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The incidence of primary traumatic oculomotor nerve palsies in craniocerebral trauma is approximately 1.2% and is usually persistent and associated with loss of consciousness, other neurologic deficits, and skull base or orbital fractures. This case is a rare demonstration of complete left third nerve palsy from uncal herniation after trauma without any loss of consciousness., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Importance: Although glioblastoma is the most common primary brain tumor, primary intraventricular locations are extremely rare; only 21 cases have been reported to date., Methods: A retrospectively acquired database of all intracranial glioblastomas treated in 2 different neurosurgical departments during the last 10 years was queried. Patients with histologically proven intraventricular glioblastomas were included in the study., Results: Eight patients were identified as having a histologically confirmed intraventricular glioblastoma. Patient age at diagnosis ranged from 6 to 74 years (mean 29.6 years) and the male/female ratio was 5:3. Increased intracranial pressure due to hydrocephalus was the main cause of the clinical manifestations. The tumor was located within the lateral ventricle in 6 cases and the anterior third ventricle in 2 others. Gross total tumor excision was achieved in 3 patients, whereas the surgical resection was subtotal in 4 cases and a surgical biopsy was performed in 1 patient. Postoperative adjuvant therapies were administered in 5 patients. Median survival time was 32.1 months, and 3 patients were alive at the end of study. All of them had isocitrate dehydrogenase-mutated tumors., Conclusions: Intraventricular glioblastoma is extremely rare and can affect younger individuals including children. This malignant tumor should be included in the differential diagnosis of intraventricular lesions, especially in the lateral ventricles. Radical surgical resection can be associated with remarkable disease-free survival, especially in isocitrate dehydrogenase-mutated tumors. Because recurrence virtually is unavoidable, long-term follow-up is mandatory., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Gliosarcomas are rare, malignant primary brain tumors, most commonly located in the temporal lobe, that contain both glial and mesenchymal elements. Gliosarcomas located within the cerebellum are exceedingly rare. The previously unreported finding of a cerebellar gliosarcoma concurrently with an extracranial metastasis to the lungs is discussed here., Case Description: A 57-year-old man presented with a 3-month history of chest pain, weight loss, headaches, and vomiting. Physical examination revealed a left cerebellar dysfunction, and the radiological work-up revealed a 6 × 6-cm right apical pulmonary tumor and a 4 × 3.5 × 3.8-cm peripherally enhancing left cerebellar mass. On the basis of a smoking history in the setting of a lung lesion and cerebellar mass, the presumptive diagnosis was primary lung cancer with metastasis to the cerebellum. Gross total resection of a firm pseudo-encapsulated cerebellar mass was performed. The microscopic features and the immunohistochemical profile confirmed the diagnosis of Gliosarcoma. The thoracic lesion was removed subsequently, and pathology confirmed it as an extracranial metastasis from the cerebellar gliosarcoma. Adjuvant radiation and chemotherapy were then administered. No clinical or radiographic evidence of recurrence was observed during one year of follow-up monitoring., Conclusions: To the best of our knowledge, a primary infratentorial gliosarcoma with extracranial metastases has not been previously described., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Precise surgical localization of small arteriovenous malformations (AVMs), arteriovenous fistulae (AVFs), and aneurysms located in the distal portions of the intracranial arteries can be difficult., Objective: We describe a simple and accurate intraoperative angiographic localization technique for small AVMs, AVFs, and distal aneurysms., Methods: All 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., Results: The 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., Conclusion: Intraoperative 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.

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.

Background: The treatment of large and high-grade (Spetzler-Martin III-V) AVMs remains a challenge. There is a paucity of literature addressing the efficacy of radiosurgery in this group. We retrospectively analyze our experience with repeat radiosurgery with such AVMs., Methods: Between 1989 and 2004, 14 patients with large and high-grade AVMs deemed to be nonoperative candidates were treated with repeat radiosurgery. Patients were treated either on a LINAC or gamma knife-based system at 2- to 3-year intervals with targeting of the entire nidus with each treatment. Patients who did not receive their full treatment course or follow-up at the institution were excluded., Results: Mean follow-up was 18 months. The complete obliteration rate was 35.7%, with a mean volume reduction of 53% in the remaining lesions. Twenty percent of grade III and 50% of grade IV lesions experienced cure. Complications included persistent headaches (2 patients). Statistical analysis revealed no difference between obliterated and partially obliterated groups with regard to mean pretreatment volume (24.87 cm(3)), median Spetzler-Martin grade (IV), mean follow-up (30.5 months), total delivered dose (3550 cGy), mean dose per stage (13 Gy), median number of stages (2), or mean interval between treatment stages (40 months)., Conclusion: The present study demonstrates the potential role of repeat radiosurgery in the treatment of this cohort in the context of our short follow-up. The benefits of repeat therapy could be derived from using lower doses per session and repeat targeting of the lesion in an effort to increase response and decrease complication rates.

