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ABSTRACT: Treatment of cerebral aneurysms by endovascular deployment of liquid embolic agents has been proposed as an alternative strategy to conventional coiling, and new materials are being developed for embolization. In this study, the authors used a single-injection, biocompatible, biodegradable and pH-responsive acrylated chitosan (aCHN) with conjugated vascular endothelial growth factor (rhVEGF) in a rat aneurysm model.
The efficacy of the aCHN formulation with rhVEGF was tested using a common carotid artery occlusion model in rats, and the extent of embolization was evaluated using quantitative, qualitative, and histopathological techniques after 14 days of implantation.
The mean occlusion was significantly greater for the rhVEGF/aCHN-treated group (96.8 +/- 3.0%) than for the group receiving aCHN (74.7 +/- 5.6%) (p < 0.01). Through qualitative evaluation, intimal and medial proliferation were significantly greater with rhVEGF/aCHN than with aCHN and controls (p < 0.001). Degradation of the aCHN filler was monitored in concert with the production of extracellular matrix components. Macrophages migrated in and proliferated inside the occluded carotid artery lumens were identified by histological and immunostainings. Results showed resorption of chitosan with concurrent development of collagen and elastin into the vessel lumen, suggesting clot maturation into fibrosis.
Chitosan with a bioactive agent such as rhVEGF showed excellent results in occluding aneurysms in a rat model.
Journal of Neurosurgery 08/2009; 112(3):658-65. · 2.96 Impact Factor
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ABSTRACT: One mechanism that contributes to cerebral vasospasm is the impairment of potassium channels in vascular smooth muscles. Adenosine triphosphate-sensitive potassium channel openers (PCOs) appear to be particularly effective for dilating cerebral arteries in experimental models of subarachnoid hemorrhage (SAH). A mode of safe administration that provides timed release of PCO drugs is still a subject of investigation. The authors tested the efficacy of locally delivered intrathecal cromakalim, a PCO, incorporated into a controlled-release system to prevent cerebral vasospasm in a rat model of SAH.
Cromakalim was coupled to a viscous carrier, hyaluronan, 15% by weight. In vitro release kinetics studies showed a steady release of cromakalim over days. Fifty adult male Sprague-Dawley rats weighing 350-400 g each were divided into 10 groups and treated with various doses of cromakalim or cromakalim/hyaluronan in a rat double SAH model. Treatment was started 30 minutes after the second SAH induction. Animals were killed 3 days after treatment, and the basilar arteries were processed for morphometric measurements and histological analysis.
Controlled release of cromakalim from the cromakalim/hyaluronan implant at a dose of 0.055 mg/kg significantly increased lumen patency in a dose-dependent manner up to 94 +/- 8% (mean +/- standard error of the mean) of the basilar arteries of the sham group compared with the empty polymer group (p = 0.006). Results in the empty polymer group were not different from those in the SAH-only group, with a lumen patency of 65 +/- 12%. Lumen patencies of the cromakalim-only groups did not differ in statistical significance at low (64 +/- 9%) or high (66 +/- 7%) doses compared to the SAH-only group.
Treatment of SAH with a controlled-release cromakalim/hyaluronan implant prevented experimental cerebral vasospasm in this rat double hemorrhage model; this inhibition was dose-dependent. The authors' results confirm that sustained delivery of cromakalim perivascularly to cerebral vessels could be an effective therapeutic strategy in the treatment of cerebral vasospasm after SAH.
Journal of Neurosurgery 02/2009; 110(5):1015-20. · 2.96 Impact Factor
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ABSTRACT: The pharmacological treatment of cerebral vasospasm (CVS) now includes the experimental use of controlled-release biocompatible compounds that deliver a desired drug locally into the subarachnoid space. A controlled-release system consists of an active material that is incorporated into a carrier, usually in the form of a pellet or a gel. With such systems, the desired agent is delivered slowly and continuously, for long periods of time, directly to the desired site. This technology makes it possible to achieve high local concentrations of therapeutic agents while minimizing systemic toxicity and circumventing the need to cross the blood-brain barrier. This review describes controlled-release systems developed to date for local drug delivery in the treatment of CVS in both animal models and humans.
