Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

PURPOSE: Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity. PATIENTS AND METHODS: Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enrolled in a multisite research and treatment protocol, which included surgery, risk-adapted craniospinal irradiation (average risk, n = 186; high risk, n = 74), and chemotherapy, were analyzed using linear mixed models. Participants were assessed at baseline and up to 5 years after diagnosis and grouped according to degree of SNHL. Included were 196 children with intact hearing or mild to moderate SNHL (Chang grade 0, 1a, 1b, or 2a) and 64 children with severe SNHL (Chang grade 2b or greater). Performance on eight neurocognitive variables targeting reading outcomes (eg, phonemics, fluency, comprehension) and contributory cognitive processes (eg, working memory, processing speed) was analyzed. RESULTS: Participants with severe SNHL performed significantly worse on all variables compared with children with normal or mild to moderate SNHL (P ≤ .05), except for tasks assessing awareness of sounds and working memory. Controlling for age at diagnosis and risk-adapted craniospinal irradiation dose, performance on the following four variables remained significantly lower for children with severe SNHL: phonemic skills, phonetic decoding, reading comprehension, and speed of information processing (P ≤ .05). CONCLUSION: Children with severe SNHL exhibit greater reading difficulties over time. Specifically, they seem to struggle most with phonological skills and processing speed, which affect higher level skills such as reading comprehension.

Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study.

BACKGROUND: Patients treated for medulloblastoma who experience posterior fossa syndrome (PFS) demonstrate increased risk for neurocognitive impairment at one year post diagnosis. The aim of the study was to examine longitudinal trajectories of neuropsychological outcomes in patients who experienced PFS compared with patients who did not. METHODS: Participants were 36 patients (22 males) who experienced PFS and 36 comparison patients (21 males) who were matched on age at diagnosis and treatment exposure but did not experience PFS. All patients underwent serial evaluation of neurocognitive functioning spanning 1 to 5 years post diagnosis. RESULTS: The PFS group demonstrated lower estimated mean scores at 1, 3, and 5 years post diagnosis on measures of general intellectual ability, processing speed, broad attention, working memory, and spatial relations compared with the non-PFS group. The PFS group exhibited estimated mean scores that were at least one standard deviation below the mean for intellectual ability, processing speed, and broad attention across all time points and for working memory by 5 years post diagnosis. Processing speed was stable over time. Attention and working memory declined over time. Despite some change over time, caregiver ratings of executive function and behavior problem symptoms remained within the average range. CONCLUSION: Compared with patients who do not experience PFS, patients who experience PFS exhibit greater neurocognitive impairment, show little recovery over time, and decline further in some domains. Findings highlight the particularly high risk for long-term neurocognitive problems in patients who experience PFS and the need for close follow-up and intervention.

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.

Functional MRI in medulloblastoma survivors supports prophylactic reading intervention during tumor treatment.

Development of reading skills is vulnerable to disruption in children treated for brain tumors. Interventions, remedial and prophylactic, are needed to mitigate reading and other learning difficulties faced by survivors. A functional magnetic resonance imaging (fMRI) study was conducted to investigate long-term effects of a prophylactic reading intervention administered during radiation therapy in children treated for medulloblastoma. The fMRI study included 19 reading-intervention (age 11.7 ± 0.6 years) and 21 standard-of-care (age 12.1 ± 0.6 years) medulloblastoma survivors, and 21 typically developing children (age 12.3 ± 0.6 years). The survivors were 2.5 [1.2, 5.4] years after completion of tumor therapies and reading-intervention survivors were 2.9 [1.6, 5.9] years after intervention. Five fMRI tasks (Rapid Automatized Naming, Continuous Performance Test using faces and letters, orthographic and phonological processing of letter pairs, implicit word reading, and story reading) were used to probe reading-related neural activation. Woodcock-Johnson Reading Fluency, Word Attack, and Sound Awareness subtests were used to evaluate reading abilities. At the time of fMRI, Sound Awareness scores were significantly higher in the reading-intervention group than in the standard-of-care group (p = 0.046). Brain activation during the fMRI tasks was detected in left inferior frontal, temporal, ventral occipitotemporal, and subcortical regions, and differed among the groups (p < 0.05, FWE). The pattern of group activation differences, across brain areas and tasks, was a normative trend in the reading-intervention group. Standardized reading scores and patterns of brain activation provide evidence of long-term effects of prophylactic reading intervention in children treated for medulloblastoma.

