialist children's hospital. Twenty seven children, median age 6yrs, (range 1-16 yrs), were identified with giant VEPs (P100 amplitude range 65-163 μV). Most, 22/27 (81%), had conditions associated with a risk of raised ICP. Sixteen of these twenty two children had craniosynostosis; six multi-sutural and eight single suture disease. Others had Idiopathic Intracranial Hypertension, arachnoid cyst, NF1 with shunted hydrocephalus, chronic infantile neurological cutaneous and articular (CINCA) syndrome, nephrotic cystinosis and obstructive sleep apnoea. Five children presented with a range of conditions, some associated with seizures some symptomatic, but as yet undiagnosed. Frequent structural associations were optical coherence tomography measures of optic disc maximum anterior axial horizontal retinal thickness projection >160 μm and neuro-radiological findings of CSF effacement and copper beaten appearance. Ultrasonography measures of optic nerve sheath diameters varied, but in one child took 2 years to resolve after treatment for raised ICP. Optic disc gradings by fundoscopy were mostly normal, as were visual acuities. Raised ICP was confirmed by gold standard ICP bolt measurements in five of seven children tested. These data suggest that rICP should be considered if a child has sustained giant amplitude VEPs at normal latency.
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http://dx.doi.org/10.1016/j.ejpn.2021.07.008DOI Listing
July 2021

Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.

Acta Neuropathol 2021 10 4;142(4):761-776. Epub 2021 Aug 4.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, USA.

Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.
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http://dx.doi.org/10.1007/s00401-021-02355-7DOI Listing
October 2021

Magnetic resonance features and cranial nerve involvement in pediatric head and neck rhabdomyosarcomas.

Neuroradiology 2021 Jul 25. Epub 2021 Jul 25.

Neuroradiology Department, Great Ormond Street Hospital for Children, London, UK.

Purpose: Rhabdomyosarcoma (RMS) is a malignant tumor frequent in children. The frequency and characteristics of cranial nerve involvement in pediatric head and neck (H&N) RMS have been scarcely reported. The aim of this study is to review a large cohort of pediatric head and neck RMS with an emphasis on cranial nerve involvement.

Methods: We retrospectively reviewed H&N RMS cases from 3 tertiary hospitals over a 10-year period. Cranial nerve involvement was defined as radiologically apparent tumor extension along a nerve and/or the presence of secondary signs. Scans were reviewed by two pediatric neuroradiologists, blinded to clinical data.

Results: A total of 52 patients met the inclusion criteria. Histologically, 39/52 were embryonal RMS, while 13/52 were alveolar RMS. Regional lymph nodes metastases were present in 19.2%. Cranial nerve involvement was present in 36.5%. Nerves were mainly involved as a direct extension of the mass through skull base foramina or after invasion of cavernous sinus, Meckel's cave, orbital apex, or stylomastoid foramen.

Conclusion: Cranial nerve involvement is frequent in pediatric head and neck RMS and occurs secondary to "geographic" invasion due to direct extension through skull base foramina or cavernous sinus. These tumors never showed distant perineural metastatic disease as is seen in cases of adult head and neck carcinomas. This implies a different biological interaction between the nerves and these tumors in comparison to adult H&N tumors.
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http://dx.doi.org/10.1007/s00234-021-02765-0DOI Listing
July 2021

2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.

Lancet Neurol 2021 08 14;20(8):653-670. Epub 2021 Jun 14.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
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http://dx.doi.org/10.1016/S1474-4422(21)00095-8DOI Listing
August 2021

Patterns of spinal cord malformation in cloacal exstrophy.

J Neurosurg Pediatr 2021 Jun 4:1-8. Epub 2021 Jun 4.

2Radiology, and.

Objective: The objective of this study was to assess the prevalence and spectrum of spinal dysraphism in a cohort of children with cloacal exstrophy (CEX) using MRI.

Methods: Children with CEX presenting between 1999 and 2019 with baseline spinal MRI were included. The images were reviewed in consensus to assess the type of dysraphism. The dysraphisms were initially reviewed and described based on their descriptive anatomy, and then classified according to anomalies of gastrulation, primary neurulation, or secondary neurulation.

