Quoc Anh Thai

Inhibition of Experimental Vasospasm in Rats With the Periadventitial Administration of Ibuprofen Using Controlled-Release Polymers

BACKGROUND AND PURPOSE The chronic phase of vasospasm after an aneurysmal subarachnoid hemorrhage may be mediated in part by early leukocyte-endothelial cell interactions. Ibuprofen is an anti-inflammatory agent that inhibits expression of certain cell adhesion molecules and therefore disrupts leukocyte-endothelial cell interactions. Its systemic administration, however, has dose-limiting side effects. We evaluated the effect of the periadventitial delivery of ibuprofen using controlled-release polymers in the rat femoral artery model of chronic posthemorrhagic vasospasm. METHODS Before the animal studies, the release pharmacokinetics of the ibuprofen-loaded ethylene-vinyl acetate polymers were determined in vitro. Subsequently, the femoral arteries (n=266) of Fischer 344 rats (n=133) were enclosed in latex pouches bilaterally. In the toxicity study (n=15 rats), the animals were randomized into 5 dose groups in which 0%-, 10%-, 20%-, 30%-, or 50%-loaded ibuprofen polymers were evaluated. In the efficacy study, the animals were randomized into 5 time groups in which 50%-loaded ibuprofen polymers were inserted at 0 (n=58 rats), 6 (n=16), 12 (n=13), 24 (n=11), or 48 hours (n=12) after blood injection into the pouch. The rats were killed 12 days after blood exposure, at the time of maximal vasospasm in this model. Vasospasm was expressed as percent lumen patency. To evaluate the effect of ibuprofen on leukocyte migration, 8 rats were randomized into 2 groups. Macrophages and granulocytes were stained by immunohistochemistry with the use of a mouse OX-41 monoclonal antibody and counted in the periadventitial space 24 hours after blood exposure. RESULTS In vitro pharmacokinetics showed that the 50%-loaded ibuprofen polymer released its total drug load over a 12-day period. In the toxicity study, a nonsignificant arterial vasodilatation with ibuprofen treatment was seen at higher doses, and no deleterious effects were noted on the vessel wall histologically. In the efficacy study, ibuprofen treatment resulted in significant vasospasm inhibition when treatment was initiated at 0 hour (73.7+/-4.9% versus 94.5+/-3.3% [mean+/-SEM percent lumen patency]; P<0.001) and 6 hours (69.2+/-5.7% versus 98.0+/-3.9%; P=0. 002) after blood exposure, but not at 12, 24, or 48 hours. Leukocyte immunohistochemistry showed that ibuprofen treatment resulted in significantly lower periadventitial macrophage and granulocyte counts of 25.0+/-3.9 cells per high-powered field compared with counts of 140.5+/-18.2 cells per high-powered field in the untreated vessels (P<0.001). CONCLUSIONS The periadventitial, controlled release of ibuprofen from surgically implanted polymers significantly inhibits chronic posthemorrhagic vasospasm in this model when treatment is initiated within 6 hours of blood exposure. Vasospasm inhibition with ibuprofen correlates with a significant decrease in the number of macrophages and granulocytes in the periadventitial space. This study supports the hypothesis that inflammation mediates in part the chronic phase of posthemorrhagic vasospasm and suggests a potential alternative treatment for this condition.

Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm.

OBJECTIVE:Experimental evidence suggests that intercellular adhesion molecule-1 mediated leukocyte extravasation contributes to the pathogenesis of cerebral vasospasm. Simvastatin, an HMG-CoA reductase inhibitor, decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. We hypothesized that administration of simvastatin after the onset of subarachnoid hemorrhage (SAH) would attenuate perivascular granulocyte migration and ameliorate cerebral vasospasm in a rabbit model of SAH. METHODS:New Zealand white rabbits (n = 15) underwent injection of autologous blood into the cisterna magna or sham surgery followed by subcutaneous injection of simvastatin (40 mg/kg) or vehicle 30 minutes, 24 hours, and 48 hours after SAH or sham surgery. Seventy-two hours later, basilar artery lumen diameter was measured by in situ perfusion/fixation and image analysis. CD-18 monoclonal antibody stained perivascular granulocytes and macrophages were counted under light microscopy. RESULTS:In vehicle treated rabbits, mean ± standard deviation basilar artery diameter was reduced 3 days after SAH (n = 5) versus sham (n = 5) rabbits (0.49 ± 0.08 mm versus 0.75 ± 0.03 mm, P < 0.01). After SAH, mean ± standard deviation basilar artery diameter was greater in simvastatin (n = 5) treated rabbits versus vehicle (n = 5) (0.63 ± 0.04 mm versus 0.49 ± 0.08 mm, P < 0.01). In vehicle treated rabbits, SAH resulted in an increase in the mean ± standard deviation perivascular CD18 cell count (sham-vehicle, 2.8 ± 2; SAH-vehicle 90 ± 27; P < 0.01). Subcutaneous administration of simvastatin attenuated this increase in perivascular CD18-positive cells after SAH (SAH statin, 41.6 ± 13; SAH vehicle, 90 ± 27; P < 0.001). CONCLUSION:Subcutaneous administration of simvastatin after the onset of SAH attenuates perivascular granulocyte migration and ameliorates basilar artery vasospasm after experimental SAH in rabbits. 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, may potentially serve as agents in the prevention of cerebral vasospasm after SAH.

