Hydroxyurea maintains working memory function in pediatric sickle cell disease.

Pediatric patients with sickle cell disease (SCD) have decreased oxygen-carrying capacity in the blood and reduced or restricted cerebral blood flow resulting in neurocognitive deficits and cerebral infarcts. The standard treatment for children with SCD is hydroxyurea; however, the treatment-related neurocognitive effects are unclear. A key area of impairment in SCD is working memory, which is implicated in other cognitive and academic skills. N-back tasks are commonly used to investigate neural correlates of working memory. We analyzed functional magnetic resonance imaging (fMRI) of patients with SCD while they performed n-back tasks by assessing the blood-oxygenation level-dependent (BOLD) signals during working memory processing. Twenty hydroxyurea-treated and 11 control pediatric patients with SCD (7-18 years old) performed 0-, 1-, and 2-back tasks at 2 time points, once before hydroxyurea treatment (baseline) and ~1 year after treatment (follow-up). Neurocognitive measures (e.g., verbal comprehension, processing speed, full-scale intelligence quotient, etc.) were assessed at both time points. Although no significant changes in behavior performance of n-back tasks and neurocognitive measures were observed in the treated group, we observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- > 0-back contrast. Through searchlight-pattern classifications in the treated and control groups to identify changes in brain activation between time points during the 2-back task, we found more brain areas, especially the posterior region, with changes in the pattern and magnitude of BOLD signals in the control group compared to the treated group. In the control group, increases in 2-back BOLD signals were observed in the right crus I cerebellum, right inferior parietal lobe, right inferior temporal lobe, right angular gyrus, left cuneus and left middle frontal gyrus at 1-year follow-up. Moreover, BOLD signals elevated as the working memory load increased from 0- to 1-back but did not increase further from 1- to 2-back in the right inferior temporal lobe, right angular gyrus, and right superior frontal gyrus. These observations may result from increased cognitive effort during working memory processing with no hydroxyurea treatment. In contrast, we found fewer changes in the pattern and magnitude of BOLD signals across time points in the treated group. Furthermore, BOLD signals in the left crus I cerebellum, right angular gyrus, left cuneus and right superior frontal gyrus of the treated group increased continuously with increasing working memory load from 0- to 2-back, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. Collectively, these findings suggest that hydroxyurea treatment helped maintain working memory function in SCD.

Developmental patterns of CBF and BOLD responses to visual stimulus.

To investigate the developmental changes of cerebral blood flow (CBF) and hemodynamic responses to changing neural activity, we used the arterial spin label (ASL) technique to measure resting CBF and simultaneous CBF / blood-oxygen-level dependent (BOLD) signal changes during visual stimulation in 97 typically developing children and young adults (age 13.35 [6.02, 25.25] (median [min, max]) years old at the first time point). The longitudinal study protocol included three MRIs (2.7 ± 0.06 obtained), one year apart, for each participant. Mixed-effect linear and non-linear statistical models were used to analyze age effects on CBF and BOLD signals. Resting CBF decreased exponentially with age (p = 0.0001) throughout the brain, and developmental trajectories differed across brain lobes. The absolute CBF increase in visual cortex during stimulation was constant over the age range, but the fractional CBF change increased with age (p = 0.0001) and the fractional BOLD signal increased with age (p = 0.0001) correspondingly. These findings suggest that the apparent neural hemodynamic coupling in visual cortex does not change after age six years, but age-related BOLD signal changes continue through adolescence primarily due to the changes with age in resting CBF.

Removal of Arterial Vessel Contributions in Susceptibility-Weighted Images for Quantification of Normalized Visible Venous Volume in Children with Sickle Cell Disease.