Results: Thirty-four children were included. Thirty-three of these children had closed spinal dysraphism, and 1 had a normal spine. Of the 33 cases of closed spinal dysraphism, the conus and/or filum terminale were involved in all cases. The most common malformations were spinal lipoma (n = 20) and terminal myelocystocele (n = 11). The lipomas were heterogeneous: 4 dorsal, 9 transitional, 4 chaotic, and 3 terminal. A large subgroup (10/20, 50%) within the lipomas had an unusual morphology of noncontiguous double lipomas, the proximal fat related to the conus and the distal fat within the filum. These were difficult to characterize using existing classifications. In 2 cases, only a thickened filum was noted. The majority of these malformations were compatible with a disorder of secondary neurulation.

Conclusions: Complex spinal dysraphisms are consistently associated with CEX. The unusual dysraphism patterns found in this group of patients highlight the limitations of current embryological classifications. Given the propensity for neurological deterioration in this group of patients, spinal MRI should be routinely performed. The type and distribution of malformations seen have implications for the wider understanding of the pathogenesis and classification of lumbosacral lipomas.
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http://dx.doi.org/10.3171/2021.1.PEDS20648DOI Listing
June 2021

Use of Disease-Modifying Therapies in Pediatric Relapsing-Remitting Multiple Sclerosis in the United Kingdom.

Neurol Neuroimmunol Neuroinflamm 2021 07 21;8(4). Epub 2021 May 21.

From the Queen Square MS Centre (O.A.A., W.B., O.C., C.H., Y.H.), UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London; Department of Neurology (O.A.A., O.C., C.H., Y.H.), Great Ormond Street Hospital for Children, London; Children's Neurosciences (C.M.), Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation; Department of Paediatric Neurology (T.R., M.C.), Addenbrooke's Hospital, Cambridge; Department of Neurology (J.-C.S., R.K.), Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom; Queen Square Institute of Neurology (C.T.), Faculty of Brain Sciences, University College London; Multiple Sclerosis Centre of Catalonia (Cemcat) (C.T.), Vall d'Hebron Institute of Research, Vall d'Hebron Barcelona Hospital Campus, Spain; Children's Neurosciences (S.B.), Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London; Department of Clinical Neurosciences (A.C.), Addenbrooke's Hospital, Cambridge; Translational and Clinical Research Institute (R.F.), Newcastle University; Department of Neuroradiology (K.M.), Great Ormond Street Hospital for Children, London; Department of Neurology (D.R., S. West), Royal Manchester Children's Hospital, Manchester; Department of Neurology (S. Wright, E.W.), Birmingham Children's Hospital, Birmingham; Aston Neuroscience Institute (S. Wright, E.W.), College of Health and Life Sciences, Aston University, Birmingham, United Kingdom; Evelina London Children's Hospital (M.L.), Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, United Kingdom; and NIHR University College London Hospitals Biomedical Research Centre (O.C.).

Objectives: To compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS).

Methods: In this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records. Annualized relapse rates (ARRs) before and on treatment, time to relapse, time to new MRI lesions, and change in Expanded Disability Status Scale (EDSS) score were calculated.

Results: Of 103 children treated with DMTs, followed up for 3.8 years, relapses on treatment were recorded in 53/89 (59.5%) on injectables vs 8/54 (15%) on newer DMTs. The ARR was reduced from 1.9 to 1.1 on injectables ( < 0.001) vs 1.6 to 0.3 on newer DMTs ( = 0.002). New MRI lesions occurred in 77/89 (86.5%) of patients on injectables vs 26/54 (47%) on newer DMTs ( = 0.0001). Children on newer DMTs showed longer time to relapse, time to switch treatment, and time to new radiologic activity than patients on injectables (log-rank < 0.01). After adjustment for potential confounders, multivariable analysis showed that injectables were associated with 12-fold increased risk of clinical relapse (adjusted hazard ratio [HR] = 12.12, 95% CI = 1.64-89.87, = 0.015) and a 2-fold increased risk of new radiologic activity (adjusted HR = 2.78, 95% CI = 1.08-7.13, = 0.034) compared with newer DMTs. At 2 years from treatment initiation, 38/103 (37%) patients had MRI activity in the absence of clinical relapses. The EDSS score did not change during the follow-up, and only 2 patients had cognitive impairment.

