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Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments. H3K27-alterations initiate the disease but additional drivers are required for malignant growth. Hence, there is an urgent unmet need to develop new multi-modality therapeutic strategies, including alternative methods of drug delivery. ONC201 (DRD2 antagonist and mitochondrial ClpP agonist) is the most widely evaluated investigational drug. Encouraging early data is emerging for CAR T-cells and oncolytic viruses. GD2, B7-H3 and PI3K signalling are ubiquitous targets across all subtypes and therapeutics directed to these targets would potentially benefit the largest number of children. PI3K, ACVR1, MAPK and PDGFRA pathways should be targeted in rational biological combinations. Drug discovery is a very high priority. New specific and potent epigenetic modifiers (PROTACS e.g. SMARCA4 degraders), with blood-brain penetrance are needed. Cancer neuroscience therapeutics are in early development. Overall survival is the preferred regulatory endpoint. However, the evaluation of this can be influenced by the use of re-irradiation at the time of progression. An efficient clinical trial design fit for regulatory purposes for the evaluation of new therapeutics would aid industry and facilitate more efficient therapy development. Challenges in conducting clinical trials such as the need for comparator data and defining endpoints, could be addressed through an international, first-in-child, randomised, complex innovative design trial. To achieve progress: i) drug discovery; ii) new multi-modality, efficient, collaborative, pre-clinical approaches, possibly including artificial intelligence and, iii) efficient clinical trial designs fit for regulatory purposes are required., Competing Interests: Declaration of Competing Interest MR is an employee of Novartis and holds Novartis stock. JAE is an employee of Chimerix. EB is an employee of SonALAsence. JF is an employee of Kazia Therapeutics. MJ is an employee of Brainchild Bio and holds Brainchild Bio stock. MWK is an employee of Day One Biopharmaceuticals. HK is an employee of Loxo Oncology. AGM is an employee of Laminar Pharma. AR is an employee of AstraZeneca. DZ is an employee of Biodexa Pharmaceuticals (Midatech). ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tumors of the central nervous system are the most common solid malignancies in children and the most common cause of pediatric cancer-related mortality. Imaging plays a central role in diagnosis, staging, treatment planning, and response assessment of pediatric brain tumors. However, the substantial variability in brain tumor imaging protocols across institutions leads to variability in patient risk stratification and treatment decisions, and complicates comparisons of clinical trial results. This White Paper provides consensus-based imaging recommendations for evaluating pediatric patients with primary brain tumors. The proposed brain magnetic resonance imaging protocol recommendations balance advancements in imaging techniques with the practicality of deployment across most imaging centers., (© 2022 Wiley Periodicals LLC.)

Objective: We aimed to determine if T2-weighted hyperintense white matter lesions (WMLs) on brain magnetic resonance imaging (MRI) occur more frequently in pediatric patients with migraine and other primary headache disorders compared to the general pediatric population., Background: Small foci of T2 hyperintensity in the white matter are frequently identified on brain MRI during the workup of pediatric headache. Such lesions have been reported to be more common among adults with migraine versus adults without migraine; however, this association has not been well established in the pediatric population., Methods: We performed a retrospective cross-sectional single-center study of electronic medical records and radiologic studies, examining pediatric patients from 3 to 18 years old who underwent brain MRI between 2016 and 2021. Patients with existing intracranial disease or abnormalities were excluded. Patients with reports of headache were categorized. Imaging was reviewed to determine the number and location of WMLs. Headache-associated disability scores (Pediatric Migraine Disability Assessment) were noted, when available., Results: Brain MRI of 248 patients with a diagnosis of headache (144 with migraine, 42 with non-migraine primary headache, and 62 with headache that could not be further classified) and 490 controls were reviewed. WMLs were encountered commonly among all study participants, with a prevalence of 40.5% (17/42) to 54.1% (265/490). There was no statistically significant difference comparing the number of lesions between each of the headache groups and the control group: migraine group versus control group median [interquartile range (IQR)], 0 [0-3] versus 1 [0-4], incidence rate ratio [95% confidence interval (CI)], 0.99 [0.69-1.44], p = 0.989, non-migraine headache group versus control group median [IQR], 0 [0-3] versus 1 [0-4], 0.71 [0.46-1.31], p = 0.156, headache not otherwise specified group versus control group median [IQR], 0 [0-4] versus 1 [0-4], 0.77 [0.45-1.31], p = 0.291. There was no significant correlation between headache-associated disability and the number of WMLs (0.07 [-0.30 to 0.17], rho [95% CI])., Conclusion: T2 hyperintense WMLs are common within the pediatric population and are not encountered more frequently in pediatric patients with migraine or other primary headache disorders. Thus, such lesions are presumably incidental and unlikely related to headache history., (© 2023 American Headache Society.)

