IL-1ß and HMGB1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus.

BACKGROUND: The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility. METHODS: We isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it. RESULTS: 3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1ß. IL-1ß and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture. CONCLUSION: Our results demonstrate a HMGB1 and IL-1ß-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.

Neurosurgery activity levels in the United Kingdom and republic of Ireland during the first wave of the covid-19 pandemic - a retrospective cross-sectional cohort study.

The impact of Covid-19 on surgical patients worldwide has been substantial. In the United Kingdom (UK) and the Republic of Ireland (RoI), the first wave of the pandemic occurred in March 2020. The aims of this study were to: (1) evaluate the volume of neurosurgical operative activity levels, Covid-19 infection rate and mortality rate in April 2020 with a retrospective cross-sectional cohort study conducted across 16 UK and RoI neurosurgical centres, and (2) compare patient outcomes in a single institution in April-June 2020 with a comparative cohort in 2019. Across the UK and RoI, 818 patients were included. There were 594 emergency and 224 elective operations. The incidence rate of Covid-19 infection was 2.6% (21/818). The overall mortality rate in patients with a Covid-19 infection was 28.6% (6/21). In the single centre cohort analysis, an overall reduction in neurosurgical operative activity by 65% was observed between 2020 (n = 304) and 2019 (n = 868). The current and future impact on UK neurosurgical operative activity has implications for service delivery and neurosurgical training.

C-reactive protein kinetics post elective cranial surgery. A prospective observational study.

Introduction: Post cranial surgery readmission, largely caused by surgical site infection (SSI), is a marker of patient-care quality requiring comprehensive discharge planning. Currently, discharge assessment is based on clinical recovery and basic laboratory tests, including C-reactive protein (CRP). Although CRP kinetics have been examined postoperatively in a handful of papers, the validity of CRP as a standalone test to predict SSI is yet to be explored.Methods: A prospective observational study was performed on adult patients undergoing elective cranial surgery over a 3-month period. Laboratory data; CRP, white cell count (WCC), neutrophil cell count (NCC), and clinical data were assessed pre and post-operatively and were evaluated as predictors for safe discharge. Readmission rates within 1 month were recorded.Results: In this study, 68 patients were included. About 8.6% were readmitted due to SSI. A postoperativepeak in CRP was seen on day 2 with a value of 57 in the non-readmitted group, and 115 in the readmitted group. CRP dropped gradually to normal levels by day 5 in the non-readmitted group. A secondary CRP rise at day 5 was noted in the readmitted group with a sensitivity, specificity, and negative predictive value of 71%, 90%, and 96%, respectively. Interestingly, our ROC analysis indicates that a CRP value of less than 65 predicts safe discharge with a sensitivity of 86%, specificity of 89% and negative predictive value of 98% of safe discharge (area under the curve, AUC: 0.782). No significant difference in other inflammatory markers was found between both groups.Conclusions: CRP increases postoperatively for 4-5 d which could be a physiological response to surgery, however, prolonged elevation or a secondary increase in CRP may indicate an ongoing infection. Our data validate the potential use of CRP levels to predict SSI. A multicentre study is warranted to investigate the role of CRP in predicting SSI.

Unusual cause of a painless soft tissue mass of the scalp: a rare presentation of primary intracranial neuroendocrine neoplasm.

Incidental soft tissue lumps in the scalp are a common presenting complaint in clinical practice. However, they may signify more sinister underlying pathologies. Our report examines a 63-year-old man presenting with impaired co-ordination in his left hand following a 3-month history of a painless left retroauricular scalp lump. MRI revealed a large left occipital soft tissue mass eroding through the underlying skull with infiltration into the underlying cerebellum and temporal lobe. Open biopsy confirmed a diagnosis of high-grade intracranial neuroendocrine tumour (NET). At approximately 5 months following successful tumour resection and adjuvant chemotherapy, he developed tumour recurrence and was subsequently palliated, and died at 1 year post diagnosis. Herein, we review other cases of primary intracranial NET, clinical findings, histopathological features and prognosis.

Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington's disease.

