Kathleen J. Helton

Summary: Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long‐term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1–17·3) enrolled in the Hydroxyurea Study of Long‐Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3‐ to 6‐year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI.

Purpose: Elevated cerebral blood flow (CBF) in sickle cell anemia (SCA) is an adaptive pathophysiologic response associated with decreased vascular reserve and increased risk for ischemia. We compared manual (M) and semiautomated (SA) vascular territory delineation to facilitate standardized evaluation of CBF in children with SCA.Materials and Methods: ASL perfusion values from 21 children were compared for gray matter and white matter (WM) in vascular territories defined by M and SA delineation. SA delineated CBF was compared with clinical and hematologic variables acquired within 4 weeks of the MRI.Results: CBF measurements from M (MCA 82 left, 79 right) and SA (MCA 81 left, 81 right) delineated territories were highly correlated (R = 0.99, P < 0.0001). Bland‐Altman plots had close‐fitting limits of agreement of −1.8 to −3.5 lower limit and 0 to 1.8 upper limit. SA vascular territory delineation was comparable to the expert delineation with a kappa index of 0.62–0.85 and was considerably faster. Median territorial CBF values did not differ by gender or age. WM perfusion in the posterior cerebral artery territories was positively correlated with degree of hemolysis (R = 0.58, P = 0.01 left, 0.73, P < 0.001 right) and negatively correlated with hemoglobin (R = −0.48; P = 0.03 left; −0.47; P = 0.04 right) and hemoglobin F (R = −0.42; P = .09 left; −0.47; P = 0.049 right).Conclusion: We established the validity of the SA method, which in our experience was much faster than the M method for delineation of vascular territories. Associations between CBF and hematologic variables may demonstrate pathophysiologic changes that contribute to clinical variation in CBF. J. Magn. Reson. Imaging 2015;41:439–446.© 2013 Wiley Periodicals, Inc.

Key Points: Children with SCA and stroke show severe parenchymal and vascular abnormalities that can be assessed using a vasculopathy grading scale. Results from the SWiTCH Trial support concerns about ineffectiveness of transfusion therapy in preventing cerebrovascular injury progression.

Purpose: Elevated cerebral blood flow (CBF) in sickle cell anemia (SCA) is an adaptive pathophysiologic response associated with decreased vascular reserve and increased risk for ischemia. We compared manual (M) and semiautomated (SA) vascular territory delineation to facilitate standardized evaluation of CBF in children with SCA.Materials and Methods: ASL perfusion values from 21 children were compared for gray matter and white matter (WM) in vascular territories defined by M and SA delineation. SA delineated CBF was compared with clinical and hematologic variables acquired within 4 weeks of the MRI.Results: CBF measurements from M (MCA 82 left, 79 right) and SA (MCA 81 left, 81 right) delineated territories were highly correlated (R = 0.99,P < 0.0001). Bland‐Altman plots had close‐fitting limits of agreement of −1.8 to −3.5 lower limit and 0 to 1.8 upper limit. SA vascular territory delineation was comparable to the expert delineation with a kappa index of 0.62–0.85 and was considerably faster. Median territorial CBF values did not differ by gender or age. WM perfusion in the posterior cerebral artery territories was positively correlated with degree of hemolysis (R = 0.58,P = 0.01 left, 0.73,P < 0.001 right) and negatively correlated with hemoglobin (R = −0.48;P = 0.03 left; −0.47;P = 0.04 right) and hemoglobin F (R = −0.42;P = .09 left; −0.47;P = 0.049 right).Conclusion: We established the validity of the SA method, which in our experience was much faster than the M method for delineation of vascular territories. Associations between CBF and hematologic variables may demonstrate pathophysiologic changes that contribute to clinical variation in CBF.J. Magn. Reson. Imaging 2015;41:439–446.©2013 Wiley Periodicals, Inc.