Introduction: Prompt detection of traumatic cervical spine injury is important as delayed or missed diagnosis can have disastrous consequences. Given the understood mechanism of non-accidental trauma (NAT), it is reasonable to suspect that cervical spine injury can occur. Current management of young children being evaluated for NAT includes placement of a rigid collar until clinical clearance or an MRI can be obtained. Currently, there exists a lack of robust data to guide cervical bracing. Anecdotally, our group has not observed a single patient with a diagnosis of NAT who required operative stabilization for cervical spine instability. This study will be the largest series to date and aims to systematically investigate this observation to determine the likelihood that children with a diagnosis of NAT harbor cervical spine instability related to their injuries., Methods: Patient data from the Children's Hospital Colorado Trauma Registry diagnosed with non-burn-only NAT were reviewed retrospectively. Children less than 4 years of age pulled from the registry from January 1, 2005, to March 31, 2021, were included. Demographic, admission/discharge, imaging, and clinic management data were collected for each patient and analyzed., Results: There were 1008 patients included in the cohort. The age at presentation ranged from 5 days to 4 years (mean 10.4 months). No patient had X-ray or CT findings concerning for cervical instability. Three patients had MRI findings concerning for cervical instability. Two of these underwent external bracing, and the third died from unrelated injuries during their hospitalization. Only four patients were discharged in a cervical collar, and all were ultimately cleared from bracing. No patient underwent a spinal stabilization procedure., Conclusions: While the mechanism of injury in many NAT cases would seem to make significant cervical spine injury possible, this single-center retrospective review of a large experience indicates that such injury is exceedingly rare. Further study is merited to understand the underlying pathophysiology. However, it is reasonable to consider cervical collar clearance in the setting of normal radiographs and a reassuring neurological exam. Furthermore, if concerns exist regarding cervical spine instability on MRI, an initial trial of conservative management is warranted., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cataract surgery is among the most common medical procedures, and accurate ocular biometry measurements are key for successful visual outcome. The current study evaluated data obtained by the Eyestar 900, Anterion, IOLMaster700 biometers and the Pentacam corneal topographer. Compared values were axial length (AL), anterior chamber depth (ACD), steep- and flat-K, cylinder and axis. Clinical impact was assessed by calculating intraocular lens (IOL) power using the mean values of every parameter and the Barrett and Kane formulas, stratified by device and amount of cylinder. IOL was re-calculated for each device substituting Pentacam K-values. This study included 196 eyes (98 participants) of cataract surgery candidates. When comparing the IOLMaster to the Eyestar (157 eyes), no difference was found in mean AL or ACD measurements (P > 0.05). Steep-K measurements differed between these devices and the Pentacam (P = 0.01). AL and ACD measurements differed between the IOLMaster and Anterion (38 eyes; P < 0.05). Strong correlations (range 0.72-0.99) were found between all four devices. Bland-Altman analysis demonstrated excellent agreement between biometry devices other than ACD between the IOLMaster and Eyestar. Calculated IOL power was 0.50-1.00 diopter (D) lower with the IOLMaster. Cylinder power was 0.75D higher in all biometers when Pentacam K-values were substituted., (© 2022. The Author(s).)

Background: Younger stroke patients may suffer worse outcomes than older patients; however, the extent to which age at stroke impacts remote areas of the brain remains unclear. The objective of this study was to determine thalamic volume changes ipsilateral to middle cerebral artery territory strokes based on age at acute ischemic stroke onset. Methods: Acute ischemic stroke patients <9 years, 9-18 years, and >18 years old were retrospectively recruited from a large quaternary care system. Each subject underwent an acute (<72 hours from AIS) and chronic (>90 days) magnetic resonance imaging (MRI) scan. Manual thalamic segmentation was performed. Results: Younger and older children had significantly greater stroke-side thalamic volume loss compared to adults (48.2%, P  = .022; 40.7%, P  = .044, respectively). Conclusions: Stroke-side thalamic volumes decreased across the age spectrum but to a greater degree in pediatric patients. This observation can affect functional and cognitive outcomes post stroke and warrants further research.

