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1.  Investigating the Relationship between COMT Polymorphisms and Working Memory Performance among Childhood Brain Tumor Survivors 
Pediatric blood & cancer  2013;61(1):40-45.
Background
Survivors of childhood brain tumors are at increased risk for neurocognitive impairments, including deficits in abilities supported by frontal brain regions. Catechol-O-methyltransferase (COMT) metabolizes dopamine in the prefrontal cortex, with the Met allele resulting in greater dopamine availability and better performance on frontally-mediated tasks compared to the Val allele. Given the importance of identifying resiliency factors against the emergence of cognitive late effects, the current study examined the relationship between COMT genotype and working memory performance among childhood brain tumor survivors.
Procedure
Children treated for a brain tumor with conformal radiation therapy (N=50; mean age at irradiation=7.41 ± 3.41; mean age at assessment=13.18 ± 2.88) were administered two computerized measures of working memory (self-ordered search verbal and object tasks). Buccal (cheek) swabs were used to provide tissue from which DNA was extracted.
Results
Findings revealed an association between COMT genotype and performance on the self-ordered verbal (p=0.03) but not object task (p=0.33). Better performance was found for the Met/Val group compared to either Met/Met or Val/Val.
Conclusions
COMT may indicate a potential resiliency factor against neurocognitive effects of cancer and its treatment; however, there is a need for replication with larger samples of childhood brain tumor survivors.
doi:10.1002/pbc.24649
PMCID: PMC4101980  PMID: 23956130
cancer; late effects; genetics; dopamine; prefrontal cortex; working memory
2.  Dexamethasone Exposure and Memory Function in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the SJLIFE Cohort 
Pediatric blood & cancer  2013;60(11):1778-1784.
Background
Dexamethasone is used in acute lymphoblastic leukemia (ALL) treatment, though long-term impact on central nervous system (CNS) function is unclear. As glucocorticoids influence hippocampal function, we investigated memory networks in survivors of childhood ALL treated with dexamethasone or prednisone.
Procedure
Neurocognitive assessment and functional magnetic resonance imaging (fMRI) were conducted in 38 adult survivors randomly recruited from cohorts treated on one of two standard treatment protocols, which differed primarily in the glucocorticoid administered during continuation therapy (dexamethasone [n=18] vs. prednisone [n=20]). Groups did not differ in age at diagnosis, age at evaluation, or cumulative intravenous or intrathecal methotrexate exposure.
Results
Survivors treated with dexamethasone demonstrated lower performance on multiple memory-dependent measures, including story memory (p=0.01) and word recognition (p=0.04), compared to survivors treated with only prednisone. Dexamethasone treatment was associated with decreased fMRI activity in the left retrosplenial brain region (effect size =1.3), though the small sample size limited statistical significance (p=0.08). Story memory was associated with altered activation in left inferior frontal-temporal brain regions (p=0.007).
Conclusions
Results from this pilot study suggest that adult survivors of ALL treated with dexamethasone are at increased risk for memory deficits and altered neural activity in specific brain regions and networks associated with memory function.
doi:10.1002/pbc.24644
PMCID: PMC3928631  PMID: 23775832
Leukemia; fMRI; memory; survivors; glucocorticoid; retrosplenium
3.  Incidental Detection of Late Subsequent Intracranial Neoplasms with Magnetic Resonance Imaging Among Adult Survivors of Childhood Cancer 
Purpose
Survivors of childhood cancer are at increased risk of developing subsequent neoplasms. In long term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms.
Methods
To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. 164 of the survivors had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT), and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms.
Results
Nineteen of the 219 survivors (8.7%) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4% (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review.
Conclusion
Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated.
Implications for Cancer Survivors
The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.
doi:10.1007/s11764-014-0344-8
PMCID: PMC4119575  PMID: 24488818
Survivors of Childhood Cancer; Cranial Radiation Therapy; Subsequent Intracranial Neoplasms; Meningiomas
4.  Evaluation of Memory Impairment in Aging Adult Survivors of Childhood Acute Lymphoblastic Leukemia Treated With Cranial Radiotherapy 
Background
Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood cancer and may increase risk for mild cognitive impairment and dementia in adulthood.
