Cerebellar Mutism Syndrome and Dentato-Thalamo-Cortical Tract Disruption in Diffusion Tractography Following Surgery for Medulloblastoma.

Background Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentato-thalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS-related symptoms has not been investigated. Purpose To investigate the association between severity of CMS-related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods This retrospective case-control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma. CMS was divided into types 1 (CMS1) and 2 (CMS2). Multivariable logistic regression was used to investigate the relationship between CMS likelihood and DTCT injury. Results Overall, 82 participants with medulloblastoma (mean age, 11.0 years ± 5.2 [SD]; 53 male) and 35 healthy controls (mean age, 18.0 years ± 3.06; 18 female) were included. In participants with medulloblastoma, DTCT was absent bilaterally (AB), absent on the right side (AR), absent on the left side (AL), or present bilaterally (PB), while it was PB in all healthy controls. Odds of having CMS were associated with higher degree of DTCT damage (AB, odds ratio = 272.7 [95% CI: 269.68, 275.75; P < .001]; AR, odds ratio = 14.40 [95% CI: 2.84, 101.48; P < .001]; and AL, odds ratio = 8.55 [95% CI: 1.15, 74.14; P < .001). Left (coefficient = -0.07, χ2 = 12.4, P < .001) and right (coefficient = -0.15, χ2 = 33.82, P < .001) DTCT volumes were negatively associated with the odds of CMS. More participants with medulloblastoma with AB showed CMS1; unilateral DTCT absence prevailed in CMS2. Lower DTCT volumes correlated with more severe ataxia. Unilateral DTCT injury caused ipsilateral dysmetria; AB caused symmetric dysmetria. PB indicated better neurologic outcome. Conclusion The severity of CMS-associated mutism, ataxia, and dysmetria was associated with DTCT damage severity. DTCT damage patterns differed between CMS1 and CMS2. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Dorigatti Soldatelli and Ertl-Wagner in this issue.

A high-dimensional mediation model for a neuroimaging mediator: Integrating clinical, neuroimaging, and neurocognitive data to mitigate late effects in pediatric cancer.

Pediatric cancer treatment, especially for brain tumors, can have profound and complicated late effects. With the survival rates increasing because of improved detection and treatment, a more comprehensive understanding of the impact of current treatments on neurocognitive function and brain structure is critically needed. A frontline medulloblastoma clinical trial (SJMB03) has collected data, including treatment, clinical, neuroimaging, and cognitive variables. Advanced methods for modeling and integrating these data are critically needed to understand the mediation pathway from the treatment through brain structure to neurocognitive outcomes. We propose an integrative Bayesian mediation analysis approach to model jointly a treatment exposure, a high-dimensional structural neuroimaging mediator, and a neurocognitive outcome and to uncover the mediation pathway. The high-dimensional imaging-related coefficients are modeled via a binary Ising-Gaussian Markov random field prior (BI-GMRF), addressing the sparsity, spatial dependency, and smoothness and increasing the power to detect brain regions with mediation effects. Numerical simulations demonstrate the estimation accuracy, power, and robustness. For the SJMB03 study, the BI-GMRF method has identified white matter microstructure that is damaged by cancer-directed treatment and impacts late neurocognitive outcomes. The results provide guidance on improving treatment planning to minimize long-term cognitive sequela for pediatric brain tumor patients.

Modified Diffusion Tensor Image Processing Pipeline for Archived Studies of Patients With Leukoencephalopathy.

