Grace H. Kim

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.

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.

Microsurgical treatment of basilar apex aneurysms: perioperative and long-term clinical outcome.

OBJECTIVEWe sought to analyze the perioperative and long-term clinical outcome data for patients with microsurgically treated basilar apex aneurysms. METHODSWe identified 98 consecutively treated basilar apex aneurysms in patients prospectively enrolled in a cerebral aneurysm database. RESULTSFifty patients presented with subarachnoid hemorrhage, and 19 aneurysms were giant. Eighty-four of 98 aneurysms were directly clipped. Surgical morbidity was 19.4% for the entire cohort and 8.8% for the unruptured, nongiant subgroup. The most common complication resulting in long-term morbidity was perforator injury. Sixty-seven percent of patients with clipped aneurysms were independent at discharge; this fraction increased to 79.0% at the 3-month follow-up examination. Good long-term outcomes (modified Rankin Scale score ≤2) were achieved in 56 (70%) of 80 cases. The mean Barthel Index of surviving patients was 95.8 ± 15.0 (median = 100, n = 66). Patients with unruptured, nongiant lesions fared considerably better than patients in other cohorts. Ninety-three percent of this subgroup was independent at discharge; this fraction increased to 100% at the 3-month follow-up examination (n = 27). In univariate analyses, poor clinical grade, giant aneurysm size, major operative complications, and operations performed early in the series were associated with worse outcomes. In the multivariate analysis, unruptured giant aneurysm status was found to confer a tremendous risk for poor outcome (risk ratio, 80.0; 95% confidence interval, 8.0–800.7; P < 0.01). Surviving patients were observed for a mean clinical follow-up period of 7.4 ± 3.7 years. The annual rate of postoperative subarachnoid hemorrhage was 0.18% for all clipped aneurysms and 0% for completely clipped lesions. CONCLUSIONIn comparison to data from the existing literature regarding Guglielmi detachable coil embolization of basilar apex aneurysms, the data presented suggest that surgical clipping should be an important component of a multimodality approach to the treatment of patients with basilar apex aneurysms.

C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent

The complement anaphylatoxin C3a contributes to injury after cerebral ischemia in mice. This study assesses the effect of C3a receptor antagonist (C3aRA) on leukocyte infiltration into the ischemic zone. Transient or permanent middle cerebral artery occlusion (MCAO) was induced in wild-type C57BI/6 mice. Intraperitoneal C3aRA or vehicle was administered 45 mins before or 1 h after occlusion. Twenty-four hours after occlusion, we harvested brain tissue and purified inflammatory cells using flow cytometry. Soluble intercellular adhesion molecule (ICAM)-1 protein levels were assessed using enzyme-linked immunosorbent assays, and ICAM-1 and C3a receptor (C3aR) expression was confirmed via immunohistochemistry. In the transient MCAO model, animals receiving C3aRA showed smaller strokes, less upregulation of C3aR-positive granulocytes, and less ICAM-1 protein on endothelial cells than vehicle-treated animals; no significant differences in other inflammatory cell populations were observed. C3a receptor antagonist-treated and vehicle-treated animals showed no differences in stroke volume or inflammatory cell populations after permanent MCAO. These data suggest that blocking the binding of C3a to C3aR modulates tissue injury in reperfused stroke by inhibiting the recruitment of neutrophils to the ischemic zone. It further establishes antagonism of the C3a anaphylatoxin as a promising strategy for ameliorating injury after ischemia/reperfusion.

C3a receptor antagonist attenuates brain injury after intracerebral hemorrhage.

Neuroprotective therapy targeting the complement cascade may reduce injury associated with intracerebral hemorrhage (ICH). We investigated the role of C3a-receptor antagonist (C3aRA) after ICH in mice. Autologous whole blood was infused into the right striatum of mice that were treated with C3aRA or vehicle, using both a pre- and postinjury dosing regimen. Hematoma volume, brain water content, and inflammatory cell profile were assessed at 72 h post-ICH. Neurologic dysfunction was assessed by evaluating both spatial memory and sensorimotor capacity. Animals pretreated with C3aRA showed significantly improved neurologic function, brain water content, and granulocyte infiltration relative to vehicle-treated animals when assessed at 72 h. There was no significant difference in hemorrhagic/nonhemorrhagic ratio of microglial activation among all groups. Hematoma volumes were also not significantly different between C3aRA-treated and vehicle-treated animals. Administration of C3aRA beginning 6 h postinjury afforded significant amelioration of neurologic dysfunction as well as a reduction in brain water content. Treatment with C3aRA improved neurologic outcome while reducing inflammatory cell infiltration and brain edema formation after experimental ICH in mice. Results of this study suggest that the C3a receptor may be a promising target for therapeutic intervention in hemorrhagic stroke.