Delayed intracranial delivery of a nitric oxide donor from a controlled-release polymer prevents experimental cerebral vasospasm in rabbits.

OBJECTIVE:Decreased local availability of nitric oxide (NO) may mediate chronic vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Previous reports have shown that early treatment with NO prevents vasospasm in animals. We evaluated the efficacy of controlled-release polymers that contain the NO donor diethylenetriamine (DETA-NO) for the delayed treatment of vasospasm in a rabbit model of SAH. METHODS:DETA-NO 20% (wt/wt) was incorporated into ethylene-vinyl acetate (EVAc) polymers. Animals (n = 52) were randomized to two experimental groups. In the first group (n = 32), animals received SAH and implantation of either 20% DETA-NO/EVAc polymer at a dose of 0.5 mg/kg of DETA-NO (n = 16) or empty EVAc polymer (n = 16). Polymers were implanted 24 (n = 16) or 48 hours (n = 16) after SAH. In the second group (n = 20), animals received SAH and implantation of either 20% DETA-NO/EVAc polymer at a dose of 1.3 mg/kg (n = 10) or empty EVAc (n = 10). Polymers were implanted 24 (n = 10) or 48 hours (n = 10) after SAH. An additional group (n = 16) underwent either sham operation (n = 6) or SAH only (n = 10). Animals were killed 3 days after hemorrhage, and the basilar arteries were processed for morphometric measurements. Results were analyzed using Student’s t test. RESULTS:Treatment with 20% DETA-NO/EVAc polymers at a dose of 1.3 mg/kg significantly increased basilar artery lumen patency when administered at 24 (97 ± 6% versus 73 ± 10%; P = 0.0396) or 48 hours (94 ± 6% versus 71 ± 9%; P = 0.03) after SAH. Treatment with 20% DETA-NO/EVAc polymers at a dose of 0.5 mg/kg administered 48 hours after SAH significantly increased lumen patency (82 ± 8% versus 68 ± 12%; P = 0.03); a dose of 0.5 mg/kg, 24 hours after SAH, did not reach statistical significance (74 ± 7% versus 65 ± 9%; P = 0.16). The SAH-only group had a lumen patency of 67 ± 12%. CONCLUSION:Delayed treatment of SAH with controlled-release DETA-NO polymers prevented experimental posthemorrhagic vasospasm in the rabbit. This inhibition was dose-dependent. This further confirms the role of NO in the pathogenesis of vasospasm.

Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer

OBJECTIVEDespite improvements in the care of patients with aneurysmal subarachnoid hemorrhage, delayed cerebral vasospasm remains a major cause of morbidity and death. There is now evidence that a decrease in the local availability of nitric oxide (NO) plays a role in delayed cerebral vasospasm. We evaluated a controlled-release polymer containing the NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) for the treatment of chronic posthemorrhagic vasospasm in the rat femoral artery model. METHODSThe release kinetics of ethylene/vinyl acetate copolymers loaded with 20% (w/w) DETA/NO were determined in vitro. Chronic vasospasm was induced in the left femoral artery of adult male Fischer 344 rats (n = 35) by exposure to autologous blood. At 1, 3, or 7 days after blood exposure, either a 5-mg polymer loaded with 20% (w/w) DETA/NO or an empty 5-mg polymer was placed in the periadventitial space next to the left femoral artery. At the same time, an empty 5-mg polymer was placed next to the right femoral artery. On the 8th day after blood exposure (at the peak of vasospasm in this model), rats were transcardially perfused with 4% paraformaldehyde, and the left and right femoral arteries were removed for histological processing and morphometric analyses. Vasospasm was expressed as the percent lumen patency of the treated left artery, compared with the control right artery. RESULTSThe in vitro release kinetics demonstrated that the 20% DETA/NO-loaded polymers released up to 15% of their total drug load during a 9-day period. DETA/NO treatments initiated at 1, 3, or 7 days after blood deposition all significantly inhibited vasospasm, compared with control values (94.6 ± 7.2% versus 67.6 ± 5.8%, 104.6 ± 5.5% versus 64.9 ± 1.7%, and 102.4 ± 5.1% versus 73.6 ± 1.4%, respectively; mean ± standard error of the mean percent lumen patency;P < 0.001). No adverse effects of treatment were observed. CONCLUSIONThe diazeniumdiolate NO donor DETA/NO can be effectively released from ethylene/vinyl acetate polymers. Administration of DETA/NO into the periadventitial space can prevent the development of chronic posthemorrhagic vasospasm in the rat femoral artery and can reverse established vasospasm. No adverse effects of DETA/NO were observed in this model.

