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Veronica L. Chiang, Phillipe Gailloud, Kieran J. Murphy, Daniele Rigamonti and Rafael J. Tamargo

Object. The routine use of intraoperative angiography as an aid in the surgical treatment of aneurysms is uncommon. The advantages of the ability to visualize residual aneurysm or unintended occlusion of parent vessels intraoperatively must be weighed against the complications associated with repeated angiography and prolonged vascular access. The authors reviewed the results of their routine use of intraoperative angiography to determine its safety and efficacy.

Methods. Prospectively gathered data from all aneurysm cases treated surgically between January 1996 and June 2000 were reviewed. A total of 303 operations were performed in 284 patients with aneurysms; 24 patients also underwent postoperative angiography. Findings on intraoperative angiographic studies prompted reexploration and clip readjustment in 37 (11%) of the 337 aneurysms clipped. Angiography revealed parent vessel occlusion in 10 cases (3%), residual aneurysm in 22 cases (6.5%), and both residual lesion and parent vessel occlusion in five cases (1.5%). When compared with subsequent postoperative imaging, false-negative results were found on two intraoperative angiograms (8.3%) and a false-positive result was found on one (4.2%). Postoperative angiograms obtained in both false-negative cases revealed residual anterior communicating artery aneurysms. Both of these aneurysms also subsequently rebled, requiring reoperation. In the group that underwent intraoperative angiography, in 303 operations eight patients (2.6%) suffered complications, of which only one was neurological.

Conclusions. In the surgical treatment of intracranial aneurysms, the use of routine intraoperative angiography is safe and helpful in a significant number of cases, although it does not replace careful intraoperative inspection of the surgical field.

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Richard E. Clatterbuck, Eric M. Oshiro, Patricia A. Hoffman, Gregory N. Dietsch, Drew M. Pardoll and Rafael J. Tamargo

Object. The authors have previously shown that a monoclonal antibody (mAb) that recognizes intercellular adhesion molecule—1 (ICAM-1), also known as CD54, when administered systemically inhibits experimental vasospasm in a rat femoral artery model, suggesting that ICAM-1 and leukocyte-endothelial adhesion play a crucial role in the molecular chain of events leading to posthemorrhagic vasospasm. In this report the authors confirm this hypothesis with mAbs directed against lymphocyte function-associated antigen—1 ([LFA-1] CD11a/CD18), the molecule on the surface of leukocytes that interacts with ICAM-1.

Methods. Femoral arteries in 38 Sprague—Dawley rats were isolated and exposed to autologous blood. Twenty-nine animals were then randomized into three groups and received intraperitoneal injections of anti—LFA-1 mAb (10 rats), anti—ICAM-1 mAb (10 rats), or an isotype-matched control mAb (nine rats). Injections were administered at 3 hours and 3, 6, and 9 days after surgery. Before their deaths, six animals underwent spleen harvest, and splenocytes were used in fluorescence-activated cell sorter (FACS) analysis to verify saturation of appropriate binding sites. Animals were killed at 12 days and vessels were harvested for histological study and measurement of the luminal cross-sectional area. Nine animals were randomized as earlier, killed 24 hours after a single injection of mAb, and evaluated for periadventitial infiltration of granulocytes and macrophages. Results of FACS analysis demonstrated saturation of both LFA-1 and ICAM-1 binding sites in animals treated with the respective mAb. The mean ratios of blood-exposed to saline-exposed luminal cross-sectional areas (expressed as the percentage of lumen patency) were 90.1 ± 5.8% (mean ± standard error of the mean) for animals treated with the anti—LFA-1 mAb (p = 0.0218), 94.2 ± 3.3% for animals treated with the anti-ICAM-1 mAb (p = 0.0067), and 62 ± 7.4% for animals treated with the isotype-matched control mAb. Macrophage and granulocyte counts in the periadventitial region were 39.5 ± 3.2/hpf for animals treated with anti—LFA-1 mAb (p = 0.001), 42 ± 3.7/hpf for animals treated with anti—ICAM-1 mAb (p = 0.003), and 72.2 ± 6.2/hpf for control animals.

