Do animal models of brain tumors replicate human peritumoral edema? a systematic literature search.

INTRODUCTION: Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature. METHODS: A systematic search was undertaken of 5 literature databases (Medline, Embase, CINAHL, PubMed and the Cochrane Library). The generic strategy was to search for various terms associated with "brain tumors", "brain edema" and "animal models". RESULTS: We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof. CONCLUSION: No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models.

Intensity standardization of MRI prior to radiomic feature extraction for artificial intelligence research in glioma-a systematic review.

OBJECTIVES: Radiomics is a promising avenue in non-invasive characterisation of diffuse glioma. Clinical translation is hampered by lack of reproducibility across centres and difficulty in standardising image intensity in MRI datasets. The study aim was to perform a systematic review of different methods of MRI intensity standardisation prior to radiomic feature extraction. METHODS: MEDLINE, EMBASE, and SCOPUS were searched for articles meeting the following eligibility criteria: MRI radiomic studies where one method of intensity normalisation was compared with another or no normalisation, and original research concerning patients diagnosed with diffuse gliomas. Using PRISMA criteria, data were extracted from short-listed studies including number of patients, MRI sequences, validation status, radiomics software, method of segmentation, and intensity standardisation. QUADAS-2 was used for quality appraisal. RESULTS: After duplicate removal, 741 results were returned from database and reference searches and, from these, 12 papers were eligible. Due to a lack of common pre-processing and different analyses, a narrative synthesis was sought. Three different intensity standardisation techniques have been studied: histogram matching (5/12), limiting or rescaling signal intensity (8/12), and deep learning (1/12)-only two papers compared different methods. From these studies, histogram matching produced the more reliable features compared to other methods of altering MRI signal intensity. CONCLUSION: Multiple methods of intensity standardisation have been described in the literature without clear consensus. Further research that directly compares different methods of intensity standardisation on glioma MRI datasets is required. KEY POINTS: • Intensity standardisation is a key pre-processing step in the development of robust radiomic signatures to evaluate diffuse glioma. • A minority of studies compared the impact of two or more methods. • Further research is required to directly compare multiple methods of MRI intensity standardisation on glioma datasets.

Systematic review of radiological cervical foraminal grading systems.

The study design of this paper is systematic review. The purpose of this review is to evaluate the existing radiological grading systems that are used to assess cervical foraminal stenosis. The importance of imaging the cervical spine using CT or MRI in evaluating cervical foraminal stenosis is widely accepted; however, there is no consensus for standardized methodology to assess the compression of the cervical nerve roots. A systematic search of Ovid Medline databases, Embase 1947 to present, Cinahl, Web of Science, Cochrane Library, ISRCTN and WHO international clinical trials was performed for reports of cervical foraminal stenosis published before 01 February 2020. In collaboration with the University of Leeds, a search strategy was developed. A total of 6952 articles were identified with 59 included. Most of the reports involved multiple imaging modalities with standard axial and sagittal imaging used most. The grading themes that came from this systematic review show that the most mature for cervical foraminal stenosis is described by (Kim et al. Korean J Radiol 16:1294, 2015) and (Park et al. Br J Radiol 86:20120515, 2013). Imaging of the cervical nerve root canals is mostly performed using MRI and is reported using subjective terminology. The Park, Kim and Modified Kim systems for classifying the degree of stenosis of the nerve root canal have been described. Clinical application of these scoring systems is limited by their reliance on nonstandard imaging (Park), limited validation against clinical symptoms and surgical outcome data. Oblique fine cut images derived from three dimensional MRI datasets may yield more consistency, better clinical correlation, enhanced surgical decision-making and outcomes.

Multiple system atrophy mimicked by multi-organ pathology.

Both multiple system atrophy and Parkinson's disease may present with parkinsonism and autonomic dysfunction. We describe a patient who initially met the diagnostic criteria for multiple system atrophy and had atypical features for Parkinson's disease including blackouts and pyramidal signs. Ultimately, he was found to have three separate diagnoses rather than a single unifying one.