Local delivery of antineoplastic agents by controlled-release polymers for the treatment of malignant brain tumours

Recent advances in the treatment of malignant brain tumours have focused on the development of targeted local delivery of therapeutic agents, which combine various antineoplastic strategies that include cytotoxic, anti-angiogenic and immunomodulatory mechanisms, among others. The introduction of local delivery devices for sustained administration of antineoplastic agents represents a new opportunity to effectively treat these malignancies by facilitating the intracranial administration of safe and clinically efficacious doses for prolonged periods of time in a controlled fashion. This technology circumvents the need for high systemic doses with potentially harmful toxicities, bypasses the blood–brain barrier and can be tailored to deliver new agents with complex pharmacological properties. Based on local delivery strategies, new delivery systems, including convection-enhanced delivery and microchips, have been developed. As a result, recent advances in tumour biology have been adopted as potentially translatable treatments and are undergoing preclinical and clinical evaluation at present. These novel approaches could improve the prognosis of patients with these tumours.

Local delivery of ibuprofen via controlled-release polymers prevents angiographic vasospasm in a monkey model of subarachnoid hemorrhage

OBJECTIVE: Adhesion and migration of leukocytes into the periadventitial space play a role in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). Intercellular adhesion molecule-1 is a determinant cell adhesion molecule involved in this process. Ibuprofen has been shown to inhibit intercellular adhesion molecule-1 upregulation and prevent vasospasm in animal models of SAH. In this study, we report the toxicity and efficacy of locally delivered ibuprofen incorporated into controlled-release polymers to prevent vasospasm in a monkey model of SAH. METHODS: Ibuprofen was incorporated into ethylene-vinyl acetate (EVAc) polymers at 45% loading (wt:wt). For the toxicity study, cynomolgus monkeys (n = 5) underwent surgical implantation of either blank/EVAc polymers (n = 3) or 45% ibuprofen/EVAc polymers (n = 2) in the subarachnoid space, were followed up for 13 weeks, and were killed for histopathological analysis. For the efficacy study, cynomolgus monkeys (n = 14) underwent cerebral angiography 7 days before and 7 days after surgery and SAH and were randomized to receive either a 45% ibuprofen/EVAc polymer (n = 7; mean dose of ibuprofen, 6 mg/kg) or blank EVAc polymers (n = 7) in the subarachnoid space. Angiographic vasospasm was determined by digital image analysis. Student’s t test was used for analysis. RESULTS: Animals implanted with ibuprofen polymers showed no signs of local or systemic toxicity. Animals treated with ibuprofen polymers had 91 ± 9% lumen patency of the middle cerebral artery, compared with 53 ± 11% of animals treated with blank/EVAc polymers (P < 0.001). CONCLUSION: Ibuprofen polymers are safe and prevent angiographic vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

Aneurysmal rupture without subarachnoid hemorrhage: case series and literature review.

OBJECTIVE:Although an aneurysmal rupture typically presents on computed tomographic (CT) imaging as only subarachnoid hemorrhage (SAH), it may be associated with intraparenchymal hemorrhage (IPH), intraventricular hemorrhage (IVH), or subdural hemorrhage. On rare occasions, however, an aneurysmal rupture may present with IPH or IVH without SAH. METHODS:The Division of Cerebrovascular Neurosurgery at The Johns Hopkins Medical Institutions maintains a prospective database of all patients treated for intracranial aneurysms at this institution since 1991. Using this database, we identified patients with ruptured aneurysms who presented with IPH or IVH in the absence of SAH on CT imaging. RESULTS:Eight hundred twenty-two patients with radiographically documented ruptured aneurysms were admitted from January 1991 through June 2004. Of these, nine patients presented with IPH only, three with IPH and IVH, and one with IVH only, for a total of 13 cases. There were seven posterior communicating artery, four middle cerebral artery, one basilar apex, and one posterior cerebral artery aneurysms. The incidence of aneurysmal rupture with IPH and/or IVH without SAH is 1.6% CONCLUSION:Initial presentation of a ruptured aneurysm without SAH is rare and may have a multifactorial cause attributable to the timing of CT imaging, physiological parameters, or location of the aneurysm. Patients presenting with a head CT scan revealing IPH in the temporal lobe or with IVH should be considered for an urgent workup of a ruptured aneurysm, even in the absence of diffuse SAH.