BACKGROUND: In archived diffusion tensor imaging (DTI) studies, a reversed-phase encoding (PE) scan required to correct the distortion in single-shot echo-planar imaging (EPI) may not have been acquired. Furthermore, DTI tractography is adversely affected by incorrect white matter segmentation due to leukoencephalopathy (LE). All these issues need to be addressed. PURPOSE: To propose and evaluate a modified DTI processing pipeline with DIstortion COrrection using pseudo T2 -weighted images (DICOT) to overcome limitations in existing acquisition protocols. STUDY TYPE: Retrospective feasibility. SUBJECTS: DICOT was assessed in simulated data and 84 acute lymphoblastic leukemia (ALL) patients with reversed PE acquired. The pipeline was then tested in 522 scans from 261 ALL patients without a reversed PE acquired. FIELD STRENGTH/SEQUENCE: A 3 T; diffusion-weighted EPI; 3D magnetization prepared rapid acquisition gradient echo (MPRAGE). STATISTICAL TESTS: Repeated measures analysis of variance and Tukey post hoc tests were performed to compare fractional anisotropy (FA) values obtained by different methods. ASSESSMENT: FA and corresponding absolute error maps were obtained using TOPUP, DICOT, INVERSION (Inverse contrast Normalization for VERy Simple registratION) and NO CORR (no correction). Each method was assessed by comparing to TOPUP. The pipeline in the ALL patients was evaluated based on the failure rate of the distortion correction using the global correlation values. RESULTS: Using DICOT reduced the mean absolute errors by an average of 32% in FA in simulation datasets. In 84 patients, the error reductions were approximately 15% in FA with DICOT, while it was 5% with INVERSION. No significant differences between the TOPUP and DICOT were observed in FA with P = 0.090/0.894(AP/PA). Only 15 of 516 examinations requiring any additional manual intervention. CONCLUSION: This modified pipeline produced better results than the INVERSION. Furthermore, robust performance was demonstrated in archived patient scans acquired without an inverse PE necessary for TOPUP correction. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Characterization of Leukoencephalopathy and Association With Later Neurocognitive Performance in Pediatric Acute Lymphoblastic Leukemia.

OBJECTIVES: The most common form of pediatric cancer is acute lymphoblastic leukemia (ALL). Magnetic resonance (MR) neuroimaging studies have revealed leukoencephalopathy (LE) in pediatric ALL, but the impact of LE on long-term neurocognitive performance remains unknown. This study aims to objectively characterize the prevalence, extent, and intensity of LE, and their association with later neurocognitive performance. MATERIALS AND METHODS: Pediatric patients (N = 377) treated for ALL without irradiation underwent MR neuroimaging at 4 time points throughout therapy (end of remission induction [MR1], end of consolidation [MR2], and week 31 [MR3] and week 120 [end therapy, MR4] of continuation treatment) and neurocognitive evaluations at the end of therapy and 2 years later. Generalized estimation equation models with logit link were developed to explore the association between LE prevalence and extent with time points throughout therapy, age at diagnosis (≤5 years or >5 years), treatment risk arm (low risk or standard/high risk), and sex. General linear models were also developed to investigate the association between neuroimaging metrics during treatment and neurocognitive performance at 2-year follow-up. RESULTS: The prevalence of LE was greatest (22.8%, 74/324) after consolidation therapy. The prevalence of LE increased at MR2 relative to MR1 regardless of treatment risk arm (both P's < 0.001), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.013). The extent of white matter affected also increased at MR2 relative to MR1 regardless of treatment risk arm (standard/high risk, P < 0.001; low risk, P = 0.004), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.001). Quantitative relaxation rates were significantly longer in LE compared with that in normal-appearing white matter in the same examination (T1, P < 0.001; T2, P < 0.001). The LE prevalence early in therapy was associated with increased parent ratings of conduct problems (P = 0.039) and learning difficulties (P = 0.036) at 2-year follow-up compared with that at the end of therapy. A greater extent of LE early in therapy was associated with decreasing performance on a measure of processing speed (P = 0.003) from the end of therapy to 2-year follow-up. A larger extent of LE at the end of therapy was associated with decreased performance in reading (P = 0.004), spelling (P = 0.003), and mathematics (P = 0.019) at 2-year follow-up and increasing problems with attention (omissions, P = 0.045; ß, P = 0.015) and memory (list A total recall, P = 0.010) at 2-year follow-up compared with that at the end of therapy. CONCLUSIONS: In this large cohort of pediatric patients treated for ALL without irradiation, asymptomatic LE during therapy can be seen in almost a quarter of patients, involves as much as 10% of the white matter volume, and is associated with decreasing neurocognitive performance, increasing parent reports of conduct problems, and learning difficulties in survivors.