Fetal MRI is a safe, noninvasive examination of the fetus and placenta, a complement to ultrasonography. MRI provides detailed CNS evaluation, including depicting parenchymal architecture and posterior fossa morphology, and is key in prenatal assessment of spinal dysraphism, neck masses, and ventriculomegaly. Fetal MRI is typically performed after 22 weeks gestation, and ultrafast T1 and T2-weighted MRI sequences are the core of the exam, with advanced sequences such as diffusion weighted imaging used for specific questions. The fetal brain grows and develops rapidly, and familiarity with gestational age specific norms is essential to MRI interpretation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The circle of Willis is a circulatory anastomosis that supplies blood to the brain. If any of the bridging segments are hypoplastic or absent, the capacity for collateral flow in the setting of large vessel occlusion may be decreased. Outside of the neonatal period, the prevalence of a complete circle of Willis (CoW) in the pediatric population has not been well described. Our objectives include determining the prevalence of a complete CoW in children and identifying if there is an age-related "loss" of arterial segments., Methods: Following IRB approval, angiograms of the CoW performed on a 3-T MR platform from 2016 to 2020 on patients 21 years or younger were retrospectively reviewed. Any patient with underlying arterial pathology that may affect the CoW was excluded. Patient age and gender at the time of imaging were obtained., Results: In total, 592 pediatric CoW were assessed. Frequencies of completeness were calculated in two different fashions: scenario 1 where a CoW was characterized as complete even if it contained hypoplastic vessels (88.8%), and scenario 2 where it was characterized as complete after excluding hypoplastic vessels (44.0%). In both scenarios, our data showed that older age was more associated with an incomplete CoW (p < 0.0001). In addition, we found a higher percentage of males with an incomplete CoW compared with females (p < 0.0001)., Conclusions: The presence of a complete CoW is greater in our pediatric population than what has been reported in adults. The prevalence of an incomplete circle of Willis also increases significantly with age., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms., Method: Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease., Results: Likely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology., Interpretation: This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. High-priority candidates were identified in an additional five individuals. WES provides additional support for previously described disease-associated genes and expands their already broad mutational and phenotypic spectrum., (© 2021 Mac Keith Press.)

Background: Prenatal surgical closure of Myelomeningocele (MMC) is considered part of the current age armamentarium. Clinical data has demonstrated the need for innovative patches to maximize the benefits and decrease the risks of this approach. Our team has developed a minimally invasive reverse thermal gel (RTG) patch with cellular scaffolding properties. Here, we demonstrate the initial gross and microscopic histological effects of this RTG patch in the fetal ovine model of MMC., Materials and Methods: A fetal ovine MMC defect was created at 68-75 days gestation, RTG patch application or untreated at 100-103 days, and harvest at 135-140 days. The RTG was applied to the defect and secured in place with an overlay sealant. Defect areas underwent gross and microscopic analysis for inflammation and skin development. Brains were analyzed for hindbrain herniation and hydrocephalus., Results: The untreated fetus (n = 1) demonstrated an open defect lacking tissue coverage, evidence of spinal cord injury, increased caspase-3, Iba1 and GFAP in spinal cord tissues, and hindbrain herniation and ventricular dilation. RTG treated fetuses (n = 3) demonstrated defect healing with well-organized dermal and epidermal layers throughout the entire healed tissue area overlaying the defect with minimal inflammation, reduced caspase-3, Iba1 and GFAP in spinal cord tissues, and no hindbrain herniation or ventricular dilation., Conclusion: An RTG patch applied to MMC defects in fetal sheep promoted skin coverage over the defect, was associated with minimal inflammation of the spinal cord tissues and prevented brain abnormalities. The present findings provide exciting results for future comprehensive radiological, functional, and mechanistic evaluation of the RTG., (Copyright © 2021. Published by Elsevier Inc.)

Relapsing demyelinating syndromes (RDS) in children encompass a diverse spectrum of entities including multiple sclerosis (MS) acute disseminated encephalomyelitis (ADEM), aquaporin-4 antibody associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to these, there are "antibody-negative" demyelinating syndromes which are yet to be fully characterized and defined. The paucity of specific biomarkers and overlap in clinical presentations makes the distinction between these disease entities difficult at initial presentation and, as such, there is a heavy reliance on magnetic resonance imaging (MRI) findings to satisfy the criteria for treatment initiation and optimization. Misdiagnosis is not uncommon and is usually related to the inaccurate application of criteria or failure to identify potential clinical and radiological mimics. It is also notable that there are instances where AQP4 and MOG antibody testing may be falsely negative during initial clinical episodes, further complicating the issue. This article illustrates the typical clinico-radiological phenotypes associated with the known pediatric RDS at presentation and describes the neuroimaging mimics of these using a pattern-based approach in the brain, optic nerves, and spinal cord. Practical guidance on key distinguishing features in the form of clinical and radiological red flags are incorporated. A subsection on clinical mimics with characteristic imaging patterns that assist in establishing alternative diagnoses is also included., (Copyright © 2020 Chhabda, Malik, Reddy, Muthusamy, Mirsky, Sudhakar and Mankad.)

Background and Purpose: Cervical arterial dissection is one of the frequent causes of pediatric arterial ischemic stroke. Out of concern for missing cervical arterial dissection in patients in whom pediatric stroke is suspected, our tertiary children's hospital added contrast-enhanced 3D neck MR angiography to every pediatric stoke work-up. This research investigated whether the routine use of contrast-enhanced neck MRA in our MR imaging stroke protocol ever detected a cervical arterial abnormality when the DWI, SWI/gradient recalled-echo, or circle of Willis MRA findings from the brain MR imaging were reported as normal., Materials and Methods: The institutional PACS data base was searched for stroke protocol MRIs that included DWI, gradient recalled-echo or SWI, circle of Willis MRA, and 3D contrast-enhanced neck MRA in patients younger than 18 years of age with examinations performed between September 2010 and June 2017., Results: In only a single case (0.15%) were the DWI, SWI/gradient recalled-echo, or circle of Willis MRA findings all separately reported as normal and the contrast-enhanced neck MRA findings reported as abnormal. To reach these findings, we screened 681 patients, which would have resulted in an estimated >$200,000 in Medicare charges and $80,000 in of out-of-pocket cost to patients., Conclusions: In our large series, the addition of a routine contrast-enhanced neck MRA to our pediatric stroke MR imaging protocol was of extremely low yield. We believe the use of neck MRA should reasonably be limited to cases in which abnormalities are initially detected on standard brain sequences or to patients with atypical presentation or recurrent pathology., (© 2019 by American Journal of Neuroradiology.)

