Donald Mabbott

Change in neurocognitive functioning after treatment with cranial radiation in childhood.

PURPOSE To evaluate the pattern of stability and change over time across multiple domains of neurocognitive function in radiated survivors of posterior fossa (PF) tumors. PATIENTS AND METHODS Thirty-four children (25 males) treated for malignant PF tumors were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Twelve patients were treated with reduced-dose and 21 patients were treated with standard-dose cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized neuropsychologic tests were administered at different times after diagnosis for each child. The rate of change in scores was determined using a mixed model regression. RESULTS Results showed a 2- to 4-point decline per year in intelligence scores. For our relatively young sample, intellectual function declined quickly in the first few years after treatment, and then more gradually. Significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning were also documented. No decline was evident for verbal memory and receptive vocabulary. CONCLUSION Cranial radiation is associated with a decline in multiple neurocognitive domains, with a few notable exceptions. Our results must be interpreted in the context of common limitations of clinical research, including patient variability, changes in test versions, small sample size, and clinical referral bias.

Serial Evaluation of Academic and Behavioral Outcome After Treatment With Cranial Radiation in Childhood

PURPOSE To evaluate academic and behavioral outcome in radiated survivors of posterior fossa (PF) tumors. PATIENTS AND METHODS Fifty-three patients (36 males) treated for malignant PF tumors were seen for evaluation of academics and/or behavioral functioning. Forty-six patients were treated for medulloblastoma, and seven patients were treated for ependymoma. Fourteen patients were treated with reduced-dose cranial radiation, and 34 patients were treated with standard-dose cranial radiation (dose was not available for four patients). All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized achievement tests and behavioral questionnaires were administered at different times after diagnosis for each child. First, the influence of demographic and medical variables on outcome was examined. Second, the rate of change in scores was determined using mixed model regression for patients seen for serial assessment. RESULTS The presence of hydrocephalus was related to poorer academics, but outcome was not related to radiation dose, extent of surgery, or treatment with chemotherapy. Younger age predicted poor reading ability and lower parent rating of academic achievement. Childrens performance declined for spelling, mathematics, and reading. Significant declines were also evident in parent and teachers ratings of academic ability. Behavioral functioning was generally not related to medical and demographic variables, and few clinically significant problems in externalizing behavior were evident. Increases in social and attention problems emerged over time. CONCLUSION Cranial radiation is associated with declines in academic ability, social skills, and attention. However, neither psychological distress nor behavior problems were a significant concern for this sample.

Diffusion tensor imaging of white matter after cranial radiation in children for medulloblastoma: Correlation with IQ

Treatment of children with cranial-spinal radiation (CSR) for brain tumors is associated with adverse intellectual outcome and white matter damage. However, the correlation between IQ and measures of white matter integrity has received little attention. We examined apparent diffusion coefficient (ADC), fractional anisotropy (FA), and intelligence in pediatric patients treated with CSR for medulloblastoma relative to control subjects. ADC and FA measures were obtained for eight patients and eight control children and evaluated in multiple regions of interest in the cerebral hemispheres. Mean ADC and mean FA for each region were calculated, group differences were evaluated, and the relationship between these measures and intelligence were examined. In our study group, decreased IQ was associated with increased ADC and decreased FA (P < 0.01). Mean IQ for the CSR group was lower than that for the control group, but the difference was not significant when controlling for overall mean FA or ADC (P > 0.10). Overall mean FA was lower and ADC was higher in the CSR group relative to controls (P < 0.01). Specifically, FA was lower in the genu of the corpus callosum, the anterior and posterior limbs of the internal capsule, inferior frontal white matter, and high frontal white matter, and ADC was higher in all regions in patients relative to controls (P < 0.01). Compromised white matter integrity was observed for multiple regions within the cerebral hemispheres following CSR. A novel finding was that microscopic damage in normal-appearing white matter, as indexed by higher ADC and lower FA, was related to poor intellectual outcome relative to age-matched controls.

Core neurocognitive functions in children treated for posterior fossa tumors.

