Evaluation of the Implementation of the Response Assessment in Neuro-Oncology Criteria in the HERBY Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas.

BACKGROUND AND PURPOSE: HERBY was a Phase II multicenter trial setup to establish the efficacy and safety of adding bevacizumab to radiation therapy and temozolomide in pediatric patients with newly diagnosed non-brain stem high-grade gliomas. This study evaluates the implementation of the radiologic aspects of HERBY. MATERIALS AND METHODS: We analyzed multimodal imaging compliance rates and scan quality for participating sites, adjudication rates and reading times for the central review process, the influence of different Response Assessment in Neuro-Oncology criteria in the final response, the incidence of pseudoprogression, and the benefit of incorporating multimodal imaging into the decision process. RESULTS: Multimodal imaging compliance rates were the following: diffusion, 82%; perfusion, 60%; and spectroscopy, 48%. Neuroradiologists' responses differed for 50% of scans, requiring adjudication, with a total average reading time per patient of approximately 3 hours. Pseudoprogression occurred in 10/116 (9%) cases, 8 in the radiation therapy/temozolomide arm and 2 in the bevacizumab arm (P < .01). Increased target enhancing lesion diameter was a reason for progression in 8/86 cases (9.3%) but never the only radiologic or clinical reason. Event-free survival was predicted earlier in 5/86 (5.8%) patients by multimodal imaging (diffusion, n = 4; perfusion, n = 1). CONCLUSIONS: The addition of multimodal imaging to the response criteria modified the assessment in a small number of cases, determining progression earlier than structural imaging alone. Increased target lesion diameter, accounting for a large proportion of reading time, was never the only reason to designate disease progression.

Response Assessment in Pediatric Neuro-Oncology: Implementation and Expansion of the RANO Criteria in a Randomized Phase II Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas.

Determination of tumor response to treatment in neuro-oncology is challenging, particularly when antiangiogenic agents are considered. Nontumoral factors (eg, blood-brain barrier disruption, edema, and necrosis) can alter contrast enhancement independent of true tumor response/progression. Furthermore, gliomas are often infiltrative, with nonenhancing components. In adults, the Response Assessment in Neuro-Oncology (RANO) criteria attempted to address these issues. No such guidelines exist yet for children. The ongoing randomized phase II trial, A Study of Avastin (bevacizumab) in Combination With Temolozomide (TMZ) and Radiotherapy in Paediatric and Adolescent Patients With High-Grade Glioma (HERBY), will establish the efficacy and safety of the antiangiogenic agent bevacizumab for the first-line treatment of newly diagnosed high-grade glioma in children (n = 121 patients, enrollment complete). The primary end point is event-free survival (tumor progression/recurrence by central review, second primary malignancy, or death). Determination of progression or response is based on predefined clinical and radiographic criteria, modeled on the RANO criteria and supported by expert pseudoprogression review and the use of standardized imaging protocols. The HERBY trial will also compare conventional MR imaging (T1-weighted and T2/fluid-attenuated inversion recovery sequences) with conventional MR imaging plus diffusion/perfusion imaging for response assessment. It is anticipated that HERBY will provide new insights into antiangiogenic-treated pediatric brain tumors. HERBY will also investigate the practicality of obtaining adequate quality diffusion/perfusion scans in a trial setting, and the feasibility of implementing standard imaging protocols across multiple sites. To date, 61/73 (83.6%) patients with available data have completed diffusion-weighted imaging (uptake of other nonconventional techniques has been limited). Harmonization of imaging protocols and techniques may improve the robustness of pediatric neuro-oncology studies and aid future trial comparability.

Metrics and textural features of MRI diffusion to improve classification of pediatric posterior fossa tumors.