Preoperative diagnosis for tumors arising in the optic chiasm/sellar/suprasellar region in children is helpful to determine surgical necessity and approach, given the high operative risk in this area. We evaluated the ability to differentiate tumor type by preoperative neuroimaging. Thirty-eight of 53 tumors were correctly diagnosed by neuroimaging based on final pathologic diagnosis (prediction accuracy 72%). Prediction accuracies were 87% (20/23) for craniopharyngioma, 79% (11/14) for optic pathway glioma, 64% (7/11) for germ cell tumor, and 0% (0/5) for Langerhans cell histiocytosis. Diagnosis of optic chiasm/sellar/suprasellar tumors in children by imaging alone should be considered when biopsy is considered high risk., (© 2019 Wiley Periodicals, Inc.)

Purpose: Sacral abnormalities range from missing the coccyx, a few sacral vertebrae, or hemi-sacrum, to complete absence with fused iliac bones. The purpose of this study was to review the association between sacral agenesis and fecal incontinence to help inform patient prognosis., Methods: A retrospective review was performed of patients who presented for bowel management due to sacral agenesis at a tertiary care children's hospital between 2016 and 2017 (n = 10). Data collection included: gender, time of diagnosis, sacral ratio, and associated anomalies. Patients with anorectal malformation and sacrococcygeal teratomas were excluded., Results: Four patients were female. Seven patients had a delayed diagnosis ranging from 22 months of age to 9 years. Most common symptoms included failure of age-appropriate toilet training and severe diaper rash. The sacral ratio was zero (6), 0.3 and 0.4 (2), and hemi-sacrum (2). Associated anomalies were present in five patients., Conclusion: Sacral abnormalities should be suspected in patients who present with early severe diaper rash and those who fail to toilet train. An abdominal radiograph can evaluate the sacrum, when the sacral ratio is 0.4 or less, parents should be counseled regarding fecal incontinence and neurogenic bladder.

Purpose: Approximately 25% of patients with anorectal malformation have tethered cord. The traditional way of determining conus medullaris level on magnetic resonance imaging (MRI) relies on counting vertebrae, which may be challenging due to vertebral numeric variation, segmentation anomalies, as well as transitional vertebral body anatomy. The purpose of this study was to utilize more reliable anatomic landmarks (foramen magnum, conus termination, and the upper limit of the iliac crest) to establish a consistent ratio that may differentiate patients with normal and low-lying conus., Methods: A single institution database search identified two groups of patients: 255 with normal and 85 with abnormal spinal MRI, who underwent tethered cord release. The conus medullaris ratio was calculated in both groups. The ratio was obtained by dividing the distance between the conus level and the iliac crest by the distance between the foramen magnum and the conus level (IRB # 16-2330)., Results: The mean ratio was significantly higher in the non-tethered group compared to the tethered patients (0.184 [sd 0.03] versus 0.118 [sd 0.09]; P < .0001). The ratio proved to be a good discriminator between normal and abnormal patients, with area under the curve (AUC) equal to 0.749, meaning that at random, there is a 75% chance that the tethered cord patient will have a lower ratio than the non-tethered cord patient., Conclusion: "The Conus Medullaris Ratio" is a good predictor of low-lying conus level on MRI and offers an easy alternative to counting vertebral body levels, particularly in patients with variant or abnormal vertebral body anatomy., Level of Evidence: II, Study of Diagnostic Test., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Studies evaluating small patient cohorts have found a high, but variable, rate of occult head injury in children <2 years old with concern for physical abuse. The American College of Radiology (ACR) recommends clinicians have a low threshold to obtain neuroimaging in these patients., Objectives: Our aim was to determine the prevalence of occult head injury in a large patient cohort with suspected physical abuse using similar selection criteria from previous studies. Additionally, we evaluated proposed risk factors for associations with occult head injury., Materials and Methods: This was a retrospective, secondary analysis of data collected by an observational study of 20 U.S. child abuse teams that evaluated children who underwent subspecialty evaluation for concern of abuse. We evaluated children <2 years old and excluded those with abnormal mental status, bulging fontanelle, seizure, respiratory arrest, underlying neurological condition, focal neurological deficit or scalp injury., Results: One thousand one hundred forty-three subjects met inclusion criteria and 62.5% (714) underwent neuroimaging with either head computed tomography or magnetic resonance imaging. We found an occult head injury prevalence of 19.7% (141). Subjects with emesis (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.8-6.8), macrocephaly (OR 8.5, 95% CI 3.7-20.2), and loss of consciousness (OR 5.1, 95% CI 1.2-22.9) had higher odds of occult head injury., Conclusion: Our results show a high prevalence of occult head injury in patients <2 years old with suspected physical abuse. Our data support the ACR recommendation that clinicians should have a low threshold to perform neuroimaging in patients <2 years of age.

