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Malformations of cortical development (MCD) are a rare group of disorders with heterogeneous clinical, neuroimaging, and genetic features. MCDs consist of disruptions in the development of the cerebral cortex secondary to genetic, metabolic, infectious or vascular etiologies. MCDs are typically classified by stage of disrupted cortical development as secondary abnormal: (1) neuronal proliferation or apoptosis, (2) neuronal migration, or (3) postmigrational cortical development. MCDs are typically detected with brain magnetic resonance imaging (MRI) when an infant or child becomes symptomatic, presenting with seizures, developmental delay, or cerebral palsy. With recent advances in neuroimaging, cortical malformations can be detected using ultrasound or MRI during the fetal period, or in the neonatal period. Interestingly, preterm infants are born at a time when many cortical developmental processes are still occurring. However, there is a paucity of literature describing the neonatal imaging findings, clinical presentation, and evolution over time of cortical malformations in preterm infants. Here, we present the neuroimaging findings from early life to term-equivalent age as well as childhood neurodevelopmental outcomes of an infant born very preterm (

Background: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. Objective: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. Methods: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. Results: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (−0.26 nU, p = 0.0023), and in both in the ON (−0.62 nU, p Conclusions: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Variants in JAM3 have been reported in four families manifesting a severe autosomal recessive disorder characterized by hemorrhagic destruction of the brain, subependymal calcification, and cataracts. We describe a 7-year-old male with a similar presentation found by research-based quad genome sequencing to have two novel splicing variants in trans in JAM3, including one deep intronic variant (NM_032801.4: c.256+1260G>C) not detectable by standard exome sequencing. Targeted sequencing of RNA isolated from transformed lymphoblastoid cell lines confirmed that each of the two variants has a deleterious effect on JAM3 mRNA splicing. The role for genome sequencing as a clinical diagnostic test extends to those patients with phenotypes strongly suggestive of a specific Mendelian disorder, especially when the causal genetic variant(s) are not found by a more targeted approach. Barriers to diagnosis via identification of pathogenic deep intronic variation include lack of laboratory consensus regarding in silico splicing prediction tools and limited access to clinically validated confirmatory RNA experiments.

Summary Background Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. Methods In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. Findings 58 children with AFM (median age 5·1 years, IQR 3·8–8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV–) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1–9·5 vs EDSS 4·0, IQR 3·0–6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0–7·4 vs EDSS 3·0, IQR 1·5–4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0–7·0 vs EDSS 3·0, IQR 1·0–4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0–6·9 vs EDSS 2·5 IQR 0·3–3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). Interpretation Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. Funding None.

Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW,1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification.We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes.This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV).EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P 0.05).In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.

To study the association between perinatal sentinel events (PSE) and brain MRI/neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH). This is a retrospective single-center study. Data collection included perinatal history, brain MRI, and neurodevelopmental outcome. Out of the 182 neonates, 53 (29%) neonates had PSE and 129 (71%) neonates did not have PSE. Neonates with PSE had more normal MRIs (76%) compared with neonates without PSE (55%), p = 0.01. PSE was associated with favorable motor (p = 0.02), language outcome (p = 0.03), and trend to better cognitive scores (p = 0.13). In PSE, favorable motor outcome persisted (OR for impairment 0.15 (0.003–0.84), p = 0.03) after adjusting for the degree of encephalopathy and brain MRI injury. Injury on brain MRI despite TH after PSE was associated with unfavorable neurodevelopmental outcome (p

Rare Brain Tumor Registry., [Background] Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease., [Methods] Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors., [Findings] 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18–36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47–68) at 6 months and 31% (21–42) at 2 years; overall survival was 29% (20–38) at 2 years and 27% (18–37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28–0·80; p=0·0057) and non-brainstem location (0·42 [0·22–0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16–0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19–0·67; p=0·0020), and radiotherapy (0·21, 0·10–0·41; p, [Interpretation] Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival., Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