BACKGROUND AND PURPOSE: Qualitative radiologic MR imaging review affords limited differentiation among types of pediatric posterior fossa brain tumors and cannot detect histologic or molecular subtypes, which could help to stratify treatment. This study aimed to improve current posterior fossa discrimination of histologic tumor type by using support vector machine classifiers on quantitative MR imaging features. MATERIALS AND METHODS: This retrospective study included preoperative MRI in 40 children with posterior fossa tumors (17 medulloblastomas, 16 pilocytic astrocytomas, and 7 ependymomas). Shape, histogram, and textural features were computed from contrast-enhanced T2WI and T1WI and diffusivity (ADC) maps. Combinations of features were used to train tumor-type-specific classifiers for medulloblastoma, pilocytic astrocytoma, and ependymoma types in separation and as a joint posterior fossa classifier. A tumor-subtype classifier was also produced for classic medulloblastoma. The performance of different classifiers was assessed and compared by using randomly selected subsets of training and test data. RESULTS: ADC histogram features (25th and 75th percentiles and skewness) yielded the best classification of tumor type (on average >95.8% of medulloblastomas, >96.9% of pilocytic astrocytomas, and >94.3% of ependymomas by using 8 training samples). The resulting joint posterior fossa classifier correctly assigned >91.4% of the posterior fossa tumors. For subtype classification, 89.4% of classic medulloblastomas were correctly classified on the basis of ADC texture features extracted from the Gray-Level Co-Occurence Matrix. CONCLUSIONS: Support vector machine-based classifiers using ADC histogram features yielded very good discrimination among pediatric posterior fossa tumor types, and ADC textural features show promise for further subtype discrimination. These findings suggest an added diagnostic value of quantitative feature analysis of diffusion MR imaging in pediatric neuro-oncology.

Patterns of accidental craniocerebral injury occurring in early childhood.

OBJECTIVE: To describe the range of intracranial injuries encountered in 0-2-year-olds in cases of accidental head injury where the mechanism of trauma was well characterised and to assess the clinical consequences. DESIGN: A retrospective review of imaging and clinical data. SETTING: Two tertiary paediatric referral centres. PATIENTS: All children aged 0-2 undergoing cranial CT as indicated by National Institute for Health and Clinical Excellence guidance for head injury from 2006 to 2011. After exclusion criteria, 149 patients were included. MAIN OUTCOME MEASURES: Rates of skull fracture, intracranial haemorrhage, parenchymal injuries and ischaemic change per type of mechanism of injury. Rates of neurological sequelae on follow-up. RESULTS: Skull fractures were demonstrated in 54 (36%) patients of whom 17 (11%) had thin underlying subdural haemorrhage (SDH). Extradural haemorrhage complicated one fracture and two cases of isolated subdural haematomas were seen without skull fracture. Radiologically evident brain parenchymal injuries were present in three patients, all with mechanisms of injury involving high levels of force; severe neurological sequelae were only seen in one patient, who had diffuse hypoxic-ischaemic damage at presentation and whose (accidental) mechanism of injury involved extensive acceleration/deceleration/translational forces. CONCLUSIONS: Skull fractures and focal SDH are relatively common following minor trauma in this age group but in the vast majority of cases there are no long-term neurological sequelae. Conversely, diffuse brain injury with severe subsequent neurological impairment was only seen in patients with a correspondingly severe mechanism of injury.

Pattern of brain metastatic disease according to HER-2 and ER receptor status in breast cancer patients.