PURPOSE: To evaluate a new postprocessing framework that eliminates arterial vessel signal contributions in the quantification of normalized visible venous volume (NVVV, a ratio between venous and brain volume) in susceptibility-weighted imaging (SWI) exams in patients with sickle cell disease (SCD). MATERIALS AND METHODS: We conducted a retrospective study and qualitatively reviewed for hypointense arterial vessel contamination in SWI exams from 21 children with SCD. We developed a postprocessing framework using magnetic resonance angiography in combination with SWI to provide a more accurate quantification of NVVV. NVVV was calculated before and after removing arterial vessel contributions to determine the error from hypointense arterial vessels in quantifying NVVV. RESULTS: Hypointense arterial vessel contamination was observed in 86% SWI exams and was successfully corrected by the proposed method. The contributions of hypointense arterial vessels in the original SWI were significant and accounted for approximately 33% of the NVVV [uncorrected NVVV = 0.012 ± 0.005 versus corrected NVVV = 0.008 ± 0.003 (mean ± SD), P < 0.01]. CONCLUSION: Hypointense arterial vessel contamination occurred in the majority of SWI exams and led to a sizeable overestimation of the visible venous volume. A prospective longitudinal study is needed to evaluate if quantitation of NVVV was improved and to assess the role of NVVV as a biomarker of SCD severity or stroke risk.

Removal of Arterial Vessel Contributions in Susceptibility-Weighted Images for Quantification of Normalized Visible Venous Volume in Children with Sickle Cell Disease

Purpose: To evaluate a new postprocessing framework that eliminates arterial vessel signal contributions in the quantification of normalized visible venous volume (NVVV, a ratio between venous and brain volume) in susceptibility-weighted imaging (SWI) exams in patients with sickle cell disease (SCD). Materials and Methods: We conducted a retrospective study and qualitatively reviewed for hypointense arterial vessel contamination in SWI exams from 21 children with SCD. We developed a postprocessing framework using magnetic resonance angiography in combination with SWI to provide a more accurate quantification of NVVV. NVVV was calculated before and after removing arterial vessel contributions to determine the error from hypointense arterial vessels in quantifying NVVV. Results: Hypointense arterial vessel contamination was observed in 86% SWI exams and was successfully corrected by the proposed method. The contributions of hypointense arterial vessels in the original SWI were significant and accounted for approximately 33% of the NVVV [uncorrected NVVV = 0.012 ± 0.005 versus corrected NVVV = 0.008 ± 0.003 (mean ± SD), P < 0.01]. Conclusion: Hypointense arterial vessel contamination occurred in the majority of SWI exams and led to a sizeable overestimation of the visible venous volume. A prospective longitudinal study is needed to evaluate if quantitation of NVVV was improved and to assess the role of NVVV as a biomarker of SCD severity or stroke risk.

Imaging in viral infections of the central nervous system: can images speak for an acutely ill brain?

Viral infections involving the central nervous system (CNS) may result from a wide variety of agents and have clinically overlapping manifestations. The diagnosis is often made based on a combination of the clinical exam, local epidemiology, imaging, and biochemical findings. Despite the advances in medicine and imaging, the diagnosis often remains elusive. Imaging, however, still plays a vital role in suggesting the diagnosis in typical cases, excluding potential mimics, and in evaluating changes with therapy. Herein, the authors present a review of various common and rare viral encephalitides with emphasis on the imaging literature.

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia.

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.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.

Spatiotemporal Patterns of Tumor Occurrence in Children with Intraocular Retinoblastoma.