BACKGROUND Among the known complications of ventriculoperitoneal (VP) shunts, subcutaneous or subgaleal migration of distal catheters is rare. Prior case reports have proposed several risk factors, including inadequate fixation of the shunt device, presence of a large subgaleal space filled with cerebrospinal fluid (CSF), and repetitive flexion/extension movement of the head producing a “windlass effect.” Tight coiling of a distal catheter around the valve without a large subgaleal space has not been reported. OBSERVATIONS The patient was born prematurely and underwent VP shunt placement for posthemorrhagic ventricular dilatation at 3 months of age with reassuring postoperative imaging. At approximately 3 years of age, shunt radiography and head computed tomography unexpectedly showed excess tubing coiled extracranially around the shunt valve. The patient did not exhibit any clinical symptoms of shunt malfunction and underwent an uneventful revision of the VP shunt system. No CSF-filled subgaleal space was observed intraoperatively. LESSONS Distal catheter migration can occur without the clear presence of a subgaleal CSF collection and symptoms of acute hydrocephalus. Appropriate fixation of the shunt system using nonabsorbable stitches is recommended to prevent catheter migration caused by the windlass effect.

Infants born at very low birth weight (, Graphical Abstract Graphical Abstract

Background Central nervous system (CNS) relapse is rare in childhood anaplastic large cell lymphoma (ALCL) and is associated with a poor prognosis. Case We describe an 8‐year‐old boy with ALCL who developed an early CNS relapse without initial CNS disease. Despite aggressive medical management, the patient's neurological status deteriorated rapidly and he died shortly after. Conclusion Optimal treatment for children with relapsed ALCL involving the CNS remains unclear. Novel agents, including ALK inhibitors, that have CNS‐penetration might be helpful and pediatric studies are warranted.

Highlights • White matter was assessed in very low birth weight (VLBW) and full-term children. • VLBW children showed widespread alterations in white matter microstructure. • White matter microstructure was associated with processing speed in VLBW children. • Birth weight was associated with white matter metrics in VLBW and full-term groups. • These results highlight the factors contributing to poor outcomes in VLBW children., Background Very low birth weight (VLBW) infants are at risk for disrupted white matter maturation, yet little is known about the contributing factors, particularly at preschool-age when cognitive difficulties begin to emerge. We examined white matter microstructure in five-year-old VLBW and full-term (FT) children, and its association with cognitive outcomes and birth weight. Methods Multi-shell diffusion and MR images were obtained for 41 VLBW (mean birth weight: 1028.6 ± 256.8 g) and 26 FT (3295.4 ± 493.9 g) children. Fractional anisotropy (FA), radial diffusivity (RD), neurite orientation dispersion index (ODI) and density index (NDI) were estimated using diffusion tensor and neurite orientation dispersion and density imaging models. Between-group analyses used a general linear model with group and sex as explanatory variables. Within-group associations between white matter microstructure, cognitive outcomes and birth weight were also investigated. Results VLBW compared to FT children showed lower FA and NDI across widespread white matter regions. Smaller clusters of atypical ODI were also found in VLBW children. Within-group analyses in FT children revealed that lower RD and higher NDI were associated with vocabulary acquisition and working memory. In VLBW children, higher FA and NDI, and lower RD and ODI, were associated with improved processing speed. In both groups, FA was positively associated with birth weight. Conclusions Our findings demonstrate white matter alterations in young VLBW children, including widespread reductions in axon density that may reflect sustained myelination disruptions. The associations with cognitive outcomes may also highlight which of the VLBW children are at higher risk for later cognitive difficulties.

BackgroundETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease.MethodsPrimary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses.FindingsETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=InterpretationPrompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.FundingThis work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Tali’s Funds, Garron Cancer Centre, Grace’s Walk, Meagan’s Walk, Nelina’s Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Children’s Cancer Foundation and the Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía Project EF-0451-2017.

Brain tumors are the most common solid tumors in the pediatric population. Pediatric neuro-oncology has changed tremendously during the past decade owing to ongoing genomic advances. The diagnosis, prognosis, and treatment of pediatric brain tumors are now highly reliant on the genetic profile and histopathologic features of the tumor rather than the histopathologic features alone, which previously were the reference standard. The clinical information expected to be gleaned from radiologic interpretations also has evolved. Imaging is now expected to not only lead to a relevant short differential diagnosis but in certain instances also aid in predicting the specific tumor and subtype and possibly the prognosis. These processes fall under the umbrella of radiogenomics. Therefore, to continue to actively participate in patient care and/or radiogenomic research, it is important that radiologists have a basic understanding of the molecular mechanisms of common pediatric central nervous system tumors. The genetic features of pediatric low-grade gliomas, high-grade gliomas, medulloblastomas, and ependymomas are reviewed; differences between pediatric and adult gliomas are highlighted; and the critical oncogenic pathways of each tumor group are described. The role of the mitogen-activated protein kinase pathway in pediatric low-grade gliomas and of histone mutations as epigenetic regulators in pediatric high-grade gliomas is emphasized. In addition, the oncogenic drivers responsible for medulloblastoma, the classification of ependymomas, and the associated imaging correlations and clinical implications are discussed. ©RSNA, 2018.

