The role of decompressive craniectomy following microsurgical repair of a ruptured aneurysm: Analysis of a South Australian cerebrovascular registry.

OBJECTIVE: Decompressive craniectomy (DC) remains a controversial intervention for intracranial hypertension among patients with aneurysmal subarachnoid haemorrhage (aSAH). METHODS: We identified aSAH patients who underwent DC following microsurgical aneurysm repair from a prospectively maintained registry and compared their outcomes with a propensity-matched cohort who did not. Logistic regression was used to identify predictors of undergoing decompressive surgery and post-operative outcome. Outcomes of interest were inpatient mortality, unfavourable outcome, NIS-Subarachnoid Hemorrhage Outcome Measure and modified Rankin Score (mRS). RESULTS: A total of 246 patients with aSAH underwent clipping of the culprit aneurysm between 01/09/2011 and 20/07/2020. Of these, 46 underwent DC and were included in the final analysis. Unsurprisingly, DC patients had a greater chance of unfavourable outcome (p < 0.001) and higher median mRS (p < 0.001) at final follow-up. Despite this, almost two-thirds (64.1 %) of DC patients had a favourable outcome at this time-point. When compared with a propensity-matched cohort who did not, patients treated with DC fared worse at all endpoints. Multivariable logistic regression revealed that the presence of intracerebral haemorrhage and increased pre-operative mid-line shift were predictive of undergoing DC, and WFNS grade ≥ 4 and a delayed ischaemic neurological deficit requiring endovascular angioplasty were associated with an unfavourable outcome. CONCLUSIONS: Our data suggest that DC can be performed with acceptable rates of morbidity and mortality. Further research is required to determine the superiority, or otherwise, of DC compared with structured medical management of intracranial hypertension in this context, and to identify predictors of requiring decompressive surgery and patient outcome.

Early minimally invasive intracerebral hemorrhage evacuation: a phase 2a feasibility, safety, and promise of surgical efficacy study.

BACKGROUND: Surgical treatment of intracerebral hemorrhage (ICH) is unproven, although meta-analyses suggest that both early conventional surgery with craniotomy and minimally invasive surgery (MIS) may be beneficial. We aimed to demonstrate the safety, feasibility, and promise of efficacy of early MIS for ICH using the Aurora Surgiscope and Evacuator. METHODS: We performed a prospective, single arm, phase IIa Simon's two stage design study at two stroke centers (10 patients with supratentorial ICH volumes ≥20 mL and National Institutes of Health Stroke Scale (NIHSS) score of ≥6, and surgery commencing <12 hours after onset). Positive outcome was defined as ≥50% 24 hour ICH volume reduction, with the safety outcome lack of significant ICH reaccumulation. RESULTS: From December 2019 to July 2020, we enrolled 10 patients at two Australian Comprehensive Stroke Centers, median age 70 years (IQR 65-74), NIHSS score 19 (IQR 19-29), ICH volume 59 mL (IQR 25-77), at a median of 227 min (IQR 175-377) post-onset. MIS was commenced at a median time of 531 min (IQR 437-628) post-onset, had a median duration of 98 min (IQR 77-110), with a median immediate postoperative hematoma evacuation of 70% (IQR 67-80%). A positive outcome was achieved in 5/5 first stage patients and in 4/5 second stage patients. One patient developed significant 24 hour ICH reaccumulation; otherwise, 24 hour stability was observed (median reduction 71% (IQR 61-80), 5/9 patients <15 mL residual). Three patients died, unrelated to surgery. There were no surgical safety concerns. At 6 months, the median modified Rankin Scale score was 4 (IQR 3-6) with 30% achieving a score of 0-3. CONCLUSION: In this study, early ICH MIS using the Aurora Surgiscope and Evacuator appeared to be feasible and safe, warranting further exploration. TRIAL REGISTRATION NUMBER: ACTRN12619001748101.

Should We Lose Sleep Over Sleep Disturbances After Sports-Related Concussion? A Scoping Review of the Literature.

OBJECTIVE: A single, severe traumatic brain injury can result in chronic sleep disturbances that can persist several years after the incident. In contrast, it is unclear whether there are sleep disturbances after a sports-related concussion (SRC). Considering growing evidence of links between sleep disturbance and neurodegeneration, this review examined the potential links between diagnosed SRCs and sleep disturbances to provide guidance for future studies. METHODS: The scoping review undertook a systematic search of key online databases (Scopus, MEDLINE, SportDiscus, and Web of Science) using predetermined search terms for any articles that examined sleep after concussion. A screening criterion using agreed inclusion and exclusion criteria was utilized to ensure inclusion of relevant articles. DESIGN: This scoping review is guided by the PRSIMA Scoping Review report. RESULTS: Ten studies met the inclusion criteria, reporting on 896 adults who had experienced an SRC. Comparison with 1327 non-SRC adults occurred in 8 studies. Nine studies subjectively examined sleep, of which all but one study reported sleep disturbances after an SRC. Three studies objectively measured sleep, with 2 studies indicating large coefficients of variation of sleep duration, suggesting a range of sleep responses after an SRC. The only study to examine overnight polysomnography showed no differences in sleep metrics between those with and without an SRC. No studies examined interventions to improve sleep outcomes in people with concussion. CONCLUSIONS: This scoping review indicates preliminary evidence of sleep disturbances following an SRC. The heterogeneity of methodology used in the included studies makes consensus on the results difficult. Given the mediating role of sleep in neurodegenerative disorders, further research is needed to identify physiological correlates and pathological mechanisms of sleep disturbances in SRC-related neurodegeneration and whether interventions for sleep problems improve recovery from concussion and reduce the risk of SRC-related neurodegeneration.