A MEDLINE PubMed database search was performed for articles published from 1975 to 2007 with the following search topics: "controlled-release system/polymer," "controlled-release implants," "cerebral vasospasm," "subarachnoid hemorrhage," "subarachnoid space," and "intracranial drug delivery."
Over the past several decades, several controlled-release systems (lactic/ glycolic acid pellets, ethylene vinyl acetate copolymer, liposomes, silicone elastomers) have been developed to deliver various pharmacological agents (papaverine, nicardipine, ibuprofen, nitric oxide donor, calcitonin gene-related peptide, fasudil, recombinant tissue plasminogen activator) intracranially to treat subarachnoid hemorrhage in animal models (rats, rabbits, dogs, and primates). Animal studies have shown promising results, and the few human studies that have been published using controlled-release systems with papaverine or nicardipine report similarly encouraging outcomes.
Controlled-release systems have evolved over the past few years and have been shown experimentally to be an effective strategy for the local delivery of drugs to treat CVS.
Neurosurgery 01/2009; 63(6):1011-9; discussion 1019-21. · 2.79 Impact Factor
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ABSTRACT: The Fisher grade (FG) is widely used to predict cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). We revisited the grading scale to determine its validity in the era of modern management.
We retrospectively reviewed the records of 134 patients with SAH. The amount and distribution of subarachnoid blood on admission computed tomography (CT) scan was quantified according to the FG and compared with development of symptomatic vasospasm.
We reviewed 134 patients (median age, 54) who presented with aneurysmal SAH. Six (5%) were FG 1, 34 (25%) were FG 2, 25 (19%) were FG 3, and 69 (51%) were FG 4. Symptomatic vasospasm developed in no (0%) FG 1, 8 (24%) FG 2, 7 (28 %) FG 3, and 13 (19%) FG 4 patients (28 of 134 total patients; 21%). Development of symptomatic vasospasm was not associated with admission FG, Hunt and Hess grade, age, sex, or location of blood on presenting CT scan. Elevated transcranial Doppler blood flow velocity was associated with blood in the basal cisterns (P = .0047), lateral ventricles (P = .026), or blood in any ventricle (P = .04). Postoperative angiograms were obtained in 57 patients; moderate to severe vasospasm was observed in 5 (15%) FG 2, 6 (24%) FG 3, and 14 (20%) FG 4 patients. Twenty patients (71%) with symptomatic vasospasm had moderate or severe angiographic vasospasm. Angiographic vasospasm was associated with intraventricular blood (P = .054) but not with FG.
Symptomatic vasospasm occurred in 21% of cases. The FG correlated with symptomatic vasospasm in only half the patients. A new predictive CT grading scale for vasospasm may be necessary.
Surgical Neurology 04/2005; 63(3):229-34; discussion 234-5. · 1.67 Impact Factor
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ABSTRACT: Nimodipine has been shown to improve neurological outcome after subarachnoid hemorrhage (SAH); the mechanism of this improvement, however, is uncertain. In addition, adverse systemic effects such as hypotension have been described. The authors investigated the effect of nimodipine on brain tissue PO2.