Conclusion: Newer DMTs were associated with a lower risk of clinical and radiologic relapses in patients compared with injectables. Our study adds weight to the argument for an imminent shift in practice toward the use of newer, more efficacious DMTs in the first instance.

Classification Of Evidence: This study provides Class IV evidence that newer DMTs (oral or infusions) are superior to injectables (interferon beta/glatiramer acetate) in reducing both clinical relapses and radiologic activity in children with RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000001008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143699PMC
July 2021

Paediatric neurosurgical implications of a ribosomopathy: illustrative case and literature review.

Childs Nerv Syst 2021 May 21. Epub 2021 May 21.

Department of Neurosurgery, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

Ribosomopathies are rare, recently defined entities. One of these, Labrune syndrome, is recognisable radiologically by its distinctive triad of leukoencephalopathy, intracranial calcifications and cysts (LCC). These cysts may have neurosurgical implications at different ages because of their progressive expansion and local mass effect. The aetiology of LCC is related to a widespread cerebral microangiopathy and is due to a genetic mutation in SNORD118, responsible for stabilisation of the large ribosomal subunit during assembly.
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http://dx.doi.org/10.1007/s00381-021-05208-6DOI Listing
May 2021

Leadership skills in radiology: five basic principles.

Transl Pediatr 2021 Apr;10(4):1244-1247

Positive Impact, Bangalore, India.

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http://dx.doi.org/10.21037/tp-20-304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107852PMC
April 2021

Clinico-radiological phenotyping and diagnostic pathways in childhood neurometabolic disorders-a practical introductory guide.

Transl Pediatr 2021 Apr;10(4):1201-1230

Neuroradiology Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

Inborn errors of metabolism (IEM) although individually rare, together constitute a significant proportion of childhood neurological disorders. Majority of these disorders occur due to deficiency of an enzyme in a specific metabolic pathway, leading to damage by accumulation of a toxic substrate or deficiency of an essential metabolite. Early diagnosis is crucial in many of these conditions to prevent or minimise brain damage. Whilst many of the neuroimaging features are nonspecific, certain disorders demonstrate specific patterns due to selective vulnerability of different structures to different insults. Along with clinical and biochemical profile, neuroimaging thus plays a pivotal role in differentiating metabolic disorders from other causes, in providing a differential diagnosis or suggesting a metabolic pathway derangement, and on occasion also helps make a specific diagnosis. This allows initiation of targeted metabolic and genetic work up and treatment. Familiarity with the clinical features, relevant biochemical features and neuroimaging findings of common metabolic disorders to facilitate a prompt diagnosis cannot thus be overemphasized. In this article, we describe the latest classification scheme, the clinical and biochemical clues and common radiological patterns. The diagnostic algorithm followed in daily practice after clinico-radiological phenotyping is alluded to and illustrated by clinical vignettes. Focused sections on neonatal metabolic disorders and mitochondrial disorders are also provided. The purpose of this article is to provide a brief overview and serve as a practical primer to clinical and radiological phenotypes and diagnostic aspects of IEM.
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http://dx.doi.org/10.21037/tp-20-335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107844PMC
April 2021

Narrative review of epilepsy: getting the most out of your neuroimaging.

Transl Pediatr 2021 Apr;10(4):1078-1099

Department of Radiology, Great Ormond Street Hospital, London, UK.

Neuroimaging represents an important step in the evaluation of pediatric epilepsy. The crucial role of brain imaging in the diagnosis, follow-up and presurgical assessment of patients with epilepsy is noted and has to be familiar to all neuroradiologists and trainees approaching pediatric brain imaging. Morphological qualitative imaging shows the majority of cerebral lesions/alterations underlying focal epilepsy and can highlight some features which are useful in the differential diagnosis of the different types of epilepsy. Recent advances in MRI acquisitions including diffusion-weighted imaging (DWI), post-acquisition image processing techniques, and quantification of imaging data are increasing the accuracy of lesion detection during the last decades. Functional MRI (fMRI) can be really useful and helps to identify cortical eloquent areas that are essential for language, motor function, and memory, and diffusion tensor imaging (DTI) can reveal white matter tracts that are vital for these functions, thus reducing the risk of epilepsy surgery causing new morbidities. Also positron emission tomography (PET), single photon emission computed tomography (SPECT), simultaneous electroencephalogram (EEG) and fMRI, and electrical and magnetic source imaging can be used to assess the exact localization of epileptic foci and help in the design of intracranial EEG recording strategies. The main role of these "hybrid" techniques is to obtain quantitative and qualitative informations, a necessary step to evaluate and demonstrate the complex relationship between abnormal structural and functional data and to manage a "patient-tailored" surgical approach in epileptic patients.
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http://dx.doi.org/10.21037/tp-20-261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107872PMC
April 2021