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.

Importance: Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). Objective: To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. Design, Setting, and Participants: This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. Exposure: ALL treatment using chemotherapy-only protocols. Main Outcomes and Measures: This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. ß values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Results: Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: ß = 55.54; SE = 25.55; P = .03; right cerebellum: ß = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: ß = 82.71; SE = 31.04; P = .009; right cerebellum: ß = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (ß = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (ß = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. Conclusions and Relevance: These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.

Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex-stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long-term problems with learning may be related to residual posttreatment brain differences.

Author Correction: The challenge of mapping the human connectome based on diffusion tractography.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A comprehensive preclinical assessment of late-term imaging markers of radiation-induced brain injury.

BACKGROUND: Cranial radiotherapy (CRT) is an important part of brain tumor treatment, and although highly effective, survivors suffer from long-term cognitive side effects. In this study we aim to establish late-term imaging markers of CRT-induced brain injury and identify functional markers indicative of cognitive performance. Specifically, we aim to identify changes in executive function, brain metabolism, and neuronal organization. METHODS: Male Sprague Dawley rats were fractionally irradiated at 28 days of age to a total dose of 30 Gy to establish a radiation-induced brain injury model. Animals were trained at 3 months after CRT using the 5-choice serial reaction time task. At 12 months after CRT, animals were evaluated for cognitive and imaging changes, which included positron emission tomography (PET) and magnetic resonance imaging (MRI). RESULTS: Cognitive deficit with signs of neuroinflammation were found at 12 months after CRT in irradiated animals. CRT resulted in significant volumetric changes in 38% of brain regions as well as overall decrease in brain volume and reduced gray matter volume. PET imaging showed higher brain glucose uptake in CRT animals. Using MRI, irradiated brains had an overall decrease in fractional anisotropy, lower global efficiency, increased transitivity, and altered regional connectivity. Cognitive measurements were found to be significantly correlated with six image features that included myelin integrity and local organization of the neural network. CONCLUSIONS: These results demonstrate that CRT leads to late-term morphological changes, reorganization of neural connections, and metabolic dysfunction. The correlation between imaging markers and cognitive deficits can be used to assess late-term side effects of brain tumor treatment and evaluate efficacy of new interventions.

Association Between Anesthesia Exposure and Neurocognitive and Neuroimaging Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia.

IMPORTANCE: Limited studies have reported associations between anesthesia and neurocognitive and neuroimaging outcomes, particularly in pediatric patients who undergo multiple exposures to anesthesia as part of chronic disease management. OBJECTIVE: To investigate whether general anesthesia is associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia. DESIGN, SETTING, AND PARTICIPANTS: A cohort study of 212 survivors of childhood acute lymphoblastic leukemia who received treatment between July 7, 2000, and November 3, 2010, and follow-up at a mean (SD) of 7.7 (1.7) years post diagnosis, was conducted at an academic medical center. Of 301 survivors who were alive and eligible for participation, 217 individuals (72.1%) agreed to participate in long-term follow-up. Data analysis was performed from August 23, 2017, to May 3, 2018. EXPOSURES: For 5699 anesthesia procedures, data on duration and cumulative doses of all anesthetics, sedatives, analgesics, anxiolytics, and neuromuscular blockers were abstracted, along with cumulative doses of high-dose intravenous methotrexate and number of triple intrathecal chemotherapy treatments. MAIN OUTCOMES AND MEASURES: Neurocognitive measures of attention, processing speed, executive function, and intelligence were examined. Brain volumes, cortical thickness, and diffusion tensor imaging of the whole brain, corpus callosum, frontal lobes, and parietal lobes were evaluated. RESULTS: Of the 217 study participants, 212 were included in both neurocognitive and brain imaging analysis. Of these, 105 were female (49.5%); mean (SD) age at diagnosis was 14.36 (4.79) years; time since diagnosis was 7.7 (1.7) years. Adjusting for chemotherapy doses and age at diagnosis, neurocognitive impairment was associated with higher propofol cumulative dose (relative risk [RR], 1.40 per 100 mg/kg; 95% CI, 1.11-1.75), flurane exposure (RR, 1.10 per exposure; 95% CI, 1.01-1.21), and longer anesthesia duration (RR, 1.03 per cumulative hour; 95% CI, 1.00-1.06). Slower processing speed was associated with higher propofol dose (estimate [est], -0.30; P = .04), greater number of exposures to fluranes (est, -0.14; P = .01), and longer anesthesia duration (est, -0.04; P = .003). Higher corpus callosum white matter diffusivity was associated with dose of propofol (est, 2.55; P = .01) and duration of anesthesia (est, 2.40; P = .02). Processing speed was significantly correlated with corpus callosum diffusivity (r = -0.26, P < .001). CONCLUSIONS AND RELEVANCE: Higher cumulative anesthesia exposure and duration may be associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia, beyond the known outcomes associated with neurotoxic chemotherapies. Anesthesia exposures should be limited in pediatric populations with chronic health conditions who undergo multiple medical procedures.

