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

Hwang, Brian Y; Bruce, Samuel S; Appelboom, Geoffrey; Piazza, Matthew A; Carpenter, Amanda M; Gigante, Paul R; Kellner, Christopher P; Ducruet, Andrew F; Kellner, Michael A; Deb-Sen, Rajeev; Vaughan, Kerry A; Meyers, Philip M; Connolly, E Sander
OBJECT/OBJECTIVE: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.
PMID: 21999319
ISSN: 1933-0693
CID: 4621252

Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke

Ducruet, Andrew F; Zacharia, Brad E; Sosunov, Sergey A; Gigante, Paul R; Yeh, Mason L; Gorski, Justin W; Otten, Marc L; Hwang, Richard Y; DeRosa, Peter A; Hickman, Zachary L; Sergot, Paulina; Connolly, E Sander
BACKGROUND AND PURPOSE/OBJECTIVE:The restoration of blood-flow following cerebral ischemia incites a series of deleterious cascades that exacerbate neuronal injury. Pharmacologic inhibition of the C3a-receptor ameliorates cerebral injury by attenuating post-ischemic inflammation. Recent reports also implicate C3a in the modulation of tissue repair, suggesting that complement may influence both injury and recovery at later post-ischemic time-points. METHODS:To evaluate the effect of C3a-receptor antagonism on post-ischemic neurogenesis and neurological outcome in the subacute period of stroke, transient focal cerebral ischemia was induced in adult male C57BL/6 mice treated with multiple regimens of a C3a receptor antagonist (C3aRA). RESULTS:Low-dose C3aRA administration during the acute phase of stroke promotes neuroblast proliferation in the subventricular zone at 7 days. Additionally, the C3a receptor is expressed on T-lymphocytes within the ischemic territory at 7 days, and this cellular infiltrate is abrogated by C3aRA administration. Finally, C3aRA treatment confers robust histologic and functional neuroprotection at this delayed time-point. CONCLUSIONS:Targeted complement inhibition through low-dose antagonism of the C3a receptor promotes post-ischemic neuroblast proliferation in the SVZ. Furthermore, C3aRA administration suppresses T-lymphocyte infiltration and improves delayed functional and histologic outcome following reperfused stroke. Post-ischemic complement activation may be pharmacologically manipulated to yield an effective therapy for stroke.
PMID: 22761695
ISSN: 1932-6203
CID: 4621272

The Neuroprotective Effect of Genetic Mannose-binding Lectin Deficiency is not Sustained in the Sub-acute Phase of Stroke

Ducruet, Andrew F; Sosunov, Sergey A; Zacharia, Brad E; Gorski, Justin; Yeh, Mason L; Derosa, Peter; Cohen, Gregory; Gigante, Paul R; Connolly, E Sander
INTRODUCTION/BACKGROUND:The complement cascade is a critical mediator of the inflammatory response following cerebral ischemia. Recent work has demonstrated that genetic-deficiency of Mannose-binding lectin(MBL) ameliorates reperfusion injury and improves outcome in the acute phase of stroke. The present study sought to further delineate the pathogenic role of MBL in stroke and to examine whether the neuroprotection associated with MBL-deficiency is sustained beyond the acute phase. We hypothesized that genetic MBL deficiency would suppress complement activation and ameliorate reperfusion injury in the acute phase, but that persistent inhibition of complement into the sub-acute phase would serve to abrogate this neuroprotective effect. METHODS:The time-course and localization of post-ischemic cerebral MBL and C3 deposition were characterized using both Western-blot and immunohistochemistry. MBL-a/c null(MBL-KO) mice subjected to transient middle cerebral artery occlusion(MCAO) were then employed to investigate the histologic injury and functional outcome associated with genetic MBL deletion at both 24 hours and 7 days. RESULTS:MBL-a/c rapidly deposit on ischemic endothelium and trigger downstream complement activation in the acute phase. Genetic deficiency of MBL abrogates C3 cleavage as well as the sub-acute accumulation of mononuclear cells in the ischemic region. Although MBL-KO mice demonstrate significantly improved outcome at 24 hours, the neuroprotective effect associated with genetic MBL deletion is not sustained. CONCLUSIONS:Development of a successful anti-complement neuroprotective strategy will require carefully-tailored inhibition coupled with a greater understanding of the functional effects of complement activation during later phases of stroke recovery.
PMID: 22505955
ISSN: 1868-4483
CID: 4621262

