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Michael M. McDowell, Yin Zhao, Christopher P. Kellner, Sunjay M. Barton, Eric Sussman, Jan Claassen, Andrew F. Ducruet and E. Sander Connolly

OBJECTIVE

Pathophysiological differences that underlie the development and subsequent growth of multiple aneurysms may exist. In this study, the authors assessed the factors associated with the occurrence of multiple aneurysms in patients presenting with aneurysmal subarachnoid hemorrhage (SAH).

METHODS

Consecutive patients presenting with aneurysmal SAH between 1996 and 2012 were prospectively enrolled in the Subarachnoid Hemorrhage Outcome Project. Patients harboring 1, 2, or 3 or more aneurysms were stratified into groups, and the clinical and radiological characteristics of each group were compared using multivariate logistic regression.

RESULTS

Of 1277 patients with ruptured intracranial aneurysms, 890 had 1 aneurysm, 267 had 2 aneurysms, and 120 had 3 or more aneurysms. On multinomial regression using the single-aneurysm cohort as base case, risk factors for patients presenting with 2 aneurysms were female sex (relative risk ratio [RRR] 1.80, p < 0.001), higher body mass index (BMI) (RRR 1.02, p = 0.003), more years of smoking (RRR = 1.01, p = 0.004), and black race (RRR 1.83, p = 0.001). The risk factors for patients presenting with 3 or more aneurysms were female sex (RRR 3.10, p < 0.001), higher BMI (RRR 1.03, p < 0.001), aneurysm in the posterior circulation (RRR 2.59, p < 0.001), and black race (RRR 2.15, p = 0.001). Female sex, longer smoking history, aneurysms in the posterior circulation, BMI, and black race were independently associated with the development of multiple aneurysms in our adjusted multivariate multinomial model.

CONCLUSIONS

Significant demographic and clinical differences are found between patients presenting with single and multiple aneurysms in the setting of aneurysmal SAH. These predictors of multiple aneurysms likely reflect a predisposition toward inflammation and endothelial injury.

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Eric S. Sussman, Christopher P. Kellner, Michael M. McDowell, Samuel S. Bruce, Simon G. Heuts, Zong Zhuang, Rachel A. Bruce, Jan Claassen and E. Sander Connolly Jr.

Intracerebral hemorrhage (ICH) is the most deadly and least treatable subtype of stroke, and at the present time there are no evidence-based therapeutic interventions for patients with this disease. Secondary injury mechanisms are known to cause substantial rates of morbidity and mortality following ICH, and the inflammatory cascade is a major contributor to this post-ICH secondary injury. The alpha-7 nicotinic acetylcholine receptor (α7-nAChR) agonists have a well-established antiinflammatory effect and have been shown to attenuate perihematomal edema volume and to improve functional outcome in experimental ICH. The authors evaluate the current evidence for the use of an α7-nAChR agonist as a novel therapeutic agent in patients with ICH.

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Charles L. Francoeur, David Roh, J. Michael Schmidt, Stephan A. Mayer, M. Cristina Falo, Sachin Agarwal, E. Sander Connolly, Jan Claassen, Mitchell S. V. Elkind and Soojin Park

OBJECTIVE

Rebleeding remains a frequent and catastrophic event leading to poor outcome after subarachnoid hemorrhage (SAH). Reduced platelet function after the initial bleed is associated with higher risk of early rebleeding. Desmopressin (DDAVP) is a well-known hemostatic agent, and recent guidelines already suggest its use in individuals exposed to antiplatelet drugs. The authors hypothesized that DDAVP administration in patients with SAH at admission would be associated with lower risks of rebleeding.

METHODS

The authors performed an observational cohort study of patients enrolled in the Columbia University SAH Outcome Project between August 1996 and July 2015. The authors compared the rate of rebleeding between patients who were and those who were not treated with DDAVP. After adjustment for known predictors, logistic regression was used to measure the association between treatment with DDAVP and risks of rebleeding.