AIMS: To document the type, location, extent, and complications of brain metastases in patients with breast cancer and identify associations with oestrogen receptor (ER) negative and human epidermal growth factor receptor 2 (HER-2) receptor expression. MATERIALS AND METHODS: Breast cancer patients with known brain metastases were included in this retrospective study, if cross-sectional imaging of the brain [computed tomography (CT)] was available to review and HER-2 and ER status was known. Two neuroradiologists, who were blinded to the receptor status, separately and for each patient, documented on a proforma the location, number, and dimensions of the deposits and the presence or absence of hydrocephalus. Adjudication was sought where there was discrepancy between the two reports. ER status, HER-2 receptor status, and patient age were also documented. The results were analysed using two-sided Fisher's exact tests with Lancaster's mid-P correction and associations were sought between the tumour characteristics and the pattern of brain disease. RESULTS: Sixty patients were included in the study. There was an association between young age (<40 years) and HER-2 positivity [10 of 24 (41.7%) versus three of 36 (8.3%); p = 0.002]. In ER-negative women, HER-2 positivity was found to be associated with a larger number (six or more) of metastases [11 of 18 (61%) versus nine of 25 (36%); p = 0.049], more brain stem metastases [11 of 18 (61%) versus three of 26 (11.5%); p = 0.035], more frequent occurrence of hydrocephalus [7 of 12 (36.8%) versus three of 26 (11.5%); p = 0.049], and a higher incidence of occipital metastases [12 of 18 (66.7%) versus eight of 26 (30.8%); p = 0.029]. CONCLUSION: ER-negative HER-2-positive women are more likely to present with a larger number of lesions, more brain stem/occipital metastases, and hydrocephalus, which may predispose them to unfavourable outcomes following treatment.

(1)H magnetic resonance spectroscopy in the diagnosis of paediatric low grade brain tumours.

INTRODUCTION: Low grade gliomas are the commonest brain tumours in children but present in a myriad of ways, each with its own treatment challenges. Conventional MRI scans play an important role in their management but have limited ability to identify likely clinical behaviour. The aim of this study is to investigate (1)H magnetic resonance spectroscopy (MRS) as a method for detecting differences between the various low grade gliomas and related tumours in children. PATIENTS AND METHODS: Short echo time single voxel (1)H MRS at 1.5 or 3.0 T was performed prior to treatment on children with low grade brain tumours at two centres and five MR scanners, 69 cases had data which passed quality control. MRS data was processed using LCModel to give mean spectra and metabolite concentrations which were compared using T-tests, ANOVA, Receiver Operator Characteristic curves and logistic regression in SPSS. RESULTS: Significant differences were found in concentrations of key metabolites between glioneuronal and glial tumours (T-test p<0.05) and between most of the individual histological subtypes of low grade gliomas. The discriminatory metabolites identified, such as choline and myoinositol, are known tumour biomarkers. In the set of pilocytic astrocytomas and unbiopsied optic pathway gliomas, significant differences (p<0.05, ANOVA) were found in metabolite profiles of tumours depending on location and patient neurofibromatosis type 1 status. Logistic regression analyses yielded equations which could be used to assess the probability of a tumour being of a specific type. CONCLUSIONS: MRS can detect subtle differences between low grade brain tumours in children and should form part of the clinical assessment of these tumours.

The thoracic anterior spinal cord adhesion syndrome.

OBJECTIVES: This study included a series of middle-aged male and female patients who presented with chronic anterior hemicord dysfunction progressing to paraplegia. Imaging of anterior thoracic cord displacement by either a dural adhesion or a dural defect with associated cord herniation is presented. METHODS: This is a retrospective review of cases referred to a tertiary neuroscience centre over a 19-year period. Imaging series were classified by two experienced neuroradiologists against several criteria and correlated with clinical examination and/or findings at surgery. RESULTS: 16 cases were available for full review. Nine were considered to represent adhesions (four confirmed surgically) and four to represent true herniation (three confirmed surgically). In the three remaining cases the diagnosis was radiologically uncertain. CONCLUSION: The authors propose "thoracic anterior spinal cord adhesion syndrome" as a novel term to describe this patient cohort and suggest appropriate clinicoradiological features for diagnosis. Several possible aetiologies are also suggested, with disc rupture and inflammation followed by disc resorption and dural pocket formation being a possible mechanism predisposing to herniation at the extreme end of a clinicopathological spectrum.

Neuroimaging: what neuroradiological features distinguish abusive from non-abusive head trauma? A systematic review.