Multiple myeloma with multiple neurological presentations.

Multiple myeloma is a haematological malignancy with clonal plasma cell proliferation and production of monoclonal immunoglobulins. Its neurological complications are relatively common, caused by both the disease and the treatment. Neurologists should therefore be familiar with its neurological manifestations and complications. We describe a 40-year-old woman who presented with lower cranial neuropathies mimicking variant Guillain-Barré syndrome, with normal brain and spinal cord imaging and cerebrospinal fluid (CSF) albuminocytological dissociation, and subsequently diagnosed with IgD myeloma. She relapsed repeatedly with differing neurological presentations: numb chin syndrome and twice with impaired vision, first from cerebral venous sinus thrombosis and later from leptomeningeal infiltration of the optic chiasm. We discuss the neurological complications of myeloma, emphasising the need to consider it in a wide variety of neurological presentations and repeatedly to reassess its associated neurological diagnoses. We also highlight the complexity of myeloma treatment.

Imaging assessment of traumatic brain injury.

Traumatic brain injury (TBI) constitutes injury that occurs to the brain as a result of trauma. It should be appreciated as a heterogeneous, dynamic pathophysiological process that starts from the moment of impact and continues over time with sequelae potentially seen many years after the initial event. Primary traumatic brain lesions that may occur at the moment of impact include contusions, haematomas, parenchymal fractures and diffuse axonal injury. The presence of extra-axial intracranial lesions such as epidural and subdural haematomas and subarachnoid haemorrhage must be anticipated as they may contribute greatly to secondary brain insult by provoking brain herniation syndromes, cranial nerve deficits, oedema and ischaemia and infarction. Imaging is fundamental to the management of patients with TBI. CT remains the imaging modality of choice for initial assessment due to its ease of access, rapid acquisition and for its sensitivity for detection of acute haemorrhagic lesions for surgical intervention. MRI is typically reserved for the detection of lesions that may explain clinical symptoms that remain unresolved despite initial CT. This is especially apparent in the setting of diffuse axonal injury, which is poorly discerned on CT. Use of particular MRI sequences may increase the sensitivity of detecting such lesions: diffusion-weighted imaging defining acute infarction, susceptibility-weighted imaging affording exquisite data on microhaemorrhage. Additional advanced MRI techniques such as diffusion tensor imaging and functional MRI may provide important information regarding coexistent structural and functional brain damage. Gaining robust prognostic information for patients following TBI remains a challenge. Advanced MRI sequences are showing potential for biomarkers of disease, but this largely remains at the research level. Various global collaborative research groups have been established in an effort to combine imaging data with clinical and epidemiological information to provide much needed evidence for improvement in the characterisation and classification of TBI and in the identity of the most effective clinical care for this patient cohort. However, analysis of collaborative imaging data is challenging: the diverse spectrum of image acquisition and postprocessing limits reproducibility, and there is a requirement for a robust quality assurance initiative. Future clinical use of advanced neuroimaging should ensure standardised approaches to image acquisition and analysis, which can be used at the individual level, with the expectation that future neuroimaging advances, personalised to the patient, may improve prognostic accuracy and facilitate the development of new therapies.

The Neuromuscular Response to Spinal Manipulation in the Presence of Pain.

