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Ryszard M. Pluta, John A. Butman, Bawarjan Schatlo, Dennis L. Johnson and Edward H. Oldfield

Object

Investigators in experimental and clinical studies have used the intrathecal route to deliver drugs to prevent or treat vasospasm. However, a clot near an artery or arteries after subarachnoid hemorrhage (SAH) may hamper distribution and limit the effects of intrathecally delivered compounds. In a primate model of right middle cerebral artery (MCA) SAH, the authors examined the distribution of Isovue-M 300 and 3% Evans blue after infusion into the cisterna magna CSF.

Methods

Ten cynomolgus monkeys were assigned to SAH and sham SAH surgery groups (5 in each group). Monkeys received CSF injections as long as 28 days after SAH and were killed 3 hours after the contrast/Evans blue injection. The authors assessed the distribution of contrast material on serial CT within 2 hours after contrast injection and during autopsy within 3 hours after Evans blue staining.

Results

Computed tomography cisternographies showed no contrast in the vicinity of the right MCA (p < 0.05 compared with left); the distribution of contrast surrounding the entire right cerebral hemisphere was substantially reduced. Postmortem analysis demonstrated much less Evans blue staining of the right hemisphere surface compared with the left. Furthermore, the Evans blue dye did not penetrate into the right sylvian fissure, which occurred surrounding the left MCA. The authors observed the same pattern of changes and differences in contrast distribution between SAH and sham SAH animals and between the right and the left hemispheres on Days 1, 3, 7, 14, 21, and 28 after SAH.

Conclusions

Intrathecal drug distribution is substantially limited by SAH. Thus, when using intrathecal drug delivery after SAH, vasoactive drugs are unlikely to reach the arteries that are at the highest risk of delayed cerebral vasospasm.

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Carla S. Jung, Edward H. Oldfield, Judith Harvey-White, Michael G. Espey, Michael Zimmermann, Volker Seifert and Ryszard M. Pluta

Object

Delayed cerebral vasospasm after subarachnoid hemorrhage (SAH) may be evoked by the decreased availability of nitric oxide (NO). Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of NO synthase (NOS), have been associated with the course and degree of cerebral vasospasm in a primate model of SAH. In this study, the authors sought to determine if similar changes in CSF ADMA levels are observed in patients with SAH, and whether these changes are associated with NO and NOS metabolite levels in the CSF and the presence of cerebral vasospasm.

Methods

Asymmetric dimethyl-l-arginine, l-arginine, l-citrulline, and nitrite levels were measured in CSF and serum samples collected during the 21-day period after a single aneurysmal SAH in 18 consecutive patients. Samples were also obtained in a control group consisting of seven patients with Chiari malformation Type I and five patients with spontaneous intracerebral hemorrhage without SAH. Vasospasm, defined as a greater than 11% reduction in the anterior circulation vessel diameter ratio compared with the ratio calculated from the initial arteriogram, was assessed on cerebral arteriography performed around Day 7.

Results

In 13 patients with SAH, arteriographic cerebral vasospasm developed. Cerebrospinal fluid ADMA levels in patients with SAH were higher than in those in the control group (p < 0.001). The CSF ADMA level remained unchanged in the five patients with SAH without vasospasm, but was significantly increased in patients with vasospasm after Day 3 (6.2 ± 1.7 μM) peaking during Days 7 through 9 (13.3 ± 6.7 μM; p < 0.001) and then gradually decreasing between Days 12 and 21 (8.8 ± 3.2 μM; p < 0.05). Nitrite levels in the CSF were lower in patients with vasospasm compared to patients without vasospasm (p < 0.03). Cerebrospinal fluid ADMA levels positively correlated with the degree of vasospasm (correlation coefficient [CC] = 0.88, p = 0.0001; 95% confidence interval [CI] 0.74–0.95) and negatively correlated with CSF nitrite levels (CC = −0.55; p = 0.017; 95% CI −0.81 to −0.12).

Conclusions

These results support the hypothesis that ADMA is involved in the progression of cerebral vasospasm. Asymmetric dimethyl-l-arginine and its metabolizing enzymes may be a future target for treatment of cerebral vasospasm after SAH.