OBJECTIVES: To identify the evidence base behind the neuroradiological features that differentiate abusive head trauma (AHT) from non-abusive head trauma (nAHT). DESIGN: Systematic review. SETTING: Literature search of 14 databases, websites, textbooks, conference abstracts and references (1970-February 2010). Studies had two independent reviews (three if disputed) and critical appraisal. PATIENTS: Primary comparative studies of children <11 years old hospitalised with AHT and nAHT diagnosed on CT or MRI. MAIN OUTCOME MEASURES: Neuroradiological features that differentiated AHT from nAHT. RESULTS: 21 studies of children predominantly <3 years old were analysed. Subdural haemorrhages (SDH) were significantly associated with AHT (OR 8.2, 95% CI 6.1 to 11). Subarachnoid haemorrhages were seen equally in AHT and nAHT and extradural haemorrhages (EDH) were significantly associated with nAHT (OR for AHT 0.1, 95% CI 0.07 to 0.18). Multiple (OR 6, 95% CI 2.5 to 14.4), interhemispheric (OR 7.9, 95% CI 4.7 to 13), convexity (OR 4.9, 95% CI 1.3 to 19.4) and posterior fossa haemorrhages (OR 2.5, 95% CI 1 to 6) were associated with AHT. Hypoxic-ischaemic injury (HII) (OR 3.7, 95% CI 1.4 to 10) and cerebral oedema (OR 2.2, 95% CI 1.0 to 4.5) were significantly associated with AHT, while focal parenchymal injury was not a discriminatory feature. SDH of low attenuation were more common in AHT than in nAHT. CONCLUSION: Multiple SDH over the convexity, interhemispheric haemorrhages, posterior fossa SDH, HII and cerebral oedema are significantly associated with AHT and should be considered together with clinical features when identifying the condition.

Is there a causal relationship between the hypoxia-ischaemia associated with cardiorespiratory arrest and subdural haematomas? An observational study.

The aim of this study was to determine the frequency of subdural haematomas (SDHs) occurring in infants presenting following atraumatic cardiorespiratory collapse. This study was a review of retrospective case notes, brain imaging and post-mortem examinations carried out in the paediatric intensive care unit (PICU) and emergency department (ED) in a tertiary paediatric centre in the UK. The study included infants and children less than 4 years old dying in the ED or admitted to the PICU after atraumatic cardiorespiratory arrest. We identified macroscopic SDHs on brain imaging or post-mortem examination. Of those children who experienced a cardiorespiratory arrest from a non-traumatic cause and met inclusion criteria, 33 presented and died in the ED and 17 were admitted to the PICU. These children had a post-mortem examination, brain imaging or both. None of these infants had a significant SDH. One child had a small clot adherent to the dura found on post-mortem and two had microscopic intradural haemorrhage, but it is unclear in each case whether this was artefact, as each had otherwise normal brains. Subdural haematoma arising in infants or young children in the context of catastrophic cardiorespiratory compromise from a non-traumatic cause was not observed.

Relapsed intracranial ependymoma in children in the UK: patterns of relapse, survival and therapeutic outcome.

Relapsed ependymoma in children poses difficult dilemmas in management. Clinico-pathological and treatment data of 108 children with relapsed ependymoma in the United Kingdom (UK) treated between 1985 and 2002 were reviewed to identify prognostic factors affecting survival. The primary site was the most common site of relapse (84%). Overall 25% had metastatic relapse. Surgery at relapse was attempted in only 55%. Radiotherapy was delivered at relapse in 66% infants and 50% of older children were re-irradiated. Overall 5-year survival was 24% and 27% for children less than 3 years of age at initial diagnosis and older children, respectively. Multivariate analysis showed that, for infants, surgery (p=0.01) and radiotherapy (p=0.001) at relapse were independent predictors of survival. For older children regardless of the previous radiotherapy, repeat irradiation was associated with better outcome (p=0.05). Relapse was associated with poor outcome in both age groups. A survival advantage conferred by both radiotherapy and surgery at relapse is independently significant.

Isolated cerebral cortical tears in children: aetiology, characterisation and differentiation from non-accidental head injury.

