HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.

Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.

Chromatin structure predicts survival in glioma patients.

The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. The authors use a large set of paired atac-seq and RNA-seq data from surgically resected glioma specimens to infer gene regulatory relationships in glioma. Thirty-eight glioma patient samples underwent atac-seq sequencing and 16 samples underwent additional RNA-seq analysis. Using an atac-seq/RNA-seq correlation matrix, atac-seq peaks were paired with genes based on high correlation values (|r2| > 0.6). Samples clustered by IDH1 status but not by grade. Surprisingly there was a trend for IDH1 mutant samples to have more peaks. The majority of peaks are positively correlated with survival and positively correlated with gene expression. Constructing a model of the top six atac-seq peaks created a highly accurate survival prediction model (r2 = 0.68). Four of these peaks were still significant after controlling for age, grade, pathology, IDH1 status and gender. Grade II, III, and IV (primary) samples have similar transcription factors and gene modules. However, grade IV (recurrent) samples have strikingly few peaks. Patient-derived glioma cultures showed decreased peak counts following radiation indicating that this may be radiation-induced. This study supports the notion that IDH1 mutant and IDH1 wildtype gliomas have different epigenetic landscapes and that accessible chromatin sites mapped by atac-seq peaks tend to be positively correlated with expression. The data in this study leads to a new model of treatment response wherein glioma cells respond to radiation therapy by closing open regions of DNA.

Injectable diblock copolypeptide hydrogel provides platform to deliver effective concentrations of paclitaxel to an intracranial xenograft model of glioblastoma.

INTRODUCTION: Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. METHODS: The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. RESULTS: The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. CONCLUSIONS: These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

Subcutaneous sumatriptan: association with decreases in postoperative pain and opioid use after elective cranial surgery.

OBJECTIVE: Sumatriptan, a serotonin receptor agonist, has been used in the management of primary headache disorders and has been shown to affect trigeminal dural afferents. There is limited literature on the safety and efficacy of sumatriptan for postcraniotomy pain management. This study aimed to identify whether subcutaneous sumatriptan is a safe and efficacious pain management strategy after elective craniotomy. METHODS: The authors retrospectively reviewed patients who underwent supratentorial or suboccipital craniotomy between 2016 and 2019 that was performed by a single provider at a single institution to identify patients given subcutaneous sumatriptan in the postoperative period. Pain scores and intravenous and oral opioid use were compared in patients with (n = 15) and without (n = 45) sumatriptan administration. RESULTS: Patients with and without sumatriptan administration had no significant differences in baseline characteristics or surgery type. There were no sumatriptan-related complications. The average pain score decreased from 3.9 to 1.3 within 1 hour after sumatriptan administration (p = 0.014). In both adult and pediatric patients there was decreased postoperative pain (adults: pain score of 1.1 vs 7.1, p < 0.001; pediatric: 1.1 vs 3.9, p = 0.007) within the first 48 hours. There were decreases in intravenous opioid use, length of intravenous opioid use, maximum dose of intravenous opioid used, oral opioid use, length of oral opioid use, and maximum dose of oral opioid used in both adult and pediatric patients. CONCLUSIONS: The authors identified subcutaneous sumatriptan as a safe and efficacious tool for postoperative pain management after craniotomy. Large multicenter randomized controlled studies are needed to further evaluate the specific role of sumatriptan in postoperative pain management after craniotomy.

Treatment of intracranial vertebral artery dissecting aneurysms involving the posterior inferior cerebellar artery origin.