A 4-year-old boy with pulmonary capillaritis, treated with rituximab, steroids, and azathioprine for 2 years, presented with a 6-month history of falls and paucity of speech. Examination revealed irritability, mutism, hyperreflexia, and wide-based gait, and he had an Expanded Disability Status Scale (EDSS) score of 6.5. MRI brain revealed volume loss with extensive, bilateral T2/fluid-attenuated inversion recovery hyperintensities in the deep subcortical white matter, mesial temporal lobes, insula, globus pallidi, thalami, brainstem, and cerebellum (figure). MRI spine revealed increased T2 signal within the central dorsal aspect of the cervical cord. Lumbar puncture showed leukocyte count of 13 × 106/L (65% lymphocytes), erythrocyte count of 1 × 106/L, glucose 2.7 mmol/L, and protein 0.36 g/L. NMDAR antibody testing was negative (serum/CSF). Nasopharyngeal and bronchoalveolar lavage samples tested positive for enterovirus/rhinovirus by multiplex PCR and enterovirus was detected by RT-PCR (serum/CSF).

Study Design Case report Objective Syndromic multi-suture craniosynostosis can result in complex dysmorphology and increased intracranial pressure. We present a case report of a child with craniometaphyseal dysplasia and syndromic multi-suture craniosynostosis who presented with increased intracranial pressure, ventriculomegaly and Chiari deformity Type 1. Methods The child underwent a posterior vault distraction to increase the intracranial volume. Results The posterior cranial expansion was successful in correcting the craniocerebral disproportion caused by multi-suture synostosis, and resolved the high intracranial pressure and papilloedema. There were no post-operative complications. Conclusions Posterior cranial vault distraction was an effective method of addressing increased intracranial pressure by correcting craniocerebral disproportion by increasing intracranial volume and also addressing the Chiari Type I deformity that resulted from syndromic multi-suture craniosynostosis in a child with craniometaphyseal dysplasia.

Objective To examine the association between cerebellar hemorrhage (CBH) size and location and preschool-age neurodevelopment in very preterm neonates. Methods Preterm magnetic resonance images of 221 very preterm neonates (median gestational age = 27.9 weeks) were manually segmented for CBH quantification and location. Neurodevelopmental assessments at chronological age 4.5 years included motor (Movement Assessment Battery for Children, 2nd Edition [MABC-2]), visuomotor integration (Beery-Buktenica Developmental Test of Visual-Motor Integration, 6th Edition), cognitive (Wechsler Primary and Preschool Scale of Intelligence, 3rd Edition), and behavioral (Child Behavior Checklist) outcomes. Multivariable linear regression models examined the association between CBH size and 4.5-year outcomes accounting for sex, gestational age, and supratentorial injury. Probabilistic maps assessed CBH location and likelihood of a lesion to predict adverse outcome. Results Thirty-six neonates had CBH: 14 (6%) with only punctate CBH and 22 (10%) with ≥1 larger CBH. CBH occurred mostly in the inferior aspect of the posterior lobes. CBH total volume was independently associated with MABC-2 motor scores at 4.5 years (β = -0.095, 95% confidence interval = -0.184 to -0.005), with a standardized β coefficient (-0.16) that was similar to that of white matter injury volume (standardized β = -0.22). CBH size was similarly associated with visuomotor integration and externalizing behavior but not cognition. Voxelwise odds ratio and lesion-symptom maps demonstrated that CBH extending more deeply into the cerebellum predicted adverse motor, visuomotor, and behavioral outcomes. Interpretation CBH size and location on preterm magnetic resonance imaging were associated with reduced preschool motor and visuomotor function and more externalizing behavior independent of supratentorial brain injury in a dose-dependent fashion. The volumetric quantification and localization of CBH, even when punctate, may allow opportunity to improve motor and behavioral outcomes by providing targeted intervention. ANN NEUROL 2020;88:1095-1108.