Methods
We performed a cross-sectional evaluation of survivors of childhood acute lymphoblastic leukemia (ALL) treated with 18 Gy (n = 127) or 24 Gy (n = 138) CRT. Impairment (age-adjusted score >1 standard deviation below expected mean, two-sided exact binomial test) on the Wechsler Memory Scale IV (WMS-IV) was measured. A subset of survivors (n = 85) completed structural and functional neuroimaging.
Results
Survivors who received 24 Gy, but not 18 Gy, CRT had impairment in immediate (impairment rate = 33.8%, 95% confidence interval [CI] = 25.9% to 42.4%; P < .001) and delayed memory (impairment rate = 30.2%, 95% CI = 22.6% to 38.6%; P < .001). The mean score for long-term narrative memory among survivors who received 24 Gy CRT was equivalent to that for individuals older than 69 years. Impaired immediate memory was associated with smaller right (P = .02) and left (P = .008) temporal lobe volumes, and impaired delayed memory was associated with thinner parietal and frontal cortices. Lower hippocampal volumes and increased functional magnetic resonance imaging activation were observed with memory impairment. Reduced cognitive status (Brief Cognitive Status Exam from the WMS-IV) was identified after 24 Gy (18.5%, 95% CI = 12.4% to 26.1%; P < .001), but not 18 Gy (8.7%, 95% CI = 4.4% to 15.0%; P = .11), CRT, suggesting a dose–response effect. Employment rates were equivalent (63.8% for 24 Gy CRT and 63.0% for 18 Gy CRT).
Conclusions
Adult survivors who received 24 Gy CRT had reduced cognitive status and memory, with reduced integrity in neuroanatomical regions essential in memory formation, consistent with early onset mild cognitive impairment.
doi:10.1093/jnci/djt089
PMCID: PMC3687368  PMID: 23584394
5.  DIFFERENCES IN BRAINSTEM FIBER TRACT RESPONSE TO RADIATION:A LONGITUDINAL DTI STUDY 
Purpose
To determine if radiation-induced changes in white matter tracts are uniform across the brainstem.
Methods and Materials
We analyzed serial diffusion tensor imaging (DTI) data, acquired before radiation therapy and over 48-72 months of follow-up, from 42 pediatric patients (age 6-20 years) with medulloblastoma. FSL software (FMRIB, Oxford, UK) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivities. For a consistent identification of volumes of interest, the parametric maps of each patient were transformed to a standard brain space (MNI152), on which we identified volumes of interest including corticospinal tract (CST), medial lemniscus (ML), transverse pontine fiber (TPF), and middle cerebellar peduncle (MCP) at the level of pons. Temporal changes of DTI parameters in VOIs were compared using a linear mixed effect model.
Results
Radiation-induced white matter injury was marked by a decline in FA after treatment. The decline was often accompanied by decreased axial diffusivity and/or increased radial diffusivity. This implied axonal damage and demyelination. We observed that the magnitude of the changes was not always uniform across substructures of the brainstem. Specifically, the changes in DTI parameters for TPF were more pronounced than in other regions (p<0.001 for FA) despite similarities in the distribution of dose. We did not find a significant difference among CST, ML, and MCP in these patients (p>0.093 for all parameters).
Conclusions
Changes in structural integrity of white matter tracts, assessed by DTI, were not uniform across the brainstem after radiation therapy. These results support a role for tract-based assessment in radiation treatment planning and determination of brainstem tolerance.
doi:10.1016/j.ijrobp.2013.01.028
PMCID: PMC3646932  PMID: 23474114
diffusion tensor imaging (DTI); brainstem; medulloblastoma; white matter injury
6.  Computerized Assessment of Cognitive Late Effects among Adolescent Brain Tumor Survivors 
Journal of neuro-oncology  2013;113(2):333-340.
BACKGROUND
Advantages of computerized assessment of neuropsychological functions include improved standardization and increased reliability of response time variables. ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) is a computerized battery developed for monitoring recovery following mild brain injuries that assesses attention, memory and processing speed. Despite evidence that core areas of deficit among cancer survivors are those assessed by ImPACT, it has not previously been used with this population.