BACKGROUND: Vertebral artery dissecting aneurysm (VADA) involving the origin of the posterior inferior cerebellar artery (PICA) is a complex disease entity in which the dual goals of preventing future rebleeding and maintaining perfusion of the lateral medulla must be considered. We present an illustrative case and review the literature surrounding treatment strategies. CASE DESCRIPTION: We report a patient presenting with extensive subarachnoid hemorrhage due to rupture of an intracranial VADA involving the PICA origin. After consideration of the patient's cerebral vasculature and robustness of collaterals, a flow-diverting stent was placed with angiographic resolution of the lesion and maintenance of antegrade PICA flow. Ultimately, the patient experienced a contralateral intraparenchymal hemorrhage leading to death. Review of the literature identified 124 cases of VADA involving the PICA origin described over the past decade. The methods of surgical and endovascular treatment of these cases were reviewed, with particular focus on the rationale of treatment, outcomes, and complications. CONCLUSION: Numerous treatment options for VADA involving PICA have been reported with different risk and benefit profiles. Flow-diverting stents appear to offer the most favorable balance of securing the aneurysm and avoiding medullary infarction, but the risks and optimal anti-thrombotic treatment strategy are incompletely understood. In select cases, in which the surgical risk is low or in which the anatomy is favorable (e.g., nondominant parent vessel or robust collateral circulation in the involved territories), parent artery trapping with or without microsurgical revascularization can be considered.

Large-scale assessment of the gliomasphere model system.

BACKGROUND: Gliomasphere cultures are widely utilized for the study of glioblastoma (GBM). However, this model system is not well characterized, and the utility of current classification methods is not clear. METHODS: We used 71 gliomasphere cultures from 68 individuals. Using gene expression-based classification, we performed unsupervised clustering and associated gene expression with gliomasphere phenotypes and patient survival. RESULTS: Some aspects of the gene expression-based classification method were robust because the gliomasphere cultures retained their classification over many passages, and IDH1 mutant gliomaspheres were all proneural. While gene expression of a subset of gliomasphere cultures was more like the parent tumor than any other tumor, gliomaspheres did not always harbor the same classification as their parent tumor. Classification was not associated with whether a sphere culture was derived from primary or recurrent GBM or associated with the presence of EGFR amplification or rearrangement. Unsupervised clustering of gliomasphere gene expression distinguished 2 general categories (mesenchymal and nonmesenchymal), while multidimensional scaling distinguished 3 main groups and a fourth minor group. Unbiased approaches revealed that PI3Kinase, protein kinase A, mTOR, ERK, Integrin, and beta-catenin pathways were associated with in vitro measures of proliferation and sphere formation. Associating gene expression with gliomasphere phenotypes and patient outcome, we identified genes not previously associated with GBM: PTGR1, which suppresses proliferation, and EFEMP2 and LGALS8, which promote cell proliferation. CONCLUSIONS: This comprehensive assessment reveals advantages and limitations of using gliomaspheres to model GBM biology, and provides a novel strategy for selecting genes for future study.

Efficacy of systemic adoptive transfer immunotherapy targeting NY-ESO-1 for glioblastoma.

BACKGROUND: Immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas. METHODS: We utilized human glioblastoma cell cultures to induce expression of New York-esophageal squamous cell carcinoma (NY-ESO-1) following in vitro treatment with the demethylating agent decitabine. We then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, we examined the in vivo application of this immune therapy using an intracranially implanted xenograft model for in situ T cell trafficking, survival, and tissue studies. RESULTS: Our studies showed that treatment of intracranial glioma-bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1-specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1-specific adoptive T cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1-specific T cells systemically was superior to intracranial administration and resulted in significantly extended and long-term survival of animals. CONCLUSION: These results reveal an innovative, clinically feasible strategy for the treatment of glioblastoma.

Integrating risk management data in quality improvement initiatives within an academic neurosurgery department.

OBJECT While malpractice litigation has had many negative impacts on health care delivery systems, information extracted from lawsuits could potentially guide toward venues to improve care. The authors present a comprehensive review of lawsuits within a tertiary academic neurosurgical department and report institutional and departmental strategies to mitigate liability by integrating risk management data with quality improvement initiatives. METHODS The Comprehensive Risk Intelligence Tool database was interrogated to extract claims/suits abstracts concerning neurosurgical cases that were closed from January 2008 to December 2012. Variables included demographics of the claimant, type of procedure performed (if any), claim description, insured information, case outcome, clinical summary, contributing factors and subfactors, amount incurred for indemnity and expenses, and independent expert opinion in regard to whether the standard of care was met. RESULTS During the study period, the Department of Neurosurgery received the most lawsuits of all surgical specialties (30 of 172), leading to a total incurred payment of $4,949,867. Of these lawsuits, 21 involved spinal pathologies and 9 cranial pathologies. The largest group of suits was from patients with challenging medical conditions who underwent uneventful surgeries and postoperative courses but filed lawsuits when they did not see the benefits for which they were hoping; 85% of these claims were withdrawn by the plaintiffs. The most commonly cited contributing factors included clinical judgment (20 of 30), technical skill (19 of 30), and communication (6 of 30). CONCLUSIONS While all medical and surgical subspecialties must deal with the issue of malpractice and liability, neurosurgery is most affected both in terms of the number of suits filed as well as monetary amounts awarded. To use the suits as learning tools for the faculty and residents and minimize the associated costs, quality initiatives addressing the most frequent contributing factors should be instituted in care redesign strategies, enabling strategic alignment of quality improvement and risk management efforts.