Background: Acute flaccid myelitis (AFM) is characterized by rapid onset of limb weakness with spinal cord grey matter abnormalities on magnetic resonance imaging (MRI). It is unclear whether detection of enterovirus (EV) in respiratory or other specimens can help predict prognosis in children with AFM. Methods: In this nationwide longitudinal study, we evaluated the significance of peripheral detection of EV in predicting outcomes in a cohort of Canadian children presenting with AFM in 2014 and 2018. Clinical data, laboratory findings, treatment, and neuroimaging were collected (follow up period up to five years). We assessed neurologic function and motor outcomes using Kurtzke’s Expanded Disability Status Scale (EDSS) and a “weakest limb score” (WLS). Findings: 58 children with AFM (median 5⋅1 years [IQR 3⋅8-8⋅3]) were identified across five provinces. Twenty-two (39%) children had detectable EV in at least one specimen: EV-D68 in 14 (64%), EV-A71 in two (9%), coxsackievirus, and untyped EV in eight (36%). Children with EV detected were more likely to have had quadriparesis (55% vs. 12%, p=0⋅005), bulbar weakness (50% vs 6%, p=0⋅004), bowel/bladder dysfunction (59% vs 24%, p=0⋅033), cardiovascular instability (36% vs 6%, p=0⋅032), and were more likely to require intensive care unit admission (59% vs. 15%, p 0⋅005). On MRI, most children with EV positivity showed brainstem pontine lesions (59%), while other MRI parameters did not correlate with EV status. EDSS of EV+ and EV- groups was significantly different at baseline (median 8⋅5 [interquartile range, IQR 4-9⋅5] vs. 4⋅8 [IQR 3⋅4-7⋅1], p=0⋅012) and 12 months (median 3 [IQR 3-7] vs. 3 [IQR 2-3], p=0⋅036). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children with detected EV than those tested negative (p=0⋅032). Interpretation: Detection of EV in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. Funding Statement: None. Declaration of Interests: EAY reports grants from Canadian Network of MS Clinics during the conduct of the study; grants from Biogen, grants from NMSS, grants from CMSC, grants from 18 MSSC/MS Foundation, grants from OIRM, grants from SCN, grants from SickKids Foundation, personal fees from ACI, personal fees from US FDA, grants from CBMH, grants from TEVA, grants from Guthy Jackson Foundation, personal fees from Juno, outside the submitted work. All other authors have no conflict of interest to disclose. Ethics Approval Statement: This study was approved by the research ethics board/committee of all above-listed participating institutions. Informed consents were obtained according to individual institutional requirements.

BackgroundThere are few data in the literature on the characteristics and natural history of intracranial arterial infundibular dilatations in children.MethodsAn institutional review board-approved retrospective review was performed of infundibula reported on MR angiography in patients ResultsWe found 60 intracranial infundibula in 60 children (male:female=27:33; mean age 9.7±5.2 years, range 2–18 years,). Family history of aneurysms was present in 2/60 (3.3%). Syndromic association was found in 14/60 (23.3%), most frequently sickle cell disease (4/14=28.6%). Mean infundibulum size was 2.2±0.5 mm, with mean ratio to parent artery of 0.54±0.17. The most common location was on the P1-posterior cerebral artery (34/63=56.7%), whereas posterior communicating infundibula were seen in only 4/60 (6.7%) cases. Other cerebrovascular variants were seen in 12/60 (20%) patients. On follow-up imaging (in 32/60 patients over 86 patient-years, mean 32.3±35.7 months), no significant change in infundibulum:parent artery ratio was noted. None of the infundibular dilatations showed interval evolution to aneurysm.ConclusionWe present the largest reported cohort of pediatric intracranial arterial infundibula, which we found to be distinct from their adult counterparts with regard to location, etiology and temporal evolution. Growth over time and/or aneurysmal formation are rare, not necessitating frequent short-term imaging surveillance during childhood.

Background: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. Methods: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. Results: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P =0.009) and older age at surgery ( P =0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = –1.0±0.90 versus early repair z = –0.33±0.64; P =0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P =0.03) and days of open chest ( P =0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P =0.02). Conclusions: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.

