Complement-Dependent Synaptic Uptake and Cognitive Decline after Stroke and Reperfusion Therapy.

Despite the success of reperfusion therapy in significantly reducing the extent of infarct expansion after stroke, the effect of revascularization on poststroke neuroinflammation and the role of anti-inflammatory strategies in postreperfusion era are yet to be explored. Here, we investigate whether the neuroinflammatory response may still contribute to neurologic deficits after reperfused stroke by using targeted complement inhibition to suppress poststroke neuroinflammation in mice with or without concurrent reperfusion therapy. Complement inhibition was achieved using B4Crry, an injury site-targeted inhibitor of C3 activation. Following embolic stroke in male C57bl/6 mice, thrombolysis using tissue-plasminogen activator (t-PA) reduced injury and improved motor deficits, but did not improve cognitive outcomes. After both reperfused and non-reperfused stroke, complement activation and opsonization of hippocampal synapses directed ongoing microglia-dependent phagocytosis of synapses for at least 30 d after stroke, leading to a loss of synaptic density that was associated with cognitive decline. B4Crry treatment, alone or in combination with tPA, limited perilesional complement deposition, reduced microgliosis and synaptic uptake, and improved cognitive outcome without affecting regenerative responses. Furthermore, complement inhibition improved the safety, efficacy, and treatment window of reperfusion therapy with t-PA by limiting hemorrhagic transformation. This work thus demonstrates that poststroke neuroinflammation contributes to hemorrhagic transformation and progression of neurodegenerative responses in the brain even following early and successful revascularization.SIGNIFICANCE STATEMENT This study addresses two major challenges facing the treatment of stroke in the era of reperfusion therapy: hemorrhagic transformation and the disconnect between successful revascularization and functional outcomes. We studied how complement-dependent neuroinflammation drives the pathophysiology behind these challenges using a translationally relevant strategy. Complement inhibition was achieved using B4Crry, an injury site-targeted inhibitor of C3 activation. Following embolic stroke, pharmacological thrombolysis limited infarct size, but did not prevent complement activation. In reperfused and non-reperfused stroke, complement activation and opsonization of hippocampal synapses resulted in synaptic phagocytosis and subsequent cognitive decline. B4Crry treatment limited perilesional complement deposition, reduced microgliosis and synaptic uptake, and improved cognitive outcomes. Complement inhibition also improved the safety, efficacy, and treatment window of thrombolytic therapy.

An Artificial Neural Network Model for Predicting Postoperative Facial Nerve Outcomes After Vestibular Schwannoma Surgery.

BACKGROUND AND OBJECTIVES: The emergence of machine learning models has significantly improved the accuracy of surgical outcome predictions. This study aims to develop and validate an artificial neural network (ANN) model for predicting facial nerve (FN) outcomes after vestibular schwannoma (VS) surgery using the proximal-to-distal amplitude ratio (P/D) along with clinical variables. METHODS: This retrospective study included 71 patients who underwent VS resection between 2018 and 2022. At the end of surgery, the FN was stimulated at the brainstem (proximal) and internal acoustic meatus (distal) and the P/D was calculated. Postoperative FN function was assessed using the House-Brackmann grading system at discharge (short-term) and after 9-12 months (long-term). House-Brackmann grades I-II were considered good outcome, whereas grades III-VI were considered fair/poor. An ANN model was constructed, and the performance of the model was evaluated using the area under the ROC curve for internal validation and accuracy, sensitivity, specificity, and positive and negative predictive values for external validation. RESULTS: The short-term FN outcome was grades I-II in 57.7% and grades III-VI in 42.3% of patients. Initially, a model using P/D had an area under the curve of 0.906 (internal validation) and an accuracy of 89.1% (95% CI: 68.3%-98.8%) (external validation) for predicting good vs fair/poor short-term FN outcomes. The model was then refined to include only muscles with a P/D with a proximal latency between 6 and 8 ms. This improved the accuracy to 100% (95% CI: 79%-100%). Integrating clinical variables (patient's age, tumor size, and preoperative HB grade) in addition to P/D into the model did not significantly improve the predative value. A model was then created to predict the long-term FN outcome using P/D with latencies between 6 and 8 ms and had an accuracy of 90.9% (95% CI: 58.7%-99.8%). CONCLUSION: ANN models incorporating P/D can be a valuable tool for predicting FN outcomes after VS surgery. Refining the model to include P/D with latencies between 6 and 8 ms further improves the model's prediction. A user-friendly interface is provided to facilitate the implementation of this model.