An evidence-based approach to the efficient use of computed tomography imaging in the neurosurgical patient.

BACKGROUND: Computed tomography (CT) is the current standard for rapidly diagnosing some of the more common structural pathologies that affect the neurosurgical patient perioperatively. With this convenience comes the potential for its overuse. OBJECTIVE: To investigate the utility of head CT scans ordered for various clinical indications. METHODS: All head CT studies ordered by the UCLA Neurosurgery Department from August 15, 2011 through December 15, 2011, were prospectively studied. Variables collected included demographic information, diagnosis, surgical procedures, indication for CT, CT findings, and whether the study led to a documentable change in management. RESULTS: There were 801 head CT studies ordered for the 462 patients who were admitted to the neurosurgical service. The authors identified 14 indications for ordering a head CT with the following probabilities of a positive finding: examination change (17/56, 30.3%), follow-up (4-6 hours after intracerebral hemorrhage; 16/126, 12.7%), CT angiography (11/30, 36.7%), routine postoperative imaging (6/126, 4.7%), postventriculostomy placement (4/62, 6.5%), immediately before (4/31, 12.9%) or after removal of (2/42, 4.8%) a ventriculostomy, surveillance (>24 hours after intracerebral hemorrhage or external ventricular drain placement) (3/66, 4.5%), headaches (2/8, 25%), ground level fall (1/8, 12.5%), intracranial pressure spikes (2/6, 33.3%), and delayed (6-24 hours after intracerebral hemorrhage; 1/25, 4%). CONCLUSION: The probability of discovering a clinically significant finding varies widely for each of the listed study indications. This prospective analysis of all CT scans ordered at a single institution suggests that imaging studies obtained without a change in neurological status were unlikely to produce a positive finding, and even when there was a positive finding, it was extremely unlikely to result in any intervention.

Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) and associated CpG island hypermethylation represent early events in the development of low-grade gliomas and secondary glioblastomas. To identify candidate tumor suppressor genes whose promoter methylation may contribute to gliomagenesis, we compared methylation profiles of IDH1 mutant (MUT) and IDH1 wild-type (WT) tumors using massively parallel reduced representation bisulfite sequencing. METHODS: Reduced representation bisulfite sequencing was performed on ten pathologically matched WT and MUT glioma samples and compared with data from a methylation-sensitive restriction enzyme technique and data from The Cancer Genome Atlas (TCGA). Methylation in the gene retinol-binding protein 1 (RBP1) was identified in IDH1 mutant tumors and further analyzed with primer-based bisulfite sequencing. Correlation between IDH1/IDH2 mutation status and RBP1 methylation was evaluated with Spearman correlation. Survival data were collected retrospectively and analyzed with Kaplan-Meier and Cox proportional hazards analysis. All statistical tests were two-sided. RESULTS: Methylome analysis identified coordinated CpG island hypermethylation in IDH1 MUT gliomas, consistent with previous reports. RBP1, important in retinoic acid metabolism, was found to be hypermethylated in 76 of 79 IDH1 MUT, 3 of 3 IDH2 MUT, and 0 of 116 IDH1/IDH2 WT tumors. IDH1/IDH2 mutation was highly correlated with RBP1 hypermethylation (n = 198; Spearman R = 0.94, 95% confidence interval = 0.92 to 0.95, P < .001). The Cancer Genome Atlas showed IDH1 MUT tumors (n = 23) to be RBP1-hypermethylated with decreased RBP1 expression compared with WT tumors (n = 124). Among patients with primary glioblastoma, patients with RBP1-unmethylated tumors (n = 102) had decreased median overall survival compared with patients with RBP1-methylated tumors (n = 22) (20.3 months vs 36.8 months, respectively; hazard ratio of death = 2.48, 95% confidence interval = 1.30 to 4.75, P = .006). CONCLUSION: RBP1 promoter hypermethylation is found in nearly all IDH1 and IDH2 mutant gliomas and is associated with improved patient survival. Because RBP1 is involved in retinoic acid synthesis, our results suggest that dysregulation of retinoic acid metabolism may contribute to glioma formation along the IDH1/IDH2-mutant pathway.