OBJECTIVE: The purpose of this study was to evaluate differences in muscle activity in participants with and without low back pain during a side-lying lumbar diversified spinal manipulation. METHODS: Surface and indwelling electromyography at eight muscle locations were recorded during lumbar side-lying manipulations in 20 asymptomatic participants and 20 participants with low back pain. The number of muscle responses and muscle activity onset delays in relation to the manipulation impulse were compared in the 2 pain groups using mixed linear regressions. Effect sizes for all comparisons were calculated using Cohen's d. RESULTS: Muscle responses occurred in 61.6% ± 23.6% of the EMG locations in the asymptomatic group and 52.8% ± 26.3% of the symptomatic group. The difference was not statistically significant but there was a small effect of pain (d = 0.350). Muscle activity onset delays were longer for the symptomatic group at every EMG location except the right side indwelling L5 electrode, and a small effect of pain was present at the left L2, quadratus lumborum and trapezius surface electrodes (d = 0.311, 0.278, and 0.265) respectively. The indwelling electrodes demonstrated greater muscle responses (P ≤ .01) and shorter muscle activity onset delays (P < .01) than the surface electrodes. CONCLUSIONS: The results revealed trends that indicate participants with low back pain have less muscle responses, and when muscle responses are present they occur with longer onset delays following the onset of a manipulation impulse.

Methods of Muscle Activation Onset Timing Recorded During Spinal Manipulation.

OBJECTIVE: The purpose of this study was to determine electromyographic threshold parameters that most reliably characterize the muscular response to spinal manipulation and compare 2 methods that detect muscle activity onset delay: the double-threshold method and cross-correlation method. METHODS: Surface and indwelling electromyography were recorded during lumbar side-lying manipulations in 17 asymptomatic participants. Muscle activity onset delays in relation to the thrusting force were compared across methods and muscles using a generalized linear model. RESULTS: The threshold combinations that resulted in the lowest Detection Failures were the "8 SD-0 milliseconds" threshold (Detection Failures = 8) and the "8 SD-10 milliseconds" threshold (Detection Failures = 9). The average muscle activity onset delay for the double-threshold method across all participants was 149 ± 152 milliseconds for the multifidus and 252 ± 204 milliseconds for the erector spinae. The average onset delay for the cross-correlation method was 26 ± 101 for the multifidus and 67 ± 116 for the erector spinae. There were no statistical interactions, and a main effect of method demonstrated that the delays were higher when using the double-threshold method compared with cross-correlation. CONCLUSIONS: The threshold parameters that best characterized activity onset delays were an 8-SD amplitude and a 10-millisecond duration threshold. The double-threshold method correlated well with visual supervision of muscle activity. The cross-correlation method provides several advantages in signal processing; however, supervision was required for some results, negating this advantage. These results help standardize methods when recording neuromuscular responses of spinal manipulation and improve comparisons within and across investigations.

Consensus paper: radiological biomarkers of cerebellar diseases.

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine.

Tumour Size and Overall Survival in a Cohort of Patients with Unifocal Glioblastoma: A Uni- and Multivariable Prognostic Modelling and Resampling Study.

Published models inconsistently associate glioblastoma size with overall survival (OS). This study aimed to investigate the prognostic effect of tumour size in a large cohort of patients diagnosed with GBM and interrogate how sample size and non-linear transformations may impact on the likelihood of finding a prognostic effect. In total, 279 patients with a IDH-wildtype unifocal WHO grade 4 GBM between 2014 and 2020 from a retrospective cohort were included. Uni-/multivariable association between core volume, whole volume (CV and WV), and diameter with OS was assessed with (1) Cox proportional hazard models +/- log transformation and (2) resampling with 1,000,000 repetitions and varying sample size to identify the percentage of models, which showed a significant effect of tumour size. Models adjusted for operation type and a diameter model adjusted for all clinical variables remained significant (p = 0.03). Multivariable resampling increased the significant effects (p < 0.05) of all size variables as sample size increased. Log transformation also had a large effect on the chances of a prognostic effect of WV. For models adjusted for operation type, 19.5% of WV vs. 26.3% log-WV (n = 50) and 69.9% WV and 89.9% log-WV (n = 279) were significant. In this large well-curated cohort, multivariable modelling and resampling suggest tumour volume is prognostic at larger sample sizes and with log transformation for WV.

Brain Re-Irradiation Or Chemotherapy: a phase II randomised trial of re-irradiation and chemotherapy in patients with recurrent glioblastoma (BRIOChe) - protocol for a multi-centre open-label randomised trial.

