Angiographic factors leading to hemorrhage in AVMs: A systematic review and meta-analysis.

For patients with unruptured intracranial arteriovenous malformations (AVMs), the risk of a hemorrhagic event is approximately 2% to 4% annually. These events have an associated 20-50% morbidity and 10% mortality rate. An understanding of risk factors that predispose these lesions to rupture is important for optimal management. We aimed to pool a large cohort of both ruptured and unruptured AVMs from the literature with the goal of identifying angiographic risk factors that contribute to rupture. A systematic review of the literature was conducted in accordance with the PRISMA guidelines using Pubmed, Embase, Scopus, and Web of Science databases. Studies that presented patient-level data from ruptured AVMs from January 1990 to January 2022 were considered for inclusion. The initial screening of 8,304 papers resulted in a quantitative analysis of 25 papers, which identified six angiographic risk factors for AVM rupture. Characteristics that significantly increase the odds of rupture include the presence of aneurysm (OR = 1.45 [1.19, 1.77], p < 0.001, deep location (OR = 3.08 [2.56, 3.70], p < 0.001), infratentorial location (OR = 2.79 [2.08, 3.75], p < 0.001), exclusive deep venous drainage (OR = 2.50 [1.73, 3.61], p < 0.001), single venous drainage (OR = 2.97 [1.93, 4.56], p < 0.001), and nidus size less than 3 cm (OR = 2.54 [1.41, 4.57], p = 0.002). Although previous literature has provided insight into AVM rupture risk factors, obscurity still exists regarding which risk factors pose the greatest risk. We have identified six major angiographic risk factors (presence of an aneurysm, deep location, infratentorial location, exclusive deep venous drainage, single venous drainage, and nidus size less than 3 cm) that, when identified by a clinician, may help to tailor patient-specific approaches and guide clinical decisions.

L1-pelvic angle: a convenient measurement to attain optimal deformity correction.

PURPOSE: (1) Evaluate the associations between L1-pelvic angle (L1PA) and both sagittal vertical axis (SVA) and T1-pelvic angle (T1PA), and (2) assess the clinical impact of L1PA. METHODS: A single-institution retrospective cohort study was undertaken for patients undergoing adult spinal deformity (ASD) surgery from 2013 to 2017. Ideal L1PA was defined as (0.5xPelvic Incidence)-21. Pearson correlation was performed to compare L1PA, SVA, and T1PA. Univariate/multivariate regression was performed to assess the effect of L1PA on mechanical complications, controlling for age, BMI, and postoperative pelvic incidence-lumbar lordosis mismatch (PI/LL). Due to the overlapping nature of patients with pseudarthrosis and rod fracture, these patients were analyzed together. RESULTS: A total of 145 patients were included. Mean preoperative L1PA, SVA, and T1PA were 15.5 ± 8.9°, 90.7 ± 66.8 mm, and 27.1 ± 13.0°, respectively. Mean postoperative L1PA, SVA, and T1PA were 15.0 ± 8.9°, 66.7 ± 52.8 mm, and 22.3 ± 11.1°, respectively. Thirty-six (24.8%) patients achieved ideal L1PA. Though the correlation was modest, preoperative L1PA was linearly correlated with preoperative SVA (r2 = 0.16, r = 0.40, 95%CI = 0.22-0.60, p < 0.001) and T1PA (r2 = 0.41, r = 0.62, 95%CI = 0.46-0.76, p < 0.001). Postoperative L1PA was linearly correlated with postoperative SVA (r2 = 0.12, r = 0.37, 95%CI = 0.18-0.56, p < 0.001) and T1PA (r2 = 0.40, r = 0.62, 95%CI = 0.45-0.74, p < 0.001). Achieving ideal L1PA ± 5° was associated with a decreased risk of rod fracture/pseudarthrosis on univariate and multivariate regression (OR = 0.33, 95%CI = 0.12-0.86, p = 0.024). No association between achieving ideal L1PA and patient-reported outcomes was observed. CONCLUSION: L1PA was modestly correlated with SVA and T1PA, and achieving ideal L1PA was associated with lower rates of rod fracture/pseudarthrosis. Future studies are warranted to better define the clinical implications of achieving a normal L1PA. LEVEL OF EVIDENCE: III.

