The Utility of Multiparametric Magnetic Resonance Imaging in Reducing Diagnostic Uncertainty for Primary Central Nervous System Lymphoma.

BACKGROUND: A key limitation in treatment initiation in primary central nervous system lymphoma (PCNSL) is the diagnostic delay caused by lack of recognition of a lesion as a possible lymphoma, steroid initiation, and lesion involution, often resulting in an inconclusive biopsy result. We highlight the importance of multiparametric magnetic resonance imaging (MRI), which incorporates diffusion-weighted imaging, dynamic susceptibility contrast-enhanced perfusion-weighted imaging, and proton magnetic resonance spectroscopy in addition to standard MRI sequences in resolving diagnostic uncertainty for PCNSL. METHODS: At our center, a consecutive series of 10 patients with histology-proven PCNSL (specifically, diffuse large B-cell lymphoma of the central nervous system) underwent multiparametric MRI. We retrospectively analyzed qualitative and semiquantitative parameters and assessed their radiological concordance for this diagnosis. RESULTS: We noted overall low apparent diffusion coefficient on diffusion-weighted imaging (mean minimum apparent diffusion coefficient of 0.74), high percentage signal recovery on perfusion-weighted imaging (mean 170%), a high choline-to-creatine ratio, and a high-grade lipid peak on proton magnetic resonance spectroscopy giving an appearance of twin towers. Of 10 patients, 9 had MRI findings concordant for PCNSL, defined as at least 3 of 4 parameters being consistent for PCNSL. CONCLUSIONS: Concordance between these imaging multiparametric modalities could be used as a radiological predictor of PCNSL, reducing diagnostic delays, providing a more accurate biopsy target, and resulting in quicker treatment initiation.

Hippocampal neurons code individual episodic memories in humans.

The hippocampus is an essential hub for episodic memory processing. However, how human hippocampal single neurons code multi-element associations remains unknown. In particular, it is debated whether each hippocampal neuron represents an invariant element within an episode or whether single neurons bind together all the elements of a discrete episodic memory. Here we provide evidence for the latter hypothesis. Using single-neuron recordings from a total of 30 participants, we show that individual neurons, which we term episode-specific neurons, code discrete episodic memories using either a rate code or a temporal firing code. These neurons were observed exclusively in the hippocampus. Importantly, these episode-specific neurons do not reflect the coding of a particular element in the episode (that is, concept or time). Instead, they code for the conjunction of the different elements that make up the episode.

Oscillations support short latency co-firing of neurons during human episodic memory formation.

Theta and gamma oscillations in the medial temporal lobe are suggested to play a critical role for human memory formation via establishing synchrony in neural assemblies. Arguably, such synchrony facilitates efficient information transfer between neurons and enhances synaptic plasticity, both of which benefit episodic memory formation. However, to date little evidence exists from humans that would provide direct evidence for such a specific role of theta and gamma oscillations for episodic memory formation. Here, we investigate how oscillations shape the temporal structure of neural firing during memory formation in the medial temporal lobe. We measured neural firing and local field potentials in human epilepsy patients via micro-wire electrode recordings to analyze whether brain oscillations are related to co-incidences of firing between neurons during successful and unsuccessful encoding of episodic memories. The results show that phase-coupling of neurons to faster theta and gamma oscillations correlates with co-firing at short latencies (~20-30 ms) and occurs during successful memory formation. Phase-coupling at slower oscillations in these same frequency bands, in contrast, correlates with longer co-firing latencies and occurs during memory failure. Thus, our findings suggest that neural oscillations play a role for the synchronization of neural firing in the medial temporal lobe during the encoding of episodic memories.

Reconfiguration from emergency to urgent elective neurosurgery for glioblastoma patients improves length of stay, surgical adjunct use, and extent of resective surgery.

