Anthony L. D'Ambrosio

Decompressive hemicraniectomy for poor-grade aneurysmal subarachnoid hemorrhage patients with associated intracerebral hemorrhage: clinical outcome and quality of life assessment.

OBJECTIVE:Decompressive hemicraniectomy has been proposed as a potential treatment strategy in patients with poor-grade aneurysmal subarachnoid hemorrhage presenting with focal intracerebral hemorrhage causing significant mass effect. Although hemicraniectomy improves overall survival rates, the long-term quality of life (QoL) for survivors in this patient population has not been reported. METHODS:Using adjudicated outcome assessments, we compare long-term clinical outcomes and QoL between a group of patients with poor-grade aneurysmal subarachnoid hemorrhage receiving decompressive hemicraniectomy (n = 12) and a control group of similar patients managed more conservatively (n = 10). RESULTS:Patients receiving decompressive hemicraniectomy experienced a statistically insignificant decrease in short-term mortality compared with controls (25 versus 42%); however, long-term QoL in hemicraniectomy survivors was generally poor. Furthermore, hemicraniectomy patients did not experience an increase in mean quality-adjusted life years over control patients (2.31 versus 2.22 yr). CONCLUSION:Decompressive hemicraniectomy prolongs short-term survival in patients with poor-grade aneurysmal subarachnoid hemorrhage with associated intracerebral hemorrhage; however, this trend is not statistically significant, and the overall QoL experienced by survivors is poor. Decompressive hemicraniectomy may be indicated if performed early in a select subset of patients. On the basis of our preliminary data, large prospective studies to investigate this issue further may not be warranted.

Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: A critical review of the literature

Abstract.Despite recent advances in the understanding of the pathophysiology of cerebral ischemia, current approaches attempting to prevent ischemic brain damage after an acute stroke remain quite inadequate. Today, ischemic stroke remains the third leading cause of death in industrialized nations, and the leading cause of disability requiring long term institutional care in the U.S and other industrialized nations. While one treatment, tissue plasminogen activator, has shown efficacy in clinical trials, safety concerns limit its role in clinical practice to a narrow time window of use.Acute cerebral ischemia has been shown to evoke a profound and deleterious upregulation of the inflammatory response, initiated within the cerebral microvasculature. Recently, research efforts have focused on targeting individual components of the inflammatory cascade, such as leukocyte activation and adhesion, in an attempt to develop potential neuroprotective agents. While these strategies have shown promise preclinically, clinical trials have yet to show clear benefit. Here, we review the current understanding of the pathophysiologic consequences of acute cerebral ischemic injury. Additionally, we discuss the role of the inflammatory cascade, with specific attention given to the deleterious role played by leukocyte activation and adhesion in stroke. Finally, relevant efforts to translate these basic science observations into clinical efficacy in acute stroke trials are critically reviewed.

An improved test of neurological dysfunction following transient focal cerebral ischemia in rats.

The Adhesive Removal (sticky-tape) test is a commonly used test of somatosensory dysfunction following cerebral ischemia in rats. This test requires several days of pre-training prior to surgery, which can be time consuming. We present our results with an improved version of the sticky-tape test. Male Wistar rats were subjected to either sham surgery (n = 4) or right middle cerebral artery occlusion (rMCAo) using an intraluminal filament (n = 9), followed by a 10-day survival period. On post-operative days (POD) 1, 3, 7, and 10 animals underwent both the conventional sticky-tape test (CST) with measurement of the time to remove the stimulus (trs), as well as a modified sticky-tape test (MST), in which a non-removable tape sleeve was placed around the animals paw. Time spent attending to this stimulus (tas) was recorded. Despite 3 days of pre-training, animals undergoing baseline CST still exhibited marked variability in pre-operative baseline test performance (trs range 1-60s). In contrast, animals undergoing MST for the first time demonstrated nearly uniformly excellent performance (% tas range 91.5-98.5% of the 30s testing period). Although, affected (left) limb performance on both CST (6.8-fold increase in trs on POD 1 compared to baseline) and MST (100% decrease in tas on POD 1 compared to baseline) was markedly altered by rMCAo, CST performance declined bilaterally, and no significant differences in the ratio of affected (left) and unaffected (right) limb performance between sham-operated and rMCAo animals were observed at any time point. In contrast, the ratio of left to right performance on the MST was significantly different at all time points (P<0.01). In conclusion, we present a simple modification of the widely used Adhesive Removal test and provide evidence that this test can accurately assess neurological dysfunction in rodents, not only with minimal pre-training, but also with improved localization of the side of injury.