Infantile neuroaxonal dystrophy (INAD), an autosomal recessive neurodegenerative disorder due to PLA2G6 mutation, is classified both as a PLA2G6-associated neurodegeneration (PLAN) disorder and as one of the neurodegeneration with brain iron accumulation (NBIA) disorders. Age of onset and clinical presentation in INAD is variable. Typically described imaging features of cerebellar atrophy, cerebellar cortex bright FLAIR signal, and globus pallidus iron deposition are variable or late findings. We characterize clinical and neuroimaging phenotypes in nine children with confirmed PLA2G6 mutations and show a useful imaging feature, clava hypertrophy, which may aid in earlier identification of patients. Measurements of the clava confirm actual enlargement, rather than apparent enlargement due to volume loss of the other brain stem structures. A retrospective clinical and MRI review was performed. Brain stem measurements were performed and compared with age-matched controls. We identified nine patients, all with novel PLA2G6 gene mutations. MRI, available in eight, showed clava hypertrophy, regardless of age or the absence of other more typically described neuroimaging findings. Brain autopsy in our cohort confirmed prominent spheroid bodies in the clava nuclei. Clava hypertrophy is an important early imaging feature which may aid in indentification of children who would benefit from specific testing for PLA2G6 mutations.

ObjectiveTo develop a simple imaging rule to predict neurodevelopmental outcomes at 4.5 years in a cohort of preterm neonates with white matter injury (WMI) based on lesion location and examine whether clinical variables enhance prediction.MethodsSixty-eight preterm neonates born 24–32 weeks' gestation (median 27.7 weeks) were diagnosed with WMI on early brain MRI scans (median 32.3 weeks). 3D T1-weighted images of 60 neonates with 4.5-year outcomes were reformatted and aligned to the posterior commissure–eye plane and WMI was classified by location: anterior or posterior-only to the midventricle line on the reformatted axial plane. Adverse outcomes at 4.5 years were defined as Wechsler Preschool and Primary Scale of Intelligence full-scale IQ ResultsSix children had adverse cognitive outcomes and 17 had adverse motor outcomes. WMI location predicted cognitive outcomes in 90% (area under receiver operating characteristic curve [AUC] 0.80) and motor outcomes in 85% (AUC 0.75). Adding IVH, BPD, and ROP to the model enhances the predictive strength for cognitive and motor outcomes (AUC 0.83 and 0.88, respectively). Rule performance was confirmed in an independent cohort of children with WMI.ConclusionsWMI on early MRI can be classified by location to predict preschool age outcomes in children born preterm. The predictive value of this WMI classification is enhanced by considering clinical factors apparent by term-equivalent age.

ObjectiveTo assess the association between daily moderate-to-vigorous physical activity (MVPA) and dentate gyrus volume (DGv) in pediatric patients with acquired demyelinating syndromes (ADSs) of the CNS.MethodsCross-sectional analysis of accelerometry (7 days) and research protocol MRI data from 12 pediatric MS and 18 children with monophasic ADS (monoADS). Total brain and DGv were quantified using standardized methods. The association of daily minutes of MVPA with normalized DGv (nDGv) was assessed using multivariable generalized linear models.ResultsMedian (interquartile range) MVPA was lower in MS patients [9.5 (14)] and exhibited less variation than in monoADS patients [24.5 (47)]. nDGv did not differ significantly between groups [mean nDGv (SD) [cm3]: MS 0.34 (0.1); monoADS 0.4 (0.1); p = 0.100]. In the monoADS group, every 1-minute increase in MVPA was associated with a 2.4-mm3 increase in nDGv (p = 0.0017), an association that was independent of age at incident demyelination, time from incident demyelination, sex, and brain white matter T2 lesion volume. No significant association was found between MVPA and nDGv (−2.6 mm3/min, p = 0.16) in the MS group.ConclusionsHigher MVPA associates with greater nDGv in children who have recovered from monophasic demyelination. Larger studies are required to determine whether MVPA can promote regional brain development, or limit tissue damage, in youth with MS.

Oral-facial-digital syndrome type 1 (OFD1; OMIM#311200) is a rare developmental disorder characterized by cra- niofacial, oral, skeletal abnormalities, cystic kidneys and neurological involvement including mental retardation. The syndrome is caused by mutations in the OFD1 gene and results in male lethality in the first or second trimester. The spectrum of phenotypes associated with mutations in OFD1 continues to expand, and genotype-phenotype correlations are beginning to be recognized. The spectrum includes Simpson-Golabi-Behmel syndrome type 2 (OMIM#300209) and X-linked Joubert syndrome (type 10) phenotype in addition to the classical OFD1 phenotype with early male lethality. We describe the neuroimaging and clinical findings in a 17-year-old male with a clinical diagnosis of Joubert syndrome associated with a novel mutation in the OFD1 gene (type 10). Our patient confirms the reported association of OFD1 mutation with X-linked recessive Joubert syndrome. This family is the fifth reported with X-linked Joubert syndrome, associated with a novel mutation in exon 17 of the OFD1 gene. We describe unique neuroimaging and clinical features associated with OFD1 mutations and highlight the utility of advanced neu- roimaging techniques in characterizing the phenotype.