PROCEDURE
Twenty four childhood brain tumor (BT) survivors treated with conformal radiation therapy (mean age= 15.7±1.6; mean age at irradiation= 9.8±2.5), twenty solid tumor (ST) survivors treated without CNS-directed therapy (mean age= 16.2±1.8) and twenty healthy siblings (mean age= 15.1± 1.6 years) were administered an age modified version of ImPACT. Additional computerized measures of working memory and recognition memory were administered.
RESULTS
Univariate ANOVAs revealed group differences (p< .05) on measures of recognition memory, spatial working memory, processing speed and reaction time, with BT survivors performing significantly worse than ST survivors and siblings. Pearson correlation coefficients revealed significant associations between ImPACT memory tasks and computerized forced choice recognition tasks (rs= .30-.33, p< .05). Multiple surgical resections, hydrocephalus and CSF shunt placement most consistently predicted worse ImPACT performance using linear mixed models (p< .05).
CONCLUSIONS
The ImPACT test battery demonstrated sensitivity to cognitive late effects experienced by some BT survivors with clinical predictors of performance consistent with the pediatric oncology literature. Correlations with measures of similar constructs provide evidence for convergent validity. Findings offer initial support for the utility of ImPACT for monitoring of cognitive late effects.
doi:10.1007/s11060-013-1123-5
PMCID: PMC3679205  PMID: 23525951
pediatric; cancer; ImPACT
7.  The Utility of Parent Report in the Assessment of Working Memory among Childhood Brain Tumor Survivors 
Childhood brain tumor survivors are at increased risk for neurocognitive impairments, including working memory (WM) problems. WM is typically assessed using performance measures. Little is known about the value of parent ratings for identifying WM difficulties, the relationship between rater and performance measures, or predictors of parent-reported WM problems in this population. Accordingly, the current study examined the utility of parent report in detecting WM difficulties among childhood brain tumor survivors treated with conformal radiation therapy (n=50) relative to siblings (n=40) and solid tumor survivors not receiving CNS-directed therapy (n=40). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants were administered WM measures (digit span, self-ordered search tasks). Findings revealed parents rated brain tumor survivors as having significantly more WM problems (p<.01) compared to controls. However, the BRIEF-WM scale demonstrated poor sensitivity and specificity for detecting performance-based problems. Significant, albeit modest, correlations were found between the BRIEF-WM scale and performance measures (r=−.24 −.22; p<.05) for the combined group. Age at testing, socioeconomic status, and IQ were significant predictors of parent reported WM problems. Rater and performance measures offer complimentary yet different information in assessing WM, which reiterates the importance of utilizing both within the context of clinical assessment.
doi:10.1017/S1355617712001567
PMCID: PMC3630283  PMID: 23351399
cancer; cognitive late effects; pediatrics; BRIEF; rater-based measures; executive functions
8.  Hemodynamic Responses to Visual Stimulation in Children with Sickle Cell Anemia 
Brain imaging and behavior  2011;5(4):295-306.
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 (rs≥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.
doi:10.1007/s11682-011-9133-4
PMCID: PMC3620037  PMID: 21881848
sickle cell anemia; functional magnetic resonance imaging; brain activation; cognitive function; blood oxygenation level- dependent; cerebral blood flow
9.  Evidence of Change in Brain Activity among Childhood Cancer Survivors Participating in a Cognitive Remediation Program 
Increased understanding of the underlying mechanisms of cognitive remediation is needed to facilitate development of intervention strategies for childhood cancer survivors experiencing cognitive late effects. Accordingly, a pilot functional magnetic resonance imaging (fMRI) study was conducted with 14 cancer survivors (12.02 ± 0.09 years old), who participated in a cognitive remediation clinical trial, and 28 healthy children (12.7 ± 0.6 years old). The ventral visual areas, cerebellum, supplementary motor area, and left inferior frontal cortex were significantly activated in the healthy participants during a continuous performance task. In survivors, brain activation in these regions was diminished at baseline, and increased upon completion of remediation and at a 6-month follow-up. The fMRI activation index for each region of interest was inversely associated with the Conners' Clinical Competence Index (p<.01). The pilot study suggests that fMRI is useful in evaluating neural responses to cognitive remediation.