Patients in whom Hunt and Hess Grade IV or V SAH had occurred who underwent aneurysm occlusion and had stable blood pressure were prospectively evaluated using continuous brain tissue PO2 monitoring. Nimodipine (60 mg) was delivered through a nasogastric or Dobhoff tube every 4 hours. Data were obtained from 11 patients and measurements of brain tissue PO2, intracranial pressure (ICP), mean arterial blood pressure (MABP), and cerebral perfusion pressure (CPP) were recorded every 15 minutes. Nimodipine resulted in a significant reduction in brain tissue PO2 in seven (64%) of 11 patients. The baseline PO2 before nimodipine administration was 38.4+/-10.9 mm Hg. The baseline MABP and CPP were 90+/-20 and 84+/-19 mm Hg, respectively. The greatest reduction in brain tissue PO2 occurred 15 minutes after administration, when the mean pressure was 26.9+/-7.7 mm Hg (p < 0.05). The PO2 remained suppressed at 30 minutes (27.5+/-7.7 mm Hg [p < 0.05]) and at 60 minutes (29.7+/-11.1 mm Hg [p < 0.05]) after nimodipine administration but returned to baseline levels 2 hours later. In the seven patients in whom brain tissue PO2 decreased, other physiological variables such as arterial saturation, end-tidal CO2, heart rate, MABP, ICP, and CPP did not demonstrate any association with the nimodipine-induced reduction in PO2. In four patients PO2 remained stable and none of these patients had a significant increase in brain tissue PO2.
Although nimodipine use is associated with improved outcome following SAH, in some patients it can temporarily reduce brain tissue PO2.
Journal of Neurosurgery 11/2004; 101(4):594-9. · 2.96 Impact Factor
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ABSTRACT: Continuous arterial spin labeling perfusion magnetic resonance imaging (CASL-pMRI) uses magnetically labeled arterial blood water as a tracer to obtain quantifiable measurements of cerebral blood flow (CBF) (mL/100 g-1/min-1). CASL-pMRI was used to assess CBF changes in major vascular distributions in patients (n = 10) prior to and 3 months after carotid endarterectomy (CEA). No significant change in the global baseline CBF before and after CEA was observed in the group as a whole (P = .81). In patients with reduced CBF prior to CEA (< 50 ml/100 g/min), a significant increase in global CBF following CEA was observed. An inverse relationship existed between percent change in CBF after CEA versus baseline CBF within the anterior circulation (r = -.78, P < .05) but not in the posterior distribution (r = .25, P = .63). CASL-pMRI may provide a convenient, inexpensive, noninvasive method for identifying CEA patients at risk for hyperperfusion following carotid revascularization.
Journal of Neuroimaging 04/2004; 14(2):133-8. · 1.51 Impact Factor
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ABSTRACT: Recent studies documenting the phenomenon of de novo neurogenesis within the adult brain have propelled this area of research to the forefront of neuroscience investigations and stroke pathogenesis and treatment. Traditional theories have suggested that the central nervous system is incapable of neural regeneration; hence the emergence of the field of stem cell biology as a discipline devoted to uncovering novel forms of neural repair. However, several recent experimental observations have shown that the adult brain is capable of ongoing neurogenesis in discrete regions of the uninjured brain and additional forms of endogenous neural regeneration in the presence of an inciting event (induction neurogenesis). Induction neurogenesis has the potential for providing new insights into the cause and treatment of acute stroke syndromes.
Neurosurgery 02/2004; 54(1):150-5; discussion 155-6. · 2.79 Impact Factor
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ABSTRACT: Ethmoidal dural arteriovenous fistulas (EDAFs) are an unusual type of intracranial vascular lesion that commonly present with acute hemorrhage. They are often best treated surgically; however, recent endovascular advances raise questions concerning the best therapeutic approach.
We present 7 cases of EDAFs managed at this institution over a 6-year period, which demonstrate the broad spectrum of clinical behavior associated with the lesions. Four patients presented with intracranial hemorrhage, 1 patient with rapidly progressive dementia, 1 patient with a proptotic, red eye, and 1 with a retro-orbital headache.
One patient underwent no treatment, 1 underwent embolization alone, 2 underwent embolization and resection, and 3 patients underwent resection alone. There was complete obliteration of the EDAF in all of the patients who underwent surgical resection. Embolization was performed through the external carotid circulation and not the ophthalmic artery. There were no treatment-related neurologic deficits.