INTRODUCTION: Glioblastoma (GBM) is the most common adult primary malignant brain tumour. The condition is incurable and, despite aggressive treatment at first presentation, almost all tumours recur after a median of 7 months. The aim of treatment at recurrence is to prolong survival and maintain health-related quality of life (HRQoL). Chemotherapy is typically employed for recurrent GBM, often using nitrosourea-based regimens. However, efficacy is limited, with reported median survivals between 5 and 9 months from recurrence. Although less commonly used in the UK, there is growing evidence that re-irradiation may produce survival outcomes at least similar to nitrosourea-based chemotherapy. However, there remains uncertainty as to the optimum approach and there is a paucity of available data, especially with regards to HRQoL. Brain Re-Irradiation Or Chemotherapy (BRIOChe) aims to assess re-irradiation, as an acceptable treatment option for recurrent IDH-wild-type GBM. METHODS AND ANALYSIS: BRIOChe is a phase II, multi-centre, open-label, randomised trial in patients with recurrent GBM. The trial uses Sargent's three-outcome design and will recruit approximately 55 participants from 10 to 15 UK radiotherapy sites, allocated (2:1) to receive re-irradiation (35 Gy in 10 daily fractions) or nitrosourea-based chemotherapy (up to six, 6-weekly cycles). The primary endpoint is overall survival rate for re-irradiation patients at 9 months. There will be no formal statistical comparison between treatment arms for the decision-making primary analysis. The chemotherapy arm will be used for calibration purposes, to collect concurrent data to aid interpretation of results. Secondary outcomes include HRQoL, dexamethasone requirement, anti-epileptic drug requirement, radiological response, treatment compliance, acute and late toxicities, progression-free survival. ETHICS AND DISSEMINATION: BRIOChe obtained ethical approval from Office for Research Ethics Committees Northern Ireland (reference no. 20/NI/0070). Final trial results will be published in peer-reviewed journals and adhere to the ICMJE guidelines. TRIAL REGISTRATION NUMBER: ISRCTN60524.

Glioblastoma and radiotherapy: A multicenter AI study for Survival Predictions from MRI (GRASP study).

BACKGROUND: The aim was to predict survival of glioblastoma at 8 months after radiotherapy (a period allowing for completing a typical course of adjuvant temozolomide), by applying deep learning to the first brain MRI after radiotherapy completion. METHODS: Retrospective and prospective data were collected from 206 consecutive glioblastoma, isocitrate dehydrogenase -wildtype patients diagnosed between March 2014 and February 2022 across 11 UK centers. Models were trained on 158 retrospective patients from 3 centers. Holdout test sets were retrospective (n = 19; internal validation), and prospective (n = 29; external validation from 8 distinct centers). Neural network branches for T2-weighted and contrast-enhanced T1-weighted inputs were concatenated to predict survival. A nonimaging branch (demographics/MGMT/treatment data) was also combined with the imaging model. We investigated the influence of individual MR sequences; nonimaging features; and weighted dense blocks pretrained for abnormality detection. RESULTS: The imaging model outperformed the nonimaging model in all test sets (area under the receiver-operating characteristic curve, AUC P = .038) and performed similarly to a combined imaging/nonimaging model (P > .05). Imaging, nonimaging, and combined models applied to amalgamated test sets gave AUCs of 0.93, 0.79, and 0.91. Initializing the imaging model with pretrained weights from 10 000s of brain MRIs improved performance considerably (amalgamated test sets without pretraining 0.64; P = .003). CONCLUSIONS: A deep learning model using MRI images after radiotherapy reliably and accurately determined survival of glioblastoma. The model serves as a prognostic biomarker identifying patients who will not survive beyond a typical course of adjuvant temozolomide, thereby stratifying patients into those who might require early second-line or clinical trial treatment.