Background: Glioblastoma (GB) is the most common intrinsic brain cancer and is notorious for its aggressive nature. Despite widespread research and optimization of clinical management, the improvement in overall survival has been limited. The aim of this study was to characterize the impact of service reconfiguration on GB outcomes in a single centre. Methods: Patients with a histopathological confirmation of a diagnosis of GB between 01/01/2014 and 31/12/2019 were retrospectively identified. Demographic and tumour characteristics, survival, treatment (surgical and oncological), admission status, use of surgical adjunct (5-aminolevulinic acid, intra-operative neuro-monitoring), the length of stay, extent of resection, and surgical complications were recorded from the hospital databases. Results: From August 2018 the neurosurgical oncology service was reconfigured to manage high-grade tumours on an urgent outpatient basis by surgeons specializing in oncology. We demonstrate that these changes resulted in an increase in elective admissions, greater use of intra-operative adjuncts resulting in the improved extent of tumour resection, and a reduction in median length of stay and associated cost-savings. Conclusions: Optimizing neuro-oncology patient management through service reconfiguration resulted in increased use of intra-operative adjuncts, improved surgical outcomes, and reduced hospital costs. These changes also have the potential to improve survival and disease-free progression for patients with GB.

Metabolite selection for machine learning in childhood brain tumour classification.

MRS can provide high accuracy in the diagnosis of childhood brain tumours when combined with machine learning. A feature selection method such as principal component analysis is commonly used to reduce the dimensionality of metabolite profiles prior to classification. However, an alternative approach of identifying the optimal set of metabolites has not been fully evaluated, possibly due to the challenges of defining this for a multi-class problem. This study aims to investigate metabolite selection from in vivo MRS for childhood brain tumour classification. Multi-site 1.5 T and 3 T cohorts of patients with a brain tumour and histological diagnosis of ependymoma, medulloblastoma and pilocytic astrocytoma were retrospectively evaluated. Dimensionality reduction was undertaken by selecting metabolite concentrations through multi-class receiver operating characteristics and compared with principal component analysis. Classification accuracy was determined through leave-one-out and k-fold cross-validation. Metabolites identified as crucial in tumour classification include myo-inositol (P < 0.05, AUC=0.81±0.01 ), total lipids and macromolecules at 0.9 ppm (P < 0.05, AUC=0.78±0.01 ) and total creatine (P < 0.05, AUC=0.77±0.01 ) for the 1.5 T cohort, and glycine (P < 0.05, AUC=0.79±0.01 ), total N-acetylaspartate (P < 0.05, AUC=0.79±0.01 ) and total choline (P < 0.05, AUC=0.75±0.01 ) for the 3 T cohort. Compared with the principal components, the selected metabolites were able to provide significantly improved discrimination between the tumours through most classifiers (P < 0.05). The highest balanced classification accuracy determined through leave-one-out cross-validation was 85% for 1.5 T 1 H-MRS through support vector machine and 75% for 3 T 1 H-MRS through linear discriminant analysis after oversampling the minority. The study suggests that a group of crucial metabolites helps to achieve better discrimination between childhood brain tumours.

Theta rhythmicity governs human behavior and hippocampal signals during memory-dependent tasks.

Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding and recall of cue-object associative memories. We find no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz). Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but significantly more for remembered than forgotten trials, providing a potential mechanistic underpinning for the theta oscillations found in behavioral responses.

The hippocampus as the switchboard between perception and memory.

Adaptive memory recall requires a rapid and flexible switch from external perceptual reminders to internal mnemonic representations. However, owing to the limited temporal or spatial resolution of brain imaging modalities used in isolation, the hippocampal-cortical dynamics supporting this process remain unknown. We thus employed an object-scene cued recall paradigm across two studies, including intracranial electroencephalography (iEEG) and high-density scalp EEG. First, a sustained increase in hippocampal high gamma power (55 to 110 Hz) emerged 500 ms after cue onset and distinguished successful vs. unsuccessful recall. This increase in gamma power for successful recall was followed by a decrease in hippocampal alpha power (8 to 12 Hz). Intriguingly, the hippocampal gamma power increase marked the moment at which extrahippocampal activation patterns shifted from perceptual cue toward mnemonic target representations. In parallel, source-localized EEG alpha power revealed that the recall signal progresses from hippocampus to posterior parietal cortex and then to medial prefrontal cortex. Together, these results identify the hippocampus as the switchboard between perception and memory and elucidate the ensuing hippocampal-cortical dynamics supporting the recall process.