Use of language mapping to aid in resection of gliomas in eloquent brain regions.

Studies looking at resection in high-grade gliomas have had mixed results. The authors briefly review the literature regarding the value of the extent of resection. They proceed to the preoperative and intraoperative tools available to the neurosurgeon to distinguish eloquent from noneloquent language cortex and fibers, including the emerging roles of functional magnetic resonance imaging diffusion tensor imaging tractography and direct cortical/subcortical stimulation in the surgical management of tumors in eloquent areas. Finally, the authors evaluate the postoperative course of these patients and the effect of language deficits on their quality of life.

Systemic expression of matrix metalloproteinase-9 in patients with cerebral arteriovenous malformations.

OBJECTIVE: Increased expression angiogenic factors, such as matrix metalloproteinases (MMPs), are associated with the formation of cerebral arteriovenous malformations (AVMs). The objective of this study was to determine plasma levels of MMP-9 of patients with AVMs. METHODS: Blood samples were drawn from 15 patients with AVMs before treatment, 24 hours postembolization, 24 hours postresection, and 30 days postresection. Blood samples were also obtained from 30 healthy controls. Plasma MMP-9 concentrations were measured via enzyme-linked immunosorbent assay. RESULTS: The mean plasma MMP-9 level in AVM patients at baseline was significantly higher than in control patients: 108.04 +/- 16.11 versus 41.44 +/- 2.44 ng/mL, respectively. The mean plasma MMP-9 level 1 day after embolization increased to 172.35 +/- 53.76 ng/mL, which was not significantly elevated over pretreatment levels. One day after resection, plasma MMP-9 levels increased significantly over pretreatment levels to 230.97 +/- 51.00 ng/mL. Mean plasma MMP-9 concentrations 30 days after resection decreased to 92.8 +/- 18.7 ng/mL, which was not different from pretreatment levels but was still significantly elevated over control levels. MMP-9 levels did not correlate with patient sex, age, presentation, or AVM size. CONCLUSION: Plasma MMP-9 levels are significantly elevated over controls at baseline, increase significantly immediately after surgery, and decrease to pretreatment levels during follow-up.

Elevated troponin levels are predictive of mortality in surgical intracerebral hemorrhage patients.

OBJECTIVE: Elevated troponin levels are a common occurrence after ischemic stroke and subarachnoid hemorrhage (SAH), and have been described as a neurogenic form of myocardial injury. The prognostic significance of this event is controversial with numerous studies citing conflicting results. The importance of cardiac stress is of particular relevance in the operative management of intracerebral hemorrhage (ICH). To this end, we investigated whether troponin levels were an independent predictor of in-hospital mortality from all causes in surgically treated ICH patients. METHODS: We performed a retrospective analysis of 110 patients admitted to Columbia Presbyterian hospital between 1999 and 2007 for ICH and subsequent clot evacuation. Those with angina or recent myocardial infarction were excluded. CT scans were reviewed to determine hematoma size, location, presence of intraventricular hemorrhage (IVH) or SAH, hydrocephalus, and midline shift. Hospital records were examined for known demographic and clinical predictors of mortality. Univariate analysis was used to screen for predictive factors (P

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.

The complement cascade: new avenues in stroke therapy.

Recent evidence has shown that after the initial occlusion, a large portion of stroke patients achieve some degree of reperfusion either through collateral circulation or clot dissolution. However, it appears that this reperfusion may lead to increased inflammation-induced damage. Even though the exact mechanism of this secondary injury is unclear, several experimental studies have indicated an intimate connection between complement and this secondary form of damage. We review the available literature and attempt to identify promising clinical therapeutic targets.