Objective: Leukocyte-endothelial cell interactions appear to play a role in the development of vasospasm after SAH. Using a purely inflammatory protein, LPS, we evaluated the effect of inflammation on the development of chronic vasospasm in the absence of blood and compared it to SAH-induced vasospasm in rabbits., Methods: Lipopolysaccharide was incorporated into EVAc polymers to produce 20% LPS/EVAc polymers (wt/wt). Rabbits (n = 23) were randomized to 4 experimental groups: (1) empty polymer (n = 6), (2) SAH (n = 5), (3) 0.7 mg/kg polymeric LPS dose (n = 6), and (4) 1.4 mg/kg polymeric LPS dose (n = 6). Blood and polymers were inserted into the cisterna magna. The rabbits were killed 3 days postoperatively, and the basilar arteries were harvested for morphometric analysis. Clinical response and lumen patencies were analyzed using ANOVA and a post hoc Newman-Keuls Multiple Comparisons test., Results: Significant narrowing of the basilar artery was observed by insertion of 20% LPS/EVAc polymers into the subarachnoid space at a polymeric dose of 1.4 mg/kg (actual dose, 66 microg kg(-1) d(-1)) (75.4% +/- 4.2%; P < .01) and by SAH (80.3% +/- 8.1%; P < .01) as compared with the empty polymer group. A trend toward narrowing was observed in the 0.7 mg/kg polymeric LPS dose group (actual dose, 33 microg kg(-1) d(-1)) (85.2% +/- 2.6%; P > .05). Symptoms associated with SAH were noted in 50% of the rabbits in the 0.7 mg/kg LPS group and in 100% of rabbits in the 1.4 mg/kg LPS group., Conclusion: Controlled release of LPS into the subarachnoid space of rabbits produced chronic vasospasm in a dose-dependent manner. At a polymeric dose of 1.4 mg/kg, LPS-induced vasospasm was equivalent to that induced by SAH. This suggests that LPS and SAH may induce vasospasm through similar mechanisms and provides further evidence that inflammation plays a central role in the etiology of chronic vasospasm.

Object: Currently no adequate surgical treatment exists for spontaneous intracerebral hemorrhage (ICH). Implantable polymers can be used effectively to deliver therapeutic agents to the local site of the pathological process, thus reducing adverse systemic effects. The authors report the use of stereotactically implanted polymers loaded with tissue plasminogen activator (tPA) to induce lysis of ICH in a rabbit model., Methods: Ethylene vinyl acetate (EVAc) polymers were loaded with bovine serum albumin (BSA) only or with BSA plus tPA. In vitro pharmacokinetic (three polymers) and thrombolysis (12 polymers) studies were performed. For the in vivo study, 12 rabbits were fixed in a stereotactic frame, and 0.2 ml of clotted autologous blood was injected into the right frontal lobe parenchyma. After 20 minutes, control BSA polymers were stereotactically implanted at the hemorrhage site in six rabbits, and experimental BSA plus tPA polymers were implanted in six rabbits. Animals were killed at 3 days, and blood clot volume was assessed. The pharmacokinetic study showed release of 146 ng of tPA over 3 days. The tPA activity correlated with in vitro thrombolysis. In the in vivo study, the six animals treated with tPA polymers had a mean (+/- standard error of the mean [SEM]) thrombus volume of 1.43 +/- 0.29 mm3 at 3 days, whereas the six animals treated with blank (BSA-only) polymers had a mean (+/- SEM) thrombus volume of 19.99 +/- 3.74 mm3 (p < 0.001)., Conclusions: Ethylene vinyl acetate polymers release tPA over the course of 3 days. Stereotactic implantation of tPA-loaded EVAc polymers significantly reduced ICH volume. Polymers loaded with tPA may be useful clinically for lysis of ICH without the side effects of systemic administration of tPA.

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.