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Ryszard M. Pluta, Carla S. Jung, Judith Harvey-White, Anne Whitehead, Sabrina Shilad, Michael G. Espey and Edward H. Oldfield

Object. Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl l-arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), are associated with delayed vasospasm after subarachnoid hemorrhage (SAH); however, the source, cellular mechanisms, and pharmacological inhibition of ADMA production following SAH are unknown.

Methods. In an in vitro experiment involving human umbilical vein endothelial cells (HUVECs), the authors examined mechanisms potentially responsible for increased ADMA levels during vasospasm and investigated whether this increase can be inhibited pharmacologically. In a second study, an in vivo experiment, the authors used probucol, which effectively inhibited ADMA increase in HUVEC cultures in vitro, in a randomized double-blind placebo-controlled experiment in a primate model of delayed cerebral vasospasm after SAH.

Oxidized low-density lipids (OxLDLs; positive control; p < 0.02) and bilirubin oxidation products (BOXes; p < 0.01), but not oxyhemoglobin (p = 0.74), increased ADMA levels in HUVECs. Probucol inhibited changes in ADMA levels evoked by either OxLDLs (p < 0.001) or BOXes (p < 0.01). Comparable changes were observed in cell lysates. In vivo probucol (100 mg/kg by mouth daily) did not alter serum ADMA levels on Days 7, 14, and 21 after SAH compared with levels before SAH, and these levels were not different from those observed in the placebo group (p = 0.3). Despite achieving therapeutic levels in plasma and measurable levels in CSF, probucol neither prevented increased CSF ADMA levels nor the development of vasospasm after SAH. Increased CSF ADMA and decreased nitrite levels in both groups were strongly associated with the degree of delayed vasospasm after SAH (correlation coefficient [CC] 0.5, 95% confidence interval [CI] 0.19–0.72, p < 0.002 and CC −0.43, 95% CI −0.7 to < 0.05, p < 0.03, respectively).

Conclusions. Bilirubin oxidation products, but not oxyhemoglobin, increased ADMA levels in the HUVEC. Despite its in vitro ability to lower ADMA levels, probucol failed to inhibit increased CSF ADMA and decreased nitrite levels, and it did not prevent delayed vasospasm in a primate SAH model.

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Carla S. Jung, Brian A. Iuliano, Judith Harvey-White, Michael G. Espey, Edward H. Oldfield and Ryszard M. Pluta

Object. Decreased availability of nitric oxide (NO) has been proposed to evoke delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). Asymmetric dimethyl-l-arginine (ADMA) inhibits endothelial NO synthase (eNOS) and, therefore, may be responsible for decreased NO availability in cases of cerebral vasospasm. The goal of this study was to determine whether ADMA levels are associated with cerebral vasospasm in a primate model of SAH.

Methods. Twenty-two cynomolgus monkeys (six control animals and 16 with SAH) were used in this study. The levels of ADMA, l-arginine, l-citrulline, nitrites, and nitrates in cerebrospinal fluid (CSF) and serum were determined on Days 0, 7, 14, and 21 following onset of SAH. Cerebral arteriography was performed to assess the degree of vasospasm. Western blot analyses of the right and left middle cerebral arteries (MCAs) were performed to assess the expression of eNOS, type I protein—arginine methyl transferase (PRMT1) and dimethylarginine dimethylaminohydrolase (DDAH2).

Cerebrospinal fluid levels of ADMA remained unchanged in the control group (six animals) and in animals with SAH that did not have vasospasm (five animals; p = 0.17), but the levels increased in animals with vasospasm (11 animals) on Day 7 post-SAH (p < 0.01) and decreased on Days 14 through 21 (p < 0.05). Cerebrospinal fluid levels of ADMA correlated directly with the degree of vasospasm (correlation coefficient = 0.7, p = 0.0001; 95% confidence interval: 0.43–0.83). Levels of nitrite and nitrate as well as those of l-citrulline in CSF were decreased in animals with vasospasm. Furthermore, DDAH2 expression was attenuated in the right spastic MCA on Day 7 post-SAH, whereas eNOS and PRMT1 expression remained unchanged.

Conclusions. Changes in the CSF levels of ADMA are associated with the development and resolution of vasospasm found on arteriograms after SAH. The results indicate that endogenous inhibition of eNOS by ADMA may be involved in the development of delayed cerebral vasospasm. Inhibition of ADMA production may provide a new therapeutic approach for cerebral vasospasm after SAH.