Working memory abilities among children treated for medulloblastoma: parent report and child performance.

OBJECTIVE: We investigated the 5-year postsurgical developmental trajectory of working memory (WM) in children with medulloblastoma using parent and performance-based measures. METHOD: This study included 167 patients treated for medulloblastoma. Serial assessments of WM occurred at predetermined time points for 5 years. RESULTS: There was a subtle, statistically significant increase in parental concern about WM, coupled with a statistically significant decrease in age-standardized scores on performance-based measures. However, whole-group mean scores on both parent and performance-based measures remained in the age-expected range. Posterior fossa syndrome was consistently associated with poorer WM. Younger age at treatment and higher treatment intensity were associated with greater negative change in WM performance only. CONCLUSIONS: Most children treated for medulloblastoma display WM within the age-appropriate range according to parent report and performance. However, the subtle negative changes over time and identified subgroups at increased risk highlight the need for ongoing monitoring of this population.

Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma.

BACKGROUND: The aim of this study was to prospectively examine the effects of hearing loss and posterior fossa syndrome (PFS), in addition to age at diagnosis and disease risk status, on change in intellectual and academic outcomes following diagnosis and treatment in a large sample of medulloblastoma patients. METHODS: Data from at least 2 cognitive and academic assessments were available from 165 patients (ages 3-21 years) treated with surgery, risk-adapted craniospinal irradiation, and 4 courses of chemotherapy with stem cell support. Patients underwent serial evaluation of cognitive and academic functioning from baseline up to 5 years post diagnosis. RESULTS: Serious hearing loss, PFS, younger age at diagnosis, and high-risk status were all significant risk factors for decline in intellectual and academic skills. Serious hearing loss and PFS independently predicted below-average estimated mean intellectual ability at 5 years post diagnosis. Patients with high-risk medulloblastoma and young age at diagnosis (<7 years) exhibited the largest drop in mean scores for intellectual and academic outcomes. CONCLUSIONS: Despite a significant decline over time, intellectual and academic outcomes remained within the average range at 5 years post diagnosis for the majority of patients. Future studies should determine if scores remain within the average range at time points further out from treatment. Patients at heightened risk should be closely monitored and provided with recommendations for appropriate interventions.

Feasibility and efficacy of a computer-based intervention aimed at preventing reading decoding deficits among children undergoing active treatment for medulloblastoma: results of a randomized trial.

OBJECTIVE: To investigate the feasibility of a computer-based reading intervention completed by patients diagnosed with a brain tumor. METHODS: Patients were randomized to the intervention (n = 43) or standard of care group (n = 38). The intervention consisted of 30 sessions using Fast ForWord® exercises in a game-like format. Change in reading decoding scores over time since diagnosis was examined. Gender, race, parent education, parent marital status, and age at diagnosis were examined as covariates. RESULTS: 17 patients (39.5%) were able to complete the target goal of 30 intervention sessions. Females had significantly greater training time than males (p = .022). Age at diagnosis was associated with average training time/session for females (r = .485, p = .041). No significant differences were found in reading scores between the randomized groups. CONCLUSIONS: The study was well accepted by families and adherence by patients undergoing radiation therapy for medulloblastoma was moderate. Suggestions for improved methodology are discussed.

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.

Parent-reported social outcomes after treatment for pediatric embryonal tumors: a prospective longitudinal study.

PURPOSE: To examine longitudinal parent-reported social outcomes for children treated for pediatric embryonal brain tumors. PATIENTS AND METHODS: Patients (N=220) were enrolled onto a multisite clinical treatment protocol. Parents completed the Child Behavior Checklist/6-18 at the time of their child's diagnosis and yearly thereafter. A generalized linear mixed effects model regression approach was used to examine longitudinal changes in parent ratings of social competence, social problems, and withdrawn/depressed behaviors with demographic and treatment factors as covariates. RESULTS: During the 5-year period following diagnosis and treatment, few patients were reported to have clinically elevated scores on measures of social functioning. Mean scores differed significantly from population norms, yet remained within the average range. Several factors associated with unfavorable patterns of change in social functioning were identified. Patients with high-risk treatment status had a greater increase in parent-reported social problems (P=.001) and withdrawn/depressed behaviors (P=.01) over time compared with average-risk patients. Patients with posterior fossa syndrome had greater parent-reported social problems over time (P=.03). Female patients showed higher withdrawn/depressed scores over time compared with male patients (P<.001). Patient intelligence, age at diagnosis, and parent education level also contributed to parent report of social functioning. CONCLUSION: Results of this study largely suggest positive social adjustment several years after diagnosis and treatment of a pediatric embryonal tumor. However, several factors, including treatment risk status and posterior fossa syndrome, may be important precursors of long-term social outcomes. Future research is needed to elucidate the trajectory of social functioning as these patients transition into adulthood.