Post-carotid endarterectomy neurocognitive decline is associated with cerebral blood flow asymmetry on post-operative magnetic resonance perfusion brain scans

Abstract Objective: Up to 25% of patients experience subtle declines in post-operative neurocognitive function following, otherwise uncomplicated, carotid endarterectomy (CEA). We sought to determine if post-CEA neurocognitive deficits are associated with cerebral blood flow (CBF) abnormalities on post-operative MR perfusion brain scans. Methods: We enrolled 22 CEA patients to undergo a battery of neuropsychometric tests pre-operatively and on post-operative day 1 (POD 1). Neurocognitive dysfunction was defined as a two standard deviation decline in performance in comparison to a similarly aged control group of lumbar laminectomy patients. All patients received MR perfusion brain scans on POD 1 that were analysed for asymmetries in CBF distribution. One patient experienced a transient ischemic attack within 24 hours before the procedure and was excluded from our analysis. Results: Twenty-nine percent of CEA patients demonstrated neurocognitive dysfunction on POD 1. One hundred percent of those patients with cognitive deficits demonstrated CBF asymmetry, in contrast to only 27% of those patients without cognitive impairment. Post-CEA cognitive dysfunction was significantly associated with CBF abnormalities (RR=3.75, 95% CI: 1.62–8.67, p=0.004). Conclusion: Post-CEA neurocognitive dysfunction is significantly associated with post-operative CBF asymmetry. These results support the hypothesis that post-CEA cognitive impairment is caused by cerebral hemodynamic changes. Further work exploring the relationship between CBF and post-CEA cognitive dysfunction is needed.

An improved functional neurological examination for use in nonhuman primate studies of focal reperfused cerebral ischemia

Abstract There is renewed interest in primate models of acute stroke for the evaluation of potential therapeutic agents prior to clinical trials. The development of more precise functional outcome measures would improve the pre-clinical assessment of neuroprotective strategies. We have constructed a grading scale that utilizes an increased number of goal-oriented tasks to assess both behavior and motor function. The new scoring system is designed to enhance precision and accuracy when compared to existing scales. Twenty-seven male baboons were subjected to 1 h of middle cerebral artery territory occlusion followed by reperfusion. Outcome was evaluated using both a standard neurological function scale and a new task-oriented scale. Each scoring system was assessed for reproducibility (inter-observer reliability) and for association with radiographic infarct volume. The task-oriented grading system was significantly less variable than the standard outcome measure (p < 0.0001). The task-oriented neurological scale demonstrated stronger correlation with radiographic infarct volume (p < 0.0001) than the standard scale (p < 0.01) and more accurately reflected infarct size in animals with small strokes. Compared to the accepted system for grading neurological function, the task-oriented scale demonstrates improved inter-observer variability and a better association with radiographic outcome measures. Incorporating this refined neurological evaluation into a baboon model of stroke may serve to increase the functional predictive value of pre-clinical studies.

Traumatic brain injury in pediatric patients: evidence for the effectiveness of decompressive surgery

Traumatic brain injury (TBI) is the current leading cause of death in children over 1 year of age. Adequate management and care of pediatric patients is critical to ensure the best functional outcome in this population. In their controversial trial, Cooper et al. concluded that decompressive craniectomy following TBI did not improve clinical outcome of the analyzed adult population. While the study did not target pediatric populations, the results do raise important and timely clinical questions regarding the effectiveness of decompressive surgery in pediatric patients. There is still a paucity of evidence regarding the effectiveness of this therapy in a pediatric population, and there is an especially noticeable knowledge gap surrounding age-stratified interventions in pediatric trauma. The purposes of this review are to first explore the anatomical variations between pediatric and adult populations in the setting of TBI. Second, the authors assess how these differences between adult and pediatric populations could translate into differences in the impact of decompressive surgery following TBI.

Quantification of the frontotemporal orbitozygomatic approach using a three-dimensional visualization and modeling application.

