Predictors of cognitive function in pediatric brain tumor patients: Pre-surgery through 24-month follow-up.

The aim of this study was to examine the feasibility of cognitive assessment from pre-surgery through 2-year follow-up in a sample of pediatric brain tumor (BT) patients. We sought to investigate cognitive function over the course of diagnosis and treatment, and as a function of presenting problems, tumor location, treatment type, and tumor severity. Using a prospective, longitudinal design, standardized IQ measures were administered to pediatric BT patients (ages 6-16) prior to surgery (n = 25), 6 months post-diagnosis (n = 24), and 24 months post-diagnosis (n = 23). Group differences emerged based on tumor severity and treatment type at multiple time points, including prior to surgical intervention; children with high grade tumors performed more poorly than children with low grade tumors, and children receiving surgery plus adjuvant therapy performed more poorly than children who received surgery only. When considered together, an analysis of covariance demonstrated that tumor grade significantly accounted for variability in cognitive functioning, while treatment type did not. Although there is overlap clinically between tumor severity and treatment received, results suggest that tumor severity is an important factor contributing to variability in cognitive functioning and should also be considered when monitoring risk for cognitive deficits in children diagnosed with BT.

Associations among diffusion tensor imaging and neurocognitive function in survivors of pediatric brain tumor: A pilot study.

The purpose of this study was to determine associations among neurocognitive outcomes and white matter integrity in the inferior fronto-occipital fasciculus (IFOF), uncinate fasciculus (UF), and genu of the corpus callosum (gCC) in survivors of pediatric brain tumor and healthy controls (HCs). Eleven survivors (ages 8-16; >2 years post-treatment) and 14 HCs underwent MRI; diffusion tensor imaging tractography (DSI Studio) was used to assess white matter integrity. Participants completed neuropsychological assessment of overall cognitive ability, executive function, processing speed, divided attention, and memory. As previously reported, survivors performed significantly worse than HCs on measures of overall IQ, working memory, processing speed, and executive function (ps < .01), but not on measures of long-delay memory. Mean fractional anisotropy was significantly lower in survivors than HC in the right IFOF, left UF, and gCC (ps < .05). Correlations with the total sample revealed a number of significant positive associations among white matter tracts and scores on neurocognitive measures. Survivors show deficits on measures of cognitive function and decreased white matter integrity compared to HCs. Results revealed a more general pattern of associations among white matter pathways and neurocognitive outcomes than initially hypothesized. It is possible that survivors with diffuse pathology from treatment effects (i.e., hydrocephalus or posterior fossa syndrome) show more general decreases in cognitive functioning and white matter integrity. Additional research with a larger and more diverse group of survivors is needed to better understand white matter integrity and neurocognitive outcome associations in this population.

Fronto-limbic white matter microstructure, behavior, and emotion regulation in survivors of pediatric brain tumor.

PURPOSE: After treatment, pediatric brain tumor survivors (PBTS) face emotional and behavioral challenges, perhaps due to tumor or treatment-related changes in brain structures involved in emotion regulation, including those with fronto-limbic connections. We hypothesized that relative to healthy controls (HCs), PBTS would exhibit greater difficulties with behavior and emotional functioning, and display reduced mean fractional anisotropy (mFA) in white matter tracts with fronto-limbic connections including the cingulum bundle (CB), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus (UF). We further predicted that mFA would account for variance in the relationship between group and emotional/behavioral outcome. METHODS: Eleven 8-16 year old PBTS and 14 HCs underwent MRI, including diffusion tensor imaging to assess white matter microstructure. Tractography quantified mFA of selected tracts. Parents rated children's emotional and behavioral functioning. RESULTS: Compared to HCs, caregivers of PBTS reported poorer behavioral regulation and greater internalizing and externalizing symptoms. Relative to HCs, PBTS had lower mFA within the bilateral CB, IFOF, and UF (ds = 0.59-1.15). Across groups, several medium-to-large correlations linked tract mFA and increased internalizing, externalizing, and poor behavioral regulation. Tract mFA also accounted for significant variance in the group-outcome association. CONCLUSIONS: Reduced mFA in fronto-limbic associated tracts may be associated with reduced behavioral regulation following pediatric brain tumor. PBTS with treatment known to impact white matter may be most susceptible. Research with larger, longitudinal samples should clarify this relationship, allow for multiple mediators across time, and consider factors like tumor and treatment type.

Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex.

Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very frequent phenotype of epilepsy. We hypothesized that aberrant expression of the astrocyte protein aquaporin-4 (AQP4) may be present in TSC and contribute to disease pathology. Characterization of AQP4 expression in epileptic cortex from TSC patients demonstrated a diffuse increase in AQP4. To determine if this was due to exposure to seizures, we examined Aqp4 expression in mouse models of TSC in which Tsc1 or Tsc2 inactivation was targeted to astrocytes or glial progenitors, respectively. Loss of either Tsc1 or Tsc2 from astrocytes resulted in a marked increase in Aqp4 expression which was sensitive to mTORC1 inhibition with rapamycin. Our findings in both TSC epileptogenic cortex and in a variety of astrocyte culture models demonstrate for the first time that AQP4 expression is dysregulated in TSC. The extent to which AQP4 contributes to epilepsy in TSC is not known, though the similarities in AQP4 expression between TSC and temporal lobe epilepsy supports further studies targeting AQP4 in TSC.

Functional neuroimaging of working memory in survivors of childhood brain tumors and healthy children: Associations with coping and psychosocial outcomes.

PURPOSE: Pediatric brain tumors are the second most common cancer diagnosis in individuals under age 20 and research has documented significant neurocognitive, psychosocial, and emotional late effects. Associations among these deficits have not been adequately considered and the role of survivors' coping with stress in relation to deficits is unknown. Further, research has yet to examine neurobiological processes related to neurocognitive, psychosocial, and emotional difficulties in survivors through the use of functional neuroimaging. METHOD: Questionnaire measures and functional neuroimaging were used to examine the neurocognitive, psychosocial, and emotional functioning and coping responses of survivors of pediatric brain tumors (N = 17; age 8-16) and healthy children (N = 15). RESULTS: Survivors experienced elevated levels of psychosocial and behavioral/emotional difficulties relative to healthy controls and normative data. Increases in brain activation in prefrontal and other anterior regions in response to a working memory task were associated with better psychosocial functioning, use of engagement coping strategies, and less use of disengagement coping strategies. Regression analyses suggest coping accounts for a significant portion of the association between brain activation and behavioral/emotional functioning. CONCLUSIONS: This study extends late-effects research by examining neurobiological processes associated with psychosocial and emotional difficulties. These findings contribute to our understanding of difficulties in survivors and provide a foundation for research exploring these associations and mediators of deficits in future longitudinal studies.

Neuroimaging of executive function in survivors of pediatric brain tumors and healthy controls.

OBJECTIVE: Research on the long-term sequelae of treatment for pediatric brain tumors has identified significant neurocognitive deficits experienced by many survivors. Despite indications of deficits based on cognitive assessment, the identification of specific neurobiological mechanisms of these deficits using neuroimaging techniques has yet to be considered. METHOD: This study used norm-referenced standardized assessment and functional MRI (fMRI) to examine attention and executive functioning deficits of survivors of pediatric brain tumors, as compared with healthy children. RESULTS: Survivors of pediatric brain tumors performed more poorly than healthy children on measures of overall cognitive ability, attention, and executive function during testing, as well as on a working memory task during fMRI. Survivors showed lower blood-oxygen level dependent (BOLD) signal in bilateral frontal regions associated with sustained attention (BA6/8) and greater BOLD signal in left cingulate regions associated with complex problem-solving and performance monitoring (BA32) during working memory task completion. Both group and brain activation accounted for significant variance in neurocognitive functioning. CONCLUSIONS: Survivors of pediatric brain tumor and healthy children differed in brain activation during completion of a working memory task, and brain activation was associated with deficits noted in testing. These findings may improve understanding of mechanisms of cognitive deficits and avenues for intervention for children with brain tumors.

Endoscopic removal of an intraventricular primitive neuroectodermal tumor: retrieval of a free-floating fragment using a urological basket retriever.

The endoscopic resection of intraventricular tumors represents a unique challenge to the neurological surgeon. These neoplasms are invested deep within the brain parenchyma and are situated among neurologically vital structures. Additionally, the cerebrospinal fluid system presents a dynamic pathway for resected tumors to be mobilized and entrapped in other regions of the brain. In 2011, the authors treated a 3-year-old girl with a third ventricular mass identified on stereotactic brain biopsy as a WHO Grade IV CNS primitive neuroectodermal tumor. After successful neoadjuvant chemotherapy, endoscopic resection was performed. Despite successful resection of the tumor, the operation was complicated by mobilization of the resected tumor and entrapment in the atrial horn of the lateral ventricle. Using a urological stone basket retriever, the authors were able to retrieve the intact tumor without additional complications. The flexibility afforded by the nitinol urological stone basket was useful in the endoscopic removal of a free-floating intraventricular tumor. This device may prove to be useful for other practitioners performing these complicated intraventricular resections.