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 < or =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.

Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with neurological injury that may be ameliorated by a neuroprotective strategy targeting the complement cascade. We investigated the role of C5a-receptor antagonist (C5aRA) solely and in combination with C3a-receptor antagonist (C3aRA) following ICH in mice. METHODS: Adult male C57BL/6J mice were randomized to receive vehicle, C5aRA alone or C3aRA and C5aRA 6 and 12 h after ICH, and every 12 h thereafter. A double injection technique was used to infuse 30 microL of autologous whole blood into the right striatum. A final group of mice received a sham procedure consisting only of needle insertion followed by vehicle injections. Brain water content and flow cytometry analysis for leukocyte and microglia infiltration and activation in both hemispheres were measured on day 3 post ICH. Neurological dysfunction was assessed using a Morris water-maze (MWM), a 28-point scale, and a corner test at 6, 12, 24, 48 and 72 h after ICH induction. RESULTS: Neurological deficits were present and comparable in all three cohorts 6 h after ICH. Animals treated with C5aRA and animals treated with combined C3aRA/C5aRA demonstrated significant improvements in neurological function assessed by both the corner turn test and a 28-point neurological scale at 24, 48 and 72 h relative to vehicle-treated animals. Similarly, C5aRA and C3aRA/C5aRA-treated mice demonstrated better spatial memory retention in the Morris water-maze test compared with vehicle-treated animals (C3aRA/C5aRA: 23.4+/-2.0 s p< or =0.0001 versus vehicle: 10.0+/-1.7 s). Relative to vehicle-treated mice, the brain water content in C3aRA/C5aRA-treated mice was significantly decreased in the ipsilateral cortex and ipsilateral striatum (ipsilateral cortex: C3aRA/C5aRA: 0.755403+/-0.008 versus 0.773327+/-0.003 p=0.01 striatum: 0.752273+/-0.007 versus 0.771163+/-0.0036 p=0.02). C5aRA-treated mice and C3aRA/C5aRA-treated mice had a decreased ratio of granulocytes (CD45(+)/CD11b(+)/Ly-6G(+)) in the hemorrhagic versus non-hemorrhagic hemispheres relative to vehicle-treated animals (C5aRA: 1.78+/-0.36 p=0.02 C3aRA/C5aRA: 1.59+/-0.22 p=0.005 versus vehicle: 3.01). CONCLUSIONS: While administration of C5aRA alone provided neuroprotection, combined C3aRA/C5aRA therapy led to synergistic improvements in neurofunctional outcome while reducing inflammatory cell infiltration and brain edema. The results of this study indicate that simultaneous blockade of the C3a and C5a receptors represents a promising neuroprotective strategy in hemorrhagic stroke.

Clinical features, surgical treatment, and long-term outcome in adult patients with moyamoya disease. Clinical article.

OBJECT: The object of this study was to report the clinical features, surgical treatment, and long-term outcomes in adults with moyamoya phenomenon treated at a single institution in the US. METHODS: Forty-three adult patients with moyamoya disease (mean age 40 +/- 11 years [SD], range 18-69 years) were treated with encephaloduroarteriosynangiosis (EDAS). Neurologists examined patients pre- and postoperatively. Follow-up was obtained in person or by structured telephone interview (median 41 months, range 4-126 months). The following outcomes were collected: transient ischemic attack (TIA), infarction, graft collateralization, change in cerebral perfusion, and functional level according to the modified Rankin scale (mRS). Kaplan-Meier estimates of infarction risk were calculated for comparison of surgically treated and contralateral hemispheres. RESULTS: The majority of patients were women (65%), were Caucasian (65%), presented with ischemic symptoms (98%), and had bilateral disease (86%). Nineteen patients underwent unilateral and 24 patients bilateral EDAS (67 treated hemispheres). Collateral vessels developed in 50 (98%) of 52 hemispheres for which imaging was available and there was evidence of increased perfusion on SPECT scans in 41 (82%) of the 50 hemispheres evaluated. Periprocedural infarction (< 48 hours) occurred in 3% of the hemispheres treated. In the follow-up period patients experienced 10 TIAs, 6 infarctions, and 1 intracranial hemorrhage. Although the hemisphere selected for surgery was based upon patients' symptoms and severity of pathology, the 5-year infarction-free survival rate was 94% in the surgically treated hemispheres versus < 36% in the untreated hemispheres (p = 0.007). After controlling for age and sex, infarction was 89% less likely to occur in the surgically treated hemispheres than in the contralateral hemispheres (hazard ratio 0.11, 95% CI 0.02-0.56). Thirty-eight (88%) of 43 patients had preserved or improved mRS scores, relative to baseline status. CONCLUSIONS: In this mixed-race population of North American patients, indirect bypass promoted adequate pial collateral development and increased perfusion in the majority of adult patients with moyamoya disease. Patients had low rates of postoperative TIAs, infarction, and hemorrhage, and the majority of patients had preserved or improved functional status.