Summary Background MRI and laboratory features have been incorporated into international diagnostic criteria for multiple sclerosis. We assessed the pattern of MRI lesions and contributions of cerebrospinal fluid (CSF) and serum antibody findings that best identifies children with multiple sclerosis, and the applicability of international diagnostic criteria in the paediatric context. Methods In this prospective cohort study, detailed clinical assessments, serum and CSF studies, and MRI scans were done in youth (aged 0·46–17·87 years) with incidental acquired demyelinating syndrome. Participants were examined prospectively to identify relapsing disease. All MRI scans were assessed using a validated scoring method. A random forest classifier identified imaging and laboratory features that best predicted a multiple sclerosis or monophasic outcome. Performance of the 2001, 2010, and 2017 international McDonald criteria for the diagnosis of multiple sclerosis, the 2016 MRI in multiple sclerosis (MAGNIMS) criteria, and our 2011 proposed (Verhey) criteria were determined; performance was adjudicated with generalised linear models. Findings Between Sept 1, 2004, and June 30, 2017, we included 324 participants with median follow-up of 72 months (range 6–150), 71 (22%) participants with multiple sclerosis, 237 (73%) with monophasic acquired demyelinating syndrome, 14 (4%) with relapsing non-multiple sclerosis, and two (1%) with alternative diagnoses. We scored 2391 brain, 444 spinal, and 67 dedicated orbital MRI scans. One or more T1 hypointense lesions plus one or more periventricular lesions (Verhey criteria) best predicted multiple sclerosis outcome. Performance of the 2017 McDonald criteria was comparable to the 2010 McDonald criteria and was easier to adjudicate. The ability of CSF oligoclonal bands to substitute for the requirement for both enhancing and non-enhancing lesions in the 2017 McDonald criteria improved its performance compared with the 2010 criteria. Myelin oligodendrocyte testing at baseline did not improve performance of the 2017 McDonald criteria. Interpretation The 2017 McDonald criteria for the diagnosis of multiple sclerosis, as applied at the time of incident attack, perform well in identifying children and youth with multiple sclerosis, indicating that the same diagnostic criteria for multiple sclerosis apply across the age span. The presence of so-called black holes on MRI and periventricular lesions at baseline (Verhey criteria) also effectively distinguish children with multiple sclerosis from children with monophasic demyelination. The presence of CSF oligoclonal bands improve diagnostic accuracy. Myelin oligodendrocyte glycoprotein antibodies identify children with acute disseminated encephalomyelitis, and those with relapsing non-multiple sclerosis, most of whom do not meet 2017 McDonald criteria at onset. Funding The Multiple Sclerosis Scientific Research Foundation and The Children's Hospital of Philadelphia.

BACKGROUND: Small vessel childhood primary angiitis of CNS (SVcPACNS) is an increasingly recognized inflammatory brain disease requiring rapid targeted investigation and initiation of tailored therapies to prevent brain damage. Spinal cord involvement has never been systematically investigated.

Thanatophoric dysplasia (TD) and hypochondroplasia are both caused by FGFR3 (fibroblast growth factor receptor 3) gene mutations. Temporal lobe dysplasia has been well described in thanatophoric dysplasia; however, only a couple of anecdotal cases of temporal lobe dysplasia in hypochondroplasia have been described.To define temporal lobe abnormalities in patients with hypochondroplasia, given that they share the same genetic mutation.We identified brain imaging studies of nine children with hypochondroplasia. The temporal lobes were assessed on CT and MRI for size and configuration of the temporal horn and aberrant sulcation of the inferior surface of the temporal lobe.All children had a triangular-shape temporal horn and deep transverse fissures of the inferior temporal lobe surface. Neuroimaging in our cohort revealed enlarged temporal lobes and oversulcation of the mesial temporal and occipital lobes, with abnormal inferomedial orientation of these redundant gyri. Hippocampal dysplasia was also universal.We confirmed frequent inferomesial temporal and occipital lobe abnormalities in our cohort of children with hypochondroplasia. Murine models with mutant fgfr3 display increased neuroprogenitor proliferation, cortical thickness and surface area in the temporo-occipital cortex. This is thought to result in excessive convolution and likely explains the imaging findings in this patient cohort. (Note that fgfr3 is the same genetic mutation in mice as FGFR3 is in humans.).

