Narrative review of roles of astrocytes in subarachnoid hemorrhage.

Background and Objective: Astrocytes play an important role in healthy brain function, including the development and maintenance of blood-brain barrier (BBB), structural support, brain homeostasis, neurovascular coupling and secretion of neuroprotective factors. Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH) including neuroinflammation, glutamate toxicity, brain edema, vasospasm, BBB disruption, cortical spreading depolarization (SD). Methods: We searched PubMed up to 31 May, 2022 and evaluated the articles for screening and inclusion for subsequent systemic review. We found 198 articles with the searched terms. After exclusion based on the selection criteria, we selected 30 articles to start the systemic review. Key Content and Findings: We summarized the response of astrocytes induced by SAH. Astrocytes are critical for brain edema formation, BBB reconstruction and neuroprotection in the acute stage of SAH. Astrocytes clear extracellular glutamate by increasing the uptake of glutamate and Na+/K+ ATPase activity after SAH. Neurotrophic factors released by astrocytes contribute to neurological recovery after SAH. Meanwhile, Astrocytes also form glial scars which hinder axon regeneration, produce proinflammatory cytokines, free radicals, and neurotoxic molecules. Conclusions: Preclinical studies showed that therapeutic targeting the astrocytes response could have a beneficial effect in ameliorating neuronal injury and cognitive impairment after SAH. Clinical trials and preclinical animal studies are still urgently needed in order to determine where astrocytes stand in various pathway of brain damage and repair after SAH and, above all, to develop therapeutic approaches which benefit patient outcomes.

PHIL and Squid Embolization of Cerebral Arteriovenous Malformation: A Retrospective Case Series of 23 Patients.

Precipitating hydrophobic injectable liquid (PHIL; MicroVention, Aliso Viejo, CA, USA) and Squid (Balt, Irvine, CA, USA) are 2 newer liquid embolic agents used in endovascular embolization of cerebral arteriovenous malformation (AVM). This study aims to investigate and compare the effectiveness and safety profile of the 2 newer liquid embolic agents in the embolization of cerebral AVM. This is a retrospective study on all patients diagnosed with cerebral AVM undergoing endovascular embolization with liquid embolic agents PHIL and Squid admitted to the Division of Neurosurgery, Department of Surgery in Prince of Wales Hospital from January 2014 to June 2021. Twenty-three patients with cerebral AVM were treated with 34 sessions of endovascular embolization with either PHIL or Squid (17 sessions each) liquid embolic agents with a male to female ratio of 2.3:1 (male 16; female 7) and mean age of 44.6 (range, 12 to 67). The mean total nidus obliteration rate per session was 57% (range, 5% to 100%). Twenty-one patients (91.3%) received further embolization, stereotactic radiosurgery, or surgical excision after initial endovascular embolization. There were 2 morbidities (1 neurological and 1 non-neurological, 6%) and no mortalities (0%). All patients had static or improvement in modified Rankin Scale at 3 to 6 months at discharge. PHIL and Squid are effective and safe liquid embolic agents for endovascular embolization of cerebral AVM, achieving satisfactory nidal obliteration rates and patient functional outcomes.

ABC/2 formula for "bedside" postoperative pneumocephalus volume measurement.

BACKGROUND: Postoperative pneumocephalus is associated with a higher risk of recurrence of chronic subdural hematoma (cSDH). However, there is no verified simple way to measure the pneumocephalus volume at the bedside for daily clinical use. The ABC/2 method was shown to be a simple and reliable technique to estimate volumes of intracranial lesions, such as intracranial hematomas. This study aims to evaluate the accuracy of the ABC/2 formula in estimating volumes of pneumocephalus, as compared to the gold standard with computer-assisted volumetric analysis. METHODS: A total of 141 postoperative computed tomographic (CT) brain scans of cSDH patients with burr-hole drainage were analysed. Pneumocephalus volume was measured independently by both the ABC/2 formula and the computer-assisted volumetric measurement. For the computer-assisted measurement, the volume of the air was semiautomatically segmented and calculated by computer software. Linear regression was used to determine the correlation between the ABC/2 method and computer-assisted measurement. RESULTS: The postoperative pneumocephalus volume after bilateral burr-hole drainage was significantly larger than that of unilateral burr-hole drainage (29.34 ml versus 12.21 ml, p < 0.001). The estimated volumes by the formula ABC/2 significantly correlated to the volumes as measured by the computer-assisted volumetric technique, with r = 0.992 (p < 0.001). The Pearson correlation coefficient is very close to 1, which signifies a very strong positive correlation, and it is statistically significant. CONCLUSIONS: An excellent correlation is observed between the ABC/2 method and the computer-assisted measurement. This study verified that the ABC/2 method is an accurate and simple "bedside" technique to estimate pneumocephalus volume.

Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury.

Over the last two decades, neurological researchers have uncovered many pathophysiological mechanisms associated with subarachnoid haemorrhage (SAH), with early brain injury and delayed cerebral ischaemia both contributing to morbidity and mortality. The current dilemma in SAH management inspired us to rethink the nature of the insult in SAH: sudden bleeding into the subarachnoid space and hypoxia due to disturbed cerebral circulation and increased intracranial pressure, generating exogenous stimuli and subsequent pathophysiological processes. Exogenous stimuli are defined as factors which the brain tissue is not normally exposed to when in the healthy state. Intersections of these initial pathogenic factors lead to secondary brain injury with related metabolic changes after SAH. Herein, we summarized the current understanding of efforts to monitor and analyse SAH-related metabolic changes to identify those precise pathophysiological processes and potential therapeutic strategies; in particular, we highlight the restoration of normal cerebrospinal fluid circulation and the normalization of brain-blood interface physiology to alleviate early brain injury and delayed neurological deterioration after SAH.

Univariate and Multivariable Analyses on Independent Predictors for Cervical Spinal Injury in Patients with Head Injury.

OBJECTIVE: This study aims to identify independent factors associated with cervical spinal injuries in head-injured patients. The extent of injuries to other body parts was assessed by the Abbreviated Injury Scale (AIS) and was included in the analysis. METHODS: Consecutive head-injured patients admitted via the emergency department from January 1, 2014 to December 31, 2016 were retrospectively reviewed. The inclusion criteria were head-injured patients with an Abbreviated Injury Scale (AIS) score ≥2 (i.e., head injuries with intracranial hematoma or skull fracture). Patients with minor head injuries with only scalp abrasions or superficial lacerations without significant intracranial injuries (i.e., head injury AIS score = 1) were excluded. The primary outcome was to identify independent predictors associated with cervical spinal injuries in these head-injured patients. Univariate and multivariable analyses were conducted. RESULTS: A total of 1105 patients were identified. Of these patients, 11.2% (n = 124) had cervical spinal injuries. Univariate and multivariable analyses identified male gender (P = 0.006), the presence of thoracic injury (including rib fracture, hemothorax, or pneumothorax) (P = 0.010), and hypotension with systolic blood pressure <90 mm Hg on admission (P = 0.009) as independent predictors for cervical spinal injury in head-injured patients. CONCLUSIONS: This study showed that about 1 in 10 patients with significant head injury had cervical spine injury, usually associated with fracture or dislocation. Male gender, the presence of thoracic injury, and hypotension on admission were independent risk factors associated with cervical spinal injuries.

A Continuum Robotic Cannula With Tip Following Capability and Distal Dexterity for Intracerebral Hemorrhage Evacuation.