Efficacy of facial nerve-sparing approach in patients with vestibular schwannomas

Haque, Raqeeb; Wojtasiewicz, Teresa J; Gigante, Paul R; Attiah, Mark A; Huang, Brendan; Isaacson, Steven R; Sisti, Michael B
OBJECT/OBJECTIVE:The goal of this article was to show that a combination of facial nerve-sparing microsurgical resection and Gamma Knife surgery (GKS) for expansion of any residual tumor can preserve good facial nerve function in patients with recurrent vestibular schwannoma (VS). METHODS:Records of individuals treated by a single surgeon with a facial nerve-sparing technique for a VS between 1998 and 2009 were retrospectively analyzed for tumor recurrence. Of the 383 patients treated for VS, 151 underwent microsurgical resection, and 20 (13.2%) of these patients required postoperative retreatment for a significant expansion of residual tumor after microsurgery. These 20 patients were re-treated with GKS. RESULTS:The rate of preservation of good facial nerve function (Grade I or II on the House-Brackmann scale) in patients treated with microsurgery for VS was 97%. Both subtotal and gross-total resection had excellent facial nerve preservation rates (97% vs 96%), although subtotal resection carried a higher risk that patients would require retreatment. In patients re-treated with GKS after microsurgery, the rate of facial nerve preservation was 95%. CONCLUSIONS:In patients with tumors that cannot be managed with radiosurgery alone, a facial nerve-sparing resection followed by GKS for any significant regrowth provides excellent facial nerve preservation rates.
PMID: 21854113
ISSN: 1933-0693
CID: 4621242

Responsive neurostimulation for the treatment of epilepsy

Gigante, Paul R; Goodman, Robert R
Neurostimulation in epilepsy has witnessed a century-long evolution that has resulted in the use of neurostimulation to both modulate and suppress abnormal neuronal firing. The recent development of advanced responsive stimulation via a closed-loop device (the RNS System) has provided evidence that surgical epilepsy treatment continues to move toward the possibility of reducing or eliminating seizures in medically refractory patients
PMID: 21939846
ISSN: 1558-1349
CID: 150268

C1-2 instability from os odontoideum mimicking intramedullary spinal cord tumor [Case Report]

Gigante, Paul R; Feldstein, Neil A; Anderson, Richard C E
Os odontoideum is a common cause of atlantoaxial instability in the pediatric population. The authors present the cases of 2 patients whose initial clinical presentation and MR imaging findings were suggestive of an intramedullary neoplasm, but whose ultimate diagnosis was determined to be cervical spine instability and cord injury due to os odontoideum.
PMID: 21961541
ISSN: 1933-0715
CID: 4619442

Alternative surgical approaches in epilepsy

Gigante, Paul R; Goodman, Robert R
The mainstay of epilepsy surgery is the resection of a presumed seizure focus or disruption of seizure propagation pathways. These approaches cannot be applied to all patients with medically refractory epilepsy (MRE). Since 1997, vagus nerve stimulation has been a palliative adjunct to the care of MRE patients. Deep brain stimulation (DBS) in select locations has been reported to reduce seizure frequency in small studies over the past three decades. Recently published results from the SANTE (Stimulation of the Anterior Nuclei of Thalamus for Epilepsy) trial-the first large-scale, randomized, double-blind trial of bilateral anterior thalamus DBS for MRE-demonstrate a significant reduction in seizure frequency with programmed stimulation. Another surgical alternative is the RNS System (NeuroPace, Mountain View, CA), which uses a closed-loop system termed responsive neurostimulation to both detect apparent seizure onsets and deliver stimulation. Recently presented results from the RNS pivotal trial demonstrate a sustained reduction in seizure frequency with stimulation, although comprehensive trial results are pending
PMID: 21584657
ISSN: 1534-6293
CID: 150269

Polymorphisms in complement component 3 (C3F) and complement factor H (Y402H) increase the risk of postoperative neurocognitive dysfunction following carotid endarterectomy

