Focal to bilateral tonic-clonic seizures predict pharmacoresistance in focal cortical dysplasia-related epilepsy.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks. METHODS: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital. INCLUSION CRITERIA: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures. RESULTS: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome. SIGNIFICANCE: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression.

Diffuse excessive high signal intensity in the preterm brain on advanced MRI represents widespread neuropathology.

Preterm brains commonly exhibit elevated signal intensity in the white matter on T2-weighted MRI at term-equivalent age. This signal, known as diffuse excessive high signal intensity (DEHSI) or diffuse white matter abnormality (DWMA) when quantitatively assessed, is associated with abnormal microstructure on diffusion tensor imaging. However, postmortem data are largely lacking and difficult to obtain, and the pathological significance of DEHSI remains in question. In a cohort of 202 infants born preterm at ≤32 weeks gestational age, we leveraged two newer diffusion MRI models - Constrained Spherical Deconvolution (CSD) and neurite orientation dispersion and density index (NODDI) - to better characterize the macro and microstructural properties of DWMA and inform the ongoing debate around the clinical significance of DWMA. With increasing DWMA volume, fiber density broadly decreased throughout the white matter and fiber cross-section decreased in the major sensorimotor tracts. Neurite orientation dispersion decreased in the centrum semiovale, corona radiata, and temporal lobe. These findings provide insight into DWMA's biological underpinnings and demonstrate that it is a serious pathology.

Magnetic resonance spectroscopy brain metabolites at term and 3-year neurodevelopmental outcomes in very preterm infants.

BACKGROUND: Noninvasive advanced neuroimaging and neurochemical assessment can identify subtle abnormalities and predict neurodevelopmental impairments. Our objective was to quantify white matter metabolite levels and evaluate their relationship with neurodevelopmental outcomes at age 3 years. METHODS: Our study evaluated a longitudinal prospective cohort of very premature infants (<32 weeks gestational age) with single-voxel proton magnetic resonance spectroscopy from the centrum semiovale performed at term-equivalent age and standardized cognitive, verbal, and motor assessments at 3 years corrected age. We separately examined metabolite ratios in the left and right centrum semiovale. We also conducted an exploratory interaction analysis for high/low socioeconomic status (SES) to evaluate the relationship between metabolites and neurodevelopmental outcomes, after adjusting for confounders. RESULTS: We found significant relationships between choline/creatine levels in the left and right centrum semiovale and motor development scores. Exploratory interaction analyses revealed that, for infants with low SES, there was a negative association between choline/creatine in the left centrum semiovale and motor assessment scores at age 3 years. CONCLUSIONS: Brain metabolites from the centrum semiovale at term-equivalent age were associated with motor outcomes for very preterm infants at 3 years corrected age. This effect may be most pronounced for infants with low SES. IMPACT: Motor development at 3 years corrected age for very preterm infants is inversely associated with choline neurochemistry within the centrum semiovale on magnetic resonance spectroscopy at term-equivalent age, especially in infants with low socioeconomic status. No prior studies have studied metabolites in the centrum semiovale to predict neurodevelopmental outcomes at 3 years corrected age based on high/low socioeconomic status. For very preterm infants with lower socioeconomic status, higher choline-to-creatine ratio in central white matter is associated with worse neurodevelopmental outcomes.

Diffuse white matter abnormality in very preterm infants at term reflects reduced brain network efficiency.