Huntington's disease is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. Currently, no disease-modifying therapies are available to slow or halt disease progression. Huntington's disease is characterized by relatively focal and specific loss of striatal medium spiny neurons, which makes it suitable for cell-replacement therapy, a process involving the transplantation of donor cells to replace those lost due to disease. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration is a phase I Trial Within a Cohort designed to assess safety and feasibility of transplanting human foetal striatal cells into the striatum of people with Huntington's disease. A minimum of 18 participants will be enrolled in the study cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million foetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) 4 weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline (6 and 12 months). Surgery will be performed 1 month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Evaluation of trial processes will also be undertaken. Transplant participants and their carers will be interviewed ∼1 month before and after surgery. Interviews will also be conducted with non-transplanted participants and healthcare staff delivering the intervention and involved in the clinical care of participants. Evaluation of clinical and functional efficacy outcomes and intervention costs will be carried out to explore plausible trial designs for subsequent randomized controlled trials aimed at evaluating efficacy and cost-effectiveness of cell-replacement therapy. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration will enable the assessment of the safety, feasibility, acceptability and cost of foetal cell transplants in people with Huntington's disease. The data collected will inform trial designs for complex intra-cranial interventions in a range of neurodegenerative conditions and facilitate the development of stable surgical pipelines for delivery of future stem cell trials. Trial Registration: ISRCTN52651778.

Dual-Task Effects on Performance of Gait and Balance in People with Knee Pain: A Systematic Scoping Review.

Dual-task paradigms have been increasingly used to assess the interaction between cognitive demands and the control of balance and gait. The interaction between functional and cognitive demands can alter movement patterns and increase knee instability in individuals with knee conditions, such as knee anterior cruciate ligament (ACL) injury or osteoarthritis (OA). However, there is no consensus on the effects of dual-task on gait mechanics and balance in those individuals. This systematic scoping review aims to examine the impact of dual-task gait and standing balance on motor and cognitive performance in individuals with knee OA or ACL injury. A comprehensive search of MEDLINE, PubMed, Web of Science, and EMBASE electronic databases up until December 2019 was carried out. Inclusion criteria was limited to include dual-task studies that combined cognitive tasks performed simultaneously with gait or standing balance in individuals with knee OA or ACL injuries. In total, fifteen studies met the inclusion criteria, nine articles examined dual-task effects on balance, and six articles reported the effects of dual-task on gait. The total number of individuals included was 230 individuals with ACL injuries, and 168 individuals with knee OA. A decline in gait and balance performance during dual-task testing is present among individuals with ACL injury and/or ACL reconstruction and knee OA. Further research is required, but dual taking assessment could potentially be used to identify individuals at risk of falling or further injury and could be used to develop targeted rehabilitation protocols. A variety of outcome measures have been used across the studies included, making comparisons difficult. The authors, therefore, recommend developing a standardized set of biomechanical balance variables.

Effect of Steroid Therapy on Risk of Subsequent Surgery for Neurologically Stable Chronic Subdural Hemorrhage-Retrospective Cohort Study and Literature Review.

BACKGROUND: Chronic subdural hemorrhage (CSDH) is a common neurosurgical pathology. While acute deterioration is managed surgically, the optimal management of patients with neurologically stable CSDH remains uncertain. Despite an increasing interest in the use of corticosteroids, it is unclear whether this reduces the rate of subsequent crossover to surgery. In this study we evaluate rate of crossover to surgery in such patients managed in our Neurosurgical unit. METHODS: A retrospective database search over a 2-year period was performed. A multi-database literature review was also conducted to identify relevant articles reporting rate of subsequent surgery in CSDH patients managed with corticosteroids. RESULTS: A total of 532 CSDH patients were identified. Subsequently, a total of 364 patients who were managed conservatively were included for further analysis. The majority (315 patients; 59.1%) were managed conservatively. Forty-nine patients (9.2%) received steroids as first-line treatment. There was considerable variation in steroid dosing regimens, with the commonest involving 4 mg dexamethasone three times daily for 5 days. Four patients in the steroid group required subsequent surgery (8.2%), compared with 22 conservatively managed patients (7.0%). Statistical analysis revealed no significant difference in the rate of surgery (chi-square 0.089, difference 1, P = 0.77). CONCLUSIONS: Current evidence implicates a potentially beneficial role of dexamethasone in the management of CSDH. However, it remains unclear whether the rate of crossover to surgery is reduced in patients treated with corticosteroids compared with those managed conservatively. A longer duration of study with detailed analysis of individual cases and appropriately randomized cohorts are necessary to draw more reliable conclusions.