PURPOSE: To accurately map the retinal area covered by tumor in a prospectively enrolled cohort of children diagnosed with retinoblastoma. METHODS: Orbital MRI in 106 consecutive retinoblastoma patients (44 bilateral) was analyzed. For MRI-visible tumors, the polar angle and angle of eccentricity of points defining tumor perimeter on the retina were determined by triangulation from images in three orthogonal planes. The centroid of the mapped area was calculated to approximate tumor origin, and the location and cumulative tumor burden were analyzed in relation to mutation type (germline vs. somatic), tumor area, and patient age at diagnosis. Location of small tumors undetected by MRI was approximated with fundoscopic images. RESULTS: Mapping was successful for 129 tumors in 91 eyes from 67 patients (39 bilateral, 43 germline mutation). Cumulative tumor burden was highest within the macula and posterior pole and was asymmetrically higher within the inferonasal periphery. Tumor incidence was lowest in the superotemporal periphery. Tumor location varied with age at diagnosis in a complex pattern. Tumor location was concentrated in the macula and superonasal periphery in patients <5.6 months, in the inferotemporal quadrant of the posterior pole in patients 5.6-8.8 months, in the inferonasal quadrant in patients 8.8-13.2 months, and in the nasal and superotemporal periphery in patients >13.2 months. The distribution of MRI-invisible tumors was consistent with the asymmetry of mapped tumors. CONCLUSIONS: MRI-based mapping revealed a previously unrecognized pattern of retinoblastoma localization that evolves with age at diagnosis. The structured spatiotemporal distribution of tumors may provide valuable clues about cellular or molecular events associated with tumorigenesis in the developing retina.

Silent cerebral infarcts in very young children with sickle cell anaemia are associated with a higher risk of stroke.

Silent cerebral infarctions (SCI) are the most common neurological injury in children with sickle cell anaemia (SCA), but their incidence/prognosis in early childhood has not been well described. We report clinical, neuroradiological, psychometric and academic follow-up over an average period of 14 years in 37 children with SCA who had magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the brain between ages 7 and 48 months. Ten patients (27%) younger than age 5 years (Group I) had SCI, as did 12 (32%) older than 5 years (Group II). Fifteen (41%) had no lesions (Group III). Overt stroke or transient ischaemic attack occurred in 5/9 (56%) in Group I. Most Group I patients had progressive MRI abnormalities, concurrent stenosis, decreased cognitive ability, attention/executive function deficits and hindered academic attainment. The proportions of subjects in Group I with subsequent neurological events (P ≤ 0·006), progressive ischaemia (P ≤ 0·001) and vascular stenosis (P ≤ 0·006) were greater than in Groups II and III. Thus, SCI in young children with SCA may predict overt central nervous system events, progressive MRI abnormalities, stenosis, cognitive dysfunction and poor academic performance. Children younger than 5 years may benefit from MRI/MRA testing and should be considered for aggressive intervention when SCI are detected.

Comparing segmented ASL perfusion of vascular territories using manual versus semiautomated techniques in children with sickle cell anemia.

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.

Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial.

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ≥Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] = 5.1, P ≤ .0001 and IRR = 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980.

Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group.

Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.

Imaging features of medulloepithelioma: report of four cases and review of the literature.

BACKGROUND: 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. OBJECTIVE: 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. MATERIALS AND METHODS: We retrospectively analyzed the clinical, histopathological and imaging data of four children with intraocular medulloepithelioma. RESULTS: All four children had medulloepithelioma arising from the ciliary body. The children were imaged with US (n = 3), MRI (n = 4), whole-body (99m)Tc-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. CONCLUSION: 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.

The effects of propofol on cerebral perfusion MRI in children.