Between 50 and 80% of very preterm infants (<32 weeks gestational age) exhibit increased white matter signal intensity on T2-weighted MRI at term-equivalent age, known as diffuse white matter abnormality (DWMA). A few studies have linked DWMA with microstructural abnormalities, but the exact relationship remains poorly understood. We related DWMA extent to graph theory measures of network efficiency at term in a representative cohort of 343 very preterm infants. We performed anatomic and diffusion MRI at term and quantified DWMA volume with our novel, semi-automated algorithm. From diffusion-weighted structural connectomes, we calculated the graph theory metrics local efficiency and clustering coefficient, which measure the ability of groups of nodes to perform specialized processing, and global efficiency, which assesses the ability of brain regions to efficiently combine information. We computed partial correlations between these measures and DWMA volume, adjusted for confounders. Increasing DWMA volume was associated with decreased global efficiency of the entire very preterm brain and decreased local efficiency and clustering coefficient in a variety of regions supporting cognitive, linguistic, and motor function. We show that DWMA is associated with widespread decreased brain network efficiency, suggesting that it is pathologic and likely has adverse developmental consequences.

Automatic Segmentation of Diffuse White Matter Abnormality on T2-weighted Brain MR Images Using Deep Learning in Very Preterm Infants.

About 50%-80% of very preterm infants (VPIs) (≤ 32 weeks gestational age) exhibit diffuse white matter abnormality (DWMA) on their MR images at term-equivalent age. It remains unknown if DWMA is associated with developmental impairments, and further study is warranted. To aid in the assessment of DWMA, a deep learning model for DWMA quantification on T2-weighted MR images was developed. This secondary analysis of prospective data was performed with an internal cohort of 98 VPIs (data collected from December 2014 to April 2016) and an external cohort of 28 VPIs (data collected from January 2012 to August 2014) who had already undergone MRI at term-equivalent age. Ground truth DWMA regions were manually annotated by two human experts with the guidance of a prior published semiautomated algorithm. In a twofold cross-validation experiment using the internal cohort of 98 infants, the three-dimensional (3D) ResU-Net model accurately segmented DWMA with a Dice similarity coefficient of 0.907 ± 0.041 (standard deviation) and balanced accuracy of 96.0% ± 2.1, outperforming multiple peer deep learning models. The 3D ResU-Net model that was trained with the whole internal cohort (n = 98) was further tested on an independent external test cohort (n = 28) and achieved a Dice similarity coefficient of 0.877 ± 0.059 and balanced accuracy of 92.3% ± 3.9. The externally validated 3D ResU-Net deep learning model for accurately segmenting DWMA may facilitate the clinical diagnosis of DWMA in VPIs. Supplemental material is available for this article. Keywords: Brain/Brain Stem, Convolutional Neural Network (CNN), MR-Imaging, Pediatrics, Segmentation, Supervised learning © RSNA, 2021.

Effects of intraventricular hemorrhage on white matter microstructural changes at term and early developmental outcomes in infants born very preterm.

PURPOSE: Very preterm (VPT) infants are at high risk for motor and behavioral deficits. We investigated microstructural differences using diffusion tensor imaging (DTI) among VPT infants with different grades of intraventricular hemorrhage (IVH), their association with early motor function and temperament ratings, and the potential moderating effect of IVH severity on the above structure-function relations. METHODS: Fifty-seven VPT (≤32 weeks gestational age) infants with IVH (Low Grade (Papile grading I/II): 42; High Grade (III/IV): 15) were studied. DTI was acquired between 39 and 44 weeks postmenstrual age and was analyzed using the tract-based spatial statistics approach. Early motor function and temperament were assessed at 3-month corrected age based on the Hammersmith Infant Neurological Examination (HINE) and Infant Behavioral Questionnaire - Revised, Short Version (IBQ-R-S), respectively. RESULTS: Significantly lower fractional anisotropy and higher mean, axial, and/or radial diffusivity were found in VPT infants with High Grade IVH compared to Low Grade IVH (p < 0.05). Significant associations were found between DTI metrics and motor function in both IVH groups and between DTI and Fear temperament ratings in the High Grade IVH Group (all p < 0.05). IVH severity had a significant moderating effect on the relation between DTI and motor and Fear ratings (p < 0.05). CONCLUSION: DTI is a sensitive neuroimaging biomarker providing a refined understanding of the impact and location of differing severities of IVH on the developing white matter of VPT infants. Early motor and behavioral outcomes are associated with microstructural changes that are influenced by severity of IVH.

