Change in Volumes and Location of Preterm White Matter Injury over a Period of 15 Years.

OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: Five hundred and twenty-eight infants born <32 weeks' gestational age from 2 sequential prospective cohorts (cohort 1: 2006 through 2012; cohort 2: 2014 through 2019) underwent early-life (median 32.7 weeks postmenstrual age) and/or term-equivalent-age MRI (median 40.7 weeks postmenstrual age). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts. RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß = -0.6, 95% CI [-0.8, -0.3], P < .001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

Prognostic Indicators of Reorientation of Care in Perinatal Hypoxic-Ischemic Encephalopathy Spectrum.

OBJECTIVE: To investigate the clinical, electrographic, and neuroimaging characteristics in neonates with perinatal hypoxic-ischemic encephalopathy who underwent reorientation of care using standardized scoring systems. STUDY DESIGN: A nested observational substudy within a prospective hypoxic-ischemic encephalopathy cohort was conducted. Group 1 comprised infants whose parents received the medical recommendation for reorientation of care, while group 2 continued to receive standard care. Encephalopathy scores were monitored daily. Amplitude-integrated and continuous-video-integrated electroencephalogram during therapeutic hypothermia were analyzed. Standardized scoring systems for cranial ultrasonography and postrewarming brain magnetic resonance imaging were deployed. RESULTS: The study included 165 infants, with 35 in group 1 and 130 in Group 2. By day 3, all infants in group 1 were encephalopathic with higher Thompson scores (median 13 [IQR 10-19] vs 0 [IQR 0-3], P < .001). Electrographic background normalization within 48 hours occurred in 3% of group 1 compared with 46% of group 2 (P < .001). Sleep-wake cycling was not observed in group 1 and emerged in 63% of group 2 within the first 72 hours (P < .001). The number of antiseizure medications received was higher in group 1 (median 3 [IQR, 2-4] vs 0 [IQR, 0-1], respectively; P < .001). Group 1 had higher cranial ultrasound injury scores (median 4 [IQR 2-7] vs 1 [IQR 0-1], P < .001) within 48 hours and postrewarming brain magnetic resonance imaging injury scores (median 33 [range 20-51] vs 4 [range 0-28], P < .001). CONCLUSIONS: Neonates with perinatal hypoxic-ischemic encephalopathy who underwent reorientation of care presented with and maintained significantly more pronounced clinical manifestations, electrographic findings, and near-total brain injury as scored objectively on all modalities. TRIAL REGISTRATION: Registration of the study cohort: NCT04913324.

Pediatric orbital lesions: ocular pathologies.

Orbital pathologies can be broadly classified as ocular, extra-ocular soft-tissue (non-neoplastic and neoplastic), osseous, and traumatic. In part 1 of this orbital series, the authors will discuss the differential diagnosis and key imaging features of pediatric ocular pathologies. These include congenital and developmental lesions (microphthalmos, anophthalmos, persistent fetal vasculature, coloboma, morning glory disc anomaly, retinopathy of prematurity, Coats disease), optic disc drusen, infective and inflammatory lesions (uveitis, toxocariasis, toxoplasmosis), and ocular neoplasms (retinoblastoma, retinal hamartoma, choroidal melanoma, choroidal nevus). This pictorial review provides a practical approach to the imaging work-up of these anomalies with a focus on ocular US as the first imaging modality and additional use of CT and/or MRI for the evaluation of intracranial abnormalities. The characteristic imaging features of the non-neoplastic mimics of retinoblastoma, such as persistent fetal vasculature and Coats disease, are also highlighted.

Pediatric orbital lesions: bony and traumatic lesions.

Orbital pathologies can be broadly classified as ocular lesions, extraocular soft-tissue pathologies (non-neoplastic and neoplastic), and bony and traumatic lesions. In this paper, we discuss the key imaging features and differential diagnoses of bony and traumatic lesions of the pediatric orbit and globe, emphasizing the role of CT and MRI as the primary imaging modalities. In addition, we highlight the adjunctive role of ocular sonography in the diagnosis of intraocular foreign bodies and discuss the primary role of sonography in the diagnosis of traumatic retinal detachment.

Pediatric orbital lesions: non-neoplastic extraocular soft-tissue lesions.