White matter integrity is associated with cognitive processing in patients treated for a posterior fossa brain tumor.

Children treated for posterior fossa tumors experience reduced cognitive processing speed and, after imaging, show damage to white matter (WM) tracts in the brain. This study explores relationships between white matter microstructure, assessed by fractional anisotropy (FA), and speed of cognitive processing using tract-based spatial statistics (TBSS). At 36 months after treatment with radiotherapy and chemotherapy, 40 patients completed an MRI examination and neuropsychological evaluation. Patients were matched with healthy control subjects based on age, sex, and race. Individual FA values were extracted from examinations for all voxels identified as having significant association between processing speed and FA using TBSS. The regions were labeled anatomically, and fiber tracts were grouped into larger fiber bundle categories based on their anatomical and functional associations. Analyses were performed between mean skeletal FA values in each of the fiber bundles and each of the cognitive processing scores controlling for age. Children 3 years after treatment for posterior fossa brain tumors demonstrate significantly lower processing speed associated with decreased FA, compared with their healthy peers. Commissural fibers in the corpus callosum were negatively affected by disease and therapy with detrimental consequence on patients' cognitive processing. Diffusion tensor imaging of the white matter tracts in the brain is relevant to determining potential mechanisms underlying clinically meaningful change in cognitive performance. Neuroprotective strategies are needed to preserve critical functions.

How parents cope with their child's diagnosis and treatment of an embryonal tumor: results of a prospective and longitudinal study.

The current study reports longitudinal coping responses among parents of children diagnosed with an embryonal brain tumor. Patients (n = 219) were enrolled on a treatment protocol for a pediatric embryonal brain tumor. Their parents (n = 251) completed the Coping Response Inventory at time of their child's diagnosis and yearly thereafter, resulting in 502 observations. Outcomes were examined with patient and parent age at diagnosis, patient risk, parent gender and education as covariates. At the time of diagnosis, the highest observed coping method was seeking guidance with well above average scores (T = 61.6). Over time, younger parents were found to seek guidance at a significantly higher rate than older parents (P = .016) and the use of acceptance resignation and seeking alternative results by all parents significantly increased (P = .011 and P < .0001 respectively). The use of emotional discharge was also observed above average at time of diagnosis (T = 55.4) with younger fathers being more likely to exhibit emotional discharge than older fathers (P = .002). Differences in coping according to age of the patient and parent education level are also discussed. Results show a high need for guidance, and above average emotional discharge, especially among younger parents. It is imperative for the healthcare team to lead with accurate information so that these parents may make informed decisions about the care of their child. This need remains high years after diagnosis. Therefore it is critical to continue a consistent level of effective communication and support, even following treatment.

Neurocognitive outcome 12 months following cerebellar mutism syndrome in pediatric patients with medulloblastoma.

The aim is to prospectively assess early neurocognitive outcome of children who developed cerebellar mutism syndrome (CMS) following surgical resection of a posterior fossa embryonal tumor, compared with carefully matched control patients. Children who were enrolled on an ongoing IRB-approved protocol for treatment of embryonal tumors, were diagnosed with postoperative CMS, and had completed prospectively planned neuropsychological evaluation at 12 months postdiagnosis were considered eligible. The cognitive outcomes of these patients were examined in comparison to patients without CMS from the same treatment protocol and matched with regard to primary diagnosis, age at diagnosis, and risk/corresponding treatment (n = 22 pairs). Seventeen were also matched according to gender, and 14 were also matched according to race. High-risk patients received 36-39.6 Gy CSI and 3D conformal boost to the primary site to 55.8-59.4 Gy. Average-risk patients received 23.4 Gy CSI and 3D conformal boost to the primary site to 55.8 Gy. Significant group differences were found on multiple cognitive outcomes. While the matched control patients exhibited performance in the average range, patients who developed CMS postsurgery were found to have significantly lower performance in processing speed, attention, working memory, executive processes, cognitive efficiency, reading, spelling, and math. Patients treated for medulloblastoma who experience postoperative CMS show an increased risk for neurocognitive impairment, evident as early as 12 months following diagnosis. This study highlights the need for careful follow-up with neuropsychological evaluation and for obtaining critical support for patients and their families.