Abusive head trauma: neuroimaging mimics and diagnostic complexities.

Pediatr Radiol 2021 May 17;51(6):947-965. Epub 2021 May 17.

Department of Radiology, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK.

Traumatic brain injury is responsible for approximately half of all childhood deaths from infancy to puberty, the majority of which are attributable to abusive head trauma (AHT). Due to the broad way patients present and the lack of a clear mechanism of injury in some cases, neuroimaging plays an integral role in the diagnostic pathway of these children. However, this nonspecific nature also presages the existence of numerous conditions that mimic both the clinical and neuroimaging findings seen in AHT. This propensity for misdiagnosis is compounded by the lack of pathognomonic patterns and clear diagnostic criteria. The repercussions of this are severe and have a profound stigmatic effect. The authors present an exhaustive review of the literature complemented by illustrative cases from their institutions with the aim of providing a framework with which to approach the neuroimaging and diagnosis of AHT.
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http://dx.doi.org/10.1007/s00247-020-04940-6DOI Listing
May 2021

Sibling screening in suspected abusive head trauma: a proposed guideline.

Pediatr Radiol 2021 May 17;51(6):872-875. Epub 2021 May 17.

Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Abusive head trauma (AHT) is the leading cause of death from child abuse in children younger than 5 years. It is well documented that the infant contacts of children presenting with suspected AHT are at an increased risk of abuse when compared to the general infant population. Despite this association, a paucity of literature stratifies this risk and translates it to the clinic such that this high-risk group is stringently screened for abusive injuries. In this light, the authors propose a standardised screening method for all contact children of the index case and call for further consensus on the subject.
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http://dx.doi.org/10.1007/s00247-020-04917-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126595PMC
May 2021

MRI-based radiomics for prognosis of pediatric diffuse intrinsic pontine glioma: an international study.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab042. Epub 2021 Mar 5.

Department of Medical Biophysics, Western University, London, Onatrio, Canada.

Background: Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors. Presently, MRI is the mainstay of disease diagnosis and surveillance. We identify clinically significant computational features from MRI and create a prognostic machine learning model.

Methods: We isolated tumor volumes of T1-post-contrast (T1) and T2-weighted (T2) MRIs from 177 treatment-naïve DIPG patients from an international cohort for model training and testing. The Quantitative Image Feature Pipeline and PyRadiomics was used for feature extraction. Ten-fold cross-validation of least absolute shrinkage and selection operator Cox regression selected optimal features to predict overall survival in the training dataset and tested in the independent testing dataset. We analyzed model performance using clinical variables (age at diagnosis and sex) only, radiomics only, and radiomics plus clinical variables.

Results: All selected features were intensity and texture-based on the wavelet-filtered images (3 T1 gray-level co-occurrence matrix (GLCM) texture features, T2 GLCM texture feature, and T2 first-order mean). This multivariable Cox model demonstrated a concordance of 0.68 (95% CI: 0.61-0.74) in the training dataset, significantly outperforming the clinical-only model ( = 0.57 [95% CI: 0.49-0.64]). Adding clinical features to radiomics slightly improved performance ( = 0.70 [95% CI: 0.64-0.77]). The combined radiomics and clinical model was validated in the independent testing dataset ( = 0.59 [95% CI: 0.51-0.67], Noether's test = .02).

Conclusions: In this international study, we demonstrate the use of radiomic signatures to create a machine learning model for DIPG prognostication. Standardized, quantitative approaches that objectively measure DIPG changes, including computational MRI evaluation, could offer new approaches to assessing tumor phenotype and serve a future role for optimizing clinical trial eligibility and tumor surveillance.
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http://dx.doi.org/10.1093/noajnl/vdab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095337PMC
March 2021

An algorithmic clinicoradiological approach to paediatric cranial vault lesions: distinguishing normal variants from pathologies.