Orbital pathologies can be broadly classified as ocular, extraocular soft-tissue (non-neoplastic and neoplastic), osseous, and traumatic. In this paper, we discuss the key imaging features and differential diagnoses of congenital and developmental lesions (dermoid cyst, dermolipoma), infective and inflammatory pathologies (pre-septal cellulitis, orbital cellulitis, optic neuritis, chalazion, thyroid ophthalmopathy, orbital pseudotumor), and non-neoplastic vascular anomalies (venous malformation, lymphatic malformation, carotid-cavernous fistula), emphasizing the key role of CT and MRI in the imaging work-up. In addition, we highlight the adjunctive role of ocular ultrasound in the diagnosis of dermoid cyst and chalazion, and discuss the primary role of ultrasound in the diagnosis of vascular malformations.

Imaging approach to pediatric calvarial bulges.

Palpable calvarial lesions in children may require multi-modality imaging for adequate characterization due to non-specific clinical features. Causative lesions range from benign incidental lesions to highly aggressive pathologies. While tissue sampling may be required for some lesions, others have a typical imaging appearance, and an informed imaging approach facilitates diagnosis. This review illustrates imaging findings of common and clinically important focal pediatric calvarial bulges to aid the radiologist in narrowing the differential diagnosis and directing appropriate referral. We focus on birth-related lesions, congenital abnormalities, and modeling disturbances (i.e., those that produce a change in calvarial contour early in development), normal variants, and neoplastic lesions with their mimics.

Pediatric orbital lesions: neoplastic extraocular soft-tissue lesions.

Pediatric neoplastic extraocular soft-tissue lesions in the orbit are uncommon. Early multimodality imaging work-up and recognition of the key imaging features of these lesions allow narrowing of the differential diagnoses in order to direct timely management. In this paper, the authors present a multimodality approach to the imaging work-up of these lesions and highlight the use of ocular ultrasound as a first imaging modality where appropriate. We will discuss vascular neoplasms (congenital hemangioma, infantile hemangioma), optic nerve lesions (meningioma, optic nerve glioma), and other neoplastic lesions (plexiform neurofibroma, teratoma, chloroma, rhabdomyosarcoma, infantile fibrosarcoma, schwannoma).

Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis.

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 < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). CONCLUSIONS: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Location and Size of Preterm Cerebellar Hemorrhage and Childhood Development.

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 (ß = -0.095, 95% confidence interval = -0.184 to -0.005), with a standardized ß coefficient (-0.16) that was similar to that of white matter injury volume (standardized ß = -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.

Genome sequencing for detection of pathogenic deep intronic variation: A clinical case report illustrating opportunities and challenges.

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.

Associations Between Age at Arterial Switch Operation, Brain Growth, and Development in Infants With Transposition of the Great Arteries.

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.

Nasal monobloc osteotomy for correction of late nasal and orbital asymmetry of unicoronal synostosis: A morphometric and outcomes study.

BACKGROUND: Craniofacial asymmetry associated with unicoronal synostosis (UCS) may persist into the teenage years despite surgery in infancy. This study evaluated outcomes following a nasal monobloc procedure by mobilizing a united nasomaxillary and bilateral medial orbital segment of bone (nasal monobloc) to perform corrective translational and rotational movement for secondary correction of residual nasal-orbital asymmetry associated with UCS. METHODS: A retrospective review of all UCS patients treated with nasal monobloc at our institution was performed. Demographic information was recorded, and pre- and postoperative 2D imaging was used for morphometric outcome analysis. Outcomes and complications were tabulated. RESULTS: The study included 14 patients (5 males, 9 females; mean age 14.6 years; range 9.6 to 22.5 years; mean follow-up 70.6 months range 12 to 132 months). Ancillary procedures (scar revision, forehead/orbital contouring, MEDPOR® augmentation) were performed in all patients at the time of the nasal monobloc. One patient underwent a repeat procedure 6 years later following technique modification. Additionally, another patient experienced late overgrowth of the frontal sinus with forehead asymmetry. The morphometric analysis demonstrated significant (p < 0.05) pre-op to post-op improvements in naso-orbital asymmetry, as demonstrated by horizontal orbital aperture ratio (0.88 vs 0.99), midline to exocanthion ratio (0.91 vs 0.98), orbital index ratio (1.15 vs 1.01), and midline discrepancy (7.1 degrees vs 2.7 degrees). CONCLUSION: Nasal monobloc osteotomy provides a reasonable surgical treatment to improve both the nasal and orbital asymmetries associated with unicoronal synostosis, including frontal nasal deviation, basal nasal deviation, and orbital aperture asymmetry. It is important to note that confounding anatomic variables such as globe dystopia, strabismus, and scleral show may affect the perception of orbital symmetry.