FRONTOZYGOMATIC TITANIUM CRANIOPLASTY IN FRONTOSPHENOTEMPORAL ( PTERIONAL ) CRANIOTOMY

OBJECTIVE One of the most common problems after frontosphenotemporal, or pterional, craniotomy is the marked depression of the frontozygomatic fossa caused by atrophy of the temporalis muscle. Although temporalis muscle reconstruction techniques have been proposed to prevent this problem, a definitive solution has not been achieved. We report the results of a titanium cranioplasty technique in a prospective series of patients who underwent frontosphenotemporal craniotomy. METHODS Between April 2002 and June 2006, 209 consecutive patients underwent a frontosphenotemporal craniotomy for aneurysms, vascular malformations, or tumors. At the time of surgery, the patients underwent a frontozygomatic fossa cranioplasty with a titanium plate, to which the temporalis muscle was attached. In this series, 194 patients had documented follow-up periods averaging 9.5 months (range, 1 mo–4 yr; median, 7.5 mo), and the cosmetic results of the cranioplasty have been assessed. RESULTS The cosmetic outcomes have been outstanding in all patients treated to date. Two patients had the cranioplasty removed due to either orbital pain or local infection secondary to sepsis. CONCLUSION The frontozygomatic cranioplasty during frontosphenotemporal craniotomy prevents the characteristic depression at the frontozygomatic fossa and accomplishes an outstanding cosmetic result.

Simple technique for intraoperative angiographic localization of small vascular lesions.

BACKGROUNDPrecise surgical localization of small arteriovenous malformations (AVMs), arteriovenous fistulae (AVFs), and aneurysms located in the distal portions of the intracranial arteries can be difficult OBJECTIVEWe describe a simple and accurate intraoperative angiographic localization technique for small AVMs, AVFs, and distal aneurysms. METHODSAll patients had routine preoperative diagnostic imaging and evaluations, including catheter angiography. Once anesthetized, the patients were prepared for intraoperative angiography following cannulation of the femoral artery. Craniometric landmarks were utilized to approximately localize the lesion. A wire in the shape of a square was placed over the proposed craniotomy site and an angiogram was performed. With use of real-time angiography, the wire localizer was manipulated until the small vascular lesion was visualized entirely within the wire frame, thus defining the extent of the required craniotomy and the surgical trajectory. RESULTSThe wire localizer was used to target small vascular lesions in 9 cases of AVMs, 4 cases of distal middle cerebral artery aneurysms, and 1 case of a diploic AVF. In all 14 cases, the lesion was accurately localized intraoperatively without further image-guided techniques, and there was no change in the craniotomy. There were no intraoperative complications, and all patients had uneventful recoveries. CONCLUSIONIntraoperative angiography with a simple wire localizer can effectively and accurately aid in the planning of surgery for a range of small and distal vascular lesions with virtually no added cost, minimal setup time, and limited potential for technical errors.

Calcified Suprasellar Xanthogranuloma Presenting with Primary Amenorrhea in a 17-Year-Old Girl: Case Report and Literature Review

BACKGROUND Xanthogranuloma, also known as cholesterol granuloma, is an extremely rare intracranial neoplasm most commonly located in the middle ear, petrous apex, or choroid plexus. Exclusively suprasellar xanthogranulomas are exceptional and this report presents a very rare case in the pediatric population, particularly unique due to the presence of calcification. CASE DESCRIPTION A 17-year-old girl presented with primary amenorrhea with computed tomography and magnetic resonance imaging showing a large calcified enhancing suprasellar mass, which was presumptively diagnosed as a craniopharyngioma on the basis of its clinical and radiologic appearance. Gross total resection of a well-encapsulated, exclusively suprasellar tumor was achieved, without postoperative neurologic deficits. Histologic examination found fibrous tissue with abundant cholesterol clefts, multinucleated giant cells, and hemosiderin deposits but no epithelial cells. The final histologic diagnosis was a xanthogranuloma. CONCLUSIONS Xanthogranuloma, although extremely rare in the pediatric population, may present as a calcified suprasellar mass and manifest with primary amenorrhea. The prognosis after gross total resection is likely favorable; however, long-term follow-up is indicated for these rare neoplasms.