The clinical utility of dual-energy CT in post-thrombectomy care: Part 2, the predictive value of contrast density and volume for delayed hemorrhagic transformation.

OBJECTIVES: Dual-energy CT allows differentiation between blood and iodinated contrast. This study aims to determine the predictive value of contrast density and volume on post-thrombectomy dual-energy CT for delayed hemorrhagic transformation and its impact on 90-day outcomes. MATERIALS AND METHODS: A retrospective analysis was performed on patients who underwent thrombectomy for anterior circulation large-vessel occlusion at a comprehensive stroke center from 2018-2021. Per institutional protocol, all patients underwent dual-energy CT immediately post-thrombectomy and MRI or CT 24 hours afterward. The presence of hemorrhage and contrast staining was evaluated by dual-energy CT. Delayed hemorrhagic transformation was determined by 24-hour imaging and classified into petechial hemorrhage or parenchymal hematoma using ECASS III criteria. Univariable and multivariable analyses were performed to determine predictors and outcomes of delayed hemorrhagic transformation. RESULTS: Of 97 patients with contrast staining and without hemorrhage on dual-energy CT, 30 and 18 patients developed delayed petechial hemorrhage and delayed parenchymal hematoma, respectively. On multivariable analysis, delayed petechial hemorrhage was predicted by anticoagulant use (OR,3.53;p=0.021;95%CI,1.19-10.48) and maximum contrast density (OR,1.21;p=0.004;95%CI,1.06-1.37;per 10 HU increase), while delayed parenchymal hematoma was predicted by contrast volume (OR,1.37;p=0.023;95%CI,1.04-1.82;per 10 mL increase) and low-density lipoprotein (OR,0.97;p=0.043;95%CI,0.94-1.00;per 1 mg/dL increase). After adjusting for potential confounders, delayed parenchymal hematoma was associated with worse functional outcomes (OR,0.07;p=0.013;95%CI,0.01-0.58) and mortality (OR,7.83;p=0.008;95%CI,1.66-37.07), while delayed petechial hemorrhage was associated with neither. CONCLUSION: Contrast volume predicted delayed parenchymal hematoma, which was associated with worse functional outcomes and mortality. Contrast volume can serve as a useful predictor of delayed parenchymal hematoma following thrombectomy and may have implications for patient management.

The clinical utility of dual-energy CT in post-thrombectomy care: Part 1, predictors and outcomes of subarachnoid and intraparenchymal hemorrhage.

OBJECTIVES: Dual-energy CT allows differentiation between blood and iodinated contrast. We aimed to determine predictors of subarachnoid and intraparenchymal hemorrhage on dual-energy CT performed immediately post-thrombectomy and the impact of these hemorrhages on 90-day outcomes. MATERIALS AND METHODS: A retrospective analysis was performed on patients who underwent thrombectomy for anterior circulation large-vessel occlusion and subsequent dual-energy CT at a comprehensive stroke center from 2018-2021. The presence of contrast, subarachnoid hemorrhage, or intraparenchymal hemorrhage immediately post-thrombectomy was assessed by dual-energy CT. Univariable and multivariable analyses were performed to identify predictors of post-thrombectomy hemorrhages and 90-day outcomes. Patients with unknown 90-day mRS were excluded. RESULTS: Of 196 patients, subarachnoid hemorrhage was seen in 17, and intraparenchymal hemorrhage in 23 on dual-energy CT performed immediately post-thrombectomy. On multivariable analysis, subarachnoid hemorrhage was predicted by stent retriever use in the M2 segment of MCA (OR,4.64;p=0.017;95%CI,1.49-14.35) and the number of thrombectomy passes (OR,1.79;p=0.019;95%CI,1.09-2.94;per an additional pass), while intraparenchymal hemorrhage was predicted by preprocedural non-contrast CT-based ASPECTS (OR,8.66;p=0.049;95%CI,0.92-81.55;per 1 score decrease) and preprocedural systolic blood pressure (OR,5.10;p=0.037;95%CI,1.04-24.93;per 10 mmHg increase). After adjusting for potential confounders, intraparenchymal hemorrhage was associated with worse functional outcomes (OR,0.25;p=0.021;95%CI,0.07-0.82) and mortality (OR,4.30;p=0.023,95%CI,1.20-15.36), while subarachnoid hemorrhage was associated with neither. CONCLUSIONS: Intraparenchymal hemorrhage immediately post-thrombectomy was associated with worse functional outcomes and mortality and can be predicted by low ASPECTS and elevated preprocedural systolic blood pressure. Future studies focusing on management strategies for patients presenting with low ASPECTS or elevated blood pressure to prevent post-thrombectomy intraparenchymal hemorrhage are warranted.