Identifying cognitive deficits associated with pediatric brain tumors and their treatment is important in delineating the mechanisms of intellectual decline often associated with these diseases. The authors evaluated sustained attention, information processing speed, working memory, and IQ in 64 patients with posterior fossa tumors, including those treated with either: (a) surgery and cranial radiation (n = 32), and (b) surgery without radiation (n = 32). Ten patients treated for non-CNS solid tumors were included as a comparison group. The authors also examined the impact of relevant demographic and medical variables on neurocognitive outcome. The authors found that neither age at, nor time since, diagnosis predicted cognitive outcome in this sample. Further, sustained attention and working memory were largely intact and there were no differences between groups. Patients treated with cranial radiation demonstrated lowered short-form IQ and slow information processing speed: Patients treated with cranial radiation and who experienced postsurgical complications demonstrated the poorest performance. The authors consider information processing speed to be an excellent candidate mechanism in understanding the impact of cranial radiation on intellectual outcome.

White matter growth as a mechanism of cognitive development in children

We examined the functional role of white matter growth in cognitive development. Specifically, we used hierarchical regression analyses to test the unique contributions of age versus white matter integrity in accounting for the development of information processing speed. Diffusion tensor imaging was acquired for 17 children and adolescents (age range 6-17 years), with apparent diffusion coefficient (ADC) and fractional anisotropy (FA) calculated for 10 anatomically defined fiber pathways and 12 regions of hemispheric white matter. Measures of speeded visual-spatial searching, rapid picture naming, reaction time in a sustained attention task, and intelligence were administered. Age-related increases were evident across tasks, as well as for white matter integrity in hemispheric white matter. ADC was related to few measures. FA within multiple hemispheric compartments predicted rapid picture naming and standard error of reaction time in sustained attention, though it did not contribute significantly to the models after controlling for age. Independent of intelligence, visual-spatial searching was related to FA in a number of hemispheric regions. A novel finding was that only right frontal-parietal regions contributed uniquely beyond the effect of age in accounting for performance: age did not contribute to visual-spatial searching when FA within these regions was first included in the models. Considering we found that both FA in right frontal-parietal regions and speed of visual-spatial searching increased with age, our findings are consistent with the growth of regional white matter organization as playing an important role in increased speed of visual searching with age.

Natural History and Outcome of Optic Pathway Gliomas in Children

The optimal management of optic pathway gliomas (OPGs) is complicated by their variable natural history, the association with neurofibromatosis type 1 (NF1) and difficulties in defining progression and response to treatment.

Processing Speed, Attention, and Working Memory After Treatment for Medulloblastoma: An International, Prospective, and Longitudinal Study

PURPOSE The current study prospectively examined processing speed (PS), broad attention (BA), and working memory (WM) ability of patients diagnosed with medulloblastoma over a 5-year period. PATIENTS AND METHODS The study included 126 patients, ages 3 to 21 years at diagnosis, enrolled onto a collaborative protocol for medulloblastoma. Patients were treated with postsurgical risk-adapted craniospinal irradiation (n = 36 high risk [HR]; n = 90 average risk) followed by four cycles of high-dose chemotherapy with stem-cell support. Patients completed 509 neuropsychological evaluations using the Woodcock-Johnson Tests of Cognitive Abilities Third Edition (median of three observations per patient). RESULTS Linear mixed effects models revealed that younger age at diagnosis, HR classification, and higher baseline scores were significantly associated with poorer outcomes in PS. Patients treated as HR and those with higher baseline scores are estimated to have less favorable outcomes in WM and BA over time. Parent education and marital status were significantly associated with BA and WM baseline scores but not change over time. CONCLUSION Of the three key domains, PS was estimated to have the lowest scores at 5 years after diagnosis. Identifying cognitive domains most vulnerable to decline should guide researchers who are aiming to develop efficacious cognitive intervention and rehabilitation programs, thereby improving the quality of survivorship for the pediatric medulloblastoma population.

The relations between white matter and declarative memory in older children and adolescents.