Acute Confusion as an Initial Presentation of SARS-CoV-2 Infection.

BACKGROUND AND PURPOSE: The respiratory manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been extensively documented. There is emerging evidence that coronavirus disease 2019 (COVID-19) has number of other presenting features which might not be related to the severity of the respiratory disease. We have previously described a case of hypoactive delirium as the first manifestation of COVID-19 without profound lung disease. Here we present five cases of elderly patients, without a prior history of dementia and had no overt COVID-19-related pneumonia, who presented with the acute onset of delirium as the primary manifestation of COVID-19. METHODS: This retrospective, single-center study performed a health informatics search to produce a list of patients who were admitted with acute confusion and tested positive for the SARS-CoV-2 virus between March 1 and June 30, 2020. The electronic medical admission notes were screened for all patients with confusion who tested positive for SARS-CoV-2. Patients with a history of dementia and a high risk of delirium were excluded, such as severe COVID-19-related pneumonia or any other infection, malignancy, drugs, or severe illness of any kind. RESULTS: During the first wave of the COVID-19 pandemic our hospital experienced just over 3,000 SARS-CoV-2 positive patients, and 45 of them had documented confusion upon admission. Secondary causes for their acute confusion were excluded. Five patients were identified as having delirium as the initial presentation of COVID-19-related illness without significant COVID-19-related pneumonitis. None of them had overt chest symptoms or a previous history of confusion, and the 3 patients who underwent head CT scans had normal findings. CONCLUSIONS: This case series illustrates the importance of recognizing acute confusion as the first manifestation of COVID-19 in susceptible individuals.

Radiation exposure during the treatment of spinal deformities.

AIMS: To benchmark the radiation dose to patients during the course of treatment for a spinal deformity. METHODS: Our radiation dose database identified 25,745 exposures of 6,017 children (under 18 years of age) and adults treated for a spinal deformity between 1 January 2008 and 31 December 2016. Patients were divided into surgical (974 patients) and non-surgical (5,043 patients) cohorts. We documented the number and doses of ionizing radiation imaging events (radiographs, CT scans, or intraoperative fluoroscopy) for each patient. All the doses for plain radiographs, CT scans, and intraoperative fluoroscopy were combined into a single effective dose by a medical physicist (milliSivert (mSv)). RESULTS: There were more ionizing radiation-based imaging events and higher radiation dose exposures in the surgical group than in the non-surgical group (p < 0.001). The difference in effective dose for children between the surgical and non-surgical groups was statistically significant, the surgical group being significantly higher (p < 0.001). This led to a higher estimated risk of cancer induction for the surgical group (1:222 surgical vs 1:1,418 non-surgical). However, the dose difference for adults was not statistically different between the surgical and non-surgical groups. In all cases the effective dose received by all cohorts was significantly higher than that from exposure to natural background radiation. CONCLUSION: The treatment of spinal deformity is radiation-heavy. The dose exposure is several times higher when surgical treatment is undertaken. Clinicians should be aware of this and review their practices in order to reduce the radiation dose where possible. Cite this article: Bone Joint J 2021;103-B(4):1-7.

Importance and Evidence of Extent of Resection in Glioblastoma.

Maximal safe resection is an essential part of the multidisciplinary care of patients with glioblastoma. A growing body of data shows that gross total resection is an independent prognostic factor associated with improved clinical outcome. The relationship between extent of glioblastoma (GB) resection and clinical benefit depends critically on the balance between cytoreduction and avoiding neurologic morbidity. The definition of the extent of tumor resection, how this is best measured pre- and postoperatively, and its relation to volume of residual tumor is still discussed. We review the literature supporting extent of resection in GB, highlighting the importance of a standardized definition and measurement of extent of resection to allow greater collaboration in research projects and trials. Recent developments in neurosurgical techniques and technologies focused on maximizing extent of resection and safety are discussed.