Perioperative Care of the Patient with Eye Pathologies Undergoing Nonocular Surgery.

The authors reviewed perioperative ocular complications and implications of ocular diseases during nonocular surgeries. Exposure keratopathy, the most common perioperative eye injury, is preventable. Ischemic optic neuropathy, the leading cause of perioperative blindness, has well-defined risk factors. The incidence of ischemic optic neuropathy after spine fusion, but not cardiac surgery, has been decreasing. Central retinal artery occlusion during spine fusion surgery can be prevented by protecting eyes from compression. Perioperative acute angle closure glaucoma is a vision-threatening emergency that can be successfully treated by rapid reduction of elevated intraocular pressure. Differential diagnoses of visual dysfunction in the perioperative period and treatments are detailed. Although glaucoma is increasingly prevalent and often questions arise concerning perioperative anesthetic management, evidence-based recommendations to guide safe anesthesia care in patients with glaucoma are currently lacking. Patients with low vision present challenges to the anesthesia provider that are becoming more common as the population ages.

Formation of a de novo intracranial arteriovenous fistula in a child with PTEN hamartoma tumor syndrome.

PURPOSE: Dural arteriovenous fistulae (dAVF) are an uncommon feature of PTEN hamartoma tumor syndrome (PHTS). We report a case of an adolescent male diagnosed with PHTS following the treatment of multiple intracranial dAVF to emphasize the association of vascular anomalies with this disorder and discuss potential implications. CASE REPORT: An adolescent male presented with bilateral proptosis secondary to intracranial venous hypertension. Workup revealed the presence of a complex intracranial dAVF which was treated with several embolization procedures. Following treatment, a de novo dAVF was identified on surveillance imaging. A genetic workup revealed a pathogenic mutation in PTEN consistent with a diagnosis of PHTS. CONCLUSIONS: Recognition that PHTS may be associated with dAVF, and potentially delayed spontaneous formation of dAVF, is critically important due to the potential for devastating yet preventable neurologic sequelae.

Perioperative Ischemic Optic Neuropathy after Cardiac Surgery: Development and Validation of a Preoperative Risk Prediction Model.

OBJECTIVE: Previous studies identified risk factors for ischemic optic neuropathy (ION) after cardiac surgery; however, there is no easy-to-use risk calculator for the physician to identify high-risk patients for ION before cardiac surgery. The authors sought to develop and validate a simple-to-use predictive model and calculator to assist with preoperative identification of risk and informed consent for this rare but serious complication. DESIGN: Retrospective case-control study. SETTING: Hospital discharge records. PATIENTS: A total of 5,561,177 discharges in the National Inpatient Sample >18 years of age, with procedure codes for coronary artery bypass grafting, heart valve repair/replacement, or left ventricular assist device insertion. INTERVENTIONS: All patients had undergone cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Known preoperative risk factors for ION after cardiac surgery were assessed to develop a risk score and prediction model. This model was validated internally using the split-sample method. There were 771 cases of ION among 5,561,177 patients in the National Inpatient Sample. The risk factors for ION used in the model were carotid artery stenosis, cataract, diabetic retinopathy, macular degeneration, glaucoma, male sex, and prior stroke; whereas uncomplicated diabetes decreased risk. With the internal validation, the predictive model had an area under the receiver operating characteristic curve of 0.66. A risk score cutoff ≥3 had 98.4% specificity. CONCLUSIONS: This predictive model, based on previously identified preoperative factors, predicted risk of perioperative ION with a fair area under the receiver operating characteristic curve. This predictive model could enable screening to provide a more accurate risk assessment for ION, and consent process for cardiac surgery.