Measurement of Projections Between Dentate Nucleus and Contralateral Frontal Cortex in Human Brain Via Diffusion Tensor Tractography.

We propose a probabilistic fiber-tracking scheme to reconstruct the fiber tracts between the dentate nucleus (DN) in the cerebellum and the entire contralateral cerebral frontal cortex in the human brain. We assessed diffusion tensor imaging (DTI) data from 39 healthy controls. The connection fibers between the DN and contralateral frontal cortex of all subjects were successfully reconstructed and studied. We demonstrated that multi-fiber probabilistic models must be used to resolve the challenge of crossing fibers. We also demonstrated that the entire pathway can be reconstructed without using any synaptic regions of interest along the path and that the reconstructed tracts connected the ipsilateral superior cerebellar peduncle, contralateral red nucleus, and ventral lateral and ventral anterior nuclei of thalamus in the path traveling to the contralateral frontal cortex. The fibers in the pathway projected into all areas of the contralateral frontal cortex but were predominantly located in the primary motor and premotor areas. A large portion of fibers terminated in the prefrontal cortex, which included dorsolateral prefrontal areas, anterior prefrontal areas, and the Broca language area. Our findings provide robust, reproducible, and direct DTI-based evidence that the DN through the efferent cerebellar pathway has considerable contribution to high-level executive functions of the human brain.

Early Imaging Based Predictive Modeling of Cognitive Performance Following Therapy for Childhood ALL.

In the United States, Acute Lymphoblastic Leukemia (ALL), the most common child and adolescent malignancy, accounts for roughly 25% of childhood cancers diagnosed annually with a 5-year survival rate as high as 94% [1]. This improved survival rate comes with an increased risk for delayed neurocognitive effects in attention, working memory, and processing speed [2]. Predictive modeling and characterization of neurocognitive effects are critical to inform the family and also to identify patients for interventions targeting. Current state-of-the-art methods mainly use hypothesis-driven statistical testing methods to characterize and model such cognitive events. While these techniques have proven to be useful in understanding cognitive abilities, they are inadequate in explaining causal relationships, as well as individuality and variations. In this study, we developed multivariate data-driven models to measure the late neurocognitive effects of ALL patients using behavioral phenotypes, Diffusion Tensor Magnetic Resonance Imaging (DTI) based tractography data, morphometry statistics, tractography measures, behavioral, and demographic variables. Alongside conventional machine learning and graph mining, we adopted "Stability Selection" to select the most relevant features and choose models that are consistent over a range of parameters. The proposed approach demonstrated substantially improved accuracy (13% - 26%) over existing models and also yielded relevant features that were verified by domain experts.

Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standard/high- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p = 0.037) and poor separation between sensorimotor, executive/attention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.