BACKGROUND AND PURPOSE: SWI is a powerful tool for imaging of the cerebral venous system. The SWI venous contrast is affected by blood flow, which may be altered in sickle cell disease. In this study, we characterized SWI venous contrast in patients with sickle cell disease and healthy control participants and examined the relationships among SWI venous contrast, and hematologic variables in the group with sickle cell disease. MATERIALS AND METHODS: A retrospective review of MR imaging and hematologic variables from 21 patients with sickle cell disease and age- and sex-matched healthy control participants was performed. A Frangi vesselness filter was used to quantify the attenuation of visible veins from the SWI. The normalized visible venous volume was calculated for quantitative analysis of venous vessel conspicuity. RESULTS: The normalized visible venous volume was significantly lower in the group with sickle cell disease vs the control group (P < .001). Normalized visible venous volume was not associated with hemoglobin, percent hemoglobin F, percent hemoglobin S, absolute reticulocyte count, or white blood cell count. A hypointense arterial signal on SWI was observed in 18 of the 21 patients with sickle cell disease and none of the 21 healthy control participants. CONCLUSIONS: This study demonstrates the variable and significantly lower normalized visible venous volume in patients with sickle cell disease compared with healthy control participants. Decreased venous contrast in sickle cell disease may reflect abnormal cerebral blood flow, volume, velocity, or oxygenation. Quantitative analysis of SWI contrast may be useful for investigation of cerebrovascular pathology in patients with sickle cell disease, and as a tool to monitor therapies. However, future studies are needed to elucidate physiologic mechanisms of decreased venous conspicuity in sickle cell disease.

Intraocular medulloepithelioma is a childhood tumor arising from the nonpigmented primitive ciliary neuroepithelium. Although rarer than retinoblastoma, it remains the second most common primary intraocular neoplasm in children. The rarity of intraocular medulloepithelioma creates the challenge in establishing a clinical diagnosis, and radiologically the tumor is often confused with other intraocular masses. To describe the clinical, imaging and pathological features of intraocular medulloepithelioma with emphasis on the role of imaging to enable its differentiation from more common intraocular pathology. We retrospectively analyzed the clinical, histopathological and imaging data of four children with intraocular medulloepithelioma. All four children had medulloepithelioma arising from the ciliary body. The children were imaged with US (n = 3), MRI (n = 4), whole-body ^99mTc-MDP scintigraphy (n = 2) and CT (n = 1). All four children had enucleation of the involved eye. One tumor was a malignant teratoid variant, two tumors were malignant nonteratoid variants and one was a nonteratoid variant of uncertain malignant potential. None of the tumors had extraocular extension on histopathology or imaging. Two children had associated retinal detachment on US and MRI examinations. All tumors were iso/hyperintense to vitreous on T1-weighted and hypointense on T2-weighted MRI and showed marked contrast enhancement of the solid components. No calcifications were identified on US or CT examinations. Our findings are consistent with previously reported cases of medulloepithelioma. This series emphasizes the roles of various imaging modalities, with pathological correlation, in differentiating the tumor from other ciliary body masses, in detecting tumor extension and in identifying associated ocular complications. In this series we also describe the results of postsurgical follow-up for tumor recurrence.

Background: Changes in cerebral perfusion are an important feature of the pathophysiology of sickle cell anemia (SCA); cerebrovascular ischemia occurs frequently and leads to neurocognitive deficits, silent infarcts, and overt stroke. Non‐invasive MRI methods to measure cerebral blood flow (CBF) by arterial spin labeling (ASL) afford new opportunities to characterize disease‐ and therapy‐induced changes in cerebral hemodynamics in patients with SCA. Recent studies have documented elevated gray matter (GM) CBF in untreated children with SCA, but no measurements of white matter (WM) CBF have been reported.Procedures: Pulsed ASL with automated brain image segmentation‐classification techniques were used to determine the CBF in GM, WM, and abnormal white matter (ABWM) of 21 children with SCA, 18 of whom were receiving hydroxyurea therapy.Results: GM and WM CBF were highly associated (R² = 0.76, P < 0.0001) and the GM to WM CBF ratio was 1.6 (95% confidence interval: 1.43–1.83). Global GM CBF in our treated cohort was 87 ± 24 mL/min/100 g, a value lower than previously reported in untreated patients with SCA. CBF was elevated in normal appearing WM (43 ± 14 mL/min/100 g) but decreased in ABWM (6 ± 12 mL/min/100 g), compared to published normal pediatric controls. Hemispheric asymmetry in CBF was noted in most patients.Conclusions: These perfusion measurements suggest that hydroxyurea may normalize GM CBF in children with SCA, but altered perfusion in WM may persist. This novel combined approach for CBF quantification will facilitate prospective studies of cerebral vasculopathy in SCA, particularly regarding the effects of treatments such as hydroxyurea. Pediatr Blood Cancer 2009;52:85–91.