Conclusions. The systemic administration of anti—LFA-1 or anti—ICAM-1 mAb initiated 3 hours after exposure to autologous blood inhibits the development of delayed chronic vasospasm at 12 days in a rat femoral artery model and leads to a significant reduction in periadventitial inflammatory cells at 24 hours. The authors conclude that blocking the migration of inflammatory cells across the endothelial surface of an artery after adventitial exposure to blood prevents the initiation of biological cascades necessary for the subsequent development of chronic vasospasm.

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David F. Antezana, Richard E. Clatterbuck, Nabil J. Alkayed, Stephanie J. Murphy, Lauren G. Anderson, James Frazier, Patricia D. Hurn, Richard J. Traystman and Rafael J. Tamargo

Object. Ibuprofen is an antiinflammatory drug that disrupts leukocyte—endothelial cell interactions by limiting expression of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), also known as CD54. The authors hypothesized that ibuprofen could reduce the size of the infarct associated with transient focal ischemia by inhibition of ICAM-1 expression, and they evaluated its effects in rats treated with middle cerebral artery (MCA) occlusion. Ibuprofen treatment was compared with mild systemic hypothermia, which is known to be neuroprotective and is commonly used during neurosurgical procedures.

Methods. The maximum ibuprofen dose (240 mg/kg/day) that could be tolerated with no systemic toxicity was established in the initial experiments. In the efficacy experiment, rats were pretreated with vehicle, ibuprofen, or hypothermia (33°C) prior to 2 hours of MCA occlusion; then their brains were harvested at 24 hours of reperfusion for histological studies. End-ischemic cerebral blood flow (CBF) was evaluated using [14C]iodoantipyrine autoradiography in additional cohorts. Expression of ICAM-1 within ischemic compared with nonischemic caudate nucleus and putamen (striatum) or cortex was evaluated using immunohistochemical studies. Compared with vehicle treatment, ibuprofen produced a 46.2% reduction (p = 0.01) in striatal infarcts, which was comparable to hypothermia (48.7% reduction, p = 0.02). Ibuprofen did not alter end-ischemic CBF in any region studied, and the ibuprofen treatment group had the lowest proportion of animals with marked ICAM-1 staining.

Conclusions. Ibuprofen given in maximum tolerated doses reduces the striatal infarct size after focal cerebral ischemia. The neuroprotective mechanism does not work through preservation of intraischemic CBF and is consistent with inhibition of ICAM-1 expression; however, at the doses used in this study, other effects of ibuprofen on platelet and endothelial function are possible.

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Richard E. Clatterbuck, Philippe Gailloud, Lynn Ogata, Abeyu Gebremariam, Gregory N. Dietsch, Kieran J. Murphy and Rafael J. Tamargo

Object. Leukocyte—endothelial cell interactions occurring in the first hours after subarachnoid hemorrhage (SAH) initiate changes in the endothelium and vessel wall that lead to an influx of leukocytes and the development of chronic vasospasm days later. Upregulation of intercellular adhesion molecule—1 (ICAM-1), also called CD54, appears to be a crucial step in this process. There is increasing experimental evidence that blocking the interaction between ICAM-1, which is expressed on endothelium, and integrins such as lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (complement receptor 3, CD11b/CD18), which are expressed on the surface of leukocytes, prevents not only inflammation of vessel walls but also chronic vasospasm. The authors extend their previous work with monoclonal antibody (mAb) blockade of leukocyte migration to a nonhuman primate model of chronic, posthemorrhagic cerebral vasospasm.