A wide spectrum of intracranial injuries has been described as complicating difficult birth, particularly following instrumental delivery. We describe five children in whom isolated cortical tears were observed on MRI. Four cases were characterised by a difficult instrumental delivery. None of the children developed long-term neurological sequelae. As far as we are aware, isolated cerebral cortical tears have not been reported previously although recognition of this injury pattern is important because of its possible misinterpretation as a marker of a non-accidental head injury. Other differential diagnoses that should be considered include cerebral infarcts, schizencephaly and accidental head injury. The importance of high-quality cross-sectional brain imaging in newborn infants with seizures is emphasised.

What neuroimaging should be performed in children in whom inflicted brain injury (iBI) is suspected? A systematic review.

AIMS: To investigate the optimal neuroradiological investigation strategy to identify inflicted brain injury (iBI). MATERIALS AND METHODS: A systematic review of studies published between 1970-2008 in any language was conducted, searching 20 databases and four websites, using over 100 keywords/phrases, supplemented by hand-searching of references. All studies underwent two independent reviews (with disagreements adjudicated by a third reviewer) by trained reviewers from paediatrics, paediatric neuroradiology and related disciplines, using standardized critical appraisal tools, and strict inclusion/exclusion criteria. We included primary studies that evaluated the diagnostic yield of magnetic resonance imaging (MRI), in addition to initial computed tomography (CT), or follow-up CT or ultrasound in children with suspected iBI. RESULTS: Of the 320 studies reviewed, 18 met the inclusion criteria, reflecting data on 367 children with iBI and 12 were published since 1998. When an MRI was conducted in addition to an abnormal early CT examination, additional information was found in 25% (95% CI: 18.3-33.16%) of children. The additional findings included further subdural haematoma, subarachnoid haemorrhage, shearing injury, ischaemia, and infarction; it also contributed to dating of injuries. Diffusion-weighted imaging (DWI) further enhanced the delineation of ischaemic changes, and assisted in prognosis. Repeat CT studies varied in timing and quality, and none were compared to the addition of an early MRI/DWI. CONCLUSIONS: In an acutely ill child, the optimal imaging strategy involves initial CT, followed by early MRI and DWI if early CT examination is abnormal, or there are ongoing clinical concerns. The role of repeat CT imaging, if early MRI is performed, is unclear, as is the place for MRI/DWI if initial CT examination is normal in an otherwise well child.

Spinal subdural haematomas in children with non-accidental head injury.

OBJECTIVE: To examine the incidence of spinal pathology in infants with non-accidental head injury. METHODS: 18 infants with non-accidental head injury were investigated between 2000 and 2007 with dedicated MRI of the brain and spine. During the earlier years, the spine was imaged only when there were suspicious features on other imaging to suggest a spinal injury (seven cases). After 2005, all suspected cases of non-accidental head injury were routinely investigated with MRI of the whole spine in addition to the brain. The spinal imaging at initial investigation and at follow-up was reviewed. RESULTS: There was a high incidence (8/18 cases, 44%) of subdural collections in the spine. They were all clinically occult and in six cases large. All eight cases were associated with subdural haematomas in the supratentorial and infratentorial compartment. The signal characteristics were analysed and compared with those of the intracranial collections. One had a small epidural haematoma. Other depicted abnormalities and appearances at follow-up were also reviewed. CONCLUSION: There is a high incidence of previously unsuspected spinal subdural haematomas associated with intracranial collections in children with non-accidental head injury. Further work is required to evaluate the clinical implications.

Radiological classification of optic pathway gliomas: experience of a modified functional classification system.

Optic pathway gliomas (OPGs) in childhood are associated with neurofibromatosis type 1 (NF1) and since 1958 have been classified anatomically using the Dodge classification (DC). MR scanning permits a more detailed anatomical description than can be classified by this historical system. A modified Dodge classification (MDC) has been applied to MRI scans from a cohort of 72 patients (36.1% NF1-positive) from 4 centres participating in an international clinical trial. The MDC was feasible, applicable and more detailed than the original DC. NF1-positive cases more commonly involved both optic nerves (p = 0.021) and other multiple locations (p = 0.001). NF1-negative tumours more commonly involved the central chiasm (p = 0.005) and hypothalamus (p = 0.003). Fewer hypothalamus-positive tumours were associated with optic nerve involvement (p = 0.009), whereas more were associated with central chiasm involvement (p<0.001). From diagnosis to follow-up, there was concordance between DC and MDC in 51/72 cases (70.8%). The MDC is therefore proposed for use in clinical trials of new treatments for OPGs.

