Patients with L-2-hydroxyglutaric aciduria are at risk for developing cerebral neoplasms, particularly gliomas, as one of the optical isomers of the known oncometabolite, 2-hydroxyglutarate is produced in L-2-hydroxyglutaric aciduria. To illustrate the concept of sustained oncogenic potential in permanent exposure to L-2-hydroxyglutarate in brain tissue, we present the medical history of a patient with L-2-hydroxyglutaric aciduria who underwent surgery to remove a right temporal anaplastic astrocytoma and developed an anatomically distinct, but histopathologically similar, tumor in the left frontal region 40 months later. This is the first reported case of successive distinct gliomas in a patient with L-2-hydroxyglutaric aciduria. While this implies a significant, cumulative lifetime risk for cerebral neoplasms in patients with this rare organic aciduria, it also allows further insight into a unique mechanism of tumorigenesis in the brain.
L-2-hydroxyglutaric aciduria; cerebral neoplasm; magnetic resonance imaging; positron emission tomography; IDH1 mutation
High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors.
Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations ([MTX]) were collected. Delayed plasma excretion was defined as [MTX] ≥1μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until [MTX] <0.1μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling.
Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m2 (41.1 CV%) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (p<0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity.
Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than one year may need additional monitoring to avoid toxicity.
Methotrexate; Pharmacokinetics; Pseudocyst; Toxicity; Cerebrospinal Fluid
Background and Purpose
Hyperintense FLAIR signal in the cerebral sulci (SSI) of anesthetized children is attributed to supplemental oxygen (FiO2), but resembles FLAIR hypersignal associated with perfusion abnormalities in Moyamoya and carotid stenosis. We investigated whether cerebral perfusion, known to be altered by anesthesia, contributes to diffuse SSI in children, and explored the relative contributions of supplemental oxygen, cerebral perfusion and anesthesia to SSI.
Supraventricular SSI on pre- and post-contrast T2-FLAIR images of 24 propofol-sedated (6.20 ± 3.28 years) breathing supplemental oxygen and 18 non-sedated (14.28 ±2.08 years) children breathing room air was graded from 0 to 3. Spearman correlation of SSI with FiO2 and age in 42 subjects, and with DSC measures of cortical CBF, CBV and MTT available in 25 subjects, were evaluated overall and compared between subgroups. Factors most influential on SSI were identified by stepwise logistic regression.
CBV was more influential on non-contrast FLAIR SSI than FiO2 or age in propofol-sedated children (CBV: r=0.612, p=0.026; FiO2: r=−0.418, p=0.042; Age: r=0.523, p=0.009) and overall (CBV: r=0.671, p=0.0002; FiO2: r=0.442, p=0.003; Age: r=−0.374, p=0.015); MTT (CBV/CBF) was influential in the overall cohort (r=0.461, p=0.020). SSI increased with contrast in 45% of subjects, decreased in none, and was greater (p<0.0001) in younger propofol-sedated subjects, in whom SSI increased with age post-contrast (r=0.600, p=0.002).
Elevated cortical CBV appears to contribute to increased SSI on non-contrast FLAIR in propofol-sedated children. Effects of propofol on age-related cerebral perfusion and vascular permeability may play a role.
In diffuse intrinsic pontine gliomas (DIPG), subtracting precontrast from postcontrast T1-weighted images (T1WI) occasionally reveals subtle, “occult” enhancement. We hypothesized that this represents intravascular enhancement related to angiogenesis and hence that these tumors should have greater blood volume fractions than do non-enhancing tumors.
We retrospectively screened MR images of 66 patients initially diagnosed with DIPG and analyzed pretreatment conventional and dynamic susceptibility contrast (DSC) perfusion-MRI studies of 61.patients. To determine the incidence of occult enhancement, cerebral blood volume values were compared in areas of occult enhancement (OcE), no enhancement (NE), and normal-appearing deep cerebellar white matter (DCWM).
Tumors of 10 patients (16.4%) had occult enhancement; those of 6 patients (9.8%) had no enhancement at all. The average cerebral blood volume in areas of occult enhancement was significantly higher than that in non-enhancing areas of the same tumor (P=.03), within DCWM in the same patient (P=.03), and when compared to anatomically paired/similar regions of interest (ROI)s in patients with non-enhancing tumors (P=.005).
Areas of OcE correspond to areas of higher CBV in DIPG, which may be an MRI marker for angiogenesis,, but larger scale studies may be needed to determine its potential relevance to grading by imaging, treatment stratification, biopsy guidance, and evaluation of response to targeted therapy.
diffuse intrinsic pontine glioma; perfusion imaging; cerebral blood volume; magnetic resonance imaging
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.
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.
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.
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.