A rare autosomal recessive disorder caused by mutations in the B3GALT6 gene on chromosome 1p36 results in deficiency of β-1,3-galactosyltransferase 6, an enzyme critical for glycosaminoglycan biosynthesis. Defects in this gene result in a phenotype that has features of both skeletal dysplasia and a connective tissue disorder. The anesthetic considerations for children with this disorder have not previously been described. We report a collaborative, multidisciplinary approach to the perioperative care of a child with B3GALT6 mutations with severe phenotypic expression.

Background: Interictal 18F-fluorodeoxyglucose-positron emission topography (FDG-PET) hypometabolism is routinely used in the presurgical workup of children with medically intractable epilepsy (MIE). FDG-PET hypermetabolism, however, is rarely seen, and the significance of this finding in the epilepsy workup is not well established., Methods: We performed a retrospective study of patients who underwent FDG-PET during the presurgical workup of MIE over a 4-year period, between 1 January 2010 and 31 December 2013, at the Children's Hospital Colorado, CO, USA., Results: Focal FDG-PET hypermetabolism was identified in 7 (2.2%) of 317 patients. The median age was 124 months, all cases with catastrophic epilepsy. Surface electroencephalography (EEG) performed concomitantly with FDG injections revealed ictal EEG discharges in 2 patients, frequent interictal epileptiform discharges (IEDs) in 3, occasional IEDs in 1, and no IEDs in 1. All 7 patients underwent functional hemispherectomies. Histopathology revealed type 1 focal cortical dysplasia in all patients. Six (86%) were completely seizure-free (Engel class I) and 1 had extremely infrequent seizures (Engel class II) (mean follow-up, 47.4 months)., Conclusion: While a rare finding, interictal PET hypermetabolism does occur, may help identify epileptogenic zones, and assessment to reveal it should be made by concomitant use of surface EEG during PET scans., (© 2018 S. Karger AG, Basel.)

Objectives: The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research., Methods: Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use., Results: The NINDS Mito CDEs and supporting documents are publicly available on the NINDS CDE website ( https://commondataelements.ninds.nih.gov/ ), organized into domain categories such as Participant/Subject Characteristics, Assessments, and Examinations., Conclusion: We developed a comprehensive set of CDE recommendations, data definitions, case report forms (CRFs), and guidelines for use in Mito clinical research. The widespread use of CDEs is intended to enhance Mito clinical research endeavors, including natural history studies, clinical trial design, and data sharing. Ongoing international collaboration will facilitate regular review, updates and online publication of Mito CDEs, and support improved consistency of data collection and reporting.

Dedicated epilepsy centers are growing in hospitals throughout the USA and abroad, with a continuously increasing role of imaging in multidisciplinary meetings. Imaging is paramount in diagnosis, treatment, and surgical decision-making in lesional and nonlesional epileptic disease. Besides being up-to-date with technical developments in imaging that may make an impact in patient care, familiarity with clinical and surgical aspects of epilepsy is fundamental to better understanding of patient management. The present article intends to revisit diagnostic, therapeutic, and surgical imaging in epilepsy. Finally, with the increase in frequency of epilepsy management-related procedures and their hardware, MRI safety issues are discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Primary amoebic meningoencephalitis (PAM) is a rare, often lethal, cause of encephalitis, for which early diagnosis and prompt initiation of combination antimicrobials may improve clinical outcomes., Methods: In this study, we sequenced a full draft assembly of the Balamuthia mandrillaris genome (44.2 Mb in size) from a rare survivor of PAM, and recovered the mitochondrial genome from six additional Balamuthia strains. We also used unbiased metagenomic next-generation sequencing (NGS) and SURPI bioinformatics analysis to diagnose an ultimately fatal case of Balamuthia mandrillaris encephalitis in a 15-year-old girl., Results and Discussion: Comparative analysis of the mitochondrial genome and high-copy number genes from six additional Balamuthia mandrillaris strains demonstrated remarkable sequence variation, and the closest Balamuthia homologs corresponded to other amoebae, hydroids, algae, slime molds, and peat moss. Real-time NGS testing of hospital day 6 CSF and brain biopsy samples detected Balamuthia on the basis of high-quality hits to 16S and 18S ribosomal RNA sequences present in the National Center for Biotechnology Information (NCBI) nt reference database. The presumptive diagnosis of PAM by visualization of amoebae on brain biopsy histopathology and NGS analysis was subsequently confirmed at the US Centers for Disease Control and Prevention (CDC) using a Balamuthia-specific PCR assay. Retrospective analysis of a day 1 CSF sample revealed that more timely identification of Balamuthia by metagenomic NGS, potentially resulting in a better clinical outcome, would have required availability of the complete genome sequence., Conclusions: These results underscore the diverse evolutionary origins of Balamuthia mandrillaris, provide new targets for diagnostic assay development, and will facilitate further investigations of the biology and pathogenesis of this eukaryotic pathogen. The failure to identify PAM from a day 1 sample without a fully sequenced Balamuthia genome in the database highlights the critical importance of whole-genome reference sequences for microbial detection by metagenomic NGS.