The challenge of mapping the human connectome based on diffusion tractography.

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.

Disrupted development and integrity of frontal white matter in patients treated for pediatric medulloblastoma.

BACKGROUND: Treatment of pediatric medulloblastoma is associated with known neurocognitive deficits that we hypothesize are caused by microstructural damage to frontal white matter (WM). METHODS: Longitudinal MRI examinations were collected from baseline (after surgery but before therapy) to 36 months in 146 patients and at 3 time points in 72 controls. Regional analyses of frontal WM volume and diffusion tensor imaging metrics were performed and verified with tract-based spatial statistics. Age-adjusted, linear mixed-effects models were used to compare patient and control images and to associate imaging changes with Woodcock-Johnson Tests of Cognitive Abilities. RESULTS: At baseline, WM volumes in patients were similar to those in controls; fractional anisotropy (FA) was lower bilaterally (P < 0.001) and was associated with decreased Processing Speed (P = 0.014) and Broad Attention (P = 0.025) performance at 36 months. During follow-up, WM volumes increased in controls but decreased in patients (P < 0.001) bilaterally. Smaller WM volumes in patients at 36 months were associated with concurrent decreased Working Memory (P = 0.026) performance. CONCLUSIONS: Lower FA in patients with pediatric medulloblastoma compared with age-similar controls indicated that patients suffer substantial acute microstructural damage to supratentorial frontal WM following surgery but before radiation therapy or chemotherapy. Additionally, this damage to the frontal WM was associated with decreased cognitive performance in executive function 36 months later. This early damage also likely contributed to posttherapeutic failure of age-appropriate WM development and to the known association between decreased WM volumes and decreased cognitive performance.

Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia.

BACKGROUND: Limited information is available regarding neurocognitive outcomes of children who experience seizures during treatment for acute lymphoblastic leukemia (ALL). Accordingly, the main objectives of this study were to determine the incidence and risk factors for treatment-related seizures among children with ALL, and the neurocognitive outcomes associated with treatment-related seizures. PROCEDURE: Prospective neuropsychological assessment and magnetic resonance imaging (MRI) were planned for all 498 patients with newly diagnosed ALL enrolled on the St. Jude Total Therapy XV (TOTXV) protocol at three time points. The study database was reviewed retrospectively to identify those with treatment-related seizure. To assess neurocognitive changes associated with seizure, each patient with treatment-related seizure was matched with two cohort patients without seizure for age at treatment, gender, race, and treatment intensity. RESULTS: Nineteen patients developed seizure, with a 2-year cumulative risk of 3.82 ± 0.86% (SE). No risk factors were identified to be associated with the development of seizure, with a possible exception of intensive chemotherapy used on the standard/high-risk arm as compared to the low-risk arm. Neuropsychological performance of the seizure group, as compared to normative scores and nonseizure control cohort, indicated problems in attention, working memory, and processing speed. Cognitive deficits persisted 2 years after therapy, with additional declines in intellectual function observed. MRI indicated early neurotoxicity among the seizure group, as evidenced by greater leukoencephalopathy on initial examinations. CONCLUSION: Treatment-related seizures were associated with leukoencephalopathy and decreased neuropsychological performance. Prospective studies are needed to detect changes in neurocognitive status associated with long-term functional impairment.

Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis.

