Brian Y. Hwang

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.

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.

A Comprehensive Review of Radiosurgery for Cerebral Arteriovenous Malformations: Outcomes, Predictive Factors, and Grading Scales

The management of cerebral arteriovenous malformations (AVMs) continues to present a challenge to neurosurgeons. The natural history of this condition, as well as the morbidity and mortality of therapeutic interventions, remains incompletely elucidated. Predictive factors and grading scales in AVM management allow risk-benefit analysis of treatment options and comparison of outcomes. Stereotactic radiosurgery is one of the established treatment modalities for AVMs and is generally used to treat lesions that are high risk for surgical resection. Radiosurgery aims to obliterate AVMs and thus prevent hemorrhage or seizure without any new or worsening of existing symptoms. Lesion characteristics and postsurgical complications differ markedly in patientstreated by radiosurgery versus microsurgery. Radiosurgery-based grading systems account for factors that have been associated with various aspects of radiosurgical outcomes including obliteration, hemorrhage, and postoperative complications, particularly those induced by radiation. The purpose of this paper is to describe the most current predictive factors and grading systems for radiosurgical treatment of cerebral AVMs.

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.

Treatment guidelines for cerebral arteriovenous malformation microsurgery

The goal of cerebral arteriovenous malformation (AVM) treatment is to eliminate intracerebral hemorrhage risk and to preserve or maximize neurological functions of the patient. Interventional planning must determine the modality or combination of modalities with the greatest success rate according to patient characteristics, AVM architecture, and the capabilities of the treatment option to fulfill the goals of treatment. Although there is a lack of data from randomized trials to guide AVM management, microsurgery is a mainstay of therapy in patients receiving definitive intervention. In this paper, we review current guidelines for surgical planning, risk-benefit analysis, and prediction of outcome in AVM patients.

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.

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.

Serum biomarkers of spontaneous intracerebral hemorrhage induced secondary brain injury

Intracerebral hemorrhage (ICH) is a devastating form of stroke associated with a high rate of morbidity and mortality. It is now believed that much of this damage occurs in the subacute period following the initial insult via a cascade of complex pathophysiologic pathways that continues to be investigated. Increased levels of certain serum proteins have been identified as biomarkers that may reflect or directly participate in the inflammation, blood brain barrier disruption, endothelial dysfunction, and neuronal and glial toxicity that occur during this secondary period of cerebral injury. Some of these biomarkers have the potential to serve as therapeutic targets or surrogate endpoints for future research or clinical trials. Others may someday augment current clinical techniques in diagnosis, risk-stratification, prognostication, treatment decision and measurement of therapeutic efficacy. While much work remains to be done, biomarkers show significant potential to expand clinical options and improve clinical management, thereby reducing mortality and improving functional outcomes in ICH patients.

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

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 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.

Severity of Intraventricular Extension Correlates With Level of Admission Glucose After Intracerebral Hemorrhage

Background and Purpose— Hyperglycemia after spontaneous intracerebral hemorrhage (ICH) is associated with poor outcome, but the pathophysiology of ICH-induced glucose dysregulation remains unclear. We sought to identify clinical and radiographic parameters of ICH that are associated with admission hyperglycemia. Methods— Patients admitted to the Columbia University Medical Center Neurological Intensive Care Unit with spontaneous ICH between January 2009 and September 2010 were prospectively enrolled in the ICH Outcomes Project. Clinical, radiographic, and laboratory data were collected prospectively. Receiver operating characteristic analysis was used to identify the glucose level with optimal sensitivity and specificity for in-hospital mortality. Logistic and linear regression analyses were used to identify independent predictors of outcome measures where appropriate. Results— One hundred four patients admitted during the study period were included in the analysis. Mean admission glucose level was 8.23±3.15 mmol/L (3.83 to 18.89 mmol/L) and 23.2% had a history of diabetes mellitus. Admission glucose was significantly associated with discharge (P=0.003) and 3-month mortality (P=0.002). Critical hyperglycemia defined at 10 mmol/L independently predicted discharge mortality (P=0.027; OR, 4.381; 95% CI, 1.186 to 16.174) and 3-month mortality (P=0.011; OR, 10.95; 95% CI, 1.886 to 62.41). Admission intraventricular extension score (P=0.038; OR, 1.117; 95% CI, 1.043 to 1.197) and diabetes mellitus (P=0.002; OR, 5.530; 95% CI, 1.833 to 16.689) were independent predictors of critical hyperglycemia. The intraventricular extension score (B=0.115, P=0.001) linearly correlated with admission glucose level (R=0.612, P=0.001) after adjusting for other clinical variables. Conclusions— Admission hyperglycemia after spontaneous ICH is associated with poor outcome and potentially related to the presence and severity of intraventricular extension.