Br J Neurosurg 2021 May 7:1-14. Epub 2021 May 7.

Department of Neuroradiology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

Lesions of the paediatric cranial vault are diverse both in their presentation and aetiology. As such, they pose a diagnostic challenge to the paediatric neurosurgeon and neuroradiologist. In this article, we delineate the spectrum of paediatric calvarial pathology into four distinct groups: (1) lytic lesion(s); (2) focal sclerotic lesion(s); (3) diffuse cranial vault sclerosis; and (4) abnormal shape of the cranial vault. It is our aim that this more pragmatic, algorithmic approach may mitigate diagnostic uncertainty and aid the more accurate diagnosis of paediatric calvarial lesions.
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http://dx.doi.org/10.1080/02688697.2021.1919599DOI Listing
May 2021

Magnetic resonance imaging findings in children with Parry-Romberg syndrome and en coup de sabre.

Pediatr Rheumatol Online J 2021 Mar 23;19(1):42. Epub 2021 Mar 23.

Department of Paediatric Rheumatology, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: The aim of this study was to: (i) describe the abnormalities seen on brain imaging in a group of children with en coup de sabre (EDCS) with/without Parry-Romberg syndrome (PRS); and (ii) identify clinical predictors of brain imaging abnormalities.

Methods: This was a single centre (Great Ormond Street Hospital, London) retrospective case series of patients with ECDS/PRS seen from 2000 to 2018. We identified patients with cutaneous manifestations consistent with the clinical descriptions of ECDS/PRS. Presenting clinical, laboratory, and radiological brain findings are described. Results are expressed as medians and ranges or frequencies and percentages. Fisher's exact test was used to identify clinical associations with magnetic resonance imaging (MRI) abnormalities.

Results: Fourteen patients were studied: 6 males and 8 females; median age 14 years (range 3-20). We observed neuroimaging abnormalities in 2/6 ECDS and 5/8 ECDS/PRS patients. White matter signal abnormality, dystrophic calcification, leptomeningeal enhancement, and sulcal crowding were the typical findings on brain imaging. A total of 50% of patients had no MRI abnormality despite some of these patients having neurological symptoms. The presence of seizures was significantly associated with ipsilateral enhanced white matter signalling on MRI (p < 0.05).

Conclusions: In summary, we observed several distinct radiographic patterns associated with ECDS/PRS. Seizure disorder was strongly associated with the presence of ipsilateral enhanced white matter signalling. Improved neuroimaging techniques that combine morphological with functional imaging may improve the detection rate of brain involvement in children with ECDS/PRS in the future.
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http://dx.doi.org/10.1186/s12969-021-00512-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986399PMC
March 2021

Neuroimaging of retinal hemorrhage utilizing adjunct orbital susceptibility-weighted imaging.

Pediatr Radiol 2021 May 12;51(6):991-996. Epub 2021 Mar 12.

Division of Pediatric Ophthalmology, Strabismus, and Adult Motility, Eye Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.

Retinal hemorrhages are an integral part of the evaluation of abusive head trauma (AHT). Timely detection of retinal hemorrhage not only facilitates the diagnosis of AHT, but has the potential to prevent further abuse to the child and the siblings and to identify the abuser. The gold standard for diagnosing retinal hemorrhage is a dilated fundoscopy exam, which requires pharmacological dilation. As such, there is a small percentage of patients for whom the dilated fundoscopy exam might be delayed. Evolving literature suggests that MRI, specifically susceptibility-weighted imaging (SWI), of the orbits might provide an alternative diagnostic tool for noninvasively detecting retinal hemorrhages, particularly when there is a delay in administering the dilated fundoscopy exam. In this paper we review the utility of SWI for detecting retinal hemorrhages in abusive head trauma, including discussion of diagnostic limitations and future research.
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http://dx.doi.org/10.1007/s00247-020-04897-6DOI Listing
May 2021

Parenchymal brain injuries in abusive head trauma.