Purpose: Most women with breast cancer are diagnosed at an early stage and more than 80% will be long-term survivors. Routine follow-up marks the transition from intensive treatment to survivorship. It is usual practice for routine follow-up to take place in specialist clinics. This study tested the hypothesis that follow-up by the patient's family physician is a safe and acceptable alternative to specialist follow-up., Patients and Methods: A multicenter, randomized, controlled trial was conducted involving 968 patients with early-stage breast cancer who had completed adjuvant treatment, were disease free, and were between 9 and 15 months after diagnosis. Patients may have continued receiving adjuvant hormonal therapy. Patients were randomly allocated to follow-up in the cancer center according to usual practice (CC group) or follow-up from their own family physician (FP group). The primary outcome was the rate of recurrence-related serious clinical events (SCEs). The secondary outcome was health-related quality of life (HRQL)., Results: In the FP group, there were 54 recurrences (11.2%) and 29 deaths (6.0%). In the CC group, there were 64 recurrences (13.2%) and 30 deaths (6.2%). In the FP group, 17 patients (3.5%) compared with 18 patients (3.7%) in the CC group experienced an SCE (0.19% difference; 95% CI, -2.26% to 2.65%). No statistically significant differences (P < .05) were detected between groups on any of the HRQL questionnaires., Conclusion: Breast cancer patients can be offered follow-up by their family physician without concern that important recurrence-related SCEs will occur more frequently or that HRQL will be negatively affected.

Objectives: To assess the available evidence on sentinel lymph-node biopsy, and to examine the long-term follow-up data from large randomized phase III trials comparing breast-conserving therapy with mastectomy in order to make recommendations on the surgical management of early invasive breast cancer (stages I and II), including the optimum management of the axillary nodes: for the breast--modified radical mastectomy or breast-conserving therapy; for the axilla--complete axillary node dissection, axillary dissection of levels I and II lymph nodes, sentinel lymph-node biopsy or no axillary node surgery., Outcomes: Overall survival, disease-free survival, local recurrence, distant recurrence and quality of life., Evidence: MEDLINE, EMBASE, the Cochrane Library databases and relevant conference proceedings were searched to identify randomized trials and meta-analyses. Two members of the Practice Guidelines Initiative, Breast Cancer Disease Site Group (BCDSG) selected and reviewed studies that met the inclusion criteria. The systematic literature review was combined with a consensus process for interpretation of the evidence to develop evidence-based recommendations. This practice guideline has been reviewed and approved by the BCDSG, comprising surgeons, medical oncologists, radiation oncologists, pathologists, a medical sociologist, a nurse representative and a community representative., Benefits, Harms and Costs: Breast-conserving therapy (lumpectomy with levels I and II axillary node dissection, plus radiotherapy) provides comparable overall and disease-free survival to modified radical mastectomy. Levels I and II axillary dissection accurately stages the axilla and minimizes the morbidity of axillary recurrence but is associated with lymphedema in approximately 20% of patients and arm pain in approximately 33%. Currently, there is insufficient data regarding locoregional recurrence and long-term morbidity associated with sentinel-node biopsy to advocate it as the standard of care. Breast-conserving therapy may offer an advantage over mastectomy in terms of body image, psychological and social adjustment but appears equivalent with regard to marital adjustment, global adjustment and fear of recurrence., Recommendations: Women who are eligible for breast-conserving surgery should be offered the choice of either breast-conserving therapy with axillary dissection or modified radical mastectomy. Removal and pathological examination of levels I and II axillary lymph nodes should be the standard practice in most cases of stages I and II breast carcinoma. There is promising but limited evidence to support recommendations regarding sentinel lymph-node biopsy alone. Patients should be encouraged to participate in clinical trials investigating this procedure., Validation: A draft version of this practice guideline and a 21-item feedback questionnaire was circulated to 201 practitioners in Ontario. Of the 131 practitioners who returned the questionnaire, 98 (75%) completed the survey and indicated that the report was relevant to their clinical practice. Eighty (82%) of these practitioners agreed that the draft document should be approved as a practice guideline.

