Christopher P. Kellner

Impact of a Protocol for Acute Antifibrinolytic Therapy on Aneurysm Rebleeding After Subarachnoid Hemorrhage

Background and Purpose— ϵ-Aminocaproic acid (EACA) is an antifibrinolytic agent used to prevent rebleeding in aneurysmal subarachnoid hemorrhage. Although studies have found that a decrease in rebleeding with long-term antifibrinolytic therapy is offset by an increase in ischemic deficits, more recent studies have indicated that early, short-term therapy may be beneficial. Methods— We instituted a protocol for acute EACA administration starting at diagnosis and continued for a maximum duration of 72 hours after subarachnoid hemorrhage onset. We compared 73 patients treated with EACA with 175 non-EACA-treated patients. We sought to identify differences in the occurrence of rebleeding, side effects, and outcome. Results— Baseline characteristics were similar in the 2 groups. There was a significant decrease in rebleeding in EACA-treated patients (2.7%) versus non-EACA patients (11.4%). There was no difference in ischemic complications between cohorts. There was a significant 8-fold increase in deep venous thrombosis in the EACA group but no increase in pulmonary embolism. There was a nonsignificant 76% reduction in mortality attributable to rebleeding, a 13.3% increase in favorable outcome in good-grade EACA-treated patients, and a 6.8% increase in poor-grade patients. Conclusions— When used acutely, short-term EACA treatment resulted in decreased rebleeding without an increase in serious side effects in our selected group of patients. Randomized placebo-controlled trials are needed to determine whether acute antifibrinolytic therapy should be accepted as the standard of care in all patients.

Advances in Neuroprotective Strategies: Potential Therapies for Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is associated with higher mortality and morbidity than any other form of stroke. However, there currently are no treatments proven to improve outcomes after ICH, and therefore, new effective therapies are urgently needed. Growing insight into ICH pathophysiology has led to the development of neuroprotective strategies that aim to improve the outcome through reduction of secondary pathologic processes. Many neuroprotectants target molecules or pathways involved in hematoma degradation, inflammation or apoptosis, and have demonstrated potential clinical benefits in experimental settings. We extensively reviewed the current understanding of ICH pathophysiology as well as promising experimental neuroprotective agents with particular focus on their mechanisms of action. Continued advances in ICH knowledge, increased understanding of neuroprotective mechanisms, and improvement in the ability to modulate molecular and pathologic events with multitargeting agents will lead to successful clinical trials and bench-to-bedside translation of neuroprotective strategies.

A mouse model of intracerebral hemorrhage using autologous blood infusion

The development of controllable and reproducible animal models of intracerebral hemorrhage (ICH) is essential for the systematic study of the pathophysiology and treatment of hemorrhagic stroke. In recent years, we have used a modified version of a murine ICH model to inject blood into mouse basal ganglia. According to our protocol, autologous blood is stereotactically infused in two stages into the right striatum to mimic the natural events of hemorrhagic stroke. Following ICH induction, animals demonstrate reproducible hematomas, brain edema formation and marked neurological deficits. Our technique has proven to be a reliable and reproducible means of creating ICH in mice in a number of acute and chronic studies. We believe that our model will serve as an ideal paradigm for investigating the complex pathophysiology of hemorrhagic stroke. The protocol for establishing this model takes about 2 h.

Brain-computer interfaces: military, neurosurgical, and ethical perspective

Brain-computer interfaces (BCIs) are devices that acquire and transform neural signals into actions intended by the user. These devices have been a rapidly developing area of research over the past 2 decades, and the military has made significant contributions to these efforts. Presently, BCIs can provide humans with rudimentary control over computer systems and robotic devices. Continued advances in BCI technology are especially pertinent in the military setting, given the potential for therapeutic applications to restore function after combat injury, and for the evolving use of BCI devices in military operations and performance enhancement. Neurosurgeons will play a central role in the further development and implementation of BCIs, but they will also have to navigate important ethical questions in the translation of this highly promising technology. In the following commentary the authors discuss realistic expectations for BCI use in the military and underscore the intersection of the neurosurgeons civic and clinical duty to care for those who serve their country.