Object: Diffusion tensor (DT) imaging has been used to predict postoperative motor function in patients with supratentorial tumors. The authors sought to determine whether DT imaging and white matter tractography could detect axonal degeneration in patients with brainstem tumors. Methods: A cross-sectional, retrospective study of 7 patients with brainstem tumors and 8 healthy volunteers was performed. The DT imaging data were normalized and regions of interest (ROIs) with the highest probability of sensory and motor connections were selected using the Talairach Atlas to identify the 3D millimetric coordinates of white matter tracts. An iterative process involving fractional anisotropy (FA), apparent diffusion coefficients (ADCs), and color maps was developed to precisely select ROIs in the bilateral sensory and motor tracts. The FA and ADC values were calculated for each ROI. Results: The FA values of sensory and motor tracts significantly differed between the patient and healthy volunteer groups (p < 0.05), whereas no significant changes were found in the splenium or genu of the corpus callosum. The FA values were altered proximal and distal to the brainstem tumors with a bimodal peak of antegrade decreased FA involving second- and third-order sensory axons and retrograde decreased FA of motor axons. Conclusions: This study demonstrates changes in diffusion properties of sensory and motor tracts consistent with degeneration to further characterize brainstem tumors in children, and the results warrant the planning of prospective trials. The rigorous methods the authors describe may provide valuable information when planning biopsies or debulking of unusual brainstem tumors, as well as improve prognostication of the possible functional tract recovery following therapy.

Although as a group, embryonal central nervous system tumors share a common background of primitive round cells, numerous distinctive histologic features allow for further subclassification. One tumor with a unique microscopic appearance is the recently described pediatric neuroblastic tumor with abundant neuropil and true rosettes (PNTANTR). We report 2 additional cases of this unusual tumor; both arose in 4-year-old children, one a midpontine tumor and the other a large cerebral lesion. The tumors contained hypercellular sheets of undifferentiated cells, broad zones of neuropil, and scattered perivascular, Homer Wright, and multilayered ependymoblastic-like rosettes. Isochromosome 17q was detected in multiple samples from one tumor, while the other tumor showed polysomy 17. No deletions of INI1 or amplifications of MYC or MYCN were detected. This report adds 2 cases to our experience of PNTANTR and is the first to demonstrate isochromosome 17q, a molecular alteration typical of medulloblastomas.

The purpose of this study was to use objective quantitative MR imaging methods to prospectively assess changes in the physiological structure of white matter during the temporal evolution of leukoencephalopathy (LE) in children treated for acute lymphoblastic leukemia. The longitudinal incidence, extent (proportion of white matter affect), and intensity (elevation of T1 and T2 relaxation rates) of LE was evaluated for 44 children. A combined imaging set consisting of T1, T2, PD, and FLAIR MR images and white matter, gray matter and CSF a priori maps from a spatially normalized atlas were analyzed with a neural network segmentation based on a Kohonen Self-Organizing Map (SOM). Quantitative T1 and T2 relaxation maps were generated using a nonlinear parametric optimization procedure to fit the corresponding multi-exponential models. A Cox proportional regression was performed to estimate the effect of intravenous methotrexate (IV-MTX) exposure on the development of LE followed by a generalized linear model to predict the probability of LE in new patients. Additional T-tests of independent samples were performed to assess differences in quantitative measures of extent and intensity at four different points in therapy. Higher doses and more courses of IV-MTX placed patients at a higher risk of developing LE and were associated with more intense changes affecting more of the white matter volume; many of the changes resolved after completion of therapy. The impact of these changes on neurocognitive functioning and quality of life in survivors remains to be determined.