Ultrarapid, Convection-Enhanced Intravascular Hypothermia A Feasibility Study in Nonhuman Primate Stroke

Background and Purpose— Hypothermia has been shown to be neuroprotective in a variety of clinical settings. Unfortunately, poor delivery techniques and insufficient data in appropriate preclinical models have hampered its development in human stroke. To address these limitations, we have devised a 10F intravascular catheter capable of rapid systemic cooling of nonhuman primates. Methods— Placed in the inferior vena cava via a transfemoral approach, the catheter was used to induce mild systemic hypothermia 3 hours after the onset of hemispheric stroke in baboons. Results— Cooling was achieved at a rate of 6.3±0.8°C/h. Target brain temperatures (32.2±0.2°C) were reached at the same time (47.7±6.32 minutes) as target esophageal temperatures (32.0±0.0°C). Hypothermia was maintained for 6 hours in all animals. Animals did not experience the infections, coagulopathy, or cerebral edema commonly seen with surface cooling methods in human stroke. Conclusions— These data suggest that a brief episode of mild core hypothermia instituted at a clinically relevant time point can be achieved in primate stroke and that our intravascular cooling technique provides safe, rapid, and reproducible hypothermia.

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.

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.

The impact of microsurgical fenestration of the lamina terminalis on shunt-dependent hydrocephalus and vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVEChronic hydrocephalus requiring shunt placement and cerebral vasospasm are common complications after aneurysmal subarachnoid hemorrhage. Recent publications have investigated the possibility that microsurgical fenestration of the lamina terminalis during aneurysm surgery may reduce the incidence of shunt-dependent hydrocephalus and cerebral vasospasm. We reviewed a single-surgeon series to compare postsurgical outcomes of patients who underwent fenestration of the lamina terminalis against those who did not. METHODSThis study is a retrospective review of the medical records of 369 consecutive patients with aneurysmal subarachnoid hemorrhage admitted to Columbia University Medical Center between January 2000 and July 2006. All patients underwent craniotomy and clipping of at least one ruptured cerebral aneurysm by a single neurosurgeon (ESC). The incidences of shunt-dependent hydrocephalus, conversion from acute hydrocephalus on admission to chronic hydrocephalus, and clinical cerebral vasospasm were compared in patients who underwent fenestration of the lamina terminalis with those who did not. The patient cohort was thus divided into three subgroups: 1) patients whose operative records clearly indicated that they underwent fenestration of the lamina terminalis, 2) patients whose operative records clearly indicated that they did not undergo fenestration of the lamina terminalis, and 3) patients whose operative records did not indicate one way or another whether they received fenestration of the lamina terminalis. We performed two separate analyses by comparing the postsurgical outcomes in those patients who were fenestrated versus those who were definitively not fenestrated and comparing the postsurgical outcomes in those patients who were fenestrated versus those who were not plus those whose records did not document fenestration. To further control for any cohort differences, we performed a comparison between patients who were fenestrated and those who were not after matching 1:1 for presenting radiographic and clinical characteristics predictive of hydrocephalus and vasospasm. Outcomes were compared using logistic regression and multivariable analysis. RESULTSIn the first model, fenestrated patients had a shunt rate, conversion rate, and rate of clinical vasospasm of 25, 50, and 23%, respectively, versus 20, 27, and 27% in nonfenestrated patients, respectively (P = 0.28, 0.21, and 0.32, respectively). In the second model, the nonfenestrated patients plus nondocumented patients had a shunt rate, conversion rate, and rate of clinical vasospasm of 16, 40, and 20%, respectively (P = 0.19, 0.33, and 0.60, respectively). In the matched cohort, fenestrated patients had a shunt rate, conversion rate, and rate of clinical vasospasm of 29, 67, and 20%, respectively, versus 20, 25, and 25% in nonfenestrated patients, respectively (P = 0.30, 0.24, and 0.20, respectively). CONCLUSIONIn contrast to other retrospective multisurgeon series, our retrospective single-surgeon series suggests that microsurgical fenestration of the lamina terminalis may not reduce the incidence of shunt-dependent hydrocephalus or cerebral vasospasm after aneurysmal subarachnoid hemorrhage. A prospective multicenter trial is needed to definitively address the use of this maneuver.

Neurologic assessment of somatosensory dysfunction following an experimental rodent model of cerebral ischemia

The modified adhesive removal (sticky-tape) test is an assessment of somatosensory dysfunction following cerebral ischemia in rats. This test is less time consuming than the original protocol by virtue of requiring minimal pre-training. We present a detailed protocol describing how to conduct the modified adhesive removal (sticky-tape) test. Following right middle cerebral artery occlusion (rMCAo) using an intraluminal filament, animals undergo the modified sticky-tape test (MST) on post-operative days 1, 3, 7 and 10. For the test, a non-removable tape sleeve is placed around the animals paw and the time to remove the stimulus is measured. The time spent attending to this stimulus is also recorded. Animals undergoing MST for the first time demonstrate nearly-uniform excellent performance. However, following rMCAo, the ratio of left to right performance on the MST is significantly different at all time points. In short, the MST accurately assesses neurological dysfunction in rodents, not only with minimal pre-training, but also with accurate localization to the side of injury.