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Brian A. Iuliano, Ryszard M. Pluta, Carla Jung and Edward H. Oldfield

Object

Although abnormalities in the control of endothelial vasomotility have been reported in both experimental and clinical studies, the mechanism of the endothelial dysfunction that occurs following subarachnoid hemorrhage (SAH) remains unclear. Because of the absence of previous in vivo studies of endothelial function in cerebral vessels in response to SAH or cerebral vasospasm, the authors investigated endothelium—dependent responses in an established primate model of vasospasm after SAH. Endothelial function was assessed by examining vascular responses to intracarotid injections of various drugs known to act via the endothelium. Drugs that have a rapid total body clearance were selected so that their pharmacological effects would be limited to the cerebral circulation after an intracarotid infusion.

Methods

Seventeen adult male cynomolgus monkeys were used. Cerebrovascular endothelium—dependent responses were examined in control animals and in animals with SAH 7, 14, and 21 days after placement of a subarachnoid clot around the right middle cerebral artery. Cortical cerebral blood flow (CBF) and cerebrovascular resistance (CVR) were recorded continuously during 5-minute intracarotid infusions of 5% dextrose vehicle, acetylcholine, histamine, bradykinin, or Calcimycin.

In control animals the intracarotid infusion of acetylcholine produced a significant (7.8 ± 9.5%) increase in CBF and a 9.3 ± 8.7% reduction in CVR in comparison with a control infusion of dextrose vehicle. The responses to acetylcholine disappeared in animals 7 days post-SAH, specifically in the subset of animals in which arteriography confirmed the presence of vasospasm. Infusion of Calcimycin produced no significant changes in CBF or CVR in control animals, but resulted in a significant reduction in CBF and increase in CVR in animals 7 days after SAH and in animals with vasospasm. An infusion of histamine or bradykinin had no significant effect on CBF or CVR.

Conclusions

An intracarotid infusion of acetylcholine, but not one of histamine, bradykinin, or Calcimycin, produced a measurable physiological response in the normal primate cerebrovasculature. Cerebral vasospasm that occurred after SAH produced a pathophysiological effect similar to the endothelial denudation shown in the in vitro experiments of Furchgott and Zawadzki, in which acetylcholine constricted the vessels via activation of receptors on smooth-muscle cells. Changes in vascular responses to acetylcholine and Calcimycin in animals with vasospasm, compared with control animals, provide evidence that endothelial dysfunction plays a key role in the development and/or sustenance of vasospasm after SAH.

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Astrid Weyerbrock, Stuart Walbridge, Ryszard M. Pluta, Joseph E. Saavedra, Larry K. Keefer and Edward H. Oldfield

Object. The response of brain tumors to systemic chemotherapy is limited by the blood—tumor barrier (BTB). Nitric oxide (NO) has been implicated in the regulation of vascular permeability and blood flow. The authors evaluated the effects of exogenous NO, which was released from a short-acting NO donor (Proli/NO), and those of NO metabolites on the capillary permeability of tumors and normal brain tissue by using quantitative autoradiography in a C6 glioma model in rats.

Methods. The Proli/NO was infused at a wide dose range (10−2 to 10−12 M) either intravenously or into the internal carotid artery (ICA) and demonstrated substantial tumor-selective increases in blood-brain barrier (BBB) permeability in response to various-sized tracers ([14C]aminoisobutyric acid, [14C]sucrose, [14C]dextran). Internal carotid artery or intravenous administration of sodium nitrite had a comparable effect on BTB permeability. The NO effect on microvascular permeability could be obtained without causing hemodynamic side effects. The effect of NO on the efficacy of carboplatin chemotherapy was investigated in intracerebral C6 gliomas. Simultaneous intravenous infusions of Proli/NO (10−6 M) and carboplatin (20 mg/kg) led to long-term survival in 40% of rats harboring intracerebral C6 gliomas compared with control animals receiving ICA or intravenous infusions of carboplatin, Proli/NO, or vehicle alone. No residual tumor was demonstrated on histological or magnetic resonance imaging studies performed in rats treated with Proli/NO and carboplatin, and no toxicity was observed.