OBJECTIVE We sought to simulate the frontotemporal orbitozygomatic (FTOZ) craniotomy in a three-dimensional virtual environment on patient-specific data and to quantify the exposure afforded by the FTOZ while simulating controlled amounts of brain retraction. METHODS Four computed tomographic angiograms were reconstructed with commercially available software (Amira 4.1.1; Mercury Computer Systems, Inc., Chelmsford, MA), and virtual FTOZ craniotomies were performed bilaterally (n = 8). Brain retraction was simulated at 1 and 2 cm. Surgical freedom and projection angle were measured and compared at each stage of the FTOZ. RESULTS At 1 cm of retraction, surgical freedom increased by 27 ± 14% for the removal of the orbital rim and by 31 ± 18% for FTOZ (P < 0.01) when compared with frontotemporal (FT) craniotomy. At 2 cm of retraction, surgical freedom increased by 15 ± 5% and 26 ± 8% for the removal of the orbital rim and FTOZ, respectively (P < 0.01). With increased retraction, surgical freedom increased by 100 ± 26%, 81 ± 15%, and 82 ± 27% for the FT, removal of the orbital rim, and FTOZ craniotomies, respectively (P < 0.001). Projection angle increased by 24.2% when orbital rim removal was added to the FT craniotomy (P < 0.01). CONCLUSION Surgical freedom increases significantly at every step of the FTOZ craniotomy. This effect is less robust when brain retraction is increased. Brain retraction alone has a greater impact on surgical freedom than bone removal alone. Projection angle is significantly increased when orbital rim removal is added to the FT craniotomy. This model overcomes two major limitations of cadaver-based models: quantification of brain retraction and incorporation of patient-specific anatomy.

A modified transorbital baboon model of reperfused stroke.

BACKGROUND AND PURPOSE Although pathophysiological studies of focal cerebral ischemia in nonhuman primates can provide important information not obtainable in rodent models, primate experimentation is limited by considerations of cost, availability, effort, and ethics. A reproducible and quantitative model that minimizes the number of animals necessary to detect differences between treatment groups is therefore crucial. METHODS Eight male baboons (weight, 22+/-2 kg) underwent left transorbital craniectomy followed by 1 hour of temporary ipsilateral internal carotid artery occlusion at the level of the anterior choroidal artery together with bilateral temporary occlusion of both anterior cerebral arteries (A1) proximal to the anterior communicating artery. A tightly controlled nitrous oxide-narcotic anesthetic allowed for intraoperative motor evoked potential confirmation of middle cerebral artery (MCA) territory ischemia. Animals survived to 72 hours or 10 days if successfully self-caring. Outcomes were assessed with a 100-point neurological grading system, and infarct volume was quantified by planimetric analysis of both MRI and triphenyltetrazolium chloride-stained sections. RESULTS Infarction volumes (on T2-weighted images) were 32+/-7% (mean+/-SEM) of the ipsilateral hemisphere, and neurological scores averaged 29+/-9. All animals demonstrated evidence of hemispheric infarction, with damage evident in both cortical and subcortical regions in the MCA vascular territory. Histologically determined infarction volumes differed by <3% and correlated with absolute neurological scores (r=0.9, P:=0.003). CONCLUSIONS Transorbital temporary occlusion of the entire anterior cerebral circulation with strict control of physiological parameters can reliably produce reperfused MCA territory infarction. The magnitude of the resultant infarct with little interanimal variability diminishes the potential number of animals required to distinguish between 2 treatment regimens. The anatomic distribution of the infarct and associated functional deficits offer comparability to human hemispheric strokes.

Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy

Purpose: Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival. Experimental Design: In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival. Results: Forty-six patients received the vaccine with a median overall survival of 23.8 months [95% confidence interval (CI), 19.8–30.2]. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0–23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4–8.6; P = 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival. Conclusions: Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy. Clin Cancer Res; 23(14); 3575–84. ©2017 AACR.

Approaches to anterior and anterolateral foramen magnum lesions: A critical review

Foramen magnum (FM) lesions represent some of the most complex cases for the modern neurosurgeon because of their location near vital brainstem structures, the vertebral arteries, and lower cranial nerves. In particular, anterior or anterolaterally located FM tumors have traditionally been most difficult to resect with high morbidity and mortality resulting from approaches through the posterior midline or transorally. For many neurosurgeons, the far lateral, extreme lateral approach, and more recently, endoscopic endonasal approaches have become the preferred modern methods for the resection of anterior or anterolateral FM tumors. In this review, we examine both operative and non-operative approaches to FM tumors, including surgical anatomy, surgical technique, and indications for operative intervention in these complex cases. In addition, we compared outcomes from prior series.