Childhood transverse myelitis is an acute inflammatory disorder of the spinal cord with a risk of permanent disability. A timely and accurate diagnosis is imperative, and the radiologist needs to discern between a variety of extra-axial and spinal cord abnormalities that produce similar symptoms but require vastly differing treatments. This article presents the range of imaging characteristics seen in childhood transverse myelitis and the differentiation from its mimics.

MRI is currently the best imaging modality to assess myelin maturation in the human brain. Myelin is the insulator for nerves and is present in both the peripheral nervous system and the central nervous system (CNS). In the CNS, it is a modified extension of the oligodendrocyte cell and is made up of multiple sheaths of protein-lipid-protein-lipid-protein. Standard T1-weighted and T2-weighted sequences can be performed on any MR imaging platform and with knowledge of normal age-related myelin maturation, myelin delay can be detected. Myelination progresses in a constant predetermined pattern from bottom to top, central to peripheral and back to front.

BACKGROUND AND PURPOSE: The degree to which MR imaging is useful in the diagnosis of MS is predicated on standardized and reliable evaluation of MR imaging parameters. We aimed to devise items for an MR imaging scoring tool that would have high inter-rater agreement and would be straightforward to apply. MATERIALS AND METHODS: On the basis of a literature search and consensus of an expert panel, we identified 48 parameters that describe acute CNS demyelination, predict MS diagnosis, or characterize demyelinating disorder mimics. MR images of children with clinically confirmed MS, monophasic ADEM, and angiography-negative biopsy-positive small-vessel primary angiitis of the CNS were scored by 2 neuroradiologists independently, using the preliminary 48-parameter tool. Parameters with Cohen κ ≥ 0.6 and deemed important in predicting diagnosis were retained. Parameters not visualized on routine clinical imaging or not important in differentiating MS, ADEM, and SV-cPACNS were discarded. RESULTS: Of 65 eligible patients, 55 children were enrolled (16 with monophasic ADEM, 27 with MS, 12 with SV-cPACNS); 10 were excluded (6 had hard-copy films, 4 did not meet MR imaging quality requirements). Of the 48 parameters, 16 were retained in the final scoring tool. The remaining 28 parameters were discarded: 4 had κ < 0.6 and were not deemed useful in predicting diagnosis; 9 were not visible on routinely acquired clinical images; and 15 had inter-rater agreement ≥0.6 but were not useful in differentiating monophasic ADEM, MS, and SV-cPACNS. CONCLUSIONS: We propose a 16-parameter MR imaging scoring tool that is straightforward to apply in the clinical setting and demonstrates high inter-rater agreement.

The updated American Heart Association/American Stroke Association guidelines include recommendation for thrombectomy in certain adult stroke cases. The safety and efficacy of thrombectomy in children are unknown. An 8-year-old girl experienced acute stroke symptoms on two occasions while therapeutically anticoagulated on Novalung. Computed tomography scans showed proximal vessel thrombi, which were retrieved using a Trevo device without hemorrhagic complications. Postprocedural assessment found respective decreases in the National Institutes of Health Stroke Scale score from 10 to 4 and 12 to 7. The indications for treatment and early benefits observed in our case are consistent with other pediatric thrombectomy cases reported. However, publication bias and the heterogeneity of reported cases prevent drawing conclusions about the safety and efficacy of thrombectomy in children. Anticipating that updates to adult stroke guidelines would likely incite stroke providers to consider thrombectomy in children, our institution developed guidelines for thrombectomy before the index patient. Establishing institutional guidelines before considering thrombectomy in children may optimize patient safety.