Conclusions. This new approach demonstrated the in vivo efficacy and safety of NO and nitrite in enhancing the delivery of systemically delivered radiolabeled tracers and carboplatin into rat gliomas. The NO-induced tumor-selective BBB disruption and intravenous carboplatin chemotherapy may be more efficacious than current chemotherapy strategies against brain tumors.

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Ryszard M. Pluta, Scott D. Wait, John A. Butman, Kathleen A. Leppig, Alexander O. Vortmeyer, Edward H. Oldfield and Russell R. Lonser

Hemangioblastomas are histologically benign neoplasms that occur sporadically or as part of von Hippel–Lindau disease. Hemangioblastomas may occur anywhere along the neuraxis, but sacral hemangioblastomas are extremely rare. To identify features that will help guide the operative and clinical management of these lesions, the authors describe the management of a large von Hippel–Lindau disease–associated sacral hemangioblastoma and review the literature.

The authors present the case of a 38-year-old woman with von Hippel–Lindau disease and a 10-year history of progressive back pain, as well as left lower-extremity pain and numbness. Neurological examination revealed decreased sensation in the left S-1 and S-2 dermatomes. Magnetic resonance imaging demonstrated a large enhancing lesion in the sacral region, with associated erosion of the sacrum. The patient underwent arteriography and embolization of the tumor and then resection. The histopathological diagnosis was consistent with hemangioblastoma and showed intrafascicular tumor infiltration of the S-2 nerve root. At 1-year follow-up examination, pain had resolved and numbness improved.

Sacral nerve root hemangioblastomas may be safely removed in most patients, resulting in stabilization or improvement in symptomatology. Generally, hemangioblastomas of the sacral nerve roots should be removed when they cause symptoms. Because they originate from the nerve root, the nerve root from which the hemangioblastoma originates must be sacrificed to achieve complete resection.

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Ryszard M. Pluta, Brian Iuliano, Hetty L. Devroom, Tung Nguyen and Edward H. Oldfield

Object. Von Hippel—Lindau (VHL) disease is an autosomal-dominant neoplastic syndrome with manifestations in multiple organs, which is evoked by the deletion or mutation of a tumor suppressor gene on chromosome 3p25. Spinal hemangioblastomas (40% of VHL disease—associated lesions of the central nervous system) arise predominantly in the posterior aspect of the spinal cord and are often associated with an intraspinal cyst. Rarely, the tumor develops in the anterior aspect of the spinal cord. Ventral spinal hemangioblastomas are a surgical challenge because of difficult access and because vessels feeding the tumor originate from the anterior spinal artery.

The goal of this study was to clarify whether an anterior or posterior surgical approach is better for management of hemangioblastomas of the ventral spinal cord.

Methods. The authors performed a retrospective analysis of clinical outcomes and findings on magnetic resonance (MR) imaging studies in eight patients (two women and six men with a mean age of 34 ± 15 years) who underwent resection of ventral spinal hemangioblastomas (nine tumors: five cervical and four thoracic). Two surgical approaches were used to resect these tumors. A posterior approach was selected to treat five patients (laminectomy and posterior myelotomy in four patients and the posterolateral approach in one patient); an anterior approach (corpectomy and arthrodesis) was selected to treat the remaining three patients.

Immediately after surgery, the ability to ambulate remained unchanged in patients in whom an anterior approach had been performed, but deteriorated significantly in patients in whom a posterior approach had been used, because of motor weakness (four of five patients) and/or proprioceptive sensory loss (three of five patients). This difference in ambulation, despite significant improvements over time among patients in the posterior access group, remained significant 6 months after surgery. In all cases, MR images revealed complete resection of the tumor and in five patients significant or complete resolution of the intramedullary cyst was demonstrated (present in six of eight patients).

Conclusions. The outcomes of these eight patients with hemangioblastomas of the ventral spinal cord indicate that both immediate and long-term results are better when an anterior approach is selected for resection.