Methods. Before surgery was performed, six young adult male cynomolgus monkeys underwent baseline selective biplane common carotid and vertebrobasilar artery cerebral angiography via a transfemoral route. On Day 0, a right frontosphenotemporal craniectomy was performed with arachnoid microdissection and placement of 2 to 3 ml of clotted autologous blood in the ipsilateral basal cisterns. The animals were given daily intravenous infusions of 2 mg/kg of either a humanized anti-CD11/CD18 or a placebo mAb beginning 30 to 60 minutes postoperatively. The monkeys were killed on Day 7 after a repeated selective cerebral angiogram was obtained. The area of contrast-containing vessels observed in each hemisphere on anteroposterior angiographic views was calculated for the angiograms obtained on Day 7 and expressed as a percentage of the area on baseline angiograms (percent control areal fraction). Review of flow cytometry and enzyme immunoassay data confirmed the presence of the anti-CD11/CD18 antibody in the serum and bound to leukocytes in the peripheral blood of treated animals. Comparisons of the groups revealed 53 ± 4.8% control vascular areal fraction in the placebo group (two animals) and 95.8 ± 9.4% in the anti-CD11/CD18—treated group (three animals), a statistically significant difference (p = 0.043, t-test).

Conclusions. These results show that blockade of leukocyte migration into the subarachnoid space by an anti-CD11/CD18 mAb is effective in preventing experimental cerebral vasospasm in nonhuman primates, despite the unaltered presence of hemoglobin in the subarachnoid space. These experimental data support the hypothesis that inflammation plays a role in cerebral vasospasm after SAH.

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Ryan M. Kretzer, Ranice W. Crosby, David A. Rini and Rafael J. Tamargo

✓ Dorcas Hager Padget was a pioneer in the fields of neurosurgical illustration and neuroembryology who practiced during the early 20th century at The Johns Hopkins University. Without a college degree, she trained as a medical illustrator in the Johns Hopkins School of Medicine's Department of Art as Applied to Medicine under Max Brödel. She began her career working for Walter Dandy as his medical artist, gaining worldwide recognition for her neurosurgical illustrations. With Dandy's encouragement, Hager Padget undertook her own scientific research, studying neurodevelopment and aneurysm formation in the circle of Willis by using human embryos from the world-renowned Carnegie Collection. She made lasting contributions to the field of neuroembryology, publishing the first major work on neurodevelopment of the cerebral arterial and venous systems. Following Dandy's death in 1946, Hager Padget began a full-time career as a scientific researcher, first at the Department of Embryology at the Carnegie Institution of Washington in Baltimore and later at the University of Maryland School of Medicine. She continued to make contributions to the field of congenital malformations of the brain and spine, coining the term “neuroschisis” to describe a possible mechanism of neural tube damage leading to the creation of a myelomeningocele. The authors describe Dorcas Hager Padget's contributions to neurosurgical illustration and neuroembryology, as well as her remarkable career.

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James L. Frazier, Gustavo Pradilla, Paul P. Wang and Rafael J. Tamargo

Object. Leukocyte—endothelial cell interactions may play a role in the development of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) because the extravasation of circulating leukocytes into the periadventitial space within 24 hours after the hemorrhage appears to be a critical event in this process. Ibuprofen is an antiinflammatory agent that inhibits the expression of specific cell adhesion molecules and, consequently, disrupts leukocyte—endothelial cell interactions. The authors investigated the efficacy of ibuprofen delivered locally from controlled-release polymers in the rabbit basilar artery (BA) model of cerebral vasospasm.

Methods. Ibuprofen was incorporated into controlled-release ethylene—vinyl acetate copolymer (EVAc) constituting 45% of the resulting polymer by weight. Fifty-four New Zealand White rabbits were randomized to 10 groups: sham operation (seven animals); SAH only (seven animals); and SAH plus either empty EVAc or ibuprofen—EVAc polymer at 30 minutes or 6, 12, or 24 hours (five animals per group; 40 total). The rabbits were killed 72 hours after induction of SAH, at the time of maximal vasospasm. The efficacy of ibuprofen in preventing vasospasm was assessed by measuring lumen patency of the rabbit's BAs. The intracranial controlled release of ibuprofen resulted in a significant inhibition of vasospasm when treatment was initiated at 30 minutes (patency 92.3 ± 5.1% compared with 52.1 ± 5.1% in animals given empty EVAc; p < 0.001) and 6 hours (patency 69.5 ± 3.5% compared with 47.2 ± 1.5% in animals given empty EVAc; p < 0.03) after blood deposition compared with treatment with empty EVAc. No effect was observed when treatment was begun at either 12 or 24 hours.