Complement-dependent neuroinflammation in spinal cord injury: from pathology to therapeutic implications.

ABSTRACT: Spinal cord injury remains a major cause of disability in young adults, and beyond acute decompression and rehabilitation, there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population. Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation, a similar role for complement in spinal neuroinflammation is a focus of ongoing research. In this work, we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins, triggers of complement activation, and role of effector functions in the pathology. We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris, and or activation via antibody binding to damage-associated molecular patterns. Several effector functions of complement have been implicated in spinal cord injury, and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury. Following this pathophysiological review, we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects. This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury, to evaluate the phases of involvement of opsonins and anaphylatoxins, and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Evaluating the comorbidities of age and cigarette smoking on stroke outcomes in the context of anti-complement mitigation strategies.

Multiple neuroprotective agents have shown beneficial effects in rodent models of stroke, but they have failed to translate in the clinic. In this perspective, we consider that a likely explanation for this failure, at least in part, is that there has been inadequate assessment of functional outcomes in preclinical stroke models, as well the use of young healthy animals that are not representative of clinical cohorts. Although the impact of older age and cigarette smoking comorbidities on stroke outcomes is well documented clinically, the impact of these (and other) stroke comorbidities on the neuroinflammatory response after stroke, as well as the response to neuroprotective agents, remains largely unexplored. We have shown that a complement inhibitor (B4Crry), that targets specifically to the ischemic penumbra and inhibits complement activation, reduces neuroinflammation and improves outcomes following murine ischemic stroke. For this perspective, we discuss the impact of age and smoking comorbidities on outcomes after stroke, and we experimentally assess whether increased complement activation contributes to worsened acute outcomes with these comorbidities. We found that the pro-inflammatory effects of aging and smoking contribute to worse stroke outcomes, and these effects are mitigated by complement inhibition.

Management and Long-Term Outcomes of Patients With Infectious Intracranial Aneurysms.

BACKGROUND: Infectious intracranial aneurysms (IIAs) are rare complications of infective endocarditis (IE). Data on management and long-term outcomes remain limited. OBJECTIVE: To retrospectively study long-term outcomes of IIAs in patients treated medically or surgically. METHODS: Adult cases of IE and/or IIAs admitted to Emory or Grady Healthcare Systems between May 2015 and May 2020 were reviewed for demographic, clinical, and radiographic variables for up to 2 years. Primary outcome measure was 2-year survival. RESULTS: Among 1714 cases of IE, intracerebral hemorrhage occurred in 322 patients and IIAs in 17 patients. The presence of IIAs in IE was associated with higher odds of disposition to hospice/death (odds ratio = 6.9). Including non-IE patients, 24 patients had 38 IIAs mainly involving the distal middle cerebral artery and 16 were ruptured on admission. IIAs were predominantly treated with antibiotics as the primary approach. Open microsurgery was the primary approach for 5 aneurysms and was used as salvage in 7 IIAs. Endovascular management was the primary approach for 2 IIAs and used as salvage for 5 IIAs with antibiotic failure. Medical management had high rate of treatment failure (15/31) which predominantly occurred within 2 weeks of onset. The 2-year survival in this cohort was 70% (17/24). CONCLUSION: IIAs are rare complications of IE with a poor prognosis. Patients treated with antibiotics have higher risk of treatment failure requiring salvage surgical or endovascular intervention. Medical treatment failure occurred mostly within 2 weeks of onset and had a negative prognostic value emphasizing the need for close follow-up and early surgical or endovascular management.