Machine learning-based radiomic, clinical and semantic feature analysis for predicting overall survival and MGMT promoter methylation status in patients with glioblastoma.

INTRODUCTION: Survival varies in patients with glioblastoma due to intratumoral heterogeneity and radiomics/imaging biomarkers have potential to demonstrate heterogeneity. The objective was to combine radiomic, semantic and clinical features to improve prediction of overall survival (OS) and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status from pre-operative MRI in patients with glioblastoma. METHODS: A retrospective study of 181 MRI studies (mean age 58 ± 13 years, mean OS 497 ± 354 days) performed in patients with histopathology-proven glioblastoma. Tumour mass, contrast-enhancement and necrosis were segmented from volumetric contrast-enhanced T1-weighted imaging (CE-T1WI). 333 radiomic features were extracted and 16 Visually Accessible Rembrandt Images (VASARI) features were evaluated by two experienced neuroradiologists. Top radiomic, VASARI and clinical features were used to build machine learning models to predict MGMT status, and all features including MGMT status were used to build Cox proportional hazards regression (Cox) and random survival forest (RSF) models for OS prediction. RESULTS: The optimal cut-off value for MGMT promoter methylation index was 12.75%; 42 radiomic features exhibited significant differences between high and low-methylation groups. However, model performance accuracy combining radiomic, VASARI and clinical features for MGMT status prediction varied between 45 and 67%. For OS predication, the RSF model based on clinical, VASARI and CE radiomic features achieved the best performance with an average iAUC of 96.2 ± 1.7 and C-index of 90.0 ± 0.3. CONCLUSIONS: VASARI features in combination with clinical and radiomic features from the enhancing tumour show promise for predicting OS with a high accuracy in patients with glioblastoma from pre-operative volumetric CE-T1WI.

Multiparametric MRI: practical approach and pictorial review of a useful tool in the evaluation of brain tumours and tumour-like lesions.

MRI has a vital role in the assessment of intracranial lesions. Conventional MRI has limited specificity and multiparametric MRI using diffusion-weighted imaging, perfusion-weighted imaging and magnetic resonance spectroscopy allows more accurate assessment of the tissue microenvironment. The purpose of this educational pictorial review is to demonstrate the role of multiparametric MRI for diagnosis, treatment planning and for assessing treatment response, as well as providing a practical approach for performing and interpreting multiparametric MRI in the clinical setting. A variety of cases are presented to demonstrate how multiparametric MRI can help differentiate neoplastic from non-neoplastic lesions compared to conventional MRI alone.

Diagnosis and management of multiple sclerosis: MRI in clinical practice.

BACKGROUND: Recent changes in the understanding and management of multiple sclerosis (MS) have increased the role of MRI in supporting diagnosis and disease monitoring. However, published guidelines on the use of MRI in MS do not translate easily into different clinical settings and considerable variation in practice remains. Here, informed by published guidelines for the use of MRI in MS, we identified a clinically informative MRI protocol applicable in a variety of clinical settings, from district general hospitals to tertiary centres. METHODS: MS specialists geographically representing the UK National Health Service and with expertise in MRI examined existing guidelines on the use of MRI in MS and identification of challenges in their applications in various clinical settings informed the formulation of a feasible MRI protocol. RESULTS: We identified a minimum set of MRI information, based on clinical relevance, as well as on applicability to various clinical settings. This informed the selection of MRI acquisitions for scanning protocols, differentiated on the basis of their purpose and stage of the disease, and indication of timing for scans. Advice on standardisation of MRI requests and reporting, and proposed timing and frequency of MRI scans were generated. CONCLUSIONS: The proposed MRI protocol can adapt to a range of clinical settings, aiding the impetus towards standardisation of practice and offering an example of research-informed service improvement to support optimisation of resources. Other neurological conditions, where a gap still exists between published guidelines and their clinical implementation, may benefit from this same approach.