OBJECTIVE: This paper aims to investigate a new continuum robot design and its motion implementation methods appropriate for a minimally invasive intracerebral hemorrhage (ICH) evacuation. METHODS: We propose a continuum robotic cannula, consisting of a precurved body and a 2-degree-of-freedom (DoF) flexible tip, monolithically fabricated. Kinematic model with cable elongation model, and a dedicated design optimization and motion planning algorithm were developed to enable the follow-the-leader (FTL) motion of the cannula. A task-dependent Jacobian-based closed loop control was also designed to track the cannula motion during the insertion and its independent tip motion. RESULTS: Comprehensive experiments were conducted to verify the kinematic model and submillimeter motion coupling between the cannula precurved body and its flexible tip. The cannula was also capable of achieving FTL motion within around 2.5 mm shape deviation and control performance within submillimeter errors. It was finally demonstrated to be capable of the nonlinear insertion and tip manipulation in the brain phantom. CONCLUSION: The new cannula design, together with the proposed algorithms, provides the unique ability to access ICH in a nonlinear trajectory and dexterous tip motion. SIGNIFICANCE: These motion capabilities of the robot in such a slender form factor will lead to more complete ICH evacuation and reduced trauma to the healthy brain tissues.

Microglia activation, classification and microglia-mediated neuroinflammatory modulators in subarachnoid hemorrhage.

Subarachnoid hemorrhage is a devastating disease with significant mortality and morbidity, despite advances in treating cerebral aneurysms. There has been recent progress in the intensive care management and monitoring of patients with subarachnoid hemorrhage, but the results remain unsatisfactory. Microglia, the resident immune cells of the brain, are increasingly recognized as playing a significant role in neurological diseases, including subarachnoid hemorrhage. In early brain injury following subarachnoid hemorrhage, microglial activation and neuroinflammation have been implicated in the development of disease complications and recovery. To understand the disease processes following subarachnoid hemorrhage, it is important to focus on the modulators of microglial activation and the pro-inflammatory/anti-inflammatory cytokines and chemokines. In this review, we summarize research on the modulators of microglia-mediated inflammation in subarachnoid hemorrhage, including transcriptome changes and the neuroinflammatory signaling pathways. We also describe the latest developments in single-cell transcriptomics for microglia and summarize advances that have been made in the transcriptome-based classification of microglia and the implications for microglial activation and neuroinflammation.

Establishment and characterization of meningioma patient-derived organoid.

Meningioma is a central nervous system tumor originated from arachnoid cells. 2D cell culture is widely used as a platform for tumor research as it enables us to culture cells in in vitro and a controlled environment. However, in 2D culture condition, 3D architecture of in vivo tumor mass is lost and phenotypic change may occur. Due to the drawbacks of 2D cell culture, organoid culture is seen as an alternative platform for disease modeling, drug testing and personalized medicine. The objective of this study was to establishing protocol for culturing cells from patient meningioma tissue in in vitro 3D environment. Eight meningiomas were collected for the 3D organoid culture. Cells of 5 meningioma tissues survived and proliferated. Under 3D culture condition, cell aggregates were formed and cytoplasmic processes linking the cell aggregates could be observed. In H&E staining, ovaloid cells and spindle cells were observed. Resembling cultured organoids observed under the light microscope, cell aggregates were also observed in the H&E staining. Epithelial Membrane Antigen (EMA) staining was positive. In 4 (80%) cultured organoids, low Ki67 index (≤6%) were measured. In one cultured organoid, a high Ki67 index (12.8%) was seen. The result of this study revealed the feasibility of culturing meningioma cells in in vitro 3D culture condition. Organoid technology showed its potential as an alternative platform for meningioma research.

Tracheostomy decannulation outcomes in 131 consecutive neurosurgical patients.

OBJECTIVES: This study was a retrospective study to investigate factors related to difficult tracheostomy decannulation, and to evaluate outcomes of tracheostomized neurosurgical patients. METHODS: All consecutive tracheostomized neurosurgical patients in the Prince of Wales Hospital between 1st September 2016 and 31st August 2019 were reviewed retrospectively. Patients were grouped into easy decannulation and difficult decannulation groups using 3 months as cut-off time. Risk factors were analysed and outcomes were compared. RESULTS: One hundred thirty-one patients were included. In univariate analyses, male gender, GCS less than or equal to 8 on admission, the presence of vocal cord palsy at 3 months, and pneumonia within 1-month post-tracheostomy were associated with difficult decannulation. In multivariable logistic regression for difficult decannulation, GCS on admission, the presence of vocal cord palsy at 3 months, and the presence of pneumonia within 1-month post-tracheostomy remained statistically significant. The easy decannulation group had a shorter length of in-patient stay, higher survival rate, and more favourable neurological outcome (GOS 4-5) than the difficult decannulation group at both 6 months and 1 year. The majority of easy decannulation group patients (54%) were discharged to home, while the majority of the difficult decannulation group (42%) of patients were discharged to the infirmary. CONCLUSION: GCS less than or equal to 8 on admission, the presence of vocal cord palsy, and the presence of pneumonia were associated with difficult tracheostomy decannulation in neurosurgical patients. Difficult decannulation is associated with a longer length of in-patient stay and poor neurological outcomes.