Dysembryoplastic neuroepithelial tumors and cognitive outcome: cure at a price?

BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNETs) are benign glioneuronal tumors that occur in children. These tumors are characterized by seizures, lack of neurologic deficits, and a seemingly benign course after resection. METHODS: A retrospective review was conducted of data relating to 11 children diagnosed with DNETs between January 1988 and December 2007 at St. Jude Children's Research Hospital. This report documented the clinical features, neurocognitive function, and treatment outcomes in this institutional series. RESULTS: The patient cohort included 8 boys and 3 girls (median age at diagnosis, 10 years); all patients presented with seizures: 4 complex partial, 3 generalized tonic-clonic, 2 absence, 1 partial simple, and 1 not classified. Of the 11 patients, 1 died of cardiac fibrosis, and tumors recurred or progressed in 4 (36%) patients. Seizure control was achieved in all patients but 1. Of the 9 patients who completed neuropsychologic testing, only 3 (33%) functioned at or above the expected level of same-age peers. CONCLUSIONS: The high recurrence and progression rates of DNETs and the high rate of abnormal neurocognitive test results noted in the current study highlight the need for regular follow-up and appropriate academic counseling of children with these tumors.

Regional white matter anisotropy and reading ability in patients treated for pediatric embryonal tumors.

Children treated with cranial irradiation for brain tumors have reduced white matter volume and deficits in reading ability. This study prospectively examined the relationship between reading and white matter integrity within this patient group. Patients (n = 54) were treated with post-surgical radiation followed by 4 cycles of high-dose chemotherapy with stem cell support. At 12 months post-diagnosis, all patients completed a neuropsychology evaluation and a diffusion tensor imaging (DTI) exam. White matter integrity was determined through measures of fractional anisotropy (FA). Significant group differences in FA were found between above average readers and below average readers within the left and right posterior limb of the internal capsule, and right knee of the internal capsule with a trend within the left temporaloccipital region. The integrity of the white matter in these regions may affect communication among visual, auditory, and language cortical areas that are engaged during reading.

Survivors of pediatric posterior fossa tumors: cognitive outcome, intervention, and risk-based care.

Adolescent and young adult survivors of posterior fossa tumors face a wide variety of functional challenges following treatment. The concept of survival needs to include plans to regularly monitor and effectively respond to those patients considered at risk for continued morbidities associated with cancer and its treatment. The nature of impairment experienced by survivors is discussed, including predominant patient- and treatment-related risk factors. A model to respond to the cognitive needs of survivors, including risk-based evaluation and intervention, is proposed. It is imperative for the success of the survivor that a team approach is taken to care. This approach must include improving the awareness and education of teachers and other education specialists who interact with this population of survivors. There is also an obligation to put forth effort in developing and validating efficacious intervention programs.

A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET.

We undertook this study to estimate the event-free survival (EFS) of patients with newly diagnosed supratentorial primitive neuroectodermal tumor (SPNET) treated with risk-adapted craniospinal irradiation (CSI) with additional radiation to the primary tumor site and subsequent high-dose chemotherapy supported by stem cell rescue. Between 1996 and 2003, 16 patients with SPNET were enrolled. High-risk (HR) disease was differentiated from average-risk (AR) disease by the presence of residual tumor (M(0) and tumor size > 1.5 cm(2)) or disseminated disease in the neuraxis (M(1)-M(3)). Patients received risk-adapted CSI: those with AR disease received 23.4 Gy; those with HR disease, 36-39.6 Gy. The tumor bed received a total of 55.8 Gy. Subsequently, all patients received four cycles of high-dose cyclophosphamide, cisplatin, and vincristine with stem cell support. The median age at diagnosis was 7.9 years; eight patients were female. Seven patients had pineal PNET. Twelve patients are alive at a median follow-up of 5.4 years. The 5-year EFS and overall survival (OS) estimates for all patients were 68% +/- 14% and 73% +/- 13%. The 5-year EFS and OS estimates were 75% +/- 17% and 88% +/- 13%, respectively, for the eight patients with AR disease and 60% +/- 19% and 58% +/- 19%, respectively, for the eight with HR disease. No deaths were due to toxicity. High-dose cyclophosphamide-based chemotherapy with stem cell support after risk-adapted CSI results in excellent EFS estimates for patients with newly diagnosed AR SPNET. Further, this chemotherapy allows for a reduction in the dose of CSI used to treat AR SPNET without compromising EFS.