Treatment is best managed with a multidisciplinary approach, which emphasizes complete resection of the lesions with assistance from interventional neuroradiology techniques. However, each patient must be evaluated independently as treatment may vary depending on the angioarchitecture of the lesion.
Surgical Neurology 01/2003; 58(6):410-6; discussion 416. · 1.67 Impact Factor
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ABSTRACT: Three-dimensional computed tomographic angiography (3-D-CTA) can be used to evaluate cerebrovascular disease. A potential limitation of this technology is obscuration of vascular anatomy by bone. In view of this, we developed a method for bone-free rendering using iterative relative fuzzy connectedness (IRFC) of 3-D-CTA to examine the cerebral vasculature without the intervening cranial base.
3-D-CTA was obtained in 10 patients with cerebrovascular disease by use of an algorithm based on IRFC. Bone structures were removed and vascular anatomy was isolated with an almost completely automated process. Bone-removed images were rendered via maximum intensity projections, compared with digital subtraction angiography, and evaluated for vascular abnormalities.
Compared with digital subtraction angiography, IRFC 3-D-CTA successfully defined the intracranial vascular anatomy in all 10 patients. An aneurysm was identified in 6 patients, bilateral carotid-cavernous fistulae in 1 patient, and no structural abnormalities in the remaining 3 patients.
In 3-D-CTA, our preliminary findings suggest that bone obscuration, one of the current limitations of CTA, can be overcome through appropriate computer algorithms. We are now working on improving the computational efficiency of these algorithms to allow routine use of IRFC 3-D-CTA in an interventional or surgical suite.
Neurosurgery 08/2002; 51(1):264-8; discussion 268-9. · 2.79 Impact Factor
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Journal of Neurosurgery 07/2002; 96(6):1160-1; author reply 1161. · 2.96 Impact Factor
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ABSTRACT: Despite the plenitude of reports concerning partial or complete third nerve palsies, especially as presenting symptoms with posterior communicating artery (PCoA) aneurysms, we present a patient with an unusual variation.
A 66-year-old woman presented with progressive right-sided headaches and diplopia and was found to have a partial, pupil-sparing third nerve palsy. A small right-sided PCoA aneurysm, nearly indistinguishable from an infundibulum, was identified on magnetic resonance angiography and subsequent digital subtraction angiography. The third nerve palsy improved before surgical repair of the aneurysm.
Microsurgical exploration revealed a small PCoA aneurysm, which was tethered to the third nerve by arachnoid adhesions. Adhesions were lysed and the aneurysm was repaired sparing the PCoA and its branches. The patient's third nerve function recovered completely postoperatively.
Even a very small PCoA aneurysm may present with an improving, pupil-sparing partial third nerve palsy. Selection of patients for imaging studies should take this unusual variant into consideration. We describe the anatomy and potential mechanisms of this pupil-sparing third nerve palsy.
Surgical Neurology 07/2002; 57(6):423-6; discussion 426-7. · 1.67 Impact Factor
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ABSTRACT: Thrombelastography is a useful technique for evaluating coagulability. We hypothesized that it could be used to determine postoperative hematologic complications during and after neurologic surgery.
Forty-six neurosurgical patients were stratified by diagnosis: subarachnoid hemorrhage from ruptured intracranially aneurysms, intracranial-axial lesions, intracranial-extra-axial lesions, and degenerative spine disease. Thromboelastograms were performed before, during, and after surgery. Hematologic data were collected preoperatively and postoperatively; computed tomography scans and lower extremity Doppler sonography were performed postoperatively. A thrombosis index (TI) was used to assess coagulability.
Coagulability increased over the course of surgery for all patients (p < 0.0001). In craniotomy patients, coagulability increased over the course of surgery (p < 0.05) with the most dramatic increase from intubation to skin incision (p < 0.05), and then after tumor removal or aneurysm clipping (p < 0.10). Univariate analysis among craniotomy patients showed that female gender (p < 0.0004) and smoking (p < 0.06) were associated with hypercoagulability. Among craniotomy patients, younger age was associated with hypercoagulability in the preoperative period (p < 0.01). There was no significant association between coagulability and aspirin or NSAID use, or intraoperative fluid volume. No patient developed a postoperative hematoma and one patient (2.2%) developed a lower extremity deep vein thrombosis.