RESULTS

Among 1639 patients with SAH, 12% were treated with DDAVP. The main indication for treatment was suspected exposure to an antiplatelet agent. The overall incidence of rebleeding was 9% (1% among patients treated with DDAVP compared with 8% among those not treated). After adjustment for antiplatelet use and known predictors, treatment with DDAVP was associated with a 45% reduction in the risks of rebleeding (adjusted OR 0.55, 95% CI 0.27–0.97). DDAVP was associated with a higher incidence of hyponatremia but not with thrombotic events or delayed cerebral ischemia.

CONCLUSIONS

Treatment with DDAVP was associated with a lower risk of rebleeding among patients with SAH. These findings support further study of DDAVP as first-line therapy for medical hemostasis in patients with SAH.

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Neha S. Dangayach, Harpreet Singh Grewal, Gian Marco De Marchis, Roberta K. Sefcik, Rachel Bruce, Aarti Chhatlani, E. Sander Connolly, M. Cristina Falo, Sachin Agarwal, Jan Claassen, J. Michael Schmidt and Stephan A. Mayer

OBJECTIVE

Being overweight or mildly obese has been associated with a decreased risk of death or hospitalization in patients with cardiovascular disease. Similarly, overweight patients admitted to an intensive care unit (ICU) have improved survival up to 1 year after admission. These counterintuitive observations are examples of the “obesity paradox.” Does the obesity paradox exist in patients with intracerebral hemorrhage (ICH)? In this study the authors examined whether there was an association between obesity and functional outcome in patients with ICH.

METHODS

The authors analyzed 202 patients admitted to the neurological ICU (NICU) who were prospectively enrolled in the Columbia University ICH Outcomes Project between September 2009 and December 2012. Patients were categorized into 2 groups: overweight (body mass index [BMI] ≥ 25 kg/m2) and not overweight (BMI < 25 kg/m2). The primary outcome was defined as survival with favorable outcome (modified Rankin Scale [mRS] score 0–3) versus death or severe disability (mRS score 4–6) at 3 months.

RESULTS

The mean age of the patients in the study was 61 years. The mean BMI was 28 ± 6 kg/m2. The mean Glasgow Coma Scale score was 10 ± 4 and the mean ICH score was 1.9 ± 1.3. The overall 90-day mortality rate was 41%. Among patients with a BMI < 25 kg/m2, 24% (17/70) had a good outcome, compared with 39% (52/132) among those with a BMI ≥ 25 kg/m2 (p = 0.03). After adjusting for ICH score, sex, do-not-resuscitate code status, and history of hypertension, being overweight or obese (BMI ≥ 25 kg/m2) was associated with twice the odds of having a good outcome compared with patients with BMI < 25 kg/m2 (adjusted odds ratio 2.05, 95% confidence interval 1.03–4.06, p = 0.04).

CONCLUSIONS

In patients with ICH admitted to the NICU, being overweight or obese (BMI ≥ 25 kg/m2) was associated with favorable outcome after adjustment for established predictors. The reason for this finding requires further study.

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Fawaz Al-Mufti, David Roh, Shouri Lahiri, Emma Meyers, Jens Witsch, Hans-Peter Frey, Neha Dangayach, Cristina Falo, Stephan A. Mayer, Sachin Agarwal, Soojin Park, Philip M. Meyers, E. Sander Connolly, Jan Claassen and J. Michael Schmidt

OBJECTIVE

The clinical significance of cerebral ultra-early angiographic vasospasm (UEAV), defined as cerebral arterial narrowing within the first 48 hours of aneurysmal subarachnoid hemorrhage (aSAH), remains poorly characterized. The authors sought to determine its frequency, predictors, and impact on functional outcome.