Context: The long-term results of randomized trials have demonstrated equivalent survival rates for mastectomy and breast-conserving therapy for the treatment of early stage breast cancer. Consequently, the choice of treatment should be based on a patient's preferences., Objective: To evaluate the impact of a decision aid regarding the different surgical treatment options on patient decision making., Design and Setting: A cluster randomized trial for which general surgeons in the communities of central-west, and eastern Ontario, Canada, were randomly assigned to use the decision aid or not in the surgical consultation. Patients received the decision aid or not based on the surgeon seen., Participants: Twenty surgeons participated in the study. Of the 208 eligible women with newly diagnosed clinical stage I or II breast cancer seen by study surgeons, 201 agreed to be evaluated: 94 were assigned to the decision board and 107 to usual practice. Patients were recruited from November 1999 to April 2002., Intervention: The decision board is a decision aid designed to help physicians inform their patients about different treatment options and to enable patients to express a preference for treatment., Main Outcome Measures: Patient knowledge about the surgical treatment of breast cancer; decisional conflict; satisfaction with decision making; and the treatment decision following the consultation., Results: Patients in the decision board group had higher knowledge scores about their treatment options (66.9 vs 58.7; P<.001), had less decisional conflict (1.40 vs 1.62, P =.02), and were more satisfied with decision making (4.50 vs 4.32, P =.05) following the consultation. Patients who used the decision board were more likely to choose BCT (94% vs 76%, P =.03)., Conclusions: The decision board was helpful in improving communication and enabling women to make a choice regarding treatment. Such instruments should be considered by surgeons when communicating the different surgical options to women with breast cancer.

The location of positive margins in lumpectomy specimens for ductal carcinoma could be predicted due to the common pattern of the geographic relationship between the intraductal and invasive carcinomas. To test this hypothesis, 62 lumpectomy specimens for ductal carcinoma of the breast were submitted for this study. The specimens were microscopically examined by serially sectioning them into giant sections in a plane parallel to the chest wall (frontal plane). The margins were identified as proximal (closest to the nipple), distal (opposite to proximal), and peripheral (nonproximal or distal). We found that the location of positive or close margins was proximal in 6 cases, peripheral in 13 cases, and none were found to be distal. Ductal carcinoma in situ (DCIS) was found to be located in the area adjacent to the invasive carcinoma. The invasive carcinoma was located at the periphery of the intraductal carcinoma. All six specimens with invasive carcinoma without DCIS had free margins. Nine of 16 specimens (56%) with extensive intraductal carcinoma (EIC) component and 7 of 40 (18%) with DCIS but negative EIC contained positive or close margins involved by DCIS. One case with multifocal invasive carcinoma measuring 3.5 cm in diameter and with DCIS but EIC negative had margins involved by both DCIS and invasive carcinoma. In conclusion, in ductal carcinoma, invasive carcinoma arose at the peripheral areas of the DCIS. DCIS tends to spread toward the nipple and the peripheral margins of the resected specimens. Incomplete excision of the ductal carcinoma and the wide positive margins are most likely caused by the failure to estimate the extent and location of DCIS.

Background: The strategy for surgical treatment of breast carcinoma proven by biopsy is mainly based on the physical and mammographic examinations. To investigate if the pathological findings in core biopsy are contributory to planning the surgical strategy, we correlated the status of ductal carcinoma in situ (DCIS) in the core needle biopsy of breast, the mammographic changes and the status of resection margins in the subsequent lumpectomy., Study Design: Consecutive 130 core needle biopsies with prior mammography and subsequent lumpectomy were reviewed. Biopsies were divided into: group I, DCIS; group II, DCIS and infiltrating carcinoma (IC); and group III, IC. Mammographic findings were categorized into four groups: (a) nonspecific findings; (b) calcification (Ca(++)); Ca(++) and mass, and mass only. The status of margins in correlating lumpectomy specimens was reviewed. Close margin was defined as a free margin at less than 0.1cm from the carcinoma., Results: The rates of positive or close margins in three groups I, II, and III were 13/18, 18/48, and 2/64 (P < 0.001); and in mammography groups of nonspecific finding, Ca(++), Ca(++) mass and mass only were 5/6, 7/15, 8/37, and 13/72 (P < 0.001), respectively. Of the total of 14 cases with positive margins of more than 0.5 cm in length, 8, 4, and 2 cases were from group I, II, and II, respectively. In addition, 13 of 21 cases with nonspecific changes or with only Ca(++) in mammograms belonged to the group I; 10 of these 13 cases were associated with positive margins. Forty-one of 72 cases presenting as a mass only in mammograms belonged to the group III; only 2 of these 41 cases were associated positive margins., Conclusions: Correlation of the extent of carcinoma with pre-operative histopathological findings was better than with mammography. Core biopsies containing only DCIS, particularly in cases with nonspecific findings or with only Ca(++) in mammograms, represent a group of breast carcinoma that pose the high risk for incomplete resection in lumpectomy. Surgical management of patients having these cores includes wider resection margins than would otherwise be taken. Most core biopsies with only IC were associated with negative margins., (Copyright 2001 Wiley-Liss, Inc.)