doi:10.1093/arclin/acs095
PMCID: PMC3500501  PMID: 23079152
Attention; Brain tumor; Childhood brain insult; Neuroimaging (functional); Rehabilitation
10.  Working Memory Performance among Childhood Brain Tumor Survivors 
While longitudinal studies of children treated for brain tumors have consistently revealed declines on measures of intellectual functioning, greater specification of cognitive changes following treatment is imperative for isolating vulnerable neural systems and developing targeted interventions. Accordingly, this cross-sectional study evaluated the performance of childhood brain tumor survivors (n= 50) treated with conformal radiation therapy, solid tumor survivors (n= 40) who had not received CNS-directed therapy, and healthy sibling controls (n= 40) on measures of working memory [Digit Span and computerized self-ordered search (SOS) tasks]. Findings revealed childhood brain tumor survivors were impaired on both traditional [Digit Span Backward- F(2, 127)= 5.98, p< .01] and experimental [SOS-Verbal- F(2, 124)= 4.18, p< .05; SOS-Object- F(2, 126)= 5.29, p< .01] measures of working memory, and performance on working memory measures correlated with intellectual functioning (Digit Span Backward- r= .45, p< .0001; SOS- r= −.32 − −.26, p< .01). Comparison of performance on working memory tasks to recognition memory tasks (computerized delayed match-to-sample) offered some support for greater working memory impairment. This pattern of findings is consistent with vulnerability in functional networks that include prefrontal brain regions and has implications for the clinical management of children with brain tumors.
doi:10.1017/S1355617712000793
PMCID: PMC3461093  PMID: 22691544
cancer; radiation therapy; cognitive late effects; prefrontal cortex; pediatric; neurodevelopment
11.  Functional Neuroimaging to Characterize Visual System Development in Children with Retinoblastoma 
Functional MRI and diffusion tensor imaging in children being treated for retinoblastoma showed that patterns of visual activation and diffusion parameters in associated white matter pathways reflected neural changes caused by disease and treatment.
Purpose.
To use functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to investigate visual system development in children being treated for retinoblastoma.
Methods.
Informed consent was obtained for all participants (N = 42) in this institutional review board–approved study. Participants were imaged with a 1.5-T scanner while under propofol sedation. Diagnostic brain and orbital imaging was followed by investigational functional neuroimaging, which included fMRI during photic stimulation through closed eyelids, to measure functional activation in the visual cortex, and DTI, to evaluate diffusion parameters of white matter tracts in the corpus callosum and the periventricular optic radiations. Analysis included 115 examinations of 39 patients with a median age of 16.4 months and age range from 1.5 to 101.5 months at first evaluation.
Results.
The blood oxygen level–dependent signal was predominantly negative and located in the anterior visual cortex. Activation was affected by tumor lateralization (unilateral or bilateral), macular involvement, and retinal detachment. Patients who had undergone unilateral enucleation showed cortical dominance corresponding to the projection from the nasal hemiretina in the unaffected eye. Diffusion parameters followed a normal developmental trajectory in the optic radiations and corpus callosum, but variability was greater in the splenium than in the genu of the corpus callosum.
Conclusions.
Longitudinal functional neuroimaging demonstrated important effects of disease and treatment. Therefore, fMRI and DTI may be useful for characterizing the impact of retinoblastoma on the developing visual system and improving the prediction of visual outcome in survivors.
doi:10.1167/iovs.10-5600
PMCID: PMC3088553  PMID: 21245407
12.  BRAIN TUMOR THERAPY-INDUCED CHANGES IN NORMAL-APPEARING BRAINSTEM MEASURED WITH LONGITUDINAL DIFFUSION TENSOR IMAGING 
Purpose
To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI).
Methods and Materials
We analyzed 109 DTI studies from 20 brain tumor patients, aged 4-23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors and atypical teratoid rhabdoid tumors (n=10) received postoperative craniospinal irradiation (23.4-39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by 4 cycles of high-dose chemotherapy. Patients with high-grade gliomas (n=10) received erlotinib during and after irradiation (54-59.4 Gy). Parametric maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6-25 years, were included in the analysis.