METHODS

The authors prospectively studied UEAV in a cohort of 1286 consecutively admitted patients with aSAH between August 1996 and June 2013. Admission clinical, radiographic, and acute clinical course information was documented during patient hospitalization. Functional outcome was assessed at 3 months using the modified Rankin Scale. Logistic regression and Cox proportional hazards models were generated to assess predictors of UEAV and its relationship to delayed cerebral ischemia (DCI) and outcome. Multiple imputation methods were used to address data lost to follow-up.

RESULTS

The cohort incidence rate of UEAV was 4.6%. Multivariable logistic regression analysis revealed that younger age, sentinel bleed, and poor admission clinical grade were significantly associated with UEAV. Patients with UEAV had a 2-fold increased risk of DCI (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.4–3.9, p = 0.002) and cerebral infarction (OR 2.0, 95% CI 1.0–3.9, p = 0.04), after adjusting for known predictors. Excluding patients who experienced sentinel bleeding did not change this effect. Patients with UEAV also had a significantly higher hazard for DCI in a multivariable model. UEAV was not found to be significantly associated with poor functional outcome (OR 0.8, 95% CI 0.4–1.6, p = 0.5).

CONCLUSIONS

UEAV may be less frequent than has been reported previously. Patients who exhibit UEAV are at higher risk for refractory DCI that results in cerebral infarction. These patients may benefit from earlier monitoring for signs of DCI and more aggressive treatment. Further study is needed to determine the long-term functional significance of UEAV.

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J. Michael Schmidt, Katja E. Wartenberg, Andres Fernandez, Jan Claassen, Fred Rincon, Noeleen D. Ostapkovich, Neeraj Badjatia, Augusto Parra, E. Sander Connolly and Stephan A. Mayer

Object

The authors sought to determine frequency, risk factors, and impact on outcome of asymptomatic cerebral infarction due to vasospasm after subarachnoid hemorrhage (SAH).

Methods

The authors prospectively studied 580 patients with SAH admitted to their center between July 1996 and May 2002. Delayed cerebral ischemia (DCI) from vasospasm was defined as 1) a new focal neurological deficit or decrease in level of consciousness, 2) a new infarct revealed by follow-up CT imaging, or both, after excluding causes other than vasospasm. Outcome at 3 months was assessed using the modified Rankin Scale.

Results

Delayed cerebral ischemia occurred in 121 (21%) of 580 patients. Of those with DCI, 36% (44 patients) experienced neurological deterioration without a corresponding infarct, 42% (51 patients) developed an infarct in conjunction with neurological deterioration, and 21% (26 patients) had a new infarct on CT without concurrent neurological deterioration. In a multivariate analysis, risk factors for asymptomatic DCI included coma on admission, placement of an external ventricular drain, and smaller volumes of SAH (all p ≤ 0.03). Patients with asymptomatic DCI were less likely to be treated with vasopressor agents than those with symptomatic DCI (64 vs 86%, p = 0.01). After adjusting for clinical grade, age, and aneurysm size, the authors found that there was a higher frequency of death or moderate-to-severe disability at 3 months (modified Rankin Scale Score 4–6) in patients with asymptomatic DCI than in patients with symptomatic DCI (73 vs 40%, adjusted odds ratio 3.9, 95% confidence interval 1.3–12.0, p = 0.017).

Conclusions

Approximately 20% of episodes of DCI after SAH are characterized by cerebral infarction in the absence of clinical symptoms. Asymptomatic DCI is particularly common in comatose patients and is associated with poor outcome. Strategies directed at diagnosing and preventing asymptomatic infarction from vasospasm in patients with poor-grade SAH are needed.

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Bartosz T. Grobelny, Andrew F. Ducruet, Peter A. DeRosa, Ivan S. Kotchetkov, Brad E. Zacharia, Zachary L. Hickman, Luis Fernandez, Reshma Narula, Jan Claassen, Kiwon Lee, Neeraj Badjatia, Stephan A. Mayer and E. Sander Connolly Jr.