Neurodevelopmental impact on children treated for medulloblastoma: a review and proposed conceptual model.

The population of survivors following diagnosis and treatment for medulloblastoma is thankfully on the rise. An increased focus on the quality of that survivorship has expanded the concept of cure to include efforts aimed at improving long-term cognitive outcome. It is well established in the literature that decline in overall intellect and academic performance is experienced by a majority of those undergoing treatment for pediatric medulloblastoma. This decline is believed to be secondary to decline in core cognitive abilities, which in turn are related to underlying damage to neuroanatomical substrates. A review of research on neurodevelopmental impacts following diagnosis and treatment for pediatric medulloblastoma is presented. Particular consideration is given to studies recently published that also reflect critical collaboration among those within the fields of neuropsychology and neuro-imaging. Results from the review are combined within a conceptual model upon which to guide future research and clinical efforts.

Brief report: sluggish cognitive tempo among pediatric survivors of acute lymphoblastic leukemia.

OBJECTIVE: The purpose of the present study was to assess sluggish cognitive tempo (SCT) behavioral symptoms among pediatric survivors of acute lymphoblastic leukemia (ALL) and to determine the relationship of these behaviors with cognitive late effects. METHODS: ALL survivors (n = 80) and a sibling control group (n = 19) were administered intelligence (IQ) testing, achievement testing and SCT behavioral items. Group differences (patients vs. siblings) were examined on the SCT behaviors and partial correlations were conducted to explore the relationship of the SCT behaviors with IQ and achievement, while controlling for age at treatment and time since treatment. RESULTS: ALL survivors exhibited significantly more SCT symptoms than the sibling control group and increased SCT symptoms were associated with lower IQ and achievement scores. CONCLUSIONS: ALL survivors are vulnerable to SCT symptoms and these behaviors are associated with cognitive late effects. SCT symptoms may represent a behavioral component of cognitive late effects.

Understanding the cognitive impact on children who are treated for medulloblastoma.

OBJECTIVE: Risk-adapted treatment approaches employed within contemporary medulloblastoma treatment protocols aim to reduce the neurotoxicity directed at the central nervous system. Despite these important steps to reduce radiation dose exposure, an overwhelming majority of medulloblastoma survivors continue to experience academic failure and significant learning delays. METHODS: A review of the current literature is presented. RESULTS: Deficits in intellectual function, academic achievement, memory, attention, and processing speed are reported. Finally, intervention programs, including pharmacotherapy and experimental cognitive intervention studies, are discussed. A review of neuroimaging studies shows changes in brain tissue following chemotherapy and radiation treatment. CONCLUSIONS: Declining IQ and academic struggles may be predated by difficulties with attention, memory, and processing speed. More clinical trials directed at treating and preventing neurocognitive late effects through cognitive rehabilitation are needed.

Early patterns of verbal memory impairment in children treated for medulloblastoma.

Children treated for medulloblastoma demonstrate a variety of cognitive deficits in addition to white matter and hippocampal neuropathology. This study examined 40 children treated for medulloblastoma as compared with 40 demographically matched controls on the California Verbal Learning Test-Children's Version (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1994). Results revealed significantly poorer performance on indices of word recall in the patient group as compared with the controls in addition to milder but still significantly poorer recognition memory. These findings suggest that children treated for medulloblastoma demonstrate a mixed profile of memory impairment consisting of both retrieval and recognition deficits. Implications of these findings for understanding neurobehavioral sequelae within pediatric medulloblastoma populations and for designing educational and remediation strategies to be used with these children are discussed.