Predictive factors for bleeding carotid artery pseudoaneurysms in patients with previous radiations for head and neck cancers.

BACKGROUND: Bleeding from carotid artery pseudoaneurysms is an emergency condition with high morbidity and mortality. We aimed to identify risk factors predicting pseudoaneurysmal bleeding as the cause of profuse epistaxis in irradiated head and neck cancer patients with suspect carotid blowout or pseudoaneurysms. METHODS: We retrospectively reviewed consecutive patients with history of radiation therapy for head and neck cancers and with nasal, oral or ear bleeding requiring in-patient treatment from hospital database. Pseudoaneurysms were subgrouped into internal carotid artery (ICA) pseudoaneurysms, and external carotid artery (ECA) pseudoaneurysms. The treatment outcomes were evaluated using 30-day mortality rate, recurrent bleeding, and cerebral infarction. RESULTS: There were 41 admissions for suspected carotid blowout or pseudoaneurysms from 1 July 2016 to 30 June 2020 with 17 bleeding pseudoaneurysms identified, including 11 internal carotid arteries (ICA) pseudoaneurysms and 6 external carotid arteries (ECA) pseudoaneurysms. Among ICA pseudoaneurysms, six patients passed Balloon occlusion test with embolization and parent artery occlusion (trapping) of ICA performed, and all ECA pseudoaneurysms were embolized with parent artery occlusion (trapping). Baseline hypertension and hypotension on arrival were predictive for pseudoaneurysmal bleeding. The degree of haemoglobin drop was not significantly different between pseudoaneurysmal bleeding and non-pseudoaneurysmal bleeding (2.1 ± 1.4 g/dL vs. 1.6 ± 1.4 g/dL, p = 0.234). CONCLUSIONS: We identified baseline hypertension and hypotension on arrival as predictive factors for pseudoaneurysmal bleeding in patients with irradiated head and neck cancer. Presence of these risk factors should alert the clinicians to the possibility of carotid pseudoaneurysms.

Integrated analysis of gait parameters and gene expression profiles in a murine model of subarachnoid hemorrhage.

Gait analysis has been widely used to examine the behavioral presentation of numerous neurological disorders. Thorough murine model evaluation of the subarachnoid hemorrhage (SAH)-associated gait deficits is missing. This study measures gait deficits using a clinically relevant murine model of SAH to examine associations between gait variability and SAH-associated gene expressions. A total of 159 dynamic and static gait parameters from the endovascular perforation murine model for simulating clinical human SAH were determined using the CatWalk system. Eighty gait parameters and the mRNA expression levels of 35 of the 88 SAH-associated genes were differentially regulated in the diseased models. Totals of 42 and 38 gait parameters correlated with the 35 SAH-associated genes positively and negatively with Pearson's correlation coefficients of >0.7 and <-0.7, respectively. p-SP1453 expression in the motor cortex in SAH animal models displays a significant correlation with a subset of gait parameters associated with muscular strength and coordination of limb movements. Our data highlights a strong correlation between gait variability and SAH-associated gene expression. p-SP1453 expression could act as a biomarker to monitor SAH pathological development and a therapeutic target for SAH.

Chronic subdural haematoma during the COVID-19 lockdown period: late presentation with a longer interval from the initial head injury to the final presentation and diagnosis.