Prolonged confusional state as first manifestation of COVID-19.

A 77-year-old gentleman, normally fit and well, was admitted with acute confusion. On admission, Glasgow Coma Scale (GCS) was 14/15, vital signs were within the normal limits and bilateral crepitation at the lung base. Head CT scan was normal. CXR showed some air space opacification. Investigations revealed hyponatraemia, raised CRP, and positive for COVID-19. Treated with antibiotics and intravenous saline, sodium returned to normal. Delirium remained unchanged 4 weeks post-incidence. Neurological manifestations were documented in patients with COVID-19; however no report has shown delirium as a primary manifestation. This case illustrates acute confusion may be the only presenting symptom of COVID-19 without overt lung disease.

Directional coupling of slow and fast hippocampal gamma with neocortical alpha/beta oscillations in human episodic memory.

Episodic memories hinge upon our ability to process a wide range of multisensory information and bind this information into a coherent, memorable representation. On a neural level, these 2 processes are thought to be supported by neocortical alpha/beta desynchronization and hippocampal theta/gamma synchronization, respectively. Intuitively, these 2 processes should couple to successfully create and retrieve episodic memories, yet this hypothesis has not been tested empirically. We address this by analyzing human intracranial electroencephalogram data recorded during 2 associative memory tasks. We find that neocortical alpha/beta (8 to 20 Hz) power decreases reliably precede and predict hippocampal "fast" gamma (60 to 80 Hz) power increases during episodic memory formation; during episodic memory retrieval, however, hippocampal "slow" gamma (40 to 50 Hz) power increases reliably precede and predict later neocortical alpha/beta power decreases. We speculate that this coupling reflects the flow of information from the neocortex to the hippocampus during memory formation, and hippocampal pattern completion inducing information reinstatement in the neocortex during memory retrieval.

Investigation into repetitive concussion in sport (RECOS): study protocol of a prospective, exploratory, observational cohort study.

INTRODUCTION: Sport-related concussion management remains a diagnostic dilemma to clinicians in all strata of care, coaching staff and players alike. The lack of objective diagnostic and prognostic biomarkers and over-reliance on subjective clinical assessments carries a significant health risk of undiagnosed concussive episodes and early return to play before full recovery increasing the risk of sustaining additional concussion, and leading to long-term sequelae and/or unfavourable outcome. OBJECTIVE: To identify a set of parameters (neuroimaging with neurophysiological, biological and neuropsychological tests) that may support pitch-side and outpatient clinical decision-making in order to objectively diagnose concussion, determine the severity of injury, guide a safe return to play and identify the potential predictors of the long-term sequelae of concussion. METHODS AND ANALYSIS: An exploratory, observational, prospective, cohort study recruiting between 2017 and 2020. The participants will have a baseline preseason screening (brain imaging, neuropsychological assessments, serum, urine and saliva sampling). If a screened player later suffers a concussion and/or multiple concussions then he/she will be assessed again with the same protocol within 72 hours, and their baseline data will be used as internal control as well as normative data. Inferential statistical analysis will be performed to determine correlations between biological, imaging techniques and neuropsychological assessments. ETHICS AND DISSEMINATION: This study was approved by the East of England-Essex Research Ethics Committee on 22 September 2017-REC 17/EE/0275; IRAS 216703. The results of this study will be presented at national and international conferences and submitted for publication in peer reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN16974791; Pre-results.

Post-traumatic stress disorder in UK civilians with traumatic brain injury: an observational study of TBI clinic attendees to estimate PTSD prevalence and its relationship with radiological markers of brain injury severity.