Technical and clinical outcomes in concurrent multivessel occlusions treated with mechanical thrombectomy: insights from the STAR collaboration.

BACKGROUND: Endovascular thrombectomy (EVT) has become the mainstay treatment for large vessel occlusion, with favorable safety and efficacy profile. However, the safety and efficacy of EVT in concurrent multi-territory occlusions (MTVOs) remains unclear. OBJECTIVE: To investigate the prevalence, clinical and technical outcomes of concurrent EVT for MTVOs. METHODS: Data were included from the Stroke Thrombectomy and Aneurysm Registry (STAR) with 32 stroke centers for EVT performed to treat bilateral anterior or concurrent anterior and posterior circulation occlusions between 2017 and 2021. Patients with MTVO were identified, and propensity score matching was used to compare this group with patients with occlusion in a single arterial territory. RESULTS: Of a total of 7723 patients who underwent EVT for acute ischemic stroke, 54 (0.7%) underwent EVT for MTVOs (mean age 69±12.5; female 50%). 28% had bilateral and 72% had anterior and posterior circulations occlusions. The rate of successful recanalization (Thrombolysis in Cerebral Infarction 2b/3), complications, modified Rankin score at 90 days, and mortality was not significantly different between the matched cohorts. Multivariate analysis confirmed that MTVOs were not associated with poor functional outcome, symptomatic intracranial hemorrhage, or longer procedure time. CONCLUSION: Compared with EVT for single vessel occlusions, EVT in appropriately selected patients with MTVOs has a similar efficacy and safety profile.

Multicenter investigation of technical and clinical outcomes after thrombectomy for distal vessel occlusion by frontline technique.

BACKGROUND: Endovascular thrombectomy (EVT) is the standard-of-care for proximal large vessel occlusion (LVO) stroke. Data on technical and clinical outcomes in distal vessel occlusions (DVOs) remain limited. METHODS: This was a retrospective study of patients undergoing EVT for stroke at 32 international centers. Patients were divided into LVOs (internal carotid artery/M1/vertebrobasilar), medium vessel occlusions (M2/A1/P1) and isolated DVOs (M3/M4/A2/A3/P2/P3) and categorized by thrombectomy technique. Primary outcome was a good functional outcome (modified Rankin Scale ≤2) at 90 days. Secondary outcomes included recanalization, procedure-time, thrombectomy attempts, hemorrhage, and mortality. Multivariate logistic regressions were used to evaluate the impact of technical variables. Propensity score matching was used to compare outcome in patients with DVO treated with aspiration versus stent retriever RESULTS: We included 7477 patients including 213 DVOs. Distal location did not independently predict good functional outcome at 90 days compared with proximal (p=0.467). In distal occlusions, successful recanalization was an independent predictor of good outcome (adjusted odds ratio (aOR) 5.11, p<0.05) irrespective of technique. Younger age, bridging therapy, and lower admission National Institutes of Health Stroke Scale (NIHSS) were also predictors of good outcome. Procedure time ≤1 hour or ≤3 thrombectomy attempts were independent predictors of good outcomes in DVOs irrespective of technique (aOR 4.5 and 2.3, respectively, p<0.05). There were no differences in outcomes in a DVO matched cohort of aspiration versus stent retriever. Rates of hemorrhage and good outcome showed an exponential relationship to procedural metrics, and were more dependent on time in the aspiration group and attempts in the stent retriever group. CONCLUSIONS: Outcomes following EVT for DVO are comparable to LVO with similar results between techniques. Techniques may exhibit different futility metrics; stent retriever thrombectomy was influenced by attempts whereas aspiration was more dependent on procedure time.

Artificial neural networks predict the need for permanent cerebrospinal fluid diversion following posterior fossa tumor resection.