Magnetic resonance spectroscopy of the normal cerebellum: what degree of variability can be expected?

The objectives of this paper are (a) to establish the reliability of relative metabolite concentrations determined with (1)H-MR spectroscopy of the cerebellum using a method appropriate to the constraints of clinical radiology and (b) to record normal values for metabolites within the cerebellum and to look for differences in metabolite concentrations between the cerebellar hemispheric white matter and the superior vermis. 3-T (1)H-MR spectra were obtained from voxels positioned in the right cerebellar hemispheric white matter and the superior vermis in 55 healthy adults (mean age 41 years, range 20 to 77) using a single voxel PRESS sequence (TR/TE = 2,000/144 ms). One volunteer (male, age 34 years) was examined in six separate sessions over a period of 3 weeks. Reliability of intra- and inter-subject metabolite fitted area ratios was determined by evaluating coefficients of variance (%). Inter- and intra-subject coefficients of variance (%) in metabolite ratios were consistently lower in the vermis (4 to 11.6) compared to those of the hemisphere (7.2 to 14.3). Cho/Cr was significantly higher in the vermis (0.83 ± 0.10) compared to the hemisphere (0.76 ± 0.11) and NAA/Cho was significantly lower in the vermis (1.19 ± 0.12) compared to the hemisphere (1.35 ± 0.16). Low inter- and intra-subject variability can be achieved when using a (1)H-MR spectroscopy technique that is appropriate to the time constraints of clinical radiology. The regional variations of Cho/Cr and NAA/Cho within the hemisphere and vermis should be considered when performing studies of diseases, which may preferentially target a particular cerebellar location.

Magnetic resonance imaging biomarkers in patients with progressive ataxia: current status and future direction.

A diagnostic challenge commonly encountered in neurology is that of an adult patient presenting with ataxia. The differential is vast and clinical assessment alone may not be sufficient due to considerable overlap between different causes of ataxia. Magnetic resonance (MR)-based biomarkers such as voxel-based morphometry, MR spectroscopy, diffusion-weighted and diffusion-tensor imaging and functional MR imaging are gaining great attention for their potential as indicators of disease. A number of studies have reported correlation with clinical severity and underlying pathophysiology, and in some cases, MR imaging has been shown to allow differentiation of conditions causing ataxia. However, despite recent advances, their sensitivity and specificity vary. In addition, questions remain over their validity and reproducibility, especially when applied in routine clinical practice. This article extensively reviews the current literature regarding MR-based biomarkers for the patient with predominantly adult-onset ataxia. Imaging features characteristic of a particular ataxia are provided and features differentiating ataxia groups and subgroups are discussed. Finally, discussion will turn to the feasibility of applying these biomarkers in routine clinical practice.

Understanding MRI: basic MR physics for physicians.

More frequently hospital clinicians are reviewing images from MR studies of their patients before seeking formal radiological opinion. This practice is driven by a multitude of factors, including an increased demand placed on hospital services, the wide availability of the picture archiving and communication system, time pressures for patient treatment (eg, in the management of acute stroke) and an inherent desire for the clinician to learn. Knowledge of the basic physical principles behind MRI is essential for correct image interpretation. This article, written for the general hospital physician, describes the basic physics of MRI taking into account the machinery, contrast weighting, spin- and gradient-echo techniques and pertinent safety issues. Examples provided are primarily referenced to neuroradiology reflecting the subspecialty for which MR currently has the greatest clinical application.

Magnetic resonance spectroscopy of the brain.