Conclusions. Local intracranial delivery of ibuprofen accomplished using controlled-release polymers prevents vasospasm in the rabbit BA model of vasospasm when administered within 6 hours after blood exposure.

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Gustavo Pradilla, Paul P. Wang, Federico G. Legnani, James L. Frazier and Rafael J. Tamargo

Object. Implantation of controlled-release polymers into the subarachnoid space to deliver drugs for treatment of vasospasm after subarachnoid hemorrhage (SAH) is currently of interest. Among the issues regarding local delivery of drugs in the subarachnoid space, however, are the extent of diffusion and the rate of release of the loaded agents. In this study Evans blue dye (EBD) was loaded into controlled-release polymers and its pharmacokinetic properties were determined in vitro and in vivo by using a rabbit model of SAH.

Methods. Ethylene—vinyl acetate copolymer (EVAc) was loaded 40% (w:w) with EBD and its pharmacokinetics were spectrophotometrically determined in vitro by examining three EBD—EVAc polymers. Additional polymers were implanted either into the frontal lobe or into the cisterna magna of 16 New Zealand White rabbits. Subarachnoid hemorrhage was induced in eight of the animals by an injection of 1.5 ml of arterial blood into the cisterna magna. The animals were killed 3 or 14 days postoperatively, their brains and spinal cords were harvested, and samples of each were placed in formamide for dye extraction and quantification. Specimens were examined macroscopically and the concentrations of EBD were determined with the aid of a spectrophotometer.

The EBD—EVAc polymers continuously released EBD over a 133-day period. The controlled release of the dye into the subarachnoid space in either location resulted in staining of the entire central nervous system (CNS) in rabbits when the polymers were placed either on the frontal lobe or in the cisterna magna. The EBD diffusion covered a distance of at least 40 cm. The presence of blood in the subarachnoid space did not interfere with the diffusion.

Conclusions. In this study the authors define the rate and extent of diffusion of EBD from controlled-release polymers placed in the subarachnoid space under conditions of SAH. Evans blue dye diffused through the entire rabbit CNS, covering a distance greater than that of the longest dimension of the hemicircumference of the subarachnoid space around the human brain. The pharmacokinetic properties of EBD—EVAc polymers are comparable to those of antivasospasm agents that are successfully used in animal models of SAH.

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Gustavo Pradilla, Paul P. Wang, Federico G. Legnani, Lynn Ogata, Gregory N. Dietsch and Rafael J. Tamargo

Object. Adhesion of leukocytes and their migration into the periadventitial space may be critical in the pathophysiology of vasospasm following subarachnoid hemorrhage (SAH). The cell adhesion molecules involved in this process are lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (CD11b/CD18), which are present on neutrophils/macrophages, and intercellular adhesion molecule—1 (CD54), which is present in endothelial cells. A humanized monoclonal antibody (mAb), Hu23F2G, targets CD11/CD18 and prevents leukocyte adhesion to endothelial cells. In this study, systemic administration of Hu23F2G prevented vasospasm in the rabbit model of SAH.

Methods. Twenty-six New Zealand White rabbits were injected with autologous blood into the cisterna magna to induce SAH, after which they were randomized to receive injections of either Hu23F2G (10 animals) or a placebo at 30 minutes and 24 and 48 hours after SAH (six animals). Control animals underwent sham operations (four animals) or SAH alone (six animals). The animals were killed 72 hours after SAH, their bodies perfused and fixed, and their basilar arteries processed for morphometric analysis. Peripheral white blood cells (WBCs) were counted at 72 hours. The percentages of lumen patency were compared using the Student t-test. The presence of neutrophils and macrophages was confirmed by immunohistochemical analysis in which a rat anti—rabbit anti-CD18 mAb and cresyl violet were used.