OBJECTIVES: To estimate the prevalence of post-traumatic stress disorder (PTSD) in a large civilian population with traumatic brain injury (TBI), and to assess whether brain injury severity is correlated with PTSD symptoms. DESIGN: Observational, cross-sectional study. SETTING AND PARTICIPANTS: Outpatient clinic in a major UK trauma centre and secondary care hospital. Estimates of PTSD prevalence are based on 171 sampled individuals attending TBI clinic within an 18-month period. Analysis of the relationship between TBI severity and PTSD was performed on the subset of 127 patients for whom injury severity data were also available. METHODS: Civilian TBI clinic attendees completed validated self-report questionnaires assessing PTSD (PTSD Checklist Civilian Version (PCL-C)) and other psychiatric symptoms. From this, the prevalence of PTSD was estimated in our cohort. Postresuscitation Glasgow Coma Score and Marshall grade on CT brain scan were recorded as indicators of brain injury severity. A hierarchical regression explored whether TBI severity may predict PTSD scores. RESULTS: A high prevalence of PTSD was estimated (21% with PCL-C score >50). Higher Marshall grading displayed a slight negative correlation with PTSD symptoms. This statistically significant relationship persisted after confounding factors such as depression and postconcussion symptoms were controlled for. CONCLUSIONS: PTSD and TBI frequently coexist, share antecedents and overlap in their resultant symptoms. This complexity has given rise to conflicting hypotheses about relationships between the two. This research reveals that PTSD is common in civilians with TBI (adding to evidence drawn from military populations). The analysis indicated that more severe brain injury may exert a slight protective influence against the development of PTSD-potentially by disrupting implicit access to traumatic memories, or via overlapping neuropsychiatric symptoms that impede diagnosis. The association suggests that further research is warranted to explore the reuse of routine clinical and neuroimaging data-investigating its potential to predict risk of psychiatric morbidity.

Salivary MicroRNAs: Diagnostic Markers of Mild Traumatic Brain Injury in Contact-Sport.

Concussion is difficult to diagnose, particularly when symptoms are atypical or late in presenting. An accurate and timely initial assessment is crucial for clinical management. Cerebral spinal fluid (CSF) and blood markers of traumatic brain injury show promising results but their clinical applicability in concussion has significant limitations. In the study, we explored saliva as a new source of biomarkers of concussion. Saliva samples of concussed players were collected after 48-72 h from concussion and analyzed by high-throughput technologies. A discovery group of 10 concussed rugby professional and semiprofessional athletes and 10 non-concussed matched controls was used for the analysis of 92 inflammatory proteins by the Proseek-Multiplex-Inflammation technology. In addition, saliva samples of 6 concussed and 6 non-concussed athletes were used to screen 800 human microRNAs (miRNAs) by the Nanostring Technology. The results were then validated by RT-qPCR in an enlarged cohort (validation group) comprising 22 concussed athletes. Results showed, no significant variations of the 65 inflammatory proteins detected in saliva between groups but 5 microRNAs, miR-27b-3p (p = 0.016), let-7i-5p (p = 0.001), miR-142-3p (p = 0.008), miR-107 (p = 0.028), miR-135b-5p (p = 0.017) significantly upregulated in concussed athletes. Univariate ROC curve analysis showed that the differentially expressed miRNAs could be considered good classifiers of concussion. Further analyses showed significant correlation between these microRNAs and Reaction Time component of the ImPACT concussion assessment tool. In addition, biocomputation analysis predicted the involvement of these microRNAs in important biological processes that might be related to trauma, such as response to hypoxia, cell death, neurogenesis, axon repair and myelination. Ease of access and non-invasiveness of saliva samples make these biomarkers particularly suitable for concussion assessment.

The Expanding Role of Radiosurgery for Brain Metastases.

Stereotactic radiosurgery (SRS) has become increasingly important in the management of brain metastases due to improving systemic disease control and rising incidence. Initial trials demonstrated SRS with whole-brain radiotherapy (WBRT) improved local control rates compared with WBRT alone. Concerns with WBRT associated neurocognitive toxicity have contributed to a greater use of SRS alone, including for patients with multiple metastases and following surgical resection. Molecular information, targeted agents, and immunotherapy have also altered the landscape for the management of brain metastases. This review summarises current and emerging data on the role of SRS in the management of brain metastases.