Novel diffuse white matter abnormality biomarker at term-equivalent age enhances prediction of long-term motor development in very preterm children.

Our objective was to evaluate the independent prognostic value of a novel MRI biomarker-objectively diagnosed diffuse white matter abnormality volume (DWMA; diffuse excessive high signal intensity)-for prediction of motor outcomes in very preterm infants. We prospectively enrolled a geographically-based cohort of very preterm infants without severe brain injury and born before 32 weeks gestational age. Structural brain MRI was obtained at term-equivalent age and DWMA volume was objectively quantified using a published validated algorithm. These results were compared with visually classified DWMA. We used multivariable linear regression to assess the value of DWMA volume, independent of known predictors, to predict motor development as assessed using the Bayley Scales of Infant & Toddler Development, Third Edition at 3 years of age. The mean (SD) gestational age of the cohort was 28.3 (2.4) weeks. In multivariable analyses, controlling for gestational age, sex, and abnormality on structural MRI, DWMA volume was an independent prognostic biomarker of Bayley Motor scores ([Formula: see text]= -12.59 [95% CI -18.70, -6.48] R2 = 0.41). Conversely, visually classified DWMA was not predictive of motor development. In conclusion, objectively quantified DWMA is an independent prognostic biomarker of long-term motor development in very preterm infants and warrants further study.

Early cortical maturation predicts neurodevelopment in very preterm infants.

OBJECTIVE: To evaluate the ability of four objectively defined, cortical maturation features-surface area, gyrification index, sulcal depth and curvature-from structural MRI at term-equivalent age (TEA) to independently predict cognitive and language development at 2 years corrected age in very preterm (VPT) infants. DESIGN: Population-based, prospective cohort study. Structural brain MRI was performed at term, between 40 and 44 weeks postmenstrual age and processed using the developing Human Connectome Project pipeline. SETTING: Multicentre study comprising four regional level III neonatal intensive care units in the Columbus, Ohio region. PATIENTS: 110 VPT infants (gestational age (GA) ≤ 31 weeks). MAIN OUTCOME MEASURES: Cognitive and language scores at 2 years corrected age on the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: Of the 94 VPT infants with high-quality T2-weighted MRI scans, 75 infants (80%) returned for Bayley-III testing. Cortical surface area was positively correlated with cognitive and language scores in nearly every brain region. Curvature of the inner cortex was negatively correlated with Bayley scores in the frontal, parietal and temporal lobes. In multivariable regression models, adjusting for GA, sex, socioeconomic status, and injury score on MRI, regional measures of surface area and curvature independently explained more than one-third of the variance in cognitive and language scores at 2 years corrected age in our cohort. CONCLUSIONS: We identified increased cortical curvature at TEA as a new prognostic biomarker of adverse neurodevelopment in very premature infants. When combined with cortical surface area, it enhanced prediction of cognitive and language development. Larger studies are needed to externally validate our findings.

Retinopathy of Prematurity and Bronchopulmonary Dysplasia are Independent Antecedents of Cortical Maturational Abnormalities in Very Preterm Infants.

Very preterm (VPT) infants are at high-risk for neurodevelopmental impairments, however there are few validated biomarkers at term-equivalent age that accurately measure abnormal brain development and predict future impairments. Our objectives were to quantify and contrast cortical features between full-term and VPT infants at term and to associate two key antecedent risk factors, bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), with cortical maturational changes in VPT infants. We prospectively enrolled a population-based cohort of 110 VPT infants (gestational age ≤31 weeks) and 51 healthy full-term infants (gestational age 38-42 weeks). Structural brain MRI was performed at term. 94 VPT infants and 46 full-term infants with high-quality T2-weighted MRI were analyzed. As compared to full-term infants, VPT infants exhibited significant global cortical maturational abnormalities, including reduced surface area (-5.9%) and gyrification (-6.7%) and increased curvature (5.9%). In multivariable regression controlled for important covariates, BPD was significantly negatively correlated with lobar and global cortical surface area and ROP was significantly negatively correlated with lobar and global sulcal depth in VPT infants. Our cohort of VPT infants exhibited widespread cortical maturation abnormalities by term-equivalent age that were in part anteceded by two of the most potent neonatal diseases, BPD and ROP.