Socioeconomic status moderates associations between hippocampal development and cognition in preterms.

OBJECTIVE: The hippocampus plays a critical role in cognitive networks. The anterior hippocampus is vulnerable to early-life stress and socioeconomic status (SES) with alterations persisting beyond childhood. How SES modifies the relationship between early hippocampal development and cognition remains poorly understood. This study examined associations between SES, structural and functional development of neonatal hippocampus, and 18-month cognition in very preterm neonates. METHODS: In total, 179 preterm neonates were followed prospectively. Structural and resting-state functional MRI were obtained early-in-life and at term-equivalent age (median 32.9 and 41.1 weeks post-menstrual age) to calculate anterior and posterior hippocampal volumes and hippocampal functional connectivity strength. Eighteen-month cognition was assessed via Bayley-III. Longitudinal statistical analysis using generalized estimating equations, accounting for birth gestational age, post-menstrual age at scan, sex, and motion, was performed. RESULTS: SES, measured as maternal education level, modified associations between anterior but not posterior hippocampal volumes and 18-month cognition (interaction term p = 0.005), and between hippocampal connectivity and cognition (interaction term p = 0.05). Greater anterior hippocampal volumes and hippocampal connectivity were associated with higher cognitive scores only in the lowest SES group. Maternal education alone did not predict neonatal hippocampal volume from early-in-life and term. INTERPRETATION: SES modified the relationship between neonatal hippocampal development and 18-month cognition in very preterm neonates. The lack of direct association between maternal education and neonatal hippocampal volumes indicates that socio-environmental factors beyond the neonatal period contribute to modifying the relationship between hippocampal development and cognition. These findings point toward opportunities to more equitably promote optimal neurodevelopmental outcomes in very preterm infants.

Early nutritional influences on brain regions related to processing speed in children born preterm: A secondary analysis of a randomized trial.

BACKGROUND: Processing speed is a foundational skill supporting intelligence and executive function, areas often delayed in preterm-born children. The impact of early-life nutrition on gray matter facilitating processing speed for this vulnerable population is unknown. METHODS: Magnetic resonance imaging and the Wechsler Preschool and Primary Scale of Intelligence-IV Processing Speed Index were acquired in forty 5-year-old children born preterm with very low birth weight. Macronutrient (grams per kilogram per day) and mother's milk (percentage of feeds) intakes were prospectively collected in the first postnatal month and associations between early-life nutrition and the primary outcome of brain regions supporting processing speed were investigated. RESULTS: Children had a mean (SD) gestational age of 27.8 (1.8) weeks and 45% were male. Macronutrient intakes were unrelated, but mother's milk was positively related, to greater volumes in brain regions, including total cortical gray matter, cingulate gyri, and occipital gyri. CONCLUSION: First postnatal month macronutrient intakes showed no association, but mother's milk was positively associated, with volumetric measures of total and regional cortical gray matter related to processing speed in preterm-born children. This exploratory analysis suggests early-life mother's milk supports processing speed by impacting structural underpinnings. Further research is needed on this potential strategy to improve preterm outcomes.

Pain Exposure and Brain Connectivity in Preterm Infants.

Importance: Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown. Objective: To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants. Design, Setting, and Participants: This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023. Exposure: Pain was quantified in the initial weeks after birth as the total number of invasive procedures. Main Outcome and Measure: Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education. Results: A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes. Conclusions and Relevance: In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

2010 McDonald criteria for diagnosing pediatric multiple sclerosis.

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.

Temporal and occipital lobe features in children with hypochondroplasia/FGFR3 gene mutation.

BACKGROUND: 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. OBJECTIVE: To define temporal lobe abnormalities in patients with hypochondroplasia, given that they share the same genetic mutation. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.).