Results
The median DTI follow-up was 3.5 years (range, 1.6-5.0 years). The median mean dose to the pons was 56 Gy (range, 7-59 Gy). Three patterns were seen in longitudinal FA and ADC changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns.
Conclusions
Variation existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years following radiation therapy.
doi:10.1016/j.ijrobp.2011.03.057
PMCID: PMC3181276  PMID: 21664060
Diffusion tensor imaging; Brainstem; Radiation therapy
13.  Surgical management of tumors producing the thalamopeduncular syndrome of childhood 
Object
Thalamopeduncular tumors arise at the junction of the inferior thalamus and cerebral peduncle and present with a common clinical syndrome of progressive spastic hemiparesis. Pathologically, these lesions are usually juvenile pilocytic astrocytomas and are best treated with resection with the intent to cure. The goals of this study are to define a common clinical syndrome produced by thalamopeduncular tumors and to discuss imaging characteristics as well as surgical adjuncts, intraoperative nuances, and postoperative complications relating to the resection of these neoplasms.
Methods
The authors present a retrospective review of their experience with 10 children presenting between 3 and 15 years of age with a thalamopeduncular syndrome. Formal preoperative MR imaging was obtained in all patients, and diffusion tensor (DT) imaging was performed in 9 patients. Postoperative MR imaging was obtained to evaluate the extent of tumor resection. A prospective analysis of clinical outcomes was then conducted by the senior author.
Results
Pilocytic astrocytoma was the pathological diagnosis in 9 cases, and the other was fibrillary astrocytoma. Seven of 9 pilocytic astrocytomas were completely resected. Radical surgery was avoided in 1 child after DT imaging revealed that the corticospinal tract (CST) coursed through the center of the tumor, consistent with the infiltrative nature of fibrillary astrocytoma as identified by stereotactic biopsy. In 8 patients, tractography served as an important adjunct for designing a surgical approach that spared the CST. In 6 cases the CSTs were pushed anterolaterally, making a transsylvian approach a poor choice, as was evidenced by the first patient in the series, who underwent operation prior to the advent of tractography, and who awoke with a dense contralateral hemiparesis. Thus, subsequent patients with this deviation pattern underwent a transcortical approach via the middle temporal gyrus. One patient exhibited medial deviation of the tracts and another had lateral deviation, facilitating a transtemporal and a transfrontal approach, respectively.
Conclusions
The thalamopeduncular syndrome of progressive spastic hemiparesis presenting in children with or without symptoms of headache should alert the examiner to the possibility of a tumoral involvement of CSTs. Preoperative tractography is a useful adjunct to surgical planning in tumors that displace motor pathways. Gross-total resection of pilocytic astrocytomas usually results in cure, and therefore should be entertained when developing a treatment strategy for thalamopeduncular tumors of childhood.
doi:10.3171/2011.4.PEDS119
PMCID: PMC3531960  PMID: 21631193
thalamopeduncular astrocytoma; juvenile pilocytic astrocytoma; diffusion tensor imaging; tractography; pediatric neurosurgery; congenital
14.  Brain Structural Abnormalities in Survivors of Pediatric Posterior Fossa Brain Tumors: a Voxel-Based Morphometry Study Using Free-Form Deformation 
NeuroImage  2008;42(1):218-229.
Voxel-based morphometry was used to compare brain structure morphology of survivors of posterior fossa brain tumor (PFBT) with that of normal sibling controls to investigate disease- or cancer treatment–induced changes. Two different spatial normalization approaches that are available in public domain software (free-form deformation (FFD) and discrete cosine transform (DCT)) were compared for accuracy of normalization in the PFBT patients. Anatomical landmark matching demonstrated that spatial normalization was more accurate with FFD than with DCT. Voxel-based morphometry of the FFD-normalized magnetic resonance images from PFBT survivors and sibling controls detected reduced gray matter density in the thalamus and entorhinal cortex and reduced white matter density in the internal capsule, hypothalamus, corpus callosum, and cuneus of the occipital lobe in the PFBT survivors. Identification of these morphologic lesions may help localize the neural substrates of disease- or therapy-induced cognitive deficits in survivors of childhood cancer.
doi:10.1016/j.neuroimage.2008.04.181
PMCID: PMC2591023  PMID: 18539046
15.  Proximal dentatothalamocortical tract involvement in posterior fossa syndrome 
Brain  2009;132(11):3087-3095.
Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.
doi:10.1093/brain/awp241
PMCID: PMC2781745  PMID: 19805491
posterior fossa; cerebellum; mutism; medulloblastoma
16.  Predicting Change in Academic Abilities After Conformal Radiation Therapy for Localized Ependymoma 
Journal of Clinical Oncology  2008;26(24):3965-3970.
Purpose
Conformal radiation therapy (CRT) aims to limit the highest radiation dose to the tissue volume at risk while sparing surrounding normal tissues. This study investigated whether treatment of childhood ependymoma with CRT would preserve cognitive function. Academic competence was chosen as the primary outcome measure given it is a measure of applied cognitive abilities in a child's natural setting.
Patients and Methods
Eighty-seven pediatric patients diagnosed with ependymoma received CRT in which doses ranging from 54.0 to 59.4 Gy were prescribed to the postoperative tumor bed with a 10-mm clinical target volume margin. Cognitive testing was conducted at the start of CRT, 6 months, and annually after the start of CRT. The median length of follow-up was 59.6 months. Academic testing included subtests from the Wechsler Individual Achievement Test (WIAT) and the Achenbach Child Behavior Checklist.
Results
Linear mixed models with random coefficients revealed a modest but significant decline in reading scores during follow-up (WIAT slope estimate −0.064 ± 0.028 points/month; P = .026). Math and spelling performance remained stable. Supratentorial tumor location and multiple surgeries were predictive of worse reading performance at CRT baseline. Male sex, longer symptomatic interval, pre-CRT chemotherapy, pre-existing endocrine deficiencies, hydrocephalus, and younger age at CRT (< 5 years) were predictive of a significant decline in reading scores over time.
Conclusion
CRT may result in better long-term cognitive outcomes when compared to conventional radiation therapy approaches. Reading appears more vulnerable than other academic skills and may decline over time despite stable intellectual functioning.
doi:10.1200/JCO.2007.15.9970
PMCID: PMC2654312  PMID: 18711186
17.  Childhood central nervous system leukemia: historical perspectives, current therapy, and acute neurological sequelae 
Neuroradiology  2007;49(11):873-888.
Introduction
During the past three decades, improvements in the treatment of childhood leukemia have resulted in high cure rates, particularly for acute lymphoblastic leukemia (ALL). Unfortunately, successful therapy has come with a price, as significant morbidity can result from neurological affects which harm the brain and spinal cord. The expectation and hope is that chemotherapy, as a primary means of CNS therapy, will result in acceptable disease control with less CNS morbidity than has been observed with combinations of chemotherapy and radiotherapy over the past several decades.
Methods and results
In this review we discuss the poignant, historical aspects of CNS leukemia therapy, outline current methods of systemic and CNS leukemia therapy, and present imaging findings we have encountered in childhood leukemia patients with a variety of acute neurological conditions. A major objective of our research is to understand the neuroimaging correlates of acute and chronic effects of cancer and therapy. Specific features related to CNS leukemia and associated short-term toxicities, both disease- and therapy-related, are emphasized in this review with the specific neuroimaging findings. Specific CNS findings are similarly important when treating acute myelogenous leukemia (AML), and details of leukemic involvement and toxicities are also presented in this entity.
Conclusion
Despite contemporary treatment approaches which favor the use of chemotherapy (including intrathecal therapy) over radiotherapy in the treatment of CNS leukemia, children still occasionally experience morbid neurotoxicity. Standard neuroimaging is sufficient to identify a variety of neurotoxic sequelae in children, and often suggest specific etiologies. Specific neuroimaging findings frequently indicate a need to alter antileukemia therapy. It is important to appreciate that intrathecal and high doses of systemic chemotherapy are not innocuous and are associated with acute, specific, recognizable, and often serious neurological consequences.
doi:10.1007/s00234-007-0300-7
PMCID: PMC2386669  PMID: 17924103
Childhood CNS leukemia; Neurotoxicity; Intrathecal therapy; CNS infection; Secondary malignancies; Methotrexate

Results 1-17 (17)