Evaluating spatiotemporal microstructural alterations following diffuse traumatic brain injury.

BACKGROUND: Diffuse traumatic brain injury (TBI) is known to lead to microstructural changes within both white and grey matter detected in vivo with diffusion tensor imaging (DTI). Numerous studies have shown alterations in fractional anisotropy (FA) and mean diffusivity (MD) within prominent white matter tracts, but few have linked these to changes within the grey matter with confirmation via histological assessment. This is especially important as alterations in the grey matter may be predictive of long-term functional deficits. METHODS: A total of 33 male Sprague Dawley rats underwent severe closed-head TBI. Eight animals underwent tensor-based morphometry (TBM) and DTI at baseline (pre-TBI), 24 hours (24 h), 7, 14, and 30 days post-TBI. Immunohistochemical analysis for the detection of ionised calcium-binding adaptor molecule 1 (IBA1) to assess microglia number and percentage of activated cells, ß-amyloid precursor protein (APP) as a marker of axonal injury, and myelin basic protein (MBP) to investigate myelination was performed at each time-point. RESULTS: DTI showed significant alterations in FA and RD in numerous white matter tracts including the corpus callosum, internal and external capsule, and optic tract and in the grey-matter in the cortex, thalamus, and hippocampus, with the most significant effects observed at 14 D post-TBI. TBM confirmed volumetric changes within the hippocampus and thalamus. Changes in DTI were in line with significant axonal injury noted at 24 h post-injury via immunohistochemical analysis of APP, with widespread microglial activation seen within prominent white matter tracts and the grey matter, which persisted to 30 D within the hippocampus and thalamus. Microstructural alterations in MBP+ve fibres were also noted within the hippocampus and thalamus, as well as the cortex. CONCLUSION: This study confirms the widespread effects of diffuse TBI on white matter tracts which could be detected via DTI and extends these findings to key grey matter regions, with a comprehensive investigation of the whole brain. In particular, the hippocampus and thalamus appear to be vulnerable to ongoing pathology post-TBI, with DTI able to detect these alterations supporting the clinical utility in evaluating these regions post-TBI.

The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury.

Following traumatic brain injury (TBI) neurological damage is ongoing through a complex cascade of primary and secondary injury events in the ensuing minutes, days and weeks. The delayed nature of secondary injury provides a valuable window of opportunity to limit the consequences with a timely treatment. Recently, the amyloid precursor protein (APP) and its derivative APP96-110 have shown encouraging neuroprotective activity following TBI following an intracerebroventricular administration. Nevertheless, its broader clinical utility would be enhanced by an intravenous (IV) administration. This study assessed the efficacy of IV APP96-110, where a dose-response for a single dose of 0.005mg/kg- 0.5mg/kg APP96-110 at either 30 minutes or 5 hours following moderate-severe diffuse impact-acceleration injury was performed. Male Sprague-Dawley rats were assessed daily for 3 or 7 days on the rotarod to examine motor outcome, with a separate cohort of animals utilised for immunohistochemistry analysis 3 days post-TBI to assess axonal injury and neuroinflammation. Animals treated with 0.05mg/kg or 0.5mg/kg APP96-110 after 30 minutes demonstrated significant improvements in motor outcome. This was accompanied by a reduction in axonal injury and neuroinflammation in the corpus callosum at 3 days post-TBI, whereas 0.005mg/kg had no effect. In contrast, treatment with 0.005m/kg or 0.5mg/kg APP96-110 at 5 hours post-TBI demonstrated significant improvements in motor outcome over 3 days, which was accompanied by a reduction in axonal injury in the corpus callosum. This demonstrates that APP96-110 remains efficacious for up to 5 hours post-TBI when administered IV, and supports its development as a novel therapeutic compound following TBI.

The Neuroprotective Properties of the Amyloid Precursor Protein Following Traumatic Brain Injury.

Despite the significant health and economic burden that traumatic brain injury (TBI) places on society, the development of successful therapeutic agents have to date not translated into efficacious therapies in human clinical trials. Injury to the brain is ongoing after TBI, through a complex cascade of primary and secondary injury events, providing a valuable window of opportunity to help limit and prevent some of the severe consequences with a timely treatment. Of note, it has been suggested that novel treatments for TBI should be multifactorial in nature, mimicking the body's own endogenous repair response. Whilst research has historically focused on the role of the amyloid precursor protein (APP) in the pathogenesis of Alzheimer's disease, recent advances in trauma research have demonstrated that APP offers considerable neuroprotective properties following TBI, suggesting that APP is an ideal therapeutic candidate. Its acute upregulation following TBI has been shown to serve a beneficial role following trauma and has lead to significant advances in understanding the neuroprotective and neurotrophic functions of APP and its metabolites. Research has focused predominantly on the APP derivative sAPPα, which has consistently demonstrated neuroprotective and neurotrophic functions both in vitro and in vivo following various traumatic insults. Its neuroprotective activity has been narrowed down to a 15 amino acid sequence, and this region is linked to both heparan binding and growth-factor-like properties. It has been proposed that APP binds to heparan sulfate proteoglycans to exert its neuroprotective action. APP presents us with a novel therapeutic compound that could overcome many of the challenges that have stalled development of efficacious TBI treatments previously.