BACKGROUND: The COVID-19 novel coronavirus is contagious, and the mortality is higher in the elderly population. Lockdown in different parts of the world has been imposed since January 2020. Chronic subdural haematoma (cSDH) has a unique natural history in which symptoms can be non-specific, and the onset is insidious. This study aims to evaluate the impact of the COVID-19 pandemic on the presentation of cSDH. METHODS: Consecutive adult cSDH patients admitted from 1 March 2020 to 30 April 2020 were reviewed. Exclusion criteria including those who had no definite history of head injury or the diagnosis of cSDH were made from a scheduled follow-up scan. Corresponding data during the same period in 2019 were reviewed for comparison. The primary outcome was the interval between the initial head injury and the final radiological diagnosis of cSDH. Secondary outcomes include Markwalder chronic subdural haematoma grade upon admission, length of stay in the acute hospital, and the modified Rankin scale (mRS) upon discharge. RESULTS: For the primary outcome, the average interval between head injury and the diagnosis of cSDH was significantly longer at 56.6 days (49 to 74 days, SD 9.83 days) during the period from March to April 2020, versus 29.4 days (17 to 42 days, SD 8.59 days) in 2019 for the corresponding period (p = 0.00703). There was no significant difference in the functional outcome upon discharge. CONCLUSIONS: cSDH patients can present late during the COVID-19 lockdown period. The functional outcome was comparable when operations for drainage were timely performed.

Development of a Delayed Cerebral Infarction Load Scoring System (DCI Score).

Delayed cerebral infarction (DCI) is related to unfavorable outcome after aneurysmal subarachnoid hemorrhage (SAH). There lacks a clear understanding how the DCI load affects cognitive function after SAH. We conducted a literature review on the clinical classification systems on brain hemorrhages and cerebral infarction and devised a Delayed Cerebral Infarction Load Scoring System (DCI Score). DCI Score significantly correlated with Symbol Digit Modalities Test (-0.334, p = 0.032), Color Trail Test (-0.310, p = 0.032), Hong Kong List Learning Test (-0.318, p = 0.036), Verbal Digit Span Forward (-0.382, p = 0.017), and Visual Digit Span Backward (-0.425, p = 0.012). In conclusion, higher DCI load impacted significantly on memory and executive function. DCI Score is a useful system for clinical quantification of DCI load and clinical research.

Topically applied adipose-derived mesenchymal stem cell treatment in experimental focal cerebral ischemia.

In this study, the neuro-modulation effect of topical mesenchymal stem cells (MSCs) was tested in a rodent middle carotid artery occlusion (MCAO) model. Twenty-four hours after MCAO, craniotomy was made and 0.8 × 106 GFP-MSCs were topically applied to the exposed parietal cortex. The MSCs were fixed in position by a thin layer of fibrin glue (N = 30). In the control group, saline were topically applied to the ipsilateral parietal cortex (N = 30). Three days after topical application, few GFP-positive cells were found in the ischemic penumbra. They expressed GFAP and NeuN. Topical MSCs triggered microglial activation, astrocytosis and cellular proliferation at day 3. The recovery of neurological functions were significantly enhanced as determined in Rotarod test and Morris Water Maze test with smaller infarct volume. PCR array showed that expressions of ten genes of neurogenesis were altered in the penumbra region (fold change > 1.25, p < 0.05) in MSCs group: Apoe, Ascl1, Efnb1, Mef2c, Nog, A100a6 and B2m were up-regulated; Pax2, Pax3 and Th were down-regulated. In conclusion, topical application provided a direct and effective transplant method for the delivery of MSCs to the surface of ipsilateral cerebral cortex and the topical MSCs could improve the neurological function from cerebral ischemia resulting from a major cerebral artery occlusion in a rodent experimental model.

The Dynamics of Microglial Polarization Reveal the Resident Neuroinflammatory Responses After Subarachnoid Hemorrhage.