We present the case of a 10-year old patient from southeastern Ontario with severe bilateral facial palsy. MRI was performed that showed extensive symmetric enhancement of cervical cranial nerve roots and multiple cranial nerves (III, V, VI, VII, VIII, X and XII). Lumbar puncture was performed that revealed pleocytosis and elevated proteins in the cerebrospinal fluid. Serology confirmed the diagnosis of neuroborreliosis. The patient was treated with a 4-week course of IV ceftriaxone, following which he returned to baseline. Keywords: Lyme disease, Neuroborreliosis, Facial nerve palsy, Cranial neuropathies

Objective: The diagnosis of multiple sclerosis (MS) rests on confirmation of central nervous system inflammatory disease that is disseminated in space and time, as evidenced clinically or by magnetic resonance imaging (MRI). The 2010 McDonald criteria simplified MRI requirements, and newly proposed that the criteria are also suitable for the diagnosis of pediatric MS. Methods: In a national prospective incident cohort study of children with acute demyelination observed for a minimum of 24 months, baseline and serial clinical and MRI examinations were used to retrospectively evaluate the 2010 and 2005 McDonald criteria using clinically relapsing disease as the gold standard. Results: Of 212 eligible participants, 34 experienced 2 or more clinical attacks, 58 met the 2010 criteria, and 42 met 2005 McDonald criteria. The 2010 criteria demonstrated high sensitivity (100%), specificity (86%), positive predictive value (76%), and negative predictive value (100%) for children older than 11 years with non–acute disseminated encephalomyelitis (ADEM) presentations, as did the 2005 McDonald criteria. In younger children with a non-ADEM presentation, PPV of the 2010 criteria was only 55%. None of the 50 children with ADEM met clinical criteria for MS, but 10 met 2010 and 4 met 2005 criteria. Interpretation: Both 2005 and 2010 McDonald criteria identify children with relapsing–remitting MS, although caution is suggested when applying these criteria in younger children. The 2010 McDonald criteria are simple and enable an early diagnosis of MS, but are not suited for application in the context of ADEM-like presentations. ANN NEUROL 2012;72:211–223.

Summary Background Multiple sclerosis (MS) diagnostic criteria incorporate MRI features that can be used to predict later diagnosis of MS in adults with acute CNS demyelination. To identify MRI predictors of a subsequent MS diagnosis in a paediatric population, we created a standardised scoring method and applied it to MRI scans from a national prospective incidence cohort of children with CNS demyelination. Methods Clinical and MRI examinations were done at the onset of acute CNS demyelination and every 3 months in the first year after that, and at the time of a second demyelinating attack. MS was diagnosed on the basis of clinical or MRI evidence of relapsing disease. Baseline MRI scans were assessed for the presence of 14 binary response parameters. Parameters were assessed with a multiple tetrachoric correlation matrix. Univariate analyses and multivariable Cox proportional hazards models were used to identify predictors of MS. Findings Between Sept 1, 2004, and June 30, 2010, 332 children and adolescents were assessed for eligibility. 1139 scans were available from 284 eligible participants who had been followed up for 3·9 (SD 1·7) years. 57 (20%) were diagnosed with MS after a median of 188 (IQR 144–337) days. Seven of 14 binary response parameters were retained. The presence of either one or more T1-weighted hypointense lesions (hazard ratio 20·6, 95% CI 5·46–78·0) or one or more periventricular lesions (3·34, 1·27–8·83) was associated with an increased likelihood of MS diagnosis (sensitivity 84%, specificity 93%, positive predictive value 76%, negative predictive value 96%). Risk for MS diagnosis was highest when both parameters were present (34·27, 16·69–70·38). Although the presence of contrast enhancement, cerebral white matter, intracallosal, and brainstem lesions was associated with MS in the univariate analyses, these parameters were not retained in the multivariable models. Interpretation Specific MRI parameters can be used to predict diagnosis of MS in children with incident demyelination of the CNS. The ability to promptly identify children with MS will enhance timely access to care and will be important for future clinical trials in paediatric MS. Funding Canadian Multiple Sclerosis Scientific Research Foundation.

Craniosynostosis is when cranial sutures fuse prematurely. It causes cosmetic deformity and may limit brain growth with more serious consequences, such as hydrocephalus. It may involve one or more sutures, may be syndromic, and is thought most likely to result from genetic causes. Specific sutural closures result in reproducible cranial appearances and head shapes. Three-dimensional computed tomography has become the standard for preoperative diagnosis to allow surgical planning as well as postsurgical assessment. Early diagnosis allows early surgical management, which improves outcome. Nonsyndromic and syndromic craniosynostoses are illustrated in this pictorial review.