Background: Resection of posterior fossa tumors (PFTs) can result in hydrocephalus that requires permanent cerebrospinal fluid (CSF) diversion. Our goal was to prospectively validate a machine-learning model to predict postoperative hydrocephalus after PFT surgery requiring permanent CSF diversion. Methods: We collected preoperative and postoperative variables on 518 patients that underwent PFT surgery at our center in a retrospective fashion to train several statistical classifiers to predict the need for permanent CSF diversion as a binary class. A total of 62 classifiers relevant to our data structure were surveyed, including regression models, decision trees, Bayesian models, and multilayer perceptron artificial neural networks (ANN). Models were trained using the (N = 518) retrospective data using 10-fold cross-validation to obtain accuracy metrics. Given the low incidence of our positive outcome (12%), we used the positive predictive value along with the area under the receiver operating characteristic curve (AUC) to compare models. The best performing model was then prospectively validated on a set of 90 patients. Results: Twelve percent of patients required permanent CSF diversion after PFT surgery. Of the trained models, 8 classifiers had an AUC greater than 0.5 on prospective testing. ANNs demonstrated the highest AUC of 0.902 with a positive predictive value of 83.3%. Despite comparable AUC, the remaining classifiers had a true positive rate below 35% (compared to ANN, P < .0001). The negative predictive value of the ANN model was 98.8%. Conclusions: ANN-based models can reliably predict the need for ventriculoperitoneal shunt after PFT surgery.

Multicenter investigation of technical and clinical outcomes after thrombectomy for Proximal Medium Vessel Occlusion (pMeVO) by frontline technique.

BACKGROUND: Endovascular thrombectomy(EVT) is the standard of care for large vessel occlusion(LVO) stroke. Data on technical and clinical outcome in proximal medium vessel occlusions(pMeVOs) comparing frontline techniques remain limited. METHODS: We report an international multicenter retrospective study of patients undergoing EVT for stroke at 32 centers between 2015-2021. Patients were divided into LVOs(ICA/M1/Vertebrobasilar) or pMeVOs(M2/A1/P1) and categorized by thrombectomy technique. Primary outcome was 90-day good functional outcome(mRS ≤ 2). Multivariate logistic regressions were used to evaluate the impact of technical variables on clinical outcomes. Propensity score matching was used to compare outcome in patients with pMeVO treated with aspiration versus stent-retriever. RESULTS: In the cohort of 5977 LVO and 1287 pMeVO patients, pMeVO did not independently predict good-outcome(p = 0.55). In pMeVO patients, successful recanalization irrespective of frontline technique(aOR = 3.2,p < 0.05), procedure time ≤ 1-h(aOR = 2.2,p < 0.05), and thrombectomy attempts ≤ 4(aOR = 2.8,p < 0.05) were independent predictors of good-outcomes.In a propensity-matched cohort of aspiration versus stent-retriever pMeVO patients, there was no difference in good-outcomes. The rates of hemorrhage were higher(9%vs.4%,p < 0.01) and procedure time longer(51-min vs. 33-min,p < 0.01) with stent-retriever, while the number of attempts was higher with aspiration(2.5vs.2,p < 0.01). Rates of hemorrhage and good-outcome showed an exponential relationship to procedural metrics, and were more dependent on time in the aspiration group compared to attempts in the stent-retriever group. CONCLUSIONS: Clinical outcomes following EVT for pMeVO are comparable to those in LVOs. The golden hour or 3-pass rules in LVO thrombectomy still apply to pMeVO thrombectomy. Different techniques may exhibit different futility metrics; SR thrombectomy was more influenced by attempts whereas aspiration was more dependent on procedure time.

Modulation of the Complement System by Neoplastic Disease of the Central Nervous System.