In vivo quantification of aortic stiffness using MR elastography in hypertensive porcine model.

PURPOSE: Aortic stiffness plays an important role in evaluating and predicting the progression of systemic arterial hypertension (SAH). The aim of this study is to determine the stiffness of aortic wall using MR elastography (MRE) in a hypertensive porcine model and compare it against invasive aortic pressure measurements. METHODS: Renal wrapping surgery was performed on eight pigs to induce SAH. Aortic MRE was performed at baseline and 2 months postsurgery using a retrospectively pulse-gated gradient-echo MRE sequence on a 1.5 tesla scanner. Mechanical waves of 70 Hz were introduced into the aorta. Invasive central aortic pressure measurements were obtained prior to each scan to calculate mean arterial pressure (MAP). MRE data were analyzed to obtain effective aortic stiffness. Spearman's rank correlation analysis was performed to assess the relationship between MAP and MRE-derived aortic stiffness. RESULTS: Significant increase in effective aortic stiffness was observed between baseline and 2 months postsurgery measurements (paired t test; P = 0.004). The average MAP, determined by pooling all animals, was 65.24 ± 9.42 mm Hg at baseline and 92.57 ± 11.80 mm Hg 2 months postsurgery with P < 0.0001. Moderate linear correlation was observed between MAP and effective aortic stiffness (ρ = 0.52; P = 0.046). CONCLUSION: This study demonstrated that, in a SAH porcine model, MRE-derived aortic stiffness increased with increase in MAP. Magn Reson Med 78:2315-2321, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Quantification and comparison of 4D-flow MRI-derived wall shear stress and MRE-derived wall stiffness of the abdominal aorta.

PURPOSE: Aortic wall shear stress (WSSFlow ) alters endothelial function, which in-turn changes aortic wall stiffness leading to remodeling in different disease states. Therefore, the aims of this study are to determine normal physiologic correlations between: (1) Magnetic Resonance Elastography (MRE)-derived aortic wall stiffness (WSMRE ) and WSSFlow ; (2) WSMRE and mean velocity; (3) WSMRE and pulse wave velocity (PWV);( 4) WSMRE and mean peak flow; and (5) WSMRE , WSSFlow and age using MRE and 4D-flow MRI in the abdominal aorta in healthy human subjects. MATERIALS AND METHODS: Cardiac-gated aortic MRE and 4D-flow MRI data were acquired in 24 healthy volunteers using a 3 Tesla scanner. For MRE, 70 Hz external motion was applied to obtain wave images in all spatial directions in a separate breathhold. Whereas, 4D-flow data was acquired under free-breathing. Wave images in all the directions were processed to obtain three-dimensional-weighted stiffness map at end-systole (ES). WSSFlow , mean velocity, PWV and mean peak flow were obtained using 4D-flow data. Pearson correlation was performed to determine association between all variables. RESULTS: A significant negative correlation was observed between: (1) ES WSMRE and WSSFlow in both axial (r = -0.62; P = 0.006) and circumferential (r = -0.52; P = 0.016) directions; (2) ES WSMRE and mean velocity (r = -0.58; P = 0.012); and (3) age and WSSFlow in both axial (r = -0.71; P < 0.0001) and circumferential (r = -0.58; P = 0.0012) directions. A significant positive correlation was observed between: (1) ES WSMRE and PWV (r = 0.69; P < 0.0001); (2) ES WSMRE and mean peak flow (r = 0.53; P = 0.016); and (3) ES WSMRE and age (r = 0.63;P = 0.006). CONCLUSION: The negative significant correlation between aortic WSSFlow and WSMRE in normal volunteers demonstrates a relationship between WSMRE and WSSFlow . LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:771-778.