QSM in canine model of acute cerebral ischemia: A pilot study.

PURPOSE: In the present study, we investigated the potential of QSM to assess the physiological state of cortical tissue in the middle cerebral artery occlusion canine model of a cerebral ischemia. METHODS: Experiments were performed in 8 anesthetized canines. Gradient echo, perfusion, and DWI data of brains at normal and ischemic states were acquired. In the postprocessed susceptibility and quantitative cerebral blood flow maps, changes in values within the middle cerebral artery-fed cortical territories were quantified both on the ischemic and normal contralateral hemisphere side. RESULTS: QSM values in critically ischemic tissue were significantly different from contralateral values-namely, susceptibility increase was observed in the cases in which cerebral perfusion was maintained above the threshold of neuronal death. Furthermore, the data indicates presence of a significant correlation between the changes in susceptibility values, cerebral perfusion, and the infarct volume and pial collateral scores. Additionally, our data suggests that difference in cortical susceptibility is prospectively indicative of the infarct growth rate. CONCLUSION: In an experimental permanent middle cerebral artery occlusion model, QSM was shown to correlate with the functional parameters characterizing viability of ischemic tissue, thus warranting further research on its ability to provide complementary information during acute stroke MRI examinations in humans.

Intermittent Hypoxia and Effects on Early Learning/Memory: Exploring the Hippocampal Cellular Effects of Pediatric Obstructive Sleep Apnea.

This review provides an update on the neurocognitive phenotype of pediatric obstructive sleep apnea (OSA). Pediatric OSA is associated with neurocognitive deficits involving memory, learning, and executive functioning. Adenotonsillectomy (AT) is presently accepted as the first-line surgical treatment for pediatric OSA, but the executive function deficits do not resolve postsurgery, and the timeline for recovery remains unknown. This finding suggests that pediatric OSA potentially causes irreversible damage to multiple areas of the brain. The focus of this review is the hippocampus, 1 of the 2 major sites of postnatal neurogenesis, where new neurons are formed and integrated into existing circuitry and the mammalian center of learning/memory functions. Here, we review the clinical phenotype of pediatric OSA, and then discuss existing studies of OSA on different cell types in the hippocampus during critical periods of development. This will set the stage for future study using preclinical models to understand the pathogenesis of persistent neurocognitive dysfunction in pediatric OSA.

Predicting Risk of Perioperative Ischemic Optic Neuropathy in Spine Fusion Surgery: A Cohort Study Using the National Inpatient Sample.

BACKGROUND: Ischemic optic neuropathy (ION) is a rare complication of anesthesia and surgery that causes vision loss in spine fusion. We sought to develop a predictive model based on known preoperative risk factors for perioperative ION to guide patient and physician preoperative decision-making. METHODS: In the National Inpatient Sample (NIS) for 1998-2012, discharges for posterior thoracic, lumbar, and sacral spine fusion were identified and classified by ION status. Variables were selected without weighting via variable clustering using Principal Component Analysis of Mixed Data (PCA-MIX). Hierarchical clustering with 4 clusters was performed, and the variable with largest squared loading in each cluster was chosen. By splitting our sample into a training and testing data set, we developed and internally validated a predictive model. The final model using variables known preoperatively was constructed to allow determination of relative and absolute risk of developing perioperative ION and was tested for calibration and discrimination. RESULTS: The final predictive model based on hierarchical clustering contained 3 preoperative factors, age, male or female sex, and the presence of obstructive sleep apnea (OSA). The predictive model based on these factors had an area under the receiver operating characteristic curve (AUC) of 0.65 and good calibration. A score cutoff of >1 had 100% sensitivity, while score of 3 had 96.5% specificity. The highest estimated absolute risk (844.5/million) and relative risk of ION (46.40) was for a man, age 40-64 years, with OSA. CONCLUSIONS: The predictive model could enable screening for patients at higher risk of ION to provide more accurate risk assessment and surgical and anesthetic planning for perioperative ION in spine fusion.