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Joseph C. Watson, Alexander M. Gorbach, Ryszard M. Pluta, Ramin Rak, John D. Heiss and Edward H. Oldfield

Object. Application of sensitive infrared imaging is ideally suited to observe blood vessels and blood flow in exposed organs, including the brain. Temporary vascular occlusion is an important part of neurosurgery, but the capacity to monitor the effects of these occlusions in real time is limited. In surgical procedures that require vascular manipulation, such as those involving aneurysms, arteriovenous malformations (AVMs), or tumors, the ability to visualize blood flow in vessels and their distribution beds would be beneficial. The authors recount their experience in the use of a sensitive (0.02°C), high-resolution (up to 50 µm/pixel) infrared camera with a rapid shutter speed (up to 2 msec/frame) for localizing cortical function intraoperatively. They observed high-resolution images of cerebral arteries and veins.

The authors hypothesized that infrared imaging of cerebral arteries, performed using a sensitive, high-resolution camera during surgery, would permit changes in arterial flow to be be seen immediately, thus providing real-time assessment of brain perfusion in the involved vascular territory.

Methods. Cynomolgus monkeys underwent extensive craniectomies, exposing the frontal, parietal, and temporal lobes. Temporary occlusions of the internal carotid artery and middle cerebral artery branches (30 events) were performed serially and were visualized with the aid of an infrared camera.

Arteries and veins of the monkey brain were clearly visualized due to cooling of the exposed brain, which contrasted with blood within the vessels that remained at core temperature. Blood flow changes in vessels were seen immediately (< 1 second) in real time during occlusion and reopening of the vessels, regardless of the duration of the occlusion. Areas of decreased cortical blood flow rapidly cooled (−0.3 to 1.3°C) and reheated in response to reperfusion. Rewarming occurred faster in arteries than in the cortex (for a 20-minute occlusion, the change in temperature per second was 2 × 10−2°C in the artery and 7 × 10−3°C in the brain). Collateral flow could be evaluated by intraoperative observations and data processing.

Conclusions. Use of high-resolution, digital infrared imaging permits real-time visualization of arterial flow. It has the potential to provide the surgeon with a means to assess collateral flow during temporary vessel occlusion and to visualize directly the flow in parent arteries or persistent filling of an aneurysm after clipping. During surgery for AVMs, the technique may provide a new way to assess arterial inflow, venous outflow, results of embolization, collateral flow, steal, and normal perfusion pressure breakthrough.

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R. Bryan Mason, Ryszard M. Pluta, Stuart Walbridge, David A. Wink, Edward H. Oldfield and Robert J. Boock

Object. Thrombolytic treatments for ischemic stroke can restore circulation, but reperfusion injury, mediated by oxygen free radicals, can limit their utility. The authors hypothesized that, during reperfusion, nitric oxide (NO) provides cytoprotection against oxygen free radical species.

Methods. Levels of NO and oxygen free radicals were determined in both reoxygenation in vitro and reperfusion in vivo models using an NO electrochemical probe and high-performance liquid chromatography with the 2,3- and 2,5-dihydroxybenzoic acid trapping method, before and after addition of the NO donor diethanolamine nitric oxide (DEA/NO).

Reoxygenation after anoxia produced a twofold increase in NO release by human fetal astrocytes and cerebral endothelial cells (p < 0.005). In both cell lines, there was also a two- to threefold increase in oxygen free radical production (p < 0.005). In human fetal astrocytes and cerebral endothelial cells given a single dose of DEA/NO, free radical production dropped fivefold compared with peak ischemic levels (p < 0.001). In a study in which a rat global cerebral ischemia model was used, NO production in a vehicle-treated group increased 48 ± 16% above baseline levels after reperfusion. After intravenous DEA/NO infusion, NO reached 1.6 times the concentration of the postischemic peak in vehicle-treated animals. In vehicle-treated animals during reperfusion, free radical production increased 4.5-fold over basal levels (p < 0.01). After intravenous DEA/NO infusion, free radical production dropped nearly 10-fold compared with peak levels in vehicle-treated animals (p < 0.006). The infarct volume in the vehicle-treated animals was 111 ± 16.9 mm3; after DEA/NO infusion it was 64.8 ± 23.4 mm3 (p < 0.01).

Conclusions. The beneficial effect of early restoration of cerebral circulation after cerebral ischemia is limited by reperfusion injury. These results indicate that NO release and oxygen free radical production increase during reperfusion, and suggest a possible early treatment of reperfusion injury using NO donors.