Gigante, Paul R; Kotchetkov, Ivan S; Kellner, Christopher P; Haque, Raqeeb; Ducruet, Andrew F; Hwang, Brian Y; Solomon, Robert A; Heyer, Eric J; Connolly, E Sander
BACKGROUND:Up to 28% of patients undergoing carotid endarterectomy (CEA) are estimated to experience neurocognitive dysfunction following surgery. The complement cascade plays a central role in ischaemia-reperfusion injury. The authors investigated the effect of common polymorphisms in the complement component 3 (C3F) and complement factor H (CFH Y402H) genes on incidence of neurocognitive dysfunction post-CEA. METHODS:This study examined a nested cohort of prospectively recruited patients receiving elective CEA, who were genotyped for the C3F or Y402H polymorphisms. Each patient underwent a standard battery of eight neuropsychometric tests before, and 1 day and 30 days after, surgery. RESULTS:57 of 142 (40%) CEA patients had at least one copy of the C3F allele (C3F+), and 17 of 137 (12%) patients had two copies of the CFH Y402H allele (Y402H++). At postoperative day 1, patients were three times (OR 3.05, p=0.045) or six times (OR 6.41, p=0.006) more likely to experience moderate-to-severe neurocognitive dysfunction if they carried the C3F+ or Y402H++ genotype, respectively. Patients with both risk genotypes had an almost eightfold risk of dysfunction (OR 7.67, p=0.046). Right-hand-dominant C3F+ subjects undergoing right-side CEA performed significantly worse on tests of visuospatial function than C3F- subjects. At day 30, C3F+ and Y402H++ genotypes trended towards significance as predictors of dysfunction (p=0.07 and p=0.22, respectively). CONCLUSION/CONCLUSIONS:The C3F and Y402H polymorphisms are strong independent predictors of moderate-to-severe neurocognitive dysfunction at 1 day following CEA. Furthermore, patients undergoing right-sided CEA are predisposed to deficits associated with cortex ipsilateral to the operative carotid artery.
PMID: 20841369
ISSN: 1468-330x
CID: 4621212

Advances in neuroprotective strategies: potential therapies for intracerebral hemorrhage

Hwang, Brian Y; Appelboom, Geoffrey; Ayer, Amit; Kellner, Christopher P; Kotchetkov, Ivan S; Gigante, Paul R; Haque, Raqeeb; Kellner, Michael; Connolly, E Sander
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.
PMID: 21178344
ISSN: 1421-9786
CID: 4621222

Isoflurane preconditioning affords functional neuroprotection in a murine model of intracerebral hemorrhage

Gigante, Paul R; Appelboom, Geoffrey; Hwang, Brian Y; Haque, Raqeeb M; Yeh, Mason L; Ducruet, Andrew F; Kellner, Christopher P; Gorski, Justin; Keesecker, Sarah E; Connolly, E Sander
INTRODUCTION/BACKGROUND:Exposure to isoflurane gas prior to neurological injury, known as anesthetic preconditioning, has been shown to provide neuroprotective benefits in animal models of ischemic stroke. Given the common mediators of cellular injury in ischemic and hemorrhagic stroke, we hypothesize that isoflurane preconditioning will provide neurological protection in intracerebral hemorrhage (ICH). METHODS:24 h prior to intracerebral hemorrhage, C57BL/6J mice were preconditioned with a 4-h exposure to 1% isoflurane gas or room air. Intracerebral hemorrhage was performed using a double infusion of 30-μL autologous whole blood. Neurological function was evaluated at 24, 48 and 72 h using the 28-point test. Mice were sacrificed at 72 h, and brain edema was measured. RESULTS:Mice preconditioned with isoflurane performed better than control mice on 28-point testing at 24 h, but not at 48 or 72 h. There was no significant difference in ipsilateral hemispheric edema between mice preconditioned with isoflurane and control mice. CONCLUSION/CONCLUSIONS:These results demonstrate the early functional neuroprotective effects of anesthetic preconditioning in ICH and suggest that methods of preconditioning that afford protection in ischemia may also provide protection in ICH.
PMID: 21725745
ISSN: 0065-1419
CID: 4621232