Absolute quantitative MR perfusion and comparison against stable-isotope microspheres.

PURPOSE: This work sought to compare a quantitative T1 bookend dynamic susceptibility contrast MRI based perfusion protocol for absolute cerebral blood flow (qCBF) against CBF measured by the stable-isotope neutron capture microsphere method, a recognized reference standard for measuring tissue blood flow, at normocapnia, hypercapnia, and in acute stroke. METHODS: CBF was measured in anesthetized female canines by MRI and microspheres over 2 consecutive days for each case. On day 1, 5 canines were measured before and during a physiological challenge induced by carbogen inhalation; on day 2, 4 canines were measured following permanent occlusion of the middle cerebral artery. CBF and cerebrovascular reactivity measured by MRI and microsphere deposition were compared. RESULTS: MRI correlated strongly with microspheres at the hemispheric level for CBF during normo- and hypercapnic states (r2 = 0.96), for individual cerebrovascular reactivity (r2 = 0.84), and for postocclusion CBF (r2 = 0.82). Correction for the delay and dispersion of the contrast bolus resulted in a significant improvement in the correlation between MRI and microsphere deposition in the ischemic state (r2 = 0.96). In all comparisons, moderate correlations were found at the regional level. CONCLUSION: In an experimental canine model with and without permanent occlusion of the middle cerebral artery, MRI-based qCBF yielded moderate to strong correlations for absolute quantitative CBF and cerebrovascular reactivity measurements during normocapnia and hypercapnia. Correction for delay and dispersion greatly improved the quantitation during occlusion of the middle cerebral artery, underscoring the importance for this correction under focal ischemic condition.

National Institutes of Health-Funded Anesthesiology Research and Anesthesiology Physician-Scientists: Trends, Promises, and Concerns.

With a difficult National Institutes of Health (NIH) funding climate, the pipeline of physician-scientists in Anesthesiology is continuing to get smaller with fewer new entrants. This article studies current NIH funding trends and offers potential solutions to continue the historical trend of academic innovation and research that has characterized academic Anesthesiology. Using publicly available data, specifically the NIH REPORTeR and Blue Ridge Institute for Medical Research, we examined NIH trends in funding in academic Anesthesiology departments that have Anesthesiology residency training programs. When adjusted for inflation, median NIH funding of departments of Anesthesiology declined approximately 15% between 2008 and 2017. The majority (55%) of NIH funding to academic Anesthesiology departments, including R01 and K-series grants, went to 10 departments in the United States. This trend has remained relatively constant for the 9-year period we studied (2009-2017). There is an inequitable distribution of NIH funding to Anesthesiology departments. Arguably, this may be a case of the "rich get richer," but the implications for those who are trying to become or remain NIH-funded investigators are that success may depend, in part, on securing a faculty position in one of these well-funded departments.

Big Data Research in Neuro-Ophthalmology: Promises and Pitfalls.

BACKGROUND: Big data clinical research involves application of large data sets to the study of disease. It is of interest to neuro-ophthalmologists but also may be a challenge because of the relative rarity of many of the diseases treated. EVIDENCE ACQUISITION: Evidence for this review was gathered from the authors' experiences performing analysis of large data sets and review of the literature. RESULTS: Big data sets are heterogeneous, and include prospective surveys, medical administrative and claims data and registries compiled from medical records. High-quality studies must pay careful attention to aspects of data set selection, including potential bias, and data management issues, such as missing data, variable definition, and statistical modeling to generate appropriate conclusions. There are many studies of neuro-ophthalmic diseases that use big data approaches. CONCLUSIONS: Big data clinical research studies complement other research methodologies to advance our understanding of human disease. A rigorous and careful approach to data set selection, data management, data analysis, and data interpretation characterizes high-quality studies.