Object

Cystathionine β-synthase (CBS) is an enzyme that metabolizes homocysteine to form H2S in the brain. Hydrogen sulfide functions as a vasodilator as well as a regulator of neuronal ion channels and multiple intracellular signaling pathways. Given the myriad effects of H2S, the authors hypothesized that patients possessing gain-of-function polymorphisms of the CBS gene will experience a decreased incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH).

Methods

Patients were enrolled in a prospective observational database of aSAH outcomes. DNA was extracted from buccal swabs and sequenced for 3 functional polymorphisms of the CBS gene (699C→T, 844ins68, and 1080C→T) by polymerase chain reaction. Serum homocysteine levels (μmol/L) were assayed. Multivariate analysis was used to determine the relationship between CBS genotype and occurrence of both angiographic vasospasm and DCI.

Results

There were 87 patients included in the study. None of the polymorphisms investigated were significantly associated with the incidence of angiographic vasospasm. However, after controlling for admission hypertension, patients with the gain-of-function 844 WT/ins genotypes were less likely to experience DCI relative to those with the 844 WT/WT genotype (86 patients, p = 0.050), while the decrease-in-function genotype 1080 TT was more likely to experience DCI relative to those with 1080 CC and CT genotypes (84 patients, p = 0.042). Serum homocysteine levels did not correlate with the extent of either angiographic vasospasm or DCI in this analysis.

Conclusions

Polymorphisms of the CBS gene that impart gain-of-function may be associated with a reduced risk of DCI after aSAH, independent of serum homocysteine. Signaling through H2S may mediate protection from DCI following aSAH through a mechanism that does not involve macrovascular vasodilation.

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Natasha Ironside, Brandon Christophe, Samuel Bruce, Amanda M. Carpenter, Trae Robison, Nina Yoh, Serge Cremers, Donald Landry, Hans-Peter Frey, Ching-Jen Chen, Brian L. Hoh, Louis J. Kim, Jan Claassen and Edward Sander Connolly Jr.

OBJECTIVE

Delayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH.

METHODS

In this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH.

RESULTS

Of the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm.

CONCLUSIONS

The power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.

Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov)

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Fred Rincon, Errol Gordon, Robert M. Starke, Manuel M. Buitrago, Andres Fernandez, J. Michael Schmidt, Jan Claassen, Katja E. Wartenberg, Jennifer Frontera, David B. Seder, David Palestrant, E. Sander Connolly, Kiwon Lee, Stephan A. Mayer and Neeraj Badjatia

Object

The purpose of this study was to identify predictors of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (SAH).

Methods

The authors evaluated the incidence of shunt-dependent hydrocephalus in a consecutive cohort of 580 patients with SAH who were admitted to the Neurological Intensive Care Unit of Columbia University Medical Center between July 1996 and September 2002. Patient demographics, 24-hour admission variables, initial CT scan characteristics, daily transcranial Doppler variables, and development of in-hospital complications were analyzed. Odds ratios and 95% CIs for candidate predictors were calculated using multivariate nominal logistic regression.

Results

Admission glucose of at least 126 mg/dl (adjusted OR 1.6; 95% CI 1.0–2.6), admission brain CT scan with a bicaudate index of at least 0.20 (adjusted OR 1.43; 95% CI 1.0–2.0), Fisher Grade 4 (adjusted OR 2.71; 95% CI 1.2–5.7), fourth ventricle hemorrhage (adjusted OR 1.78; 95% CI 1.1–2.7), and development of nosocomial meningitis (adjusted OR 2.2; 95% CI 1.4–3.7) were independently associated with shunt dependency.

Conclusions

These data suggest that permanent CSF diversion after aneurysmal SAH may be independently predicted by hyperglycemia at admission, findings on the admission CT scan (Fisher Grade 4, fourth ventricle intraventricular hemorrhage, and bicaudate index ≥ 0.20), and development of nosocomial meningitis. Future research is needed to assess if tight glycemic control, reduction of fourth ventricle clot burden, and prevention of nosocomial meningitis may reduce the need for permanent CSF diversion after aneurysmal SAH.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010