Survivors of Childhood Cancer; Cranial Radiation Therapy; Subsequent Intracranial Neoplasms; Meningiomas
Diffuse intrinsic pontine glioma (DIPG) is the deadliest central nervous system tumor in children. The survival of affected children has remained poor despite treatment with radiation therapy (RT) with or without chemotherapy. We reviewed the medical records of all surviving patients with DIPG treated at our institution between October 1, 1992 and May 31, 2011. Blinded central radiologic review of the magnetic resonance imaging at diagnosis of all surviving patients and 15 controls with DIPG was performed. All surviving patients underwent neurocognitive assessment during follow-up. Five (2.6%) of 191 patients treated during the study period were surviving at a median of 9.3 years from their diagnosis (range, 5.3 to 13.2 years). Two patients were younger than 3 years, one lacked signs of pontine cranial nerve involvement, and three had longer duration of symptoms at diagnosis. One patient had a radiologically atypical tumor and one had a tumor originating in the medulla. All five patients received RT. Chemotherapy was variable among these patients. Neurocognitive assessments were obtained after a median interval of 7.1 years. Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. Two patients experienced disease progression at 8.8 and 13 years after diagnosis. A minority of children with DIPG experienced long-term survival with currently available therapies. These patients remained at high risk for tumor progression even after long follow-ups. Four of our long-term survivors had clinical and radiologic characteristics at diagnosis associated with improved outcome.
diffuse; glioma; long-term; neurocognitive; pontine; survivors
The effects of anesthesia are infrequently considered when interpreting pediatric perfusion MRI. The objectives of this study were to test for measurable differences in MR measures of cerebral blood flow (CBF) and cerebral blood volume (CBV) between non-sedated and propofol-sedated children, and to identify influential factors.
Supratentorial cortical CBF and CBV measured by dynamic susceptibility contrast perfusion MRI in 37 children (1.8–18 years) treated for infratentorial brain tumors receiving propofol (IV, n=19) or no sedation (NS, n=18) were compared between groups and correlated with age, hematocrit, end-tidal CO2 (ETCO2), dose, weight, and history of radiation therapy (RT). The model most predictive of CBF and CBV was identified by multiple linear regression.
Anterior cerebral artery (ACA) and middle cerebral artery (MCA) territory CBF were significantly lower, and MCA territory CBV greater (p=0.03), in IV than NS patients (p=0.01, 0.04). The usual trend of decreasing CBF with age was reversed with propofol in ACA and MCA territories (r=0.53, r=0.47; p<0.05). ACA and MCA CBF (r=0.59, 0.49; p<0.05) and CBV in ACA, MCA and posterior cerebral artery (PCA) territories (r=0.73, 0.80, 0.52; p<0.05) increased with weight in propofol-sedated children, with no significant additional influence from age, ETCO2, hematocrit, or RT.
In propofol-sedated children, usual age-related decreases in CBF were reversed, and increases in CBF and CBV were weight-dependent, not previously described. Weight-dependent increases in propofol clearance may diminish suppression of CBF and CBV. Prospective study is required to establish anesthetic-specific models of CBF and CBV in children.
magnetic resonance imaging; propofol; perfusion; pediatrics; brain
PT promises to reduce side effects in children with brain tumors by sparing normal tissue when compared to 3-dimensional conformal or intensity-modulated radiation therapy. Information is lacking about the combined effects of PT and chemotherapy in young children. We describe imaging changes in eight very young children with localized brain tumors who received PT after chemotherapy. Mostly transient signal abnormalities and enhancement in brain parenchyma were observed by serial MR imaging that were consistent with radiation-induced effects on normal appearing tissue. Correlation with PT planning data revealed that the areas of imaging abnormality were located within or adjacent to the volume that received the highest radiation dose. Radiologists should be aware of these findings in children who receive PT after chemotherapy. In this report we describe the time course of these PT-related imaging findings and correlate with treatment and clinical outcomes.
Medulloblastoma, the most common pediatric malignant brain tumor often arises sporadically; however, in a subgroup of patients, there exist familial conditions such as Fanconi anemia with biallelic BRCA2 mutation that predispose patients to developing medulloblastoma. Biallelic inactivation of BRCA2 in Fanconi anemia has been previously described in only 11 patients with medulloblastoma in the literature to date. Here we report two siblings diagnosed with central nervous system embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of a spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred.
Brain tumor; Primitive Neuroectodermal tumor; Medulloblastoma; Fanconi Anemia; BRCA2 gene mutation
Medullomyoblastoma is a rare variant of medulloblastoma, a member of the family of central nervous system (CNS) embryonal tumors. The outcome of standard therapy for CNS embryonal tumors is often unpredictable in the setting of medullomyoblastoma. Here, we present the clinical course and treatment of an almost 4-year-old girl with medullomyoblastoma that was characterized by MYC amplification, isochromosome 17q and large cell/anaplastic histopathology.
medullomyoblastoma; MYC amplification; isochromosome 17q; central nervous system embryonal tumors
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.
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.
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.
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.
thalamopeduncular astrocytoma; juvenile pilocytic astrocytoma; diffusion tensor imaging; tractography; pediatric neurosurgery; congenital
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 temporal-occipital 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.
diffusion tensor imaging; reading; pediatric brain tumors
We report MRI findings from 2 pediatric clinical trials of diffuse intrinsic brainstem glioma (BSG) incorporating concurrent radiation therapy (RT) with molecularly targeted agents (gefitinib and tipifarnib). We determined associations of MRI variables with progression-free survival and overall survival and investigated effects of treatment on these variables.