Continuous Automated Model EvaluatiOn (CAMEO) complementing the critical assessment of structure prediction in CASP12.

Every second year, the community experiment "Critical Assessment of Techniques for Structure Prediction" (CASP) is conducting an independent blind assessment of structure prediction methods, providing a framework for comparing the performance of different approaches and discussing the latest developments in the field. Yet, developers of automated computational modeling methods clearly benefit from more frequent evaluations based on larger sets of data. The "Continuous Automated Model EvaluatiOn (CAMEO)" platform complements the CASP experiment by conducting fully automated blind prediction assessments based on the weekly pre-release of sequences of those structures, which are going to be published in the next release of the PDB Protein Data Bank. CAMEO publishes weekly benchmarking results based on models collected during a 4-day prediction window, on average assessing ca. 100 targets during a time frame of 5 weeks. CAMEO benchmarking data is generated consistently for all participating methods at the same point in time, enabling developers to benchmark and cross-validate their method's performance, and directly refer to the benchmarking results in publications. In order to facilitate server development and promote shorter release cycles, CAMEO sends weekly email with submission statistics and low performance warnings. Many participants of CASP have successfully employed CAMEO when preparing their methods for upcoming community experiments. CAMEO offers a variety of scores to allow benchmarking diverse aspects of structure prediction methods. By introducing new scoring schemes, CAMEO facilitates new development in areas of active research, for example, modeling quaternary structure, complexes, or ligand binding sites.

Gene expression in retinal ischemic post-conditioning.

PURPOSE: The pathophysiology of retinal ischemia involves mechanisms including inflammation and apoptosis. Ischemic post-conditioning (Post-C), a brief non-lethal ischemia, induces a long-term ischemic tolerance, but the mechanisms of ischemic post-conditioning in the retina have only been described on a limited basis. Accordingly, we conducted this study to determine the molecular events in retinal ischemic post-conditioning and to identify targets for therapeutic strategies for retinal ischemia. METHODS: To determine global molecular events in ischemic post-conditioning, a comprehensive study of the transcriptome of whole retina was performed. We utilized RNA sequencing (RNA-Seq), a recently developed, deep sequencing technique enabling quantitative gene expression, with low background noise, dynamic detection range, and discovery of novel genes. Rat retina was subjected to ischemia in vivo by elevation of intraocular pressure above systolic blood pressure. At 24 h after ischemia, Post-C or sham Post-C was performed by another, briefer period of ischemia, and 24 h later, retinas were collected and RNA processed. RESULTS: There were 71 significantly affected pathways in post-conditioned/ischemic vs. normals and 43 in sham post conditioned/ischemic vs. normals. Of these, 28 were unique to Post-C and ischemia. Seven biological pathways relevant to ischemic injury, in Post-C as opposed to sham Post-C, were examined in detail. Apoptosis, p53, cell cycle, JAK-STAT, HIF-1, MAPK and PI3K-Akt pathways significantly differed in the number as well as degree of fold change in genes between conditions. CONCLUSION: Post-C is a complex molecular signaling process with a multitude of altered molecular pathways. We identified potential gene candidates in Post-C. Studying the impact of altering expression of these factors may yield insight into new methods for treating or preventing damage from retinal ischemic disorders.

Perioperative Retinal Artery Occlusion: Incidence and Risk Factors in Spinal Fusion Surgery From the US National Inpatient Sample 1998-2013.