INTRODUCTION: The effects of anesthesia are infrequently considered when interpreting pediatric perfusion magnetic resonance imaging (MRI). The objectives of this study were to test for measurable differences in MR measures of cerebral blood flow (CBF) and cerebral blood volume (CBV) between non-sedated and propofol-sedated children, and to identify influential factors. METHODS: Supratentorial cortical CBF and CBV measured by dynamic susceptibility contrast perfusion MRI in 37 children (1.8-18 years) treated for infratentorial brain tumors receiving propofol (IV, n = 19) or no sedation (NS, n = 18) were compared between groups and correlated with age, hematocrit (Hct), end-tidal CO2 (ETCO2), dose, weight, and history of radiation therapy (RT). The model most predictive of CBF and CBV was identified by multiple linear regression. RESULTS: Anterior cerebral artery (ACA) and middle cerebral artery (MCA) territory CBF were significantly lower, and MCA territory CBV greater (p = 0.03), in IV than NS patients (p = 0.01, 0.04). The usual trend of decreasing CBF with age was reversed with propofol in ACA and MCA territories (r = 0.53, r = 0.47; p < 0.05). ACA and MCA CBF (r = 0.59, 0.49; p < 0.05) and CBV in ACA, MCA, and posterior cerebral artery territories (r = 0.73, 0.80, 0.52; p < 0.05) increased with weight in propofol-sedated children, with no significant additional influence from age, ETCO2, hematocrit, or RT. CONCLUSION: In propofol-sedated children, usual age-related decreases in CBF were reversed, and increases in CBF and CBV were weight-dependent, not previously described. Weight-dependent increases in propofol clearance may diminish suppression of CBF and CBV. Prospective study is required to establish anesthetic-specific models of CBF and CBV in children.

The impact of preparation and support procedures for children with sickle cell disease undergoing MRI.

BACKGROUND: Children with sickle cell disease (SCD) often undergo MRI studies to assess brain injury or to quantify hepatic iron. MRI requires the child to lie motionless for 30-60 min, thus sedation/anesthesia might be used to facilitate successful completion of exams, but this poses additional risks for SCD patients. To improve children's ability to cope with MRI examinations and avoid sedation, our institution established preparation and support procedures (PSP). OBJECTIVE: To investigate the impact of PSP in reducing the need for sedation during MRI exams among children with SCD. MATERIALS AND METHODS: Data on successful completion of MRI testing were compared among 5- to 12-year-olds who underwent brain MRI or liver R2*MRI with or without receiving PSP. RESULTS: Seventy-one children with SCD (median age 9.85 years, range 5.57-12.99 years) underwent a brain MRI (n = 60) or liver R2*MRI (n = 11). Children who received PSP were more likely to complete an interpretable MRI exam than those who did not (30 of 33; 91% vs. 27 of 38; 71%, unadjusted OR = 4.1 (P = 0.04) and OR = 8.5 (P < 0.01) when adjusting for age. CONCLUSION: PSP can help young children with SCD complete clinically interpretable, nonsedated MRI exams, avoiding the risks of sedation/anesthesia.

US and MRI of pediatric ocular masses with histopathological correlation.

We review our experience with unusual ocular pathologies, some mimicking retinoblastoma, that were referred to our institution during the past two decades. After presenting the imaging anatomy of the normal eye, we discuss pertinent clinical and pathological features, and illustrate the US and MRI appearance of retinoblastoma, medulloepithelioma, uveal melanoma, persistent fetal vasculature, Coats disease, corneal dermoid, retinal dysplasia and toxocara granuloma. Features useful in discriminating among these entities are emphasized.

Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system.

PURPOSE: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). METHODS AND MATERIALS: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. RESULTS: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. CONCLUSIONS: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.

Hemodynamic responses to visual stimulation in children with sickle cell anemia.

Blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF)-based functional magnetic resonance imaging (fMRI) were used to measure primary visual cortex responses to photic stimulation in 23 children (12.4 ± 0.7 years old) with sickle cell anemia (SCA) and 21 clinical controls (11 ± 1.0 years old). The objectives were to investigate the effect of SCA on detection of brain activation with fMRI and to explore the relationship between fMRI responses and global cognitive function. The BOLD responses were diminished in children with SCA. Clinical indicators of disease severity were greatest in patients without detectable visual cortex activation, but blood hemoglobin concentration and resting CBF were not predictive of BOLD signal amplitude in the SCA patients. Unexpectedly, the BOLD signal amplitude was positively associated (r(s) ≥ 0.8, p ≤ 0.05) with Wechsler Abbreviated Scale of Intelligence scores, suggesting that fMRI may help clarify medical, hemodynamic, and neural factors that mediate adverse effects of SCA on neurocognitive function.