Glycyrrhizin Blocks the Detrimental Effects of HMGB1 on Cortical Neurogenesis After Traumatic Neuronal Injury.

Despite medical advances, neurological recovery after severe traumatic brain injury (TBI) remains poor. Elevated levels of high mobility group box protein-1 (HMGB1) are associated with poor outcomes; likely via interaction with receptors for advanced-glycation-end-products (RAGE). We examined the hypothesis that HMGB1 post-TBI is anti-neurogenic and whether this is pharmacologically reversible. Post-natal rat cortical mixed neuro-glial cell cultures were subjected to needle-scratch injury and examined for HMGB1-activation/neuroinflammation. HMGB1-related genes/networks were examined using genome-wide RNA-seq studies in cortical perilesional tissue samples from adult mice. Post-natal rat cortical neural stem/progenitor cell cultures were generated to quantify effects of injury-condition medium (ICM) on neurogenesis with/without RAGE antagonist glycyrrhizin. Needle-injury upregulated TNF-α/NOS-2 mRNA-expressions at 6 h, increased proportions of activated microglia, and caused neuronal loss at 24 h. Transcriptome analysis revealed activation of HMGB1 pathway genes/canonical pathways in vivo at 24 h. A 50% increase in HMGB1 protein expression, and nuclear-to-cytoplasmic translocation of HMGB1 in neurons and microglia at 24 h post-injury was demonstrated in vitro. ICM reduced total numbers/proportions of neuronal cells, but reversed by 0.5 µM glycyrrhizin. HMGB1 is activated following in vivo post mechanical injury, and glycyrrhizin alleviates detrimental effects of ICM on cortical neurogenesis. Our findings highlight glycyrrhizin as a potential therapeutic agent post-TBI.

Risk factors for the development of seizures after cranioplasty in patients that sustained traumatic brain injury: A systematic review.

Decompressive craniectomy (DC) is used for the treatment of raised intracranial pressure secondary to traumatic brain injury. Cranioplasty is a reconstructive procedure that restores the structural integrity of the skull following (DC). Seizures are a recognised complication of cranioplasty but its incidence and risk factors in TBI patients are unclear. Accurate prognostication can help direct prophylactic and treatment strategies for seizures. In this systematic review, we aim to evaluate current literature on these factors. A PROSPERO-registered systematic review was performed in accordance with PRISMA guidelines. Data was synthesised qualitatively and quantitatively in meta-analysis where appropriate. A total of 8 relevant studies were identified, reporting 919 cranioplasty patients. Random-effects meta-analysis reveals a pooled incidence of post-cranioplasty seizures (PCS) of 5.1% (95% CI 2.6-8.2%). Identified risk factors from a single study included increasing age (OR 6.1, p = 0.006), contusion at cranioplasty location (OR 4.8, p = 0.015), and use of monopolar diathermy at cranioplasty (OR 3.5, p = 0.04). There is an association between an extended DC-cranioplasty interval and PCS risk although it did not reach statistical significance (p = 0.062). Predictive factors for PCS are poorly investigated in the TBI population to date. Heterogeneity of included studies preclude meta-analysis of risk factors. Further studies are required to define the true incidence of PCS in TBI and its predictors, and trials are needed to inform management of these patients.

Analysis of neuro-theatre utilisation and reasons for cancellation to improve efficiency and productivity.

In neurosurgery, much emphasis has recently been placed on theatre cancellation and time utilization as a key hospital management performance indicator. We sought to evaluate our unit's theatre throughput efficiency and identify the causes of elective surgery cancellations. We retrospectively audited all scheduled elective neurosurgical procedures over a period of nine months. Mean theatre utilization time was 47.0%. The common causes of cancellations were lack of theatre time (32%), non-availability of beds in recovery room (18.6%), and insufficient preoperative patient preparation (5.5%). Inefficiencies were noted in turnover of patients and inaccurate prediction of operative time. Our theatre utilization time is consistent with available literature; however, cancellations of elective surgery waste valuable operative time and resources. The study concludes that a multi-dimensional approach must be taken to improve theatre utilization and reduce cancellation rates. A pre-assessment clinic has been introduced in order to reduce cancellation rates.