Pediatr Radiol 2021 May 27;51(6):898-910. Epub 2021 Feb 27.

Department of Radiology, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK.

The consequences of abusive head trauma (AHT) can be devastating for both the individual child and for wider society. Death is undoubtedly a very real possibility, but even for those children who survive, there is often very significant morbidity with the potential for gross motor and cognitive impairment, behavioural problems, blindness and epilepsy, which can greatly affect their quality of life. Caring for such children places a vast financial and infrastructural burden on society that frequently extends well into adulthood. While few struggle to have any sympathy for the perpetrator, frequently the infant's father, it should be noted that a single solitary and momentary loss of complete control can have horrific and unforeseen consequences. A number of papers within this edition describe features of AHT and include descriptions of skull fractures and extra-axial haemorrhage, along with mimics of such phenomena. However, in this review we concentrate our attention on the myriad of parenchymal findings that can occur. Such parenchymal injuries include hypoxic-ischaemic damage, clefts, contusion and focal haemorrhage. We offer our perspectives on current thinking on these entities and put them in the context of the immensely important question - how do we recognise abusive head trauma?
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http://dx.doi.org/10.1007/s00247-021-04981-5DOI Listing
May 2021

AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination.

Am J Med Genet A 2021 04 13;185(4):1228-1235. Epub 2021 Jan 13.

Department of Clinical Genetics, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom.

Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination. Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1. We describe their clinical course and radiological and genetic findings, providing further insight into the natural history of this condition.
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http://dx.doi.org/10.1002/ajmg.a.62072DOI Listing
April 2021

Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy.

Epilepsia 2021 02 7;62(2):e35-e41. Epub 2021 Jan 7.

Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, UK.

The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.
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http://dx.doi.org/10.1111/epi.16801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898547PMC
February 2021

Neuroimaging manifestations of epidermal nevus syndrome.

Quant Imaging Med Surg 2021 Jan;11(1):415-422

Department of Radiology, Great Ormond Street Hospital, London, UK.

Epidermal nevus syndrome (ENS) represents a diverse group of rare neurocutaneous diseases associated with the presence of characteristic epidermal nevi (EN) in the skin and extracutaneous manifestations in the eyes, skeletal, urogenital and central nervous systems. We present a case series of 7 children with ENS, with specific attention to the neuroradiological characteristics of this entity.
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http://dx.doi.org/10.21037/qims-20-634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719931PMC
January 2021

Imaging characteristics of H3 K27M histone-mutant diffuse midline glioma in teenagers and adults.

Quant Imaging Med Surg 2021 Jan;11(1):43-56

Teenage and Young Persons' Cancer Unit, Department of Paediatric Oncology, University College London Hospitals NHS Foundation Trust, London, UK.

Background: To assess anatomical and quantitative diffusion-weighted MR imaging features in a recently classified lethal neoplasm, H3 K27M histone-mutant diffuse midline glioma [World Health Organization (WHO) IV].

Methods: Fifteen untreated gliomas in teenagers and adults (median age 19, range, 14-64) with confirmed H3 K27M histone-mutant genotype were analysed at a national referral centre. Morphological characteristics including tumour epicentre(s), T2/FLAIR and Gadolinium enhancement patterns, calcification, haemorrhage and cyst formation were recorded. Multiple apparent diffusion coefficient (ADC, ADC) regions of interest were sited in solid tumour and normal appearing white matter (ADC) using post-processing software (Olea Sphere v2.3, Olea Medical). ADC histogram data (2, 5, 10 percentile, median, mean, kurtosis, skewness) were calculated from volumetric tumour segmentations and tested against the regions of interest (ROI) data (Wilcoxon signed rank test).

Results: The median interval from imaging to tissue diagnosis was 9 (range, 0-74) days. The structural MR imaging findings varied between individuals and within tumours, often featuring signal heterogeneity on all MR sequences. All gliomas demonstrated contact with the brain midline, and 67% exhibited rim-enhancing necrosis. The mean ROI ADC value was 0.84 (±0.15 standard deviation, SD) ×10 mm/s. In the largest tumour cross-section (excluding necrosis), an average ADC value of 1.12 (±0.25)×10 mm/s was observed. The mean ADC ratio was 1.097 (±0.149), and the mean ADC ratio measured 1.466 (±0.299). With the exception of the 2 centile, no statistical difference was observed between the regional and histogram derived ADC results.