BACKGROUND: Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukaemia, although its effects on long-term outcomes is unknown. This study examines the associations between acute leukoencephalopathy and neurobehavioural, neurocognitive, and brain white matter imaging outcomes in long-term survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy without cranial radiation. METHODS: In this longitudinal analysis, we used data of children with acute lymphoblastic leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA) who had been treated between June 1, 2000, and Oct 31, 2010. Eligible patients were diagnosed with non-B-cell acute lymphoblastic leukaemia, aged at least 8 years, and survivors with at least 5 years since their initial diagnosis. Brain MRIs obtained during active therapy were systematically coded for leukoencephalopathy using Common Terminology Criteria for Adverse Event version 4. At least 5 years after their diagnosis, survivors completed neurocognitive testing, another brain MRI, and their parents completed neurobehavioural ratings of their child (Behavior Rating Inventory of Executive Function [BRIEF]). Follow-up MRI included diffusion tensor imaging to assess white matter integrity, with indices of fractional anisotropy, axial diffusivity, and radial diffusivity from frontal lobes, parietal lobes, and in the frontostriatal tract. The neuroradiologist, who assessed abnormal MRIs, was masked to both group assignment of survivors and the neurobehavioural and neurocognitive outcomes. The primary outcomes were neurobehavioural function, assessed from completed BRIEF, and neurocognitive performance, measured by direct neurocognitive tests (Delis-Kaplan Executive Function System, Wechsler Intelligence Scale for Children-IV/Wechsler Adult Intelligence Scale-III, Rey-Osterrieth Complex Figure Test, and Lafayette Grooved Pegboard Test). This study had completed enrolment in October, 2014, and is registered as an observational study at ClinicalTrials.gov, number NCT01014195. FINDINGS: Between Feb 18, 2010, and Oct 22, 2014, 210 (70%) of 301 eligible survivors participated in our study of whom 190 were evaluable, 162 had an MRI. 56 participants had quantitative brain imaging data and were included in evaluable population analyses. 51 (27%) of the 190 evaluable participants had acute leukoencephalopathy. Compared with population norms, survivors were reported to have more neurobehavioural problems with working memory, organisation, initiation, and planning (p<0·001 for all). Survivors had worse scores than the general population on direct measures of memory span, processing speed, and executive function (p<0·05 for all). Survivors with a history of acute leukoencephalopathy had more neurobehavioural problems than survivors with no history of leukoencephalopathy on organisation (adjusted T-score 56·2 [95% CI 53·3-59·1] vs 52·2 [50·4-53·9], p=0·020) and initiation (55·5 [52·7-58·3] vs 52·1 [50·4-53·8], p=0·045). Survivors with acute leukoencephalopathy also had reduced white matter integrity in the frontostriatal tract at follow-up: lower fractional anisotropy (p=0·069), higher axial diffusivity (p=0·020), and higher radial diffusivity (p=0·0077). A one-unit change in the radial diffusivity index corresponded with a 15·0 increase in raw score points on initiation, 30·3 on planning, and 28·0 on working memory (p<0·05 for all). INTERPRETATION: Acute leukoencephalopathy during chemotherapy treatment, without cranial radiation, for childhood acute lymphoblastic leukaemia predicted higher risk for long-term neurobehavioural problems and reduced white matter integrity in frontal brain regions. Survivors of childhood acute lymphoblastic leukaemia might benefit from preventive cognitive or behavioural interventions, particularly those who develop acute leukoencephalopathy. FUNDING: National Institute of Mental Health, National Cancer Institute, American Lebanese Syrian Associated Charities.

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.

Diffusion tensor imaging and neurocognition in survivors of childhood acute lymphoblastic leukaemia.

Survivors of childhood acute lymphoblastic leukaemia are at risk for neurocognitive impairment, though little information is available on its association with brain integrity, particularly for survivors treated without cranial radiation therapy. This study compares neurocognitive function and brain morphology in long-term adult survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy alone (n = 36) to those treated with cranial radiation therapy (n = 39) and to healthy control subjects (n = 23). Mean (standard deviation) age at evaluation was 24.9 (3.6) years for the chemotherapy group and 26.7 (3.4) years for the cranial radiation therapy group, while time since diagnosis was 15.0 (1.7) and 23.9 (3.1) years, respectively. Brain grey and white matter volume and diffusion tensor imaging was compared between survivor groups and to 23 healthy controls with a mean (standard deviation) age of 23.1 (2.6) years. Survivors treated with chemotherapy alone had higher fractional anisotropy in fibre tracts within the left (P < 0.05), but not in the right, hemisphere when compared to controls. Survivors of acute lymphoblastic leukaemia, regardless of treatment, had a lower ratio of white matter to intracranial volume in frontal and temporal lobes (P < 0.05) compared with control subjects. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone performed worse in processing speed (P < 0.001), verbal selective reminding (P = 0.01), and academics (P < 0.05) compared to population norms and performed better than survivors treated with cranial radiation therapy on verbal selective reminding (P = 0.02), processing speed (P = 0.05) and memory span (P = 0.009). There were significant associations between neurocognitive performance and brain imaging, particularly for frontal and temporal white and grey matter volume. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone demonstrated significant long-term differences in neurocognitive function and altered neuroanatomical integrity. These results suggest substantial region-specific white matter alterations in survivors of acute lymphoblastic leukaemia possibly resulting in restricted radial diffusion due to the compaction of neuronal fibres.