The complement system is a highly conserved component of innate immunity that is involved in recognizing and responding to pathogens. The system serves as a bridge between innate and adaptive immunity, and modulation of the complement system can affect the entire host immune response to a foreign insult. Neoplastic diseases have been shown to engage the complement system in order to evade the immune system, gain a selective growth advantage, and co-opt the surrounding environment for tumor proliferation. Historically, the central nervous system has been considered to be an immune-privileged environment, but it is now clear that there are active roles for both innate and adaptive immunity within the central nervous system. Much of the research on the role of immunological modulation of neoplastic disease within the central nervous system has focused on adaptive immunity, even though innate immunity still plays a critical role in the natural history of central nervous system neoplasms. Here, we review the modulation of the complement system by a variety of neoplastic diseases of the central nervous system. We also discuss gaps in the current body of knowledge and comment on future directions for investigation.

Contralateral C7 Nerve Transfer for Stroke Recovery: New Frontier for Peripheral Nerve Surgery.

Ischemic stroke remains a major cause of disability in the United States and worldwide. Following the large-scale implementation of stroke thrombectomy and the optimization of treatment protocols for acute stroke, the reduction in stroke-associated mortality has resulted in an increased proportion of stroke survivors, many of whom have moderate to severe disability. To date, the treatment of subacute and chronic stroke has remained a challenge. Several approaches, involving pharmacological interventions to promote neuroplasticity, brain stimulation strategies and rehabilitative interventions, are currently being explored at different stages of the translational spectrum, yet level 1 evidence is still limited. In a recent landmark study, surgical intervention using contralateral C7 nerve transfer, an approach used to treat brachial plexus injury, was implemented in patients with chronic stroke, demonstrating an added benefit to standard rehabilitation strategies, leading to improved motor performance and reduced spasticity. The procedure involved the transfer of the C7 nerve root and middle trunk from the uninjured extremity to the injured extremity using a short conduit that allows for faster regeneration and innervation of the injured upper extremity via the ipsilateral (contralesional) hemisphere. In this work, we review the rationale for using contralateral C7 nerve transfer in stroke, describe the surgical intervention with associated variations and limitations, and discuss the current evidence for the efficacy of this technique in ischemic stroke research.

Thrombectomy Technique Predicts Outcome in Posterior Circulation Stroke-Insights from the STAR Collaboration.

BACKGROUND: Randomized controlled trials evaluating mechanical thrombectomy (MT) for acute ischemic stroke predominantly studied anterior circulation patients. Both procedural and clinical predictors of outcome in posterior circulation patients have not been evaluated in large cohort studies. OBJECTIVE: To investigate technical and clinical predictors of functional independence after posterior circulation MT while comparing different frontline thrombectomy techniques. METHODS: In a retrospective multicenter international study of 3045 patients undergoing MT for stroke between 06/2014 and 12/2018, 345 patients had posterior circulation strokes. MT was performed using aspiration, stent retriever, or combined approach. Functional outcomes were assessed using the 90-d modified Rankin score dichotomized into good (0-2) and poor outcomes (3-6). RESULTS: We included 2700 patients with anterior circulation and 345 patients with posterior circulation strokes. Posterior patients (age: 60 ± 14, 46% females) presented with mainly basilar occlusion (80%) and were treated using contact aspiration or ADAPT (39%), stent retriever (31%) or combined approach (19%). Compared to anterior strokes, posterior strokes had delayed treatment (500 vs 340 min, P < .001), higher national institute of health stroke scale (NIHSS) (17.1 vs 15.7, P < .01) and lower rates of good outcomes (31% vs 43%, P < .01). In posterior MT, diabetes (OR = 0.28, 95%CI: 0.12-0.65), admission NIHSS (OR = 0.9, 95%CI: 0.86-0.94), and use of stent retriever (OR = 0.26, 95%CI: 0.11-0.62) or combined approach (OR = 0.35, 95%CI: 0.12-1.01) vs ADAPT were associated with lower odds of good outcome. Stent retriever use was associated with lower odds of good outcomes compared to ADAPT even when including patients with only basilar occlusion or with successful recanalization only. CONCLUSION: Despite similar safety profiles, use of ADAPT is associated with higher rates of functional independence after posterior circulation thrombectomy compared to stent retriever or combined approach in large "real-world" retrospective study.