Increased coagulability begins between induction of anesthesia and skin incision, and continues to increase throughout surgery. These changes are more pronounced in patients undergoing craniotomy compared to patients undergoing spine procedures.
Surgical Neurology 07/2002; 58(1):5-11; discussion 11-2. · 1.67 Impact Factor
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ABSTRACT: Endovascular microcoils are widely used in interventional procedures to treat cerebral aneurysms. In the present study we report for the first time successful use of an endovascular microcoil as a gene delivery system.
Anti-adenoviral monoclonal antibodies were covalently attached to the collagen-coated surface of either platinum or polyglycolic acid microcoils. These antibodies were used to tether replication-deficient adenovirus (Ad-GFP [encoding green fluorescent protein] or Ad-LacZ [encoding beta-galactosidase]). Cell culture studies with rat arterial smooth muscle cells (A10) assessed transduction on or near the coil. Platinum coils coated with Ad-GFP were implanted into the ligated common carotid artery (CCA) of adult rats in a model of arterial stasis and pressurization. After 7 days, CCA segments were harvested, and coils were removed for histopathology and GFP expression studies, while organs were evaluated by polymerase chain reaction to assess viral biodistribution.
In cell culture studies, GFP-positive smooth muscle cells were detected only on the platinum coil surface, while LacZ-positive cells were detected only on the polyglycolic acid coil surface, thus demonstrating localized gene delivery. After 7-day implantation, GFP (according to fluorescence microscopy and confirmed with immunohistochemistry) was detected on the harvested platinum coil and in the organizing thrombus within the CCA but not in the arterial wall. Morphometric analyses revealed that 13.3+2.0% of cells within the organized thrombus were transduced with Ad-GFP via the gene delivery system. However, arterial smooth muscle cells were negative for GFP according to fluorescence microscopy and immunohistochemistry. Ad-GFP was not detectable by polymerase chain reaction in lung, liver, or kidney.
It is concluded that catheter deployment of platinum or biodegradable gene delivery endovascular microcoils represents an interventional device-based gene therapy system that can serve as a suitable platform for either single or multiple gene therapy vectors.
Stroke 06/2002; 33(5):1376-82. · 5.73 Impact Factor
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ABSTRACT: A case of iatrogenic intramedullary contrast injection during a C1-C2 cervical myelography is reported.
To investigate the occurrence of iatrogenic intramedullary contrast injection during a current C1-C2 cervical myelography.
Intramedullary injection of contrast is a rare but serious complication of C1-C2 cervical myelography that has not been reported since the widespread use of magnetic resonance imaging and the NASCIS III study protocol.
A 39-year-old woman received an iatrogenic intramedullary contrast injection during a C1-C2 cervical myelography.
During the procedure the patient reported right-side face, neck, and arm pain and parethesias. After the procedure, right arm weakness and diffuse hyperreflexia developed. Postmyelography imaging demonstrated intramedullary contrast and cord swelling. High-dose methylprednisolone was administered intravenously and the patient's symptoms improved. The literature and management of this rare complication are reviewed.
Intramedullary cord injection is a rare complication of cervical myelography. The mechanism of spinal cord injury appears to involve a combination of physical compression from the injected liquid and neurotoxicity of the contrast material. Iohexol rather than metrizamide should be used when C1-C2 myelography is indicated in patients who are unable to undergo magnetic resonance imaging, or those whose pathology is inadequately demonstrated magnetic resonance imaging alone. In the event of contrast injection into the spinal cord, administration of high-dose methylprednisolone is recommended.
Spine 06/2002; 27(10):E274-7. · 2.08 Impact Factor