The relationship between working memory and cerebral white matter volume in survivors of childhood brain tumors treated with conformal radiation therapy.

Survivors of childhood brain tumors (BTs) treated with CNS-directed therapy show changes in cerebral white matter that are related to neurocognitive late effects. We examined the association between white matter volume and working memory ability in survivors treated with conformal radiation therapy (CRT). Fifty survivors (25 males, age at assessment = 13.14 ± 2.88, age at CRT = 7.41 ± 3.41 years) completed Digit Span from the Wechsler Intelligence Scales for Children, 4th Edition and experimental Self-Ordered Search (SOS) tasks as measures of working memory. Caregiver ratings were obtained using the Behavior Rating Inventory of Executive Function. MRI exams were acquired on a 1.5 T scanner. Volumes of normal appearing white matter (NAWM) were quantified using a well-validated automated segmentation and classification program. Correlational analyses demonstrated that NAWM volumes were significantly larger in males and participants with tumors located in the infratentorial space. Correlations between NAWM volume and Digit Span Backward were distributed across anterior and posterior regions, with evidence for greater right hemisphere involvement (r = .32-.34, p ≤ .05). Correlations between NAWM volume with Digit Span Backward (r = .44-.52; p ≤ .05) and NAWM volume with SOS-Object Total (r = .45-.52, p ≤ .05) were of greater magnitude in females. No relationship was found between NAWM volume and caregiver report. Working memory performance in survivors of pediatric BTs treated with CRT are related to regionally specific NAWM volume. Developmental differences in cerebral myelination may explain findings of greater risk for neurocognitive late effects in female survivors. Future studies are needed to better isolate vulnerable white matter pathways, thus facilitating the development of neuroprotective interventions.

"Occult" post-contrast signal enhancement in pediatric diffuse intrinsic pontine glioma is the MRI marker of angiogenesis?

INTRODUCTION: In diffuse intrinsic pontine gliomas (DIPG), subtracting pre-contrast from post-contrast T1-weighted images (T1WI) occasionally reveals subtle, "occult" enhancement. We hypothesized that this represents intravascular enhancement related to angiogenesis and hence that these tumors should have greater blood volume fractions than do non-enhancing tumors. METHODS: We retrospectively screened MR images of 66 patients initially diagnosed with DIPG and analyzed pretreatment conventional and dynamic susceptibility contrast (DSC) perfusion MRI studies of 61 patients. To determine the incidence of occult enhancement, cerebral blood volume (CBV) values were compared in areas of occult enhancement (OcE), no enhancement (NE), and normal-appearing deep cerebellar white matter (DCWM). RESULTS: Tumors of 10 patients (16.4 %) had occult enhancement; those of 6 patients (9.8 %) had no enhancement at all. The average CBV in areas of occult enhancement was significantly higher than that in non-enhancing areas of the same tumor (P = .03), within DCWM in the same patient (P = .03), and when compared to anatomically paired/similar regions of interest (ROI) in patients with non-enhancing tumors (P = .005). CONCLUSION: Areas of OcE correspond to areas of higher CBV in DIPG, which may be an MRI marker for angiogenesis, but larger scale studies may be needed to determine its potential relevance to grading by imaging, treatment stratification, biopsy guidance, and evaluation of response to targeted therapy.