Proton magnetic resonance (MR) spectroscopy of the brain is a non-invasive, in vivo technique that allows investigation into regional chemical environments. Its complementary use with MR imaging sequences provides valuable insights into brain tumour characteristics, progression and response to treatment. Additionally, its sensitivity to brain dysfunction in the presence of apparently normal structural imaging has galvanised interest in its use as a biomarker of neurodegenerative disorders such as Alzheimer's disease. Accordingly, its integration into clinical imaging protocols within many neuroscience centres throughout the world is increasing. This growing attention is encouraging but if the potential of MR spectroscopy is to be realised, fundamental questions need to be addressed, such as reproducibility of the technique and the biochemistry that underpins the neurometabolites measured. Failure to resolve these issues will continue to hinder the extent and accuracy of conclusions that can be drawn from its data. In this review we discuss the issues regarding MR spectroscopy in the brain with particular attention paid to its technique. Key examples of current clinical applications are provided and future directions are discussed.

Literature Review of Automated Grading Systems Utilizing MRI for Neuroforaminal Stenosis.

BACKGROUND: Cervical neural foraminal stenosis is a common and debilitating condition affecting people between the ages 40-60. Although it is established that MRI is the best method of scanning the neural foramen, the question remains whether there is a role for three-dimensional MRIs and whether it is possible to develop a computer-aided automated grading system to establish the degree of clinically relevant cervical foraminal stenosis. OBJECTIVE: The study's objective is to conduct a literature review of existing or recently developed automated grading systems for the cervical neural foramen, including volumetric MRI evaluations of the foramen. METHODS: A systematic search of Cochrane Library, Cochrane Clinical Trials, Ovid MEDLINE, EMBASE, CINAHL, ACM Digital Library and Institute of Electrical and Electronics Engineers (IEEE), and Web of Science was performed for reports examining automated systems and volumetric scanning foraminal stenosis published before 31.07.2021. RESULTS: 3971 articles were identified of which 8 were included in the study. The automated grading systems of the neural foramen focus largely on the lumbar spine with elements that may be applicable to the cervical spine. Although there are established studies on the automated grading of the lumbar spine, it is uncertain whether any of these are reproducible in the cervical spine. Visual grading systems for the cervical spine demonstrate good inter-reader reliability between radiologists and clinicians. CONCLUSION: The Park visual grading method shows strong inter-reader reliability across radiologists and clinicians despite the limited data on the correlation with neurological symptoms or surgical outcome. There is scope for further development of an automated grading system for cervical foraminal stenosis to improve the speed and consistency of image interpretation.

Treatment and Response Factors in Muscle Activation during Spinal Manipulation.

The forces applied during a spinal manipulation produce a neuromuscular response in the paraspinal muscles. A systematic evaluation of the factors involved in producing this muscle activity provides a clinical insight. The purpose of this study is to quantify the effect of treatment factors (manipulation sequence and manipulation site) and response factors (muscle layer, muscle location, and muscle side) on the neuromuscular response to spinal manipulation. The surface and indwelling electromyographies of 8 muscle sites were recorded during lumbar side-lying manipulations in 20 asymptomatic participants. The effects of the factors on the number of muscle responses and the muscle activity onset delays were compared using mixed-model linear regressions, effect sizes, and equivalence testing. The treatment factors did not reveal statistical differences between the manipulation sequences (first or second) or manipulation sites (L3 or SI) in the number of muscle responses (p = 0.11, p = 0.28, respectively), or in muscle activity onset delays (p = 0.35 p = 0.35, respectively). There were significantly shorter muscle activity onset delays in the multifidi compared to the superficial muscles (p = 0.02). A small effect size of side (d = 0.44) was observed with significantly greater number of responses (p = 0.02) and shorter muscle activity onset delays (p < 0.001) in the muscles on the left side compared to the right. The location, layer, and side of the neuromuscular responses revealed trends of decreasing muscle response rates and increasing muscle activity onset delays as the distance from the manipulation site increased. These results build on the body of work suggesting that the specificity of manipulation site may not play a role in the neuromuscular response to spinal manipulation-at least within the lumbar spine. In addition, these results demonstrate that multiple manipulations performed in similar areas (L3 and S1) do not change the response significantly, as well as contribute to the clinical understanding that the muscle response rate is higher and with a shorter delay, the closer it is to the manipulation.