David K. Hahn

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.

Adjuvant Embolization With N-Butyl Cyanoacrylate in the Treatment of Cerebral Arteriovenous Malformations Outcomes, Complications, and Predictors of Neurologic Deficits

Background and Purpose— The purpose of this study was to assess the frequency, severity, and predictors of neurological deficits after adjuvant embolization for cerebral arteriovenous malformations. Methods— From 1997 to 2006, 202 of 275 patients with arteriovenous malformation received embolization before microsurgery (n=176) or radiosurgery (n=26). Patients were examined before and after endovascular embolization and at clinical follow-up (mean, 43.4±34.6 months). Outcome was classified according to the modified Rankin Scale. New neurological deficits after embolization were defined as minimal (no change in overall modified Rankin Scale), moderate (modified Rankin Scale ≤2), or significant (modified Rankin Scale >2). Results— Two hundred two patients were treated in 377 embolization procedures. There were a total of 29 new clinical deficits after embolization (8% of procedures; 14% of patients), of which 19 were moderate or significant. Postembolization deficits resolved in a significant number of patients over time (P<0.0001). Five patients had persistent neurological deficits due to embolization (1.3% of procedures; 2.5% of patients). In multivariate analysis, the following variables significantly predicted new neurological deficit after embolization: complex arteriovenous malformation with treatment plan specifying more than one embolization procedure (OR, 2.7; 95% CI, 1.4 to 8.6), diameter <3 cm (OR, 3.2; 95% CI, 1.2 to 9.1), diameter >6 cm (OR, 6.2; 95% CI, 1.0 to 57.0), deep venous drainage (OR, 2.7; 95% CI, 1.1 to 6.9), or eloquent location (OR, 2.4; 95% CI, 1.0 to 5.7). These variables were weighted and used to compute an arteriovenous malformation Embolization Prognostic Risk Score for each patient. A score of 0 predicted no new deficits, a score of 1 predicted a new deficit rate of 6%, a score of 2 predicted a new deficit rate of 15%, a score of 3 predicted a new deficit rate of 21%, and a score of 4 predicted a new deficit rate of 50% (P<0.0001). Conclusions— Small and large size, eloquent location, deep venous drainage, and complex vascular anatomy requiring multiple embolization procedures are risk factors for the development of immediate postembolization neurological deficits. Nevertheless, a significant number of patients with treatment-related neurological deficits improve over time. The low incidence of permanent neurological deficits underscores the usefulness of this technique in carefully selected patients.

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.

Pelvic Congestion Syndrome-Associated Pelvic Pain: A Systematic Review of Diagnosis and Management

To systematically evaluate the diagnosis and treatment of female pelvic congestion syndrome (PCS). We searched the PubMed database and relevant bibliographies for English-language studies published between January 1966 and May 2009 pertaining to diagnosis and treatment of female PCS-related pelvic pain. Treatment articles were restricted to those containing at least 4 subjects and a specified length of follow-up. Diagnostic test studies were included if they included subjects with and without pelvic pain. Two reviewers abstracted characteristics and outcomes from all controlled diagnostic studies and treatment papers. Six diagnostic and 22 treatment studies met entry criteria. Diagnostic method studies (pelvic venography, magnetic resonance imaging, or ultrasound) generally lacked appropriate reference standards, blinded assessors, or proven reliability. Treatment studies (using transvenous catheter embolization, surgical ligation, hysterectomy, or hormonal suppression) reporting ordinal outcomes found improvement from 24% to 100%; a similarly wide range of improvement was found with change in continuous rating of visual analogue scale pain scores (mean follow-up 4 months to 5.6 years). Both progestins and gonadotropin-releasing hormone agonists are effective in decreasing pain symptoms. The optimal diagnostic approach for PCS-related pelvic pain remains unclear, and controlled trials comparing medical and interventional treatments are urgently needed for PCS-associated pelvic pain. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to Compare different surgical treatments for pelvic congestion syndromes associated with pelvic pain syndromes. Estimate the relative severity of pelvic congestion in women using current venographic criteria. Choose between different diagnostic methods for characterizing pelvic venous blood flow and anatomy in women presenting with pelvic pain.

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.

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.

Endothelial nitric oxide synthase gene single-nucleotide polymorphism predicts cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

Vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Studies have shown a link between single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (eNOS) gene and the incidence of coronary spasm and aneurysms. Alterations in the eNOS T-786 SNP may lead to an increased risk of post-aSAH cerebral vasospasm. In this prospective clinical study, 77 aSAH patients provided genetic material and were followed for the occurrence of vasospasm. In multivariate logistic regression analysis, genotype was the only factor predictive of vasospasm. The odds ratio (OR) for symptomatic vasospasm in patients with one T allele was 3.3 (95% confidence interval (CI): 1.1 to 10.0, P=0.034) and 10.9 for TT. Patients with angiographic spasm were 3.6 times more likely to have a T allele (95% CI: 1.3 to 9.6, P=0.013; for TT: OR 12.6). Patients with severe vasospasm requiring endovascular therapy were more likely to have a T allele (OR 3.5, 95% CI: 1.3 to 9.5, P=0.016; for TT: OR 12.0). Patients with the T allele of the eNOS gene are more likely to have severe vasospasm. Presence of this genotype may allow the identification of individuals at high risk for post-aSAH vasospasm and lead to early treatment and improved outcome.