Neural communication between the temporal and frontal cortex underlies mature declarative memory skills. The integrity of white matter pathways connecting these regions is likely critical in supporting this communication. Little is known about the relationship between white matter and declarative memory in older children and adolescents, an age period when advanced function in this domain is established. We acquired diffusion tensor imaging (DTI) data for 22 participants (9-15 years). Multiple DTI indices were calculated for the uncinate fasciculus - the major white matter tract connecting temporal and prefrontal regions. Indices were also calculated for compartments of lobar and posterior fossa white matter. Measures of visual-perceptual and auditory-verbal memory were administered. Correlation analyses were used to examine the relations between age, DTI indices, and memory. Voxel-wise analyses were also conducted. Age-related increases in FA were evident for frontal, parietal, and temporal hemispheric white matter. Proficiency in auditory-verbal memory was related to white matter integrity in the left uncinate fasciculus as well as parietal and cerebellar white matter. Proficiency in recall of a complex design was related to integrity within parietal and temporal regions. Our findings support the role of white matter in facilitating connectivity between cerebral regions important for declarative memory.

Impact of Craniospinal Dose, Boost Volume, and Neurologic Complications on Intellectual Outcome in Patients With Medulloblastoma

PURPOSE To examine the impact of radiation (ie, craniospinal irradiation [CSR] dose and boost volume) and complications (ie, hydrocephalus and other neurologic complications, including mutism) on patterns of change in intellectual functioning in medulloblastoma survivors. PATIENTS AND METHODS We conducted a retrospective review of 113 patients treated for medulloblastoma between 1983 and 2011 who were seen for neuropsychological assessment, including longitudinal follow-up of intellectual function. Patients were treated with either standard-dose CSR with a posterior fossa (PF) boost (n=51), standard-dose CSR plus tumor bed (TB) boost (n=9), reduced-dose CSR plus PF boost (n=28), or reduced-dose CSR plus TB boost (n=23), with or without chemotherapy. A subset of patients developed hydrocephalus that required cerebrospinal fluid (CSF) diversion (n=54) and/or other neurologic complications (n=40), more than half of which were postoperative mutism (n=25). Growth curve analysis was used to determine stability or change in intelligence scores over time. RESULTS Patients treated with reduced-dose CSR plus TB boost showed stable intellectual trajectories, whereas patients treated with higher doses and larger boost volumes experienced intellectual declines. Presence of complications was associated with worse intellectual outcome; however, hydrocephalus requiring CSF diversion and mutism differed in their pattern of decline. CONCLUSION These results improve our understanding of factors that impair intellectual outcome in patients treated for medulloblastoma. Lower doses of CSR and smaller boost volumes seem to mitigate intellectual decline. Our findings validate the use of TB boost and suggest PF boost should be reconsidered.

Cerebello-thalamo-cerebral connections in pediatric brain tumor patients: impact on working memory.

Brain tumors are the leading cause of death and disability from childhood disease in developed countries. Pediatric posterior fossa tumors are often effectively controlled with a combination of surgery, radiation, and chemotherapy, depending on tumor type. White matter injury following resection of tumor and radiation treatment is associated with cognitive declines, including working memory deficits. We investigated how brain injury following treatment for posterior fossa tumors results in deficits in working memory. We used diffusion tensor imaging and probabilistic tractography to examine the structural integrity of cerebello-thalamo-cerebral tracts in patients and healthy children. We also compared working memory outcome in patients versus controls, and related this function to integrity of cerebello-thalamo-cerebral tracts. Bilateral cerebello-thalamo-cerebral tracts were delineated in all participants. Patients treated with a combination of surgery and radiation had lower mean anisotropy and higher mean radial diffusivity within the cerebellar regions of the cerebello-thalamo-cerebral tract compared to patients treated with surgery only and healthy controls. Poorer working memory scores were observed for the cranial radiation group relative to controls. Reduced anisotropy and higher radial diffusivity within the entire cerebello-thalamo-cerebral pathway predicted lower working memory. Our finding that working memory function is related to the integrity of cerebello-thalamo-cerebral connections is a novel contribution to the understanding of cerebral-cerebellar communication. Identifying differences in the structural integrity of white matter for specific pathways is an essential step in attempting to localize the effects of posterior fossa tumors and their treatment methods.