Neurocognitive late effects of pediatric brain tumors of the posterior fossa: a quantitative review.

Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors; however, a quantitative analysis of the magnitude of these deficits in survivors of brain tumors of the posterior fossa has not been conducted. Despite tumor locations in the posterior regions of the brain, individual studies have documented deficits in a variety of domains, reflective of impairment in other brain regions. The current study provides a comprehensive meta-analysis of literature on neurocognitive late effects found in survivors of posterior fossa tumors. Results indicated significant deficits in both specific and broad indices of neurocognitive functioning, and the overall magnitude of effects across domains ranged from medium to large (g = -0.62 to -1.69) with a large mean overall effect size (g = -1.03). Moderator analyses indicated significantly greater effects for survivors diagnosed at a younger age and those who received radiation therapy. These findings underscore the importance of monitoring neurocognitive late effects in survivors of pediatric brain tumors of the posterior fossa, as well as the need for more consistent consideration of demographic, diagnostic, and treatment-related variables to allow for examination of factors that moderate these deficits.

Findings on preoperative brain MRI predict histopathology in children with cerebellar neoplasms.

BACKGROUND/AIMS: The majority of pediatric patients with cerebellar neoplasms harbor pilocytic astrocytomas (PAs), medulloblastomas, or ependymomas. Knowledge of a preoperative likelihood of histopathology in this group of patients has the potential to influence many aspects of care. Previous studies have demonstrated hyperintensity on diffusion-weighted imaging to correlate with medulloblastomas. Recently, measurement of T(2)-weighted signal intensity (T2SI) was shown to be useful in identification of low-grade cerebellar neoplasms. The goal of this study was to assess whether objective findings on these MRI sequences reliably correlated with the underlying histopathology. METHODS: We reviewed the radiologic findings of 50 pediatric patients who underwent resection of a cerebellar neoplasm since 2003 at our institution. Region of interest placement was used to calculate the relative diffusion-weighted signal intensity (rDWSI) and relative T2SI (rT2SI) of each neoplasm. RESULTS: Tukey's multiple comparison test demonstrated medulloblastomas to have significantly higher rDWSIs than PAs/ependymomas, and PAs to have significantly higher rT2SIs than medulloblastomas/ependymomas. A simple method consisting of sequential measurement of rDWSI and rT2SI to predict histopathology was then constructed. Using this method, 39 of 50 (78%) tumors were accurately predicted. CONCLUSION: Measurement of rDWSI and rT2SI using standard MRI of the brain can be used to predict histopathology with favorable accuracy in pediatric patients with cerebellar tumors.

Pediatric cerebellar pilomyxoid-spectrum astrocytomas.

OBJECT: Pediatric cerebellar astrocytomas with pilomyxoid features include classic pilomyxoid astrocytomas (PMAs) and intermediate pilomyxoid tumors (IPTs). Since the original description of PMA in 1999, most reports in the literature have described PMAs arising from the hypothalamic/chiasmatic region. To the authors' knowledge, PMAs arising from the posterior fossa have not been discussed in the neurosurgical literature. Intermediate pilomyxoid tumors, or tumors with pathological features of both pilocytic astrocytoma (PA) and PMA, have only recently been described. In this article, the authors present 2 cases that fall within the spectrum of pediatric cerebellar PMA-including a classic PMA and an intermediate pilomyxoid tumor. The authors compare the radiological presentation, surgical results, and postoperative course to findings in a cohort of 15 patients with cerebellar PAs. METHODS: Between 2003 and 2010, 2 patients with pilomyxoid-spectrum astrocytomas underwent treatment at Vanderbilt Children's Hospital. One was a 22-month-old girl who presented with progressive gait disturbance and falls. The other was a 4-year-old girl who presented with ataxia and generalized weakness. In a retrospective review of pediatric cerebellar neoplasms resected by the senior author during this period, these tumors comprised 4% of cerebellar neoplasms and approximately 10% of cerebellar glial neoplasms. RESULTS: Both patients were treated with midline suboccipital craniotomy for resection. In both cases, tumor invasion anteriorly into the brainstem prevented gross-total resection. the patient in Case 1 was placed on chemotherapy following pathological diagnosis and later developed definitive evidence of leptomeningeal dissemination (LD) 3 years after the operation. The patient in Case 2 was placed on chemotherapy after exhibiting progressive evidence of local recurrence (findings were negative for LD) 12 months following resection. CONCLUSIONS: Pediatric patients with cerebellar pilomyxoid-spectrum astrocytomas appear to suffer higher rates of local recurrence and LD than pediatric patients with cerebellar PAs.