Treatment with Hu23F2G resulted in the significant prevention of vasospasm. Animals treated with Hu23F2G had 90 ± 7% lumen patency compared with 65 ± 7% in the placebo group (p = 0.025). The percentage of lumen patency in the SAH-only group was 59 ± 10%. The mean WBC count was 16,300 ± 2710/µl in the treatment group, compared with 7000 ± 386/µl in the control group (p = 0.02). Administration of Hu23F2G produced increased numbers of WBCs in 70% of the animals treated.

Conclusions. This study supports the concept that leukocyte—endothelial cell interactions play an important role in the pathophysiology of chronic vasospasm after SAH. Systemic therapy with an anti-CD11/CD18 mAb prevents vasospasm after SAH by inhibiting adhesion of neutrophils and macrophages and their migration into the periadventitial space.

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Ingrid M. Burger, Rafael J. Tamargo, Jennifer Broussard and Philippe Gailloud

✓The authors report on the case of a 28-year-old woman presenting with an intraosseous arteriovenous fistula (AVF) located in the left parietal bone. The fistula was formed by direct arteriovenous shunts connecting branches of the left middle meningeal and superficial temporal arteries with a parietal diploic vein. Drainage occurred through both the external and internal jugular venous systems. Therapy consisted of combined surgical and endovascular approaches. The results of a pathological examination of the resected AVF showed mild enlargement of the diploic space. The angiographic appearance, pathological anatomy, and treatment of this rare lesion are discussed, as is a possible relationship between diploic AVFs and the development of aneurysm bone cysts.

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Richard E. Clatterbuck, Philippe Gailloud, Travis Tierney, Victoria M. Clatterbuck, Kieran J. Murphy and Rafael J. Tamargo

Object. Results of prior studies in rats and rabbits show that the alteration of vasomotor tone in vasospasm following periadventitial blood exposure may be reversed, at least in part, by the administration of compounds releasing nitric oxide (NO). The authors have now generalized this finding to nonhuman primates.

Methods. Ten cynomolgus monkeys underwent cerebral angiography before and 7 days following the induction of subarachnoid hemorrhage (SAH) by the placement of 2 to 3 ml clotted autologous blood around the supraclinoid carotid, proximal anterior cerebral, and proximal middle cerebral arteries. An ethylene vinyl acetate copolymer, either blank (five animals) or containing 20% w/w (Z)-1-[2-(2-aminoethyl)-N-(2-aminoethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO, 4.3 mg/kg; five animals) was placed adjacent to the vessels at the time of surgery. Animals were killed on Day 7 post-SAH following repeated cerebral angiography. The mean percentage of control vascular areal fraction was calculated from angiograms. Cerebral vessels were sectioned and the mean percentage of lumen patency was calculated.

One animal that had received the DETA/NO polymer died prior to repeated angiography. In the remaining animals, DETA/NO caused a significant decrease in vasospasm compared with controls, according to both angiographic (84.8 ± 8.6 compared with 56.6 ± 5.2%, respectively, p < 0.05) and histological studies (internal carotid artery 99.3 ± 1.8 compared with 60.1 ± 4.4%, respectively, p < 0.001; middle cerebral artery 98.4 ± 3 compared with 56.1 ± 3.7%, respectively, p < 0.001; and anterior cerebral artery 89.2 ± 8.5 compared with 55.8 ± 6.3%, respectively, p < 0.05).

Conclusions. The controlled release of DETA/NO is effective in preventing delayed cerebral vasospasm in an SAH model in nonhuman primates. The death of one animal in the treatment group indicates that the present dosage is at the threshold between therapeutic efficacy and toxicity.