MRI (including diffusion and perfusion) was done before treatment, every 8 weeks (first year), every 12 weeks (thereafter), and at the end of treatment or disease progression. Reduced tumor volume (P < .0001) and tumor diffusion values (P <.0001) were apparent on the first post-RT/drug studies. Decreases in tumor volume correlated with pre-RT volume (P < .0001) and pre-RT diffusion values (P < .0001); larger decreases were noted for tumors with higher volumes and diffusion values. Patients with larger pre-RT tumors had longer progression-free survival (P < .0001). Patients with ≥25% decrease in tumor volume and diffusion values after RT had longer progression-free survival (P = .028) and overall survival (P = .0009). Enhancement at baseline and over time was significantly associated with shorter survival. Tumor diffusion values with baseline enhancement were significantly lower than those without (P = .0002).
RT of BSG is associated with decreased tumor volume and intralesional diffusion values; patients with ≥25% decrease in values post-RT had relatively longer survival intervals, apparently providing an early imaging-based surrogate for relative outcomes. Patients with larger tumors and greater decreases in tumor volume and diffusion values had longer survival intervals. Tumor enhancement was associated with shorter survival, lower tumor diffusion values (increased cellularity), and a smaller drop in diffusion values after RT (P = .006). These associations justify continued investigation in other large clinical trials of brainstem glioma patients.
Pediatric; brain tumor; brainstem glioma; MRI, radiation
Trilateral retinoblastoma is characterized by the presence of retinoblastoma with an intracranial tumor. The incidence is low and prognosis poor. Due to the paucity of information regarding successful treatment, we report the case of a 6 month old female referred for leukocoria and found to have an associated suprasellar tumor and pineal enhancement. The patient, treated with standard infant brain tumor therapy, remains alive without signs of active disease 35 months after diagnosis; no surgery or irradiation was used. Early diagnosis of trilateral retinoblastoma may facilitate the use of less intensive therapeutic approaches and result in excellent outcomes in these patients.
chemotherapy; pineal tumor; quadrilateral retinoblastoma; suprasellar tumor; trilateral retinoblastoma
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor1–4. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype)3–8. The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype)1,3,4, arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.
We report the case of a 6 year old male who was referred to a tertiary oncology center with a focal brainstem lesion which was presumed to be neoplastic. Due to the symmetric nature of the lesion on magnetic resonance imaging, the evaluation was expanded to investigate other possible causes and eventual diagnosis of Alexander’s disease was made. Alexander disease is a neurodegenerative disease which must be included in the differential for tumor-like lesions within the posterior fossa.
Brainstem glioma; Alexander’s disease; brain tumor mimic; neuro-oncology
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.
posterior fossa; cerebellum; mutism; medulloblastoma
Two patients with extra-axial cavernous hemangioma who presented with headache and oculovisual disturbances were investigated with computed tomography and magnetic resonance imaging. The lesions masqueraded as basal meningioma, but this diagnosis was not supported by magnetic resonance spectroscopy in one patient. Cerebral angiography with embolization was indicated in one patient, but embolization was not justified in the other. Both patients underwent a pterional craniotomy. The lesions were extradural and highly vascular, necessitating excessive transfusion in one patient in whom gross total resection was achieved, and precluding satisfactory removal in the other. There was no mortality. Transient ophthalmoplegia, the only complication in one patient, was due to surgical manipulation of the cavernous sinus; it resolved progressively over 3 months. Extra-axial skull base cavernous hemangiomas are distinct entities with clinical and radiological characteristics that differ from those of intraparenchymal cavernous malformations. They can mimic meningiomas or pituitary tumors. In some cases, magnetic resonance spectroscopy may narrow the differential diagnoses. Surgical resection remains the treatment of choice, facilitated by preoperative embolization to reduce intraoperative bleeding and by the application of the principles of skull base surgery. Fractionated radiotherapy is an alternative in partial or difficult resections and in high-risk and elderly patients.
Cavernous hemangioma; magnetic resonance spectroscopy; skull base surgery
Aneurysmal bone cyst is a bening, non-neoplastic lesion that present most frequently under the age of 20 years. The metaphysis of long bones is the usual site of origin. The involvement of the skull is rare. In the 2.5 to 6% of such cases reported in the literature, the skull vault is more often the site than the skull base. Three cases of aneurysmal bone cyst involving the skull base have been managed at King Faisal Specialist Hospital and Research Center. Two females and one male, all 10 years of age and younger, presented with a painless, progressive swelling. The preoperative radiological studies showed characteristic findings and were highly suggestive of the diagnosis. Angiography also gave characteristic findings. Preoperative endovascular embolization of the arterial feeders to the tumor was performed in two patients who had a significant decrease in intraoperative bleeding from the tumor. All cases underwent surgical excision with a good outcome.