Monocyte chemoattractant protein–1 predicts outcome and vasospasm following aneurysmal subarachnoid hemorrhage

OBJECT Despite efforts to elucidate both the molecular mechanism and the clinical predictors of vasospasm after aneurysmal subarachnoid hemorrhage (ASAH), its pathogenesis remains unclear. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that has been firmly implicated in the pathophysiology of vasospasm and in neural tissue injury following focal ischemia in both animal models and human studies. The authors hypothesized that MCP-1 would be found in increased concentrations in the blood and cerebrospinal fluid (CSF) of patients with ASAH and would correlate with both outcome and the occurrence of vasospasm. METHODS Seventy-seven patients who presented with ASAH were prospectively enrolled in this study between July 2001 and May 2002. Using an enzyme-linked immunosorbent assay, MCP-1 levels were measured in serum daily and in CSF when available. The mean serum and CSF MCP-1 concentrations were calculated for each patient throughout the entire hospital stay. Neurological outcome was evaluated at discharge or 14 days posthemorrhage using the modified Rankin Scale. Vasospasm was evaluated on angiography. RESULTS The serum MCP-1 concentrations correlated with negative outcome such that a 10% increase in concentration predicted a 25% increase in the probability of a poor outcome, whereas the serum MCP-1 levels did not correlate with vasospasm. Concentrations of MCP-1 in the CSF, however, proved to be significantly higher in patients with angiographically demonstrated vasospasm. CONCLUSIONS These findings suggest a role for MCP-1 in neurological injury and imply that it may act as a biomarker of poor outcome in the serum and of vasospasm in the CSF.

External ventricular drainage following aneurysmal subarachnoid haemorrhage

External ventricular drain (EVD) placement is standard of care in the management of aneurysmal subarachnoid haemorrhage-associated hydrocephalus (aSAH). However, there are no guidelines for EVD placement and management after aSAH. Optimal EVD insertion conditions, techniques to reduce the risk of EVD-associated infection and aneurysmal rebleeding, and methods of EVD removal are critical, yet incompletely answered management variables. The present literature consists primarily of small studies with heterogeneous populations and variable outcome measures, and suggests the following: EVDs may increase the risk of rebleeding; EVDs are increasingly placed by non-neurosurgeons with unclear results; intraparenchymal ICP monitors may be safely considered (with or without spinal drainage) in the setting of difficult EVD placement; the optimal timing and manner of EVD removal has yet to be defined; and the efficacy of prophylactic systemic antibiotics and antibiotic-coated EVDs needs further investigation. Nevertheless, there are no definitive practice guidelines for EVD placement and management techniques in aSAH patients. Large prospective randomised trials are needed to definitively address important gaps in our understanding of EVD management principles in the neurocritical care setting.

Protective Effect of C5a Receptor Inhibition after Murine Reperfused Stroke

OBJECTIVE The complement cascade has been implicated in cerebral ischemia/reperfusion injury. To develop clinically useful therapies that successfully manipulate the complement cascade, the individual roles of its components must be clearly defined. Previous studies have shown that C5 inhibition improves outcome after experimental stroke. In this study, we investigated the role of C5a in stroke injury by inhibiting its activity at the receptor level. METHODS C5a receptor antagonist or vehicle was administered to mice before temporary middle cerebral artery occlusion. Stroke outcomes were assessed 24 hours later in all mice using both neurological deficit scores and cerebral infarct volumes. RESULTS Animals treated with C5a receptor antagonist experienced significantly decreased infarct volume and demonstrated an improving trend in neurological function. CONCLUSION These findings demonstrate that modulation of C5a receptor activity significantly alters the degree of neurological damage after experimental reperfused stroke.

Early plasma complement C3a levels correlate with functional outcome after aneurysmal subarachnoid hemorrhage.

OBJECTIVE Studies have documented an inflammatory response in the circulating plasma and cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage (aSAH). In particular, early upregulation of several complement proteins, including C3a, C4a, and C5b-9, has been demonstrated after the initial hemorrhagic insult. The inflammatory actions of the complement cascade are largely mediated through the anaphylatoxins, C3a and C5a. Recent investigations have established a critical role for C3a in the pathogenesis of cerebral ischemia. We attempt to confirm that plasma C3a and C5a values are elevated in patients with aSAH and to determine whether or not these levels are reliable independent predictors of functional outcome irrespective of clinical presentation. METHODS Fifty-two patients with aSAH were prospectively enrolled and stratified according to admission Hunt and Hess grade, demographic variables, and functional status at the time of discharge (modified Rankin Scale score). Plasma C3a and C5a levels were determined at early and late time points after aSAH through enzyme-linked immunosorbent assay. RESULTS After aSAH, early C3a and C5a values were increased compared with levels in non-SAH control patients (P < 0.001). Univariate analysis demonstrated that elevations in early C3a (P = 0.010) and C5a (P = 0.041) levels and poor admission Hunt and Hess grade (P = 0.015) correlated significantly with unfavorable outcome. In our multivariate model, only early C3a levels retained a strong correlation with outcome when modeled with Hunt and Hess grade (P = 0.009). CONCLUSION These results demonstrate an association between early complement C3a levels and outcome after aSAH that seems to be independent of the initial hemorrhage. The findings suggest that inflammatory processes involving C3a may contribute to delayed morbidity and mortality after aneurysmal rupture.