Intrathecal chemotherapy delivered by a lumbar-thecal catheter in metastatic medulloblastoma: a case illustration.

BACKGROUND: Medulloblastoma is the most common malignant brain tumour in children. Despite recent advances, the prognosis in high risk patients remains poor. Further improvement in survival is dependent upon the development of strategies to attack the tumour more effectively, but with less toxicity. Intrathecal chemotherapy, is an ideal but currently underused method of directly targeting residual tumour within the area of resection and the leptomeningeal disease commonly associated with this tumour. METHOD: We describe the case of a 12 yr old child with metastatic medulloblastoma, who received intrathecal topotecan via a spinal catheter. CONCLUSION: This method represents a simple, safe and effective method of delivering an even and widespread distribution of drug within the cerebrospinal fluid (CSF) of the neuroaxis. With new agents being identified and others in the early stages of development, intrathecal chemotherapy may emerge as an important therapeutic option to consider when faced with such challenging cases.

The 'unified hypothesis' of Geddes et al. is not supported by the data.

Inflicted head injury to the developing brain frequently results in serious disability. The pathogenesis of the neuraxial and ocular findings in infants believed to have suffered inflicted head injury remains the subject of considerable debate. Recent neuropathology studies of fatal cases of inflicted head injury and of a foetal/perinatal non-traumatic model have led to the proposal that there is a 'unified hypothesis', the essential feature of which is hypoxic brain swelling secondary to cervicomedullary injury. It has been suggested that less than violent forces may be involved and even that some cases may not be due to trauma at all. The purpose of this paper is to provide a critical review of the data upon which these suppositions are based on a background of what is already known. It is submitted that there are serious flaws in the methodology; the conclusions reached cannot logically be drawn from the data; and the 'unified hypothesis' is not supported by the evidence. On the basis of the data presented, it is also difficult to sustain the secondary hypothesis purporting to describe a minority cohort with 'infantile encephalopathy with subdural and retinal bleeding' of non-traumatic causation.

Acute bilateral thalamic necrosis in a child with Mycoplasma pneumoniae.

A previously neurodevelopmentally intact 5-year-old male was admitted to hospital with a right lower lobe pneumonia with pleural effusion, subsequently confirmed to be a Mycoplasma pneumoniae infection. On the seventh day of the illness he had a prolonged generalized tonic or tonic-clonic convulsion, requiring intubation and ventilation. He was slow to regain consciousness (Child's Glasgow Coma Score 7-10 over 6 days) and brain imaging with CT and then MRI demonstrated bilateral thalamic lesions with oedema and central haemorrhage suggestive of acute bilateral thalamic necrosis, without striatal or white-matter involvement. He was treated with a 2-week course of erythromycin, and as an autoimmune process was considered possible, 5 days of intravenous methylprednisolone (20 mg/kg/day) followed by a 4-week oral prednisolone taper. He made a slow recovery over the next few weeks with almost complete neurological recovery by 2 months but with significant dysarthria, drooling, and a mild left hemiparesis. At 9 months, significant dystonia continued to affect his speech and, together with tremor, his upper-limb fine motor function bilaterally. His gait, personality, and higher cognitive functions appeared to have recovered fully. Although acute striatal necrosis, acute disseminated encephalomyelitis, and encephalitis have been reported with Mycoplasma pneumoniae and a similar picture of acute bilateral thalamic necrosis with influenza-A ('acute necrotizing encephalopathy'), this is the first reported case of Mycoplasma pneumoniae-associated isolated acute bilateral thalamic necrosis.