Quantification of abdominal aortic aneurysm stiffness using magnetic resonance elastography and its comparison to aneurysm diameter.

OBJECTIVE: Abdominal aortic aneurysm (AAA) wall stiffness has been suggested to be an important factor in the overall rupture risk assessment compared with anatomic measure. We hypothesize that AAA diameter will have no correlation to AAA wall stiffness. The aim of this study is to (1) determine magnetic resonance elastography (MRE)-derived aortic wall stiffness in AAA patients and its correlation to AAA diameter; (2) determine the correlation between AAA stiffness and amount of thrombus and calcium; and (3) compare the AAA stiffness measurements against age-matched healthy individuals. METHODS: In vivo abdominal aortic MRE was performed on 36 individuals (24 patients with AAA measuring 3-10 cm and 12 healthy volunteers), aged 36 to 78 years, after obtaining written informed consent under the approval of the Institutional Review Board. MRE images were processed to obtain spatial stiffness maps of the aorta. AAA diameter, amount of thrombus, and calcium score were reported by experienced interventional radiologists. Spearman correlation, Wilcoxon signed rank test, and Mann-Whitney test were performed to determine the correlation between AAA stiffness and diameter and to determine the significant difference in stiffness measurements between AAA patients and healthy individuals. RESULTS: No significant correlation (P > .1) was found between AAA stiffness and diameter or amount of thrombus or calcium score. AAA stiffness (mean 13.97 ± 4.2 kPa) is significantly (P ≤ .02) higher than remote normal aorta in AAA (mean 8.87 ± 2.2 kPa) patients and in normal individuals (mean 7.1 ± 1.9 kPa). CONCLUSIONS: Our results suggest that AAA wall stiffness may provide additional information independent of AAA diameter, which may contribute to our understanding of AAA pathophysiology, biomechanics, and risk for rupture.

Quantification of aortic stiffness using magnetic resonance elastography: Measurement reproducibility, pulse wave velocity comparison, changes over cardiac cycle, and relationship with age.

PURPOSE: To assess MR elastography (MRE)-derived aortic shear stiffness (µMRE ) measurements for: 1) reproducibility, 2) comparison to pulse wave velocity, 3) changes over the cardiac cycle, and 4) relationship with age. METHODS: Cardiac-gated aortic MRE was performed on 20 healthy volunteers (aged 20-73 years). For assessing reproducibility of stiffness measurements, scans were repeated per volunteer. MRE wave images were analyzed to obtain stiffness of the abdominal aorta across the cardiac cycle, and comparisons were made with subject age. RESULTS: Analysis of concordance correlation coefficient between scans 1 and 2 showed that rc = 0.86 (95% confidence interval, 0.77, 0.94) with P < 0.0001. Significantly higher µMRE was observed for all volunteers during end-systole when compared to end-diastole (P < 0.0001). µMRE increased with age; end-systolic stiffness demonstrated a relatively stronger correlation with age (r = 0.62, P = 0.003) when compared to end-diastolic stiffness (r = 0.51, P = 0.023); and the slopes of end-systole and end-diastole were found to be significantly different (P = 0.011). [Formula: see text] at end-systole and end-diastole correlated linearly with pulse wave velocity, with an r = 0.54 (P = 0.013) and r = 0.58 (P = 0.008), respectively. CONCLUSION: The results of this study indicate that MRE-derived aortic shear stiffness measurements are robust (reproducible and comparable to similar techniques). Mean µMRE was higher during end-systole when compared to end-diastole. µMRE was found to increase with age and showed a stronger correlation with end-systolic stiffness than with end-diastolic stiffness.