Neuroprotective Strategies for Intracerebral Hemorrhage Trials and Translation

Intracerebral hemorrhage is a devastating neurological illness with few treatment options. In the past 10 years, 6 clinical trials have been completed examining the potential role that putative neuroprotective agents might play in improving outcome. Although each of these trials failed to show a benefit, animal research continues to supply the translational pipeline and 5 clinical trials evaluating neuroprotective agents in intracerebral hemorrhage are currently ongoing. Despite initial failures, neuroprotective agents continue to show promise in the treatment of intracerebral hemorrhage, but improvements in clinical trial design and more accurate predictive outcome models are necessary.

Evaluation of intraventricular hemorrhage assessment methods for predicting outcome following intracerebral hemorrhage

OBJECT Intraventricular hemorrhage (IVH) associated with intracerebral hemorrhage (ICH) is an independent predictor of poor outcome. Clinical methods for evaluating IVH, however, are not well established. This study sought to determine the best IVH grading scale by evaluating the predictive accuracies of IVH, Graeb, and LeRoux scores in an independent cohort of ICH patients with IVH. Subacute IVH dynamics as well as the impact of external ventricular drain (EVD) placement on IVH and outcome were also investigated. METHODS A consecutive cohort of 142 primary ICH patients with IVH was admitted to Columbia University Medical Center between February 2009 and February 2011. Baseline demographics, clinical presentation, and hospital course were prospectively recorded. Admission CT scans performed within 24 hours of onset were reviewed for ICH location, hematoma volume, and presence of IVH. Intraventricular hemorrhage was categorized according to IVH, Graeb, and LeRoux scores. For each patient, the last scan performed within 6 days of ictus was similarly evaluated. Outcomes at discharge were assessed using the modified Rankin Scale (mRS). Receiver operating characteristic analysis was used to determine the predictive accuracies of the grading scales for poor outcome (mRS score ≥ 3). RESULTS Seventy-three primary ICH patients (51%) had IVH. Median admission IVH, Graeb, and LeRoux scores were 13, 6, and 8, respectively. Median IVH, Graeb and LeRoux scores decreased to 9 (p = 0.005), 4 (p = 0.002), and 4 (p = 0.003), respectively, within 6 days of ictus. Poor outcome was noted in 55 patients (75%). Areas under the receiver operating characteristic curve were similar among the IVH, Graeb, and LeRoux scores (0.745, 0.743, and 0.744, respectively) and within 6 days postictus (0.765, 0.722, 0.723, respectively). Moreover, the IVH, Graeb, and LeRoux scores had similar maximum Youden Indices both at admission (0.515 vs 0.477 vs 0.440, respectively) and within 6 days postictus (0.515 vs 0.339 vs 0.365, respectively). Patients who received EVDs had higher mean IVH volumes (23 ± 26 ml vs 9 ± 11 ml, p = 0.003) and increased incidence of Glasgow Coma Scale scores < 8 (67% vs 38%, p = 0.015) and hydrocephalus (82% vs 50%, p = 0.004) at admission but had similar outcome as those who did not receive an EVD. CONCLUSIONS The IVH, Graeb, and LeRoux scores predict outcome well with similarly good accuracy in ICH patients with IVH when assessed at admission and within 6 days after hemorrhage. Therefore, any of one of the scores would be equally useful for assessing IVH severity and risk-stratifying ICH patients with regard to outcome. These results suggest that EVD placement may be beneficial for patients with severe IVH, who have particularly poor prognosis at admission, but a randomized clinical trial is needed to conclusively demonstrate its therapeutic value.