Conclusions: H3 K27M-mutant gliomas demonstrate variable morphology and diffusivity, commonly featuring moderately low ADC values in solid tumour. Regional ADC measurements appeared representative of volumetric histogram data in this study.
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http://dx.doi.org/10.21037/qims-19-954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719951PMC
January 2021

Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study.

Lancet Child Adolesc Health 2021 03 16;5(3):167-177. Epub 2020 Dec 16.

Department of Medical Imaging, Division of Pediatric Neuroradiology, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL USA. Electronic address:

Background: The CNS manifestations of COVID-19 in children have primarily been described in case reports, which limit the ability to appreciate the full spectrum of the disease in paediatric patients. We aimed to identify enough cases that could be evaluated in aggregate to better understand the neuroimaging manifestations of COVID-19 in the paediatric population.

Methods: An international call for cases of children with encephalopathy related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and abnormal neuroimaging findings was made. Clinical history and associated plasma and cerebrospinal fluid data were requested. These data were reviewed by a central neuroradiology panel, a child neurologist, and a paediatric infectious diseases expert. The children were categorised on the basis of their time of probable exposure to SARS-CoV-2. In addition, cases were excluded when a direct link to SARS-CoV-2 infection could not be established or an established alternate diagnostic cause could be hypothesised. The accepted referral centre imaging data, from ten countries, were remotely reviewed by a central panel of five paediatric neuroradiologists and a consensus opinion obtained on the imaging findings.

Findings: 38 children with neurological disease related to SARS-CoV-2 infection were identified from France (n=13), the UK (n=8), the USA (n=5), Brazil (n=4), Argentina (n=4), India (n=2), Peru (n=1), and Saudi Arabia (n=1). Recurring patterns of disease were identified, with neuroimaging abnormalities ranging from mild to severe. The most common imaging patterns were postinfectious immune-mediated acute disseminated encephalomyelitis-like changes of the brain (16 patients), myelitis (eight patients), and neural enhancement (13 patients). Cranial nerve enhancement could occur in the absence of corresponding neurological symptoms. Splenial lesions (seven patients) and myositis (four patients) were predominantly observed in children with multisystem inflammatory syndrome. Cerebrovascular complications in children were less common than in adults. Significant pre-existing conditions were absent and most children had favourable outcomes. However, fatal atypical CNS co-infections developed in four previously healthy children infected with SARS-CoV-2.

Interpretation: Acute-phase and delayed-phase SARS-CoV-2-related CNS abnormalities are seen in children. Recurring patterns of disease and atypical neuroimaging manifestations can be found and should be recognised being as potentially due to SARS-CoV-2 infection as an underlying aetiological factor. Studies of paediatric specific cohorts are needed to better understand the effects of SARS-CoV-2 infection on the CNS at presentation and on long-term follow-up in children.

Funding: American Society of Pediatric Neuroradiology, University of Manchester (Manchester, UK). VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/S2352-4642(20)30362-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744016PMC
March 2021

A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

Neuropathol Appl Neurobiol 2021 04 12;47(3):464-467. Epub 2021 Jan 12.

Developmental Biology and Cancer (DBC) Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.

In this study, we report three paediatric cases of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).
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http://dx.doi.org/10.1111/nan.12680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048648PMC
April 2021

Constitutional mismatch repair deficiency (CMMRD) presenting with high-grade glioma, multiple developmental venous anomalies and malformations of cortical development-a multidisciplinary/multicentre approach and neuroimaging clues to clinching the diagnosis.

Childs Nerv Syst 2021 07 27;37(7):2375-2379. Epub 2020 Nov 27.

Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.

Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare cancer-predisposition syndrome associated with a high risk of developing a spectrum of malignancies in childhood and adolescence, including brain tumours. In this report, we present the case of an 8-year-old boy with acute headache, vomiting and an episode of unconsciousness in whom brain imaging revealed a high-grade glioma (HGG). The possibility of an underlying diagnosis of CMMRD was suspected radiologically on the basis of additional neuroimaging findings, specifically the presence of multiple supratentorial and infratentorial developmental venous anomalies (DVAs) and malformations of cortical development (MCD), namely, heterotopic grey matter. The tumour was debulked and confirmed to be a HGG on histopathology. The suspected diagnosis of CMMRD was confirmed on immunohistochemistry and genetic testing which revealed mutations in PMS2 and MSH6. The combination of a HGG, multiple DVAs and MCD in a paediatric or young adult patient should prompt the neuroradiologist to suggest an underlying diagnosis of CMMRD. A diagnosis of CMMRD has an important treatment and surveillance implications not only for the child but also the family in terms of genetic counselling.
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http://dx.doi.org/10.1007/s00381-020-04986-9DOI Listing
July 2021

Surveillance imaging of grade 1 astrocytomas in children: can duration and frequency of follow-up imaging and the use of contrast agents be reduced?

Neuroradiology 2021 Jun 25;63(6):953-958. Epub 2020 Nov 25.

Radiology Department, Great Ormond Street Hospital, London, UK.

Purpose: The optimum strategy for the surveillance of low-grade gliomas in children has not been established, and there is concern about the use of gadolinium-based contrast agents (GBCAs), particularly in children, due to their deposition in the brain. The number of surveillance scans and the use of GBCAs in surveillance of low-risk tumours should ideally be limited. We aimed to investigate the consistency and utility of our surveillance imaging and also determine to what extent the use of GBCAs contributed to decisions to escalate treatment in children with grade 1 astrocytomas.

Methods: This was a retrospective single-centre study at a tertiary paediatric hospital. All children with a new diagnosis of a non-syndromic World Health Organization (WHO) grade 1 astrocytoma between 2007 and 2013 were included, with surveillance imaging up to December 2018 included in analysis. The intervals of surveillance imaging were recorded, and imaging and electronic health records were examined for decisions related to treatment escalation.

Results: Eighty-eight patients had 690 surveillance scans in the study period. Thirty-one patients had recurrence or progression leading to treatment escalation, 30 of whom were identified on surveillance imaging. The use of GBCAs did not appear to contribute to multidisciplinary team (MDT) decisions in the majority of cases.

Conclusion: Surveillance imaging could be reduced in number and duration for completely resected cerebellar tumours. MDT decisions were rarely made on the basis of post-contrast imaging, and GBCA administration could therefore potentially be restricted in the setting of surveillance of grade 1 astrocytomas in children.
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http://dx.doi.org/10.1007/s00234-020-02609-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688203PMC
June 2021

Progress in the Management of Paediatric-Onset Multiple Sclerosis.

Children (Basel) 2020 Nov 9;7(11). Epub 2020 Nov 9.

Department of Neurology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.

Considerable progress has been made in the understanding and treatment of paediatric-onset multiple sclerosis (POMS); how this has translated into more effective care is less well understood. Here, we evaluate how recent advances have affected patient management and outcomes with a retrospective review of POMS patients managed at two paediatric neuroimmunology centres. Two cohorts, seen within a decade, were compared to investigate associations between management approaches and outcomes. Demographic, clinical and neurocognitive data were extracted from case notes and analysed. Of 51 patients, 24 were seen during the period 2007-2010 and 27 during the period 2015-2016. Median age at onset was 13.7 years; time from symptom onset to diagnosis was 9 months. Disease-modifying therapies were commenced in 19 earlier-cohort and 24 later-cohort patients. Median time from diagnosis to treatment was 9 months for earlier vs. 3.5 months in later patients ( 0.013). A wider variety of treatments were used in the later cohort (four medications earlier vs. seven in the later and two clinical trials), with increased quality of life and neurocognitive monitoring (8% vs. 48% completed PedsQL quality of life inventory; 58% vs. 89% completed neurocognitive assessment). In both cohorts, patients were responsive to disease-modifying therapy (mean annualised relapse rate pre-treatment 2.7 vs. 1.7, mean post-treatment 0.74 vs. 0.37 in earlier vs. later cohorts). In conclusion, over the years, POMS patients were treated sooner with a wider variety of medications and monitored more comprehensively. However, this hugely uncontrolled cohort did not allow us to identify key determinants for the improvements observed.
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http://dx.doi.org/10.3390/children7110222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695340PMC
November 2020
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