Background: Delay to breast cancer diagnosis following an abnormal screening result is associated with anxiety and personal disruption. We assessed the patterns and timeliness of diagnostic follow-up after breast cancer screening for women with abnormal results who attended organized screening programs in 7 provinces., Methods: Using data from the Canadian Breast Cancer Screening Database, we identified 203,141 women aged 50-69 years who underwent screening in 1996 through provincially organized breast cancer screening programs in British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Nova Scotia and Newfoundland. We prospectively followed women with an abnormal screening result through to the completion of the assessment process. We evaluated the waiting times from screening examination to first assessment, from screening examination to first imaging, from screening examination to diagnosis and from first assessment to diagnosis for 13,958 women, stratified according to screening program, mode of detection, whether a biopsy was performed and whether cancer was diagnosed., Results: We observed considerable variations between and within programs in the time to diagnosis. The median time from screening examination to first assessment was 2.6 weeks. The median time from screening examination to diagnosis was 3.7 weeks; this time increased to 6.9 weeks for women undergoing biopsy. Even when no biopsy was performed, 10% of the women waited 9.6 weeks or longer for a diagnosis, as compared with 15.0 weeks or longer for 10% of the women undergoing biopsy. Among the women who had a biopsy, the use of core biopsy was associated with a shorter median time to diagnosis than was open biopsy, and those found to have cancer had shorter waiting times than women with benign biopsy findings., Interpretation: Women undergoing assessment of an abnormal breast cancer screening result waited many weeks for a diagnosis, especially when a biopsy was performed. To ensure that targets for timeliness, adopted nationally in 1999, are realized, improved models of care or dissemination of existing efficient techniques to reach a diagnosis will be needed.

Purpose: To develop an instrument to help clinicians inform their patients about surgical treatment options for the treatment of breast cancer and to evaluate the impact of the instrument on the clinical encounter., Methods: We developed an instrument, called the Decision Board, to present information regarding the benefits and risks of breast-conserving therapy (lumpectomy plus radiation therapy) and mastectomy to women with early-stage breast cancer to enable them to express a preference for the type of surgery. Seven surgeons from different communities in Ontario administered the instrument to women with newly diagnosed clinical stage I or II breast cancer over an 18-month period. Patients and surgeons were interviewed regarding acceptability of the instrument. The rates of breast-conserving surgery performed by surgeons before and after the introduction of the instrument were compared., Results: The Decision Board was administered to 175 patients; 98% reported that the Decision Board was easy to understand, and 81% indicated that it helped them make a decision. The average score on a true/false test of comprehension was 11.8 of 14 (84%) (range, 6 to 14). Surgeons found the Decision Board to be helpful in presenting information to patients in 91% of consultations. The rate of breast-conserving surgery decreased when the Decision Board was introduced (88% v 73%, P =.001), Conclusion: The Decision Board is a simple method to improve communication and facilitate shared decision making. It was well accepted by patients and surgeons and easily applied in the community.

Guideline Question: What is the optimal surgical management of early stage invasive breast cancer (stage I and II)? More specifically, what is the relative efficacy (and safety) of breast conservation therapy (lumpectomy with axillary dissection) compared with modified radical mastectomy?, Objective: To make recommendations about surgical management and techniques in the treatment of early stage invasive breast disease (stage I and II)., Outcomes: Survival, local recurrence (for lumpectomy patients) and quality of life are the primary outcomes of interest., Perspective (values): Evidence was selected and reviewed by 6 members of the Ontario Cancer Treatment Practice Guidelines Initiative, Disease Site Group for Breast Cancer (Breast DSG). Earlier drafts of this evidence-based recommendation have been reviewed, discussed and approved by the Breast DSG, which comprises surgeons, medical oncologists, radiation oncologists, epidemiologists, a pathologist and a medical sociologist. There was no consumer participation in the development of this guideline., Quality of Evidence: There are 7 randomized controlled trials (RCTs) comparing breast conservation therapy with mastectomy in women with early stage breast cancer., Benefits: In 6 RCTs, no statistically significant differences were detected in survival rate between the mastectomy and conservative therapy (lumpectomy) groups. In 1 RCT, a statistically significant differences was detected in favour of the mastectomy arm; however, this was an early trial with substantial methodologic weaknesses., Harms: None., Practice Guideline: Women with early stage invasive breast cancer (stage I and II) who are candidates for breast conservation therapy (see discussion of technical factors) should be offered the choice of either breast conservation therapy (excision of tumour with clear margins and axillary dissection) or modified radical mastectomy. The choice is an individual one for the patient, and thus she should be fully informed of the options, including the risks and benefits of each procedure. She should be informed that breast irradiation is part of the procedure for breast conservation therapy. In addition, she should be aware of the potential need for further surgery if the margins are positive. For further information about the use of radiotherapy in the management of early stage breast cancer, please refer to the Ontario Cancer Treatment Practice Guidelines Initiative's practice guideline Breast Irradiation in Women with Early Stage Invasive Breast Cancer Following Breast Conserving Surgery.