The role of polyamine metabolism in neuronal injury following cerebral ischemia.

Stroke is a leading cause of morbidity and mortality in the US, with secondary damage following the initial insult contributing significantly to overall poor outcome. Prior investigations have shown that the metabolism of certain polyamines such as spermine, spermidine, and putrescine are elevated in ischemic parenchyma, resulting in an increase in their metabolite concentration. Polyamine metabolites tend to be cytotoxic, leading to neuronal injury in the penumbra following stroke and expansion of the area of infarcted tissue. Although the precise mechanism is unclear, the presence of reactive aldehydes produced through polyamine metabolism, such as 3-aminopropanal and acrolein, have been shown to correlate with the incidence of cerebral vasospasm, disruption of oxidative metabolism and mitochondrial functioning, and disturbance of cellular calcium ion channels. Regulation of the polyamine metabolic pathway, therefore, may have the potential to limit injury following cerebral ischemia. To this end, we review this pathway in detail with an emphasis on clinical applicability.

Efficacy of lamina terminalis fenestration in reducing shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage: a systematic review. Clinical article.

OBJECT: Chronic hydrocephalus requiring shunt placement is a common complication following aneurysmal subarachnoid hemorrhage (SAH). Controversy exists over whether microsurgical fenestration of the lamina terminalis during aneurysm surgery affords a reduction in the development of shunt-dependent hydrocephalus. To resolve this debate, the authors performed a systematic review and quantitative analysis of the literature to determine the efficacy of lamina terminalis fenestration in reducing aneurysmal SAH-associated shunt-dependent hydrocephalus. METHODS: A MEDLINE (1950-2007) database search was performed using the following keywords, singly and in combination: "ventriculoperitoneal shunt," "hydrocephalus," "subarachnoid hemorrhage," "aneurysm," "fenestration," and "lamina terminalis." Additional studies were manually singled out by scrutinizing references from identified manuscripts, major neurosurgical journals and texts, and personal files. A recent study from the authors' institution was also incorporated into the review. Data from included studies were analyzed using the chi-square analysis and Student t-test. The Cochran-Mantel-Haenszel test was used to compare overall incidence of shunt-dependent hydrocephalus. RESULTS: The literature search revealed 19 studies, but only 11 were included in this review, involving 1973 patients. The fenestrated and nonfenestrated cohorts (combined from the various studies) differed significantly with regard to patient sex, age, and clinical grade as well as aneurysm location (p=0.0065, 0.0028, 0.0003, and 0.017, respectively). The overall incidence of shunt-dependent hydrocephalus in the fenestrated cohort was 10%, as compared with 14% in the nonfenestrated cohort (p=0.089). The relative risk of shunt-dependent hydrocephalus in the fenestrated cohort was 0.88 (95% CI 0.62-1.24). CONCLUSIONS: This systematic review revealed no significant association between lamina terminalis fenestration and a reduced incidence of shunt-dependent hydrocephalus. The interpretation of these results, however, is restricted by unmatched cohort differences as well as other inherent study limitations. Although the overall literature supports lamina terminalis fenestration, a number of authors have questioned the technique's benefits, thus rendering its efficacy in reducing shunt-dependent hydrocephalus unclear. A well-designed, multicenter, randomized controlled trial is needed to definitively address the efficacy of this microsurgical technique.