Lactacystin, a proteasome-inhibitor, has been shown to induce apoptosis of experimental gliomas in vitro. However, its systemic toxicity prevents further clinical use. To circumvent this problem, lactacystin can be delivered intratumorally. We tested the efficacy of lactacystin incorporated into controlled-release polymers for treating experimental gliomas. 9L-gliosarcoma and F98-glioma cell lines were treated with lactacystin (10-100 microg/ml) for 72 h in vitro. Cell-viability was measured with MTT-assays. Toxicity of lactacystin/polycarboxyphenoxypropane-sebacic-acid (pCPP : SA) polymers was tested in vivo using Fischer-344 rats intracranially implanted with lactacystin polymers loaded from 0.1 to 2% lactacystin by weight. The efficacy of 1, 1.3, 1.5 and 1.7% lactacystin/pCPP : SA polymers was determined in Fischer-344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. Lactacystin was cytotoxic in 9L cells, causing a 16 +/- 8% growth inhibition at 10-microg/ml that increased to 78 +/- 4% at 100-microg/ml. Similarly, lactacystin inhibited growth of F98 by 18 +/- 8% at 10-microg/ml and 74 +/- 2% at 100-microg/ml in vitro. Polymers released lactacystin for 21 days and intracranial implantation in rats neither generate local nor systemic toxicity at doses lower than 2%. Treatment with lactacystin/pCPP : SA polymers with loading concentrations of 1.0, 1.3, and 1.5% prolonged survival of animals intracranially challenged with 9L when polymers where inserted in the day of tumor implantation. In conclusion, lactacystin exhibits potent cytotoxic-activity against 9L and F98 in vitro, it can be efficiently incorporated and delivered using controlled-release polymers, and at the proposed concentrations lactacystin polymers are safe for CNS delivery and prolong survival in the 9L model.

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.

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.

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.

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.

Objective: Despite 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., Methods: The 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., Results: The 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., Conclusion: The 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.

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.

Recent evidence indicates that nitric oxide participates in the modulation of vascular tone in a variety of vascular beds, including the parenchymal microvasculature of the brain. The present study examined the role of protein kinase activity in the induction and maintenance of the contractile response when endogenous nitric oxide production is inhibited in parenchymal microvessels of the rat hippocampus. Microvessels in in vitro slices of the hippocampus were monitored using computer-assisted video microscopy. The effects of inhibitors of two kinases, protein kinase C and calcium/calmodulin-dependent protein kinase, on the vasoconstrictor response to NG-nitro-L-arginine (L-NNA) were investigated. The resting luminal diameter of the microvessels examined in this study ranged from 9 to 29 microns. Addition of 100 microM L-NNA to the medium superfusing the slice constricted microvessels by 38.8 +/- 0.6%. The addition of protein kinase inhibitors reversed this constriction in a dose-dependent manner. H-7 (50 microM), a relatively non-selective protein kinase C inhibitor, elicited an 81.4 +/- 10.0% reversal of the L-NNA-induced constriction. Bisindolylmaleimide (5 microM), a selective protein kinase C inhibitor, reversed the constriction by 69.1 +/- 13.7%. KN-62, an inhibitor of calcium/calmodulin-dependent protein kinase II, elicited a smaller yet statistically significant reversal of 17.1 +/- 5.1%. Pretreatment with H-7 or bisindolyl-maleimide blocked the LNNA-induced constriction entirely, while KN-62 did not significantly inhibit the response. These findings indicate that the contractile response observed upon removal of endogenous nitric oxidergic vasodilation is mediated by protein kinase activity, and the contribution of protein kinase C to this effect is greater than that of calcium/calmodulin-dependent protein kinase II. The results suggest that a tonic nitric oxidergic influence serves to mask the potential for protein kinase C-mediated vasoconstriction in cerebral microvessels.

Radiation-induced changes in the parietal cortex of Wistar rats were observed at various time points after gamma surgery. Maximum dosages of 50, 75, and 120 Gy were given at the iso-center of the radiation using a 4-mm collimator. Conventional histochemical and immunocytochemical analyses, and computer-assisted videomicroscopy were utilized to examine perfusion-fixed brain tissue. Irradiation at a dosage of 50 Gy elicited morphological changes of astrocytes in the parietal cortex at 3 months. Vasodilatation became obvious at 12 months; fibrin deposition was observed in the dilated capillary wall. Neither leakage of Evans Blue from the vasculature into the tissue nor necrosis was observed across the 12 month observation period. Irradiation at a dosage of 75 Gy resulted in morphological changes of astrocytes within 1 month. Dilatation of vessels and capillary thickening were observed at 3 months. Evans Blue leakage and necrosis were observed at 4 months after 75 Gy irradiation. At this time, the walls of arterioles became thickened by subintimal accumulation of fibrin and hyaline substance; this sometimes resulted in occlusion of the lumen. Significant hemispheric swelling was observed at 4 months. Irradiation at a dosage of 120 Gy elicited changes in astrocytic morphology within 3 days. Evans Blue leakage into the tissue was observed by 3 weeks. Vasodilation became marked at this time point and rarefaction was observed in the irradiated cortex. Necrosis was observed at 4 weeks, however, no significant swelling was observed. Taken together, these findings demonstrate time-dependent and dosage-dependent changes in normal cerebral tissue after Gamma Knife irradiation. These results provide a basis for gauging the impact of gamma surgery in regions of eloquent tissue. An enhanced understanding of the cellular responses to radiosurgery will contribute to developing and evaluating future applications for gamma surgery.

Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are potent dilators in a variety of vascular beds. Recent evidence suggests that NO may serve as an intermediary messenger for CGRP and/or CGRP may serve as an intermediary messenger for NO in the expression of vasodilation. The present study was designed to provide an initial characterization of the responses to NO and CGRP in parenchymal microvessels and to determine whether NO and/or CGRP act as intermediaries for one another. Microvessels in the parenchyma of in vitro hippocampal slices from rat brain were examined using computer-assisted videomicroscopy. The resting diameter of the microvessels ranged from 9 to 26 microm. Treatment with the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NNA; 100 microM) constricted vessels to 64.2% +/- 3.0% of resting luminal diameter. Sodium nitroprusside (SNP; 1 microM), a donor of NO, reversed the L-NNA-induced vasoconstriction by 77.0% +/- 15.0%. CGRP alone (10 nM) elicited a small but significant vasodilatory effect on resting vascular tone (2.3% +/- 0.6%). In the presence of L-NNA, CGRP elicited a significant dose-dependent vasodilatory response, and 10 nM CGRP elicited a sizeable response, reversing the L-NNA-induced constriction by 84.3% +/- 15.5%. This CGRP-induced dilation was inhibited by pretreatment with the CGRP receptor antagonist, CGRP fragment (8-37) (1 microM). In contrast, pretreatment with 1 microM CGRP fragment (8-37) did not attenuate the SNP-induced dilation in the presence of L-NNA. Taken together, these findings demonstrate that CGRP and NO are potent dilators of parenchymal microvessels, and that NO provides a substantial relaxant effect on resting tone. In addition, the results indicate that CGRP is not a necessary intermediary in NO-induced dilation, and that NO is not a necessary intermediary in CGRP-induced dilation in parenchymal microvessels.

Papaverine (PPV) is a nonspecific vasodilator with widespread clinical uses in the treatment of arterial spasm. It has also been utilized in an attempt to reverse cerebral vasospasm. Recent angiographic results have demonstrated significant reversal of vasospasm in large vessels after selective intra-arterial application of PPV; however, these impressive results lacked good clinical correlation. In this study, phorbol dibutyrate was used to stimulate protein kinase C in an in vitro model of cerebral microvessels. Papaverine was found to elicit a dose-dependent exacerbation of phorbol dibutyrate-induced microvascular constriction in this model system. Because protein kinase C is thought to play a key role in the development of cerebral vasospasm, PPV-induced vasoconstriction represents a potentially important deleterious effect that may not be apparent on angiography. Such a constrictor response may compromise the beneficial vasodilatory effect seen with intra-arterial injection of PPV.

The regulatory role of endothelins in cerebral microvessels was investigated in a recently developed model system which allows the study of small cerebral vessels in their normal microenvironment. Using brain slices of the rat neocortex, it was shown that the isopeptide endothelin-3 (ET-3) had no effect on cerebral microvessels, while the isopeptide endothelin-1 (ET-1) produced a potent, dose-dependent vasoconstriction. When a recently developed antagonist of ETA receptors (cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp]; ETant) was administered prior to treatment with ET-1, the vasoconstrictor response to ET-1 was inhibited in a dose-dependent manner. When ETant was administered after the establishment of a constriction by ET-1, the constrictor response to ET-1 was partially reversed, and this effect was weaker than that seen in the pre-treatment paradigm. These findings indicate that constrictor responses to ET-1 in cerebral microvessels are mediated by ETA receptors. Inasmuch as endothelins have been implicated in pathological forms of vasoconstriction in the CNS, the present findings also suggest that endothelin antagonists may be useful in the treatment of cerebral ischemia.

A model system for studying cerebral microvasculature is presented in which submerged in vitro brain slices are examined by computerized videomicroscopy. Brain slices are superfused continuously with artificial cerebrospinal fluid, while blood vessels are monitored using a transmission light microscope with water immersion objectives. The responses to well-characterized vasoactive compounds indicate that basic physiological characteristics are maintained in this preparation. This model system represents a simple and rapid technique for studying cerebrovascular responses under conditions in which vessels are surrounded by their normal cellular microenvironment. An additional advantage of this technique is the ability to perform simultaneous electrophysiological recordings in identified neurons. This will facilitate the study of interactions between neuronal and vascular elements and may help elucidate mechanisms underlying the local regulation of cerebral microvasculature.