BACKGROUND: Retinal artery occlusion (RAO) is a rare but devastating complication of spinal fusion surgery. We aimed to determine its incidence and associated risk factors. METHODS: Hospitalizations involving spinal fusion surgery were identified by searching the National Inpatient Sample, a database of hospital discharges, from 1998 to 2013. RAO cases were identified using ICD-9-CM codes. Using the STROBE guidelines, postulated risk factors were chosen based on literature review and identified using ICD-9-CM codes. Multivariate logistic models with RAO as outcome, and risk factors, race, age, admission, and surgery type evaluated associations. RESULTS: Of an estimated 4,784,275 spine fusions in the United States from 1998 to 2013, there were 363 (CI: 291-460) instances of RAO (0.76/10,000 spine fusions, CI: 0.61-0.96). Incidence ranged from 0.35/10,000 (CI: 0.11-1.73) in 2001-2002 to 1.29 (CI: 0.85-2.08) in 2012-2013, with no significant trend over time (P = 0.39). Most strongly associated with RAO were stroke, unidentified type (odds ratio, OR: 14.33, CI: 4.54-45.28, P < 0.001), diabetic retinopathy (DR) (OR: 7.00, CI: 1.18-41.66, P = 0.032), carotid stenosis (OR: 4.94, CI: 1.22-19.94, P = 0.025), aging (OR for age 71-80 years vs 41-50 years referent: 4.07, CI: 1.69-10.84, P = 0.002), and hyperlipidemia (OR: 2.96, CI: 1.85-4.73, P < 0.001). There was an association between RAO and transforaminal lumbar interbody fusion (OR: 2.95, CI: 1.29-6.75, P = 0.010). RAO was more likely to occur with spinal surgery performed urgently or emergently compared with being done electively (OR: 0.40, CI: 0.23-0.68, P < 0.001). CONCLUSIONS: Patient-specific associations with RAO in spinal fusion include aging, carotid stenosis, DR, hyperlipidemia, stroke, and specific types of surgery. DR may serve as an observable biomarker of heightened risk of RAO in patients undergoing spine fusion.

Haemodilution and head-down tilting induce functional injury in the rat optic nerve: A model for peri-operative ischemic optic neuropathy.

BACKGROUND: Mechanisms of peri-operative ischaemic optic neuropathy remain poorly understood. Both specific pre-operative and intra-operative factors have been examined by retrospective studies, but no animal model currently exists. OBJECTIVES: To develop a rodent model of peri-operative ischaemic optic neuropathy. In rats, we performed head-down tilt and/or haemodilution, theorising that the combination damages the optic nerve. DESIGN: Animal study. SETTING: Laboratory. ANIMALS: A total of 36 rats, in four groups, completed the functional examination of retina and optic nerve after the interventions. INTERVENTIONS: Anaesthetised groups (n>8) were supine (SUP) for 5 h, head-down tilted 70° for 5 h, head-down tilted/haemodiluted for 5 h or SUP/haemodiluted for 5 h. We measured blood pressure, heart rate, intra-ocular pressure and maintained constant temperature. MAIN OUTCOME MEASUREMENTS: Retinal function (electroretinography), scotopic threshold response (STR) (for retinal ganglion cells) and visual evoked potentials (VEP) (for transmission through the optic nerve). We imaged the optic nerve in vivo and evaluated retinal histology, apoptotic cells and glial activation in the optic nerve. Retinal and optic nerve function were followed to 14 and 28 days after experiments. RESULTS: At 28 days in head down tilted/haemodiluted rats, negative STR decreased (about 50% amplitude reduction, P = 0.006), VEP wave N2-P3 decreased (70% amplitude reduction, P = 0.01) and P2 latency increased (35%, P = 0.003), optic discs were swollen and glial activation was present in the optic nerve. SUP/haemodiluted rats had decreases in negative STR and increased VEP latency, but no glial activation. CONCLUSION: An injury partly resembling human ischaemic optic neuropathy can be produced in rats by combining haemodilution and head-down tilt. Significant functional changes were also present with haemodilution alone. Future studies with this partial optic nerve injury may enable understanding of mechanisms of peri-operative ischaemic optic neuropathy and could help discover preventive or treatment strategies.

Notch: A multi-functional integrating system of microenvironmental signals.

The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.