Neuroinflammation plays a critical role in the pathogenesis of subarachnoid hemorrhage (SAH). Microglia, as the resident immune cells, orchestrate neuroinflammation distinctly in neurological diseases with different polarization statuses. However, microglial polarizations in the neuroinflammatory responses after SAH are not fully understood. In this study, we investigated the dynamics of microglial reaction in an endovascular perforated SAH model. By using the Cx3cr1GFP/GFP Ccr2RFP/RFP transgenic mice, we found that the reactive immune cells were largely from resident microglia pool rather than infiltrating macrophages. Immunostaining and real-time PCR were employed to analyze the temporal microglial polarization and the resulting inflammatory responses. Our results showed that microglia accumulated immediately after SAH with a centrifugal spreading through the Cortex Adjacent to the Perforated Site (CAPS) to the remote motor cortex. Microglia polarized dynamically from M1 to M2 phenotype along with the morphological transformation from ramified to amoeboid shapes. The ramified microglia demonstrated the M1 property, which suggested the function-related microglial polarization occurred prior to morphological transformation after SAH. Bipolar-shaped microglia appeared as the intermediate and transitional status with the capacity of bidirectional polarization. The microglial polarization status is distinct in molecular inflammatory responses; M1-related pro-inflammation was predominant in the early phase and subsequently transited to the M2-related anti-inflammation. The systematic characterization of the dynamics of microglial polarization in this study contributes to the understanding of the origin of neuroinflammatory responses after SAH and provides key foundation for further investigations to develop target treatment.

The neuroprotection of hypoxic adipose tissue-derived mesenchymal stem cells in experimental traumatic brain injury.

Traumatic brain injury is one of the leading causes of mortality and morbidity worldwide. At present there is no effective treatment. Previous studies have demonstrated that topical application of adipose tissue-derived mesenchymal stem cells can improve functional recovery in experimental traumatic brain injury. In this study, we evaluated whether hypoxic preconditioned mesenchymal stem cells could enhance the recovery from traumatic brain injury. Traumatic brain injury was induced with an electromagnetically controlled cortical impact device. Two million mesenchymal stem cells derived from the adipose tissue of transgenic green fluorescent protein Sprague-Dawley rats were cultured under either hypoxic (2.5% O2 for 18 hours) (N = 30) or normoxic (18% O2) (N = 30) conditions, then topically applied to the exposed cerebral cortex within 1 hour after traumatic brain injury. A thin layer of fibrin was used to fix the cells in position. No treatment was given to the animals with traumatic brain injury (N = 30). Animals that underwent craniectomy without traumatic brain injury were treated as the sham group (N = 15). Neurological functions were evaluated with water maze, Roto-rod and gait analysis. Animals were sacrificed at days 3, 7, and 14 for microscopic examinations and real-time polymerase chain reaction analysis. The rats treated with hypoxic mesenchymal stem cells showed the greatest improvement in neurological function recovery. More green fluorescent protein-positive cells were found in the injured brain parenchyma treated with hypoxic mesenchymal stem cells that co-expressed glial fibrillary acidic protein, Nestin, and NeuN. Moreover, there was early astrocytosis triggered by the infiltration of more glial fibrillary acidic protein-positive cells and microgliosis was suppressed with fewer ionized calcium binding adapter molecule 1-positive cells in the penumbra region of hypoxic mesenchymal stem cells group at day 3. Compared with normoxic mesenchymal stem cells and traumatic brain injury only groups, there was significantly (p < 0.05) less neuronal death in both the hippocampus and penumbral regions in sections treated with hypoxic mesenchymal stem cells as determined by Cresyl violet and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining respectively. The expression of pro-inflammatory genes (interleukin 6, interleukin 1a, interleukin 1b, tumor necrosis factor α) was upregulated and apoptotic gene (Caspase-3) expression was suppressed at day 3. Anti-inflammatory (interleukin 10) and anti-apoptotic (BCL2 associated agonist of cell death) gene expression was upregulated at days 7 and 14. Our study showed that a hypoxic precondition enhanced the beneficial effects of mesenchymal stem cells on neurological recovery after traumatic brain injury.