Use of T2 signal intensity of cerebellar neoplasms in pediatric patients to guide preoperative staging of the neuraxis.

OBJECT: The question of whether to obtain routine or selective preoperative imaging of the neuraxis in pediatric patients with cerebellar neoplasms remains a controversial topic. Staging of the neuraxis is generally considered beneficial in patients with neoplasms associated with an elevated risk of leptomeningeal dissemination (LD). When these studies are obtained preoperatively, there is a decrease in the number of false-positive images related to debris in the immediate postoperative period. Additionally, knowledge of the extent of spread has the potential to affect the risk/benefit analysis of aggressive resection. Although the majority of pediatric neurosurgeons surveyed choose to obtain selective preoperative imaging of the neuraxis in cases of cerebellar neoplasms "with findings suggestive of high-grade pathology," an evidence-based protocol in the literature is lacking. The goal of this study was to assess radiological characteristics of tumors with an elevated risk of LD and identify a method to help guide preoperative imaging of the neuraxis. METHODS: The authors first reviewed the literature to gain an appreciation of the risk of LD of pediatric cerebellar neoplasms based on underlying histopathology and/or grade. Available evidence indicates preoperative imaging of the neuraxis in patients with Grade I tumors to be of questionable utility. In contrast, evidence suggested that preoperative imaging of the neuraxis in patients with Grades II-IV neoplasms was clinically warranted. The authors then evaluated an extensive base of neuroradiological literature to identify possible MR imaging and/or CT findings with the potential to differentiate Grade I from higher-grade neoplasms in pediatric patients. They analyzed the preoperative radiological findings in 50 pediatric patients who had undergone craniotomy for resection of cerebellar neoplasms at Vanderbilt Children's Hospital since 2003 with reference to 7 chosen radiological criteria. Logistic regression models were fit using radiological features to determine the best predictors of Grades II-IV tumors. Receiver operating characteristic methods were used to identify diagnostic properties of the best predictors. RESULTS: The relative T2 signal intensity (RT2SI), an indirect measure of the water content of the solid component of the tumor, was best able to identify neoplasms with an elevated risk of LD. An RT2SI value of 0.71 was selected by the authors as the best operating point on the curve. Of the 31 neoplasms retrospectively designated as hypointense T2-weighted lesions (RT2SI ≤ 0.71), 30 (97%) were Grade II or higher. All medulloblastomas, ependymomas, and high-grade (Grades III and IV) neoplasms were hypointense T2-weighted lesions. Of the 19 T2-weighted hyperintense neoplasms (RT2SI > 0.71), 16 (84%) were Grade I and 3 were Grade II. CONCLUSIONS: Measurement of the RT2SI can help predict Grade II-IV tumors at an elevated risk of leptomeningeal spread and guide staging of the neuraxis. Pediatric patients with cerebellar neoplasms found to have an RT2SI of less than or equal to 0.71 are recommended for neuraxis imaging prior to surgery.

Intramedullary spinal immature teratoma: resolution of quadriplegia following resection in a 4-week-old infant.

Intramedullary spinal cord teratomas are rare entities in infants. Management of these lesions is primarily surgical, with outcome dependent on rapid surgical decompression and complete gross-total tumor resection. The lesions are typically of the mature type, with immature teratomas displaying unique pathological features. The authors report a case of an extensive intramedullary immature teratoma in an infant with resolution of quadriplegia following gross-total radical resection. At the 1-year follow-up, there was radiographic evidence of tumor, and surgical reexploration yielded portions of immature teratoma and extensive gliosis.

Active spontaneous decompression of a suprasellar-prepontine arachnoid cyst detected with routine magnetic resonance imaging. Case report.

Arachnoid cysts are congenital CSF collections that arise adjacent to arachnoid cisterns. These lesions can be incidental neuroimaging findings but may also cause symptoms and necessitate treatment, particularly in children. The authors present their experience with a male infant harboring a large suprasellar-prepontine arachnoid cyst who underwent spontaneous decompression into the ventricular system, as evidenced by a visualized CSF flow jet observed on routine MR imaging.