Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man.

Peroxidase-containing cell bodies were found in the ipsilateral trigeminal ganglia after horseradish peroxidase was applied to the proximal segment of the middle cerebral artery in seven cats. Cell bodies containing the enzyme marker were located among clusters of cells that project via the first division. The existence of sensory pathways surrounding large cerebral arteries provides an important neuroanatomical explanation for the hemicranial distribution of headaches associated with certain strokes and migraine.

Stereotactic radiosurgery: a review and comparison of methods.

PURPOSE: Stereotactic radiosurgery (SRS) is an evolving modality for treating well-circumscribed intracranial lesions. Different physical methods have been developed to deliver highly localized dose distributions accurately. We review the different methods and the documented clinical results to present a coherent view of radiosurgery, and to aid physicians and physicists in the appropriate use of this modality. DESIGN: A review of the medical physics and clinical literature was conducted. The physical aspects of the different methods and their impact on treatment were summarized. Results were compiled from those individual clinical series with adequate follow-up data to compare the various modalities with respect to treatment outcome for benign tumors, metastases, and vascular malformations. RESULTS: The physical accuracy was comparable between radiosurgical methods. Differences between gamma radiation and linear accelerator methods had little effect on the dose distribution for single isocenter treatments. Charged particle methods could produce better dose localization for large lesions (> 25 cm3) than was possible with photon methods. Clinical results indicate similar lesion control rates between all radiosurgical methods. There was a progressive increase in the median size of treated lesions for gamma radiation, linear accelerator, and charged particle methods. CONCLUSION: For small lesions (< 5 cm3), physical dose distributions are similar for the photon methods, but linear accelerator methods offer more flexibility for the treatment of intermediate-sized (5 to 25 cm3) lesions in applying future technical developments. More clinical results are needed before firm conclusions can be drawn on the type of lesions to be treated, and the dose-volume parameters to be used.

Long-term durability of carotid endarterectomy for symptomatic stenosis and risk factors for late postoperative stroke.

BACKGROUND AND PURPOSE: Carotid endarterectomy (CEA) reduces the risk of stroke ipsilateral to recently symptomatic severe carotid stenosis. Other techniques such as percutaneous transluminal angioplasty with stenting are currently being compared with CEA. Thus far, case series and several small, randomized, controlled trials of CEA versus percutaneous transluminal angioplasty (with and without stenting) have focused primarily on the 30-day procedural risks of stroke and death. However, long-term durability is also important. To determine the long-term risk of stroke after CEA and to identify risk factors, we studied patients in the European Carotid Study Trial (ECST), the largest published cohort with long-term follow-up by physicians after CEA. METHODS: Risks of ipsilateral carotid territory ischemic stroke were calculated by Kaplan-Meier analysis starting on the 30th day after CEA in 1728 patients who underwent trial surgery. Risk factors were determined by Cox regression. For comparison, we also determined the "background" risk of stroke on medical treatment in the ECST in the territory of 558 previously asymptomatic contralateral carotid arteries with <30% angiographic stenosis (ECST method) at randomization. RESULTS: The risks of disabling ipsilateral ischemic stroke and any ipsilateral ischemic stroke were constant after CEA, reaching 4.4% [95% confidence interval (CI), 3.0 to 5.8] and 9.7% (95% CI, 7.6 to 11.7), respectively, by 10 years. The equivalent ischemic stroke risks distal to contralateral <30% asymptomatic carotid stenoses were 1.9% (95% CI, 0.8 to 3.2) and 4.5% (95% CI, 1.5 to 7.4). Presentation with cerebral symptoms, diabetes, elevated systolic blood pressure, smoking, male sex, increasing age, and a lesser severity of preoperative stenosis were associated with an increased risk of late stroke after CEA, but plaque morphology and patch grafting were not. CONCLUSIONS: Although the risk of late ipsilateral ischemic stroke after CEA for symptomatic stenosis is approximately double the background risk in the territory of <30% asymptomatic stenosis, it is still only approximately 1% per year and remains low for at least 10 years after CEA. This is the standard against which alternative treatments should be judged. Several risk factors may be useful in identifying patients at particularly high risk of late postoperative stroke.

Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hypothermia is effective in improving outcome in experimental models of brain infarction. We studied the feasibility and safety of hypothermia in patients with acute ischemic stroke treated with thrombolysis. METHODS: An open study design was used. All patients presented with major ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15) within 6 hours of onset. After informed consent, patients with a persistent NIHSS score of >8 were treated with hypothermia to 32+/-1 degrees C for 12 to 72 hours depending on vessel patency. All patients were monitored in the neurocritical care unit for complications. A modified Rankin Scale was measured at 90 days and compared with concurrent controls. RESULTS: Ten patients with a mean age of 71.1+/-14.3 years and an NIHSS score of 19.8+/-3.3 were treated with hypothermia. Nine patients served as concurrent controls. The mean time from symptom onset to thrombolysis was 3.1+/-1.4 hours and from symptom onset to initiation of hypothermia was 6.2+/-1.3 hours. The mean duration of hypothermia was 47.4+/-20.4 hours. Target temperature was achieved in 3.5+/-1.5 hours. Noncritical complications in hypothermia patients included bradycardia (n=5), ventricular ectopy (n=3), hypotension (n=3), melena (n=2), fever after rewarming (n=3), and infections (n=4). Four patients with chronic atrial fibrillation developed rapid ventricular rate, which was noncritical in 2 and critical in 2 patients. Three patients had myocardial infarctions without sequelae. There were 3 deaths in patients undergoing hypothermia. The mean modified Rankin Scale score at 3 months in hypothermia patients was 3.1+/-2.3. CONCLUSION: Induced hypothermia appears feasible and safe in patients with acute ischemic stroke even after thrombolysis. Refinements of the cooling process, optimal target temperature, duration of therapy, and, most important, clinical efficacy, require further study.

Lack of sympathetic and cholinergic influences on cerebral vasodilation caused by sciatic nerve stimulation in the rat.

We studied the influences of sympathetic and cholinergic mechanisms on pial arteriolar responses during cortical activation in the rat. Adult male Sprague-Dawley rats were anesthetized with alpha-chloralose and urethane and mechanically ventilated. Pial arterioles on the somatosensory cortex were visualized on a video monitor through a closed cranial window. Changes in arteriolar diameter induced by sciatic nerve stimulation (0.2 V, 5 Hz, 5 ms, for 20 s) were measured before and after (a) ipsilateral superior cervical ganglionectomy (n = 5), (b) intravenous (0.5 mg/kg) administration and topical (10(-5) M) application of atropine (n = 5), and (c) lesion of the nucleus basalis magnocellularis (the major source of intracerebral acetylcholine neurons, n = 7). Unilateral nucleus basalis magnocellularis lesions were performed stereotactically by injection of ibotenic acid (25 nmol/microliter). Sensory cortex cholinergic denervation was confirmed histologically. These treatments had no significant effect on arteriolar responses to sciatic nerve stimulation. Thus, the present results suggest that neither sympathetic nor cholinergic mechanisms play a significant role in somatosensory evoked cerebral vasodilation.

Trigeminal projections to supratentorial pial and dural blood vessels in cats demonstrated by horseradish peroxidase histochemistry.

Anatomical and clinical observations suggest that supratentorial vascular structures contain afferent projections from the trigeminal ganglia. To characterize this innervation, horseradish peroxidase (HRP) and HRP conjugated to wheat germ agglutinin were applied to the pial and dural arteries and sinuses of 33 cats. HRP was restricted to the site of interest by applying it dissolved in a viscous polymer, polyvinyl alcohol (PVA), to achieve slow release and minimize diffusion. The ganglia of cranial nerves V, VII, IX, and X and the superior cervical ganglia (SCGs) were examined bilaterally for the presence of retrogradely transported protein. Horseradish peroxidase applied to the proximal middle cerebral artery was located in cell bodies occupying the portion of the ipsilateral trigeminal ganglion corresponding to the ophthalmic division and throughout both SCGs. When the tracer was applied to the right anterior or posterior superior sagittal sinus, HRP-positive cells were present as above, predominantly in the ipsilateral trigeminal ganglia corresponding to the ophthalmic division and throughout both SCG. When applied to the right middle meningeal artery, HRP was observed within neurons of ipsilateral SCG and in the ophthalmic division of trigeminal ganglia; a few enzyme-containing cells were present in ipsilateral regions corresponding to the second and third divisions. These observations support the concept that supratentorial vascular structures receive afferent nervous projections from trigeminal neurons.

Advances in the genetics of cerebrovascular disease and stroke.

MEDLINE searches identified epidemiologic, experimental, and clinical studies on the genetics of cerebrovascular disease and stroke, including the following topics: genetic epidemiology of stroke; genetics of systemic disorders that cause ischemic stroke, including coagulation disorders, connective tissue disorders, vasculopathies, metabolic disorders, and disorders of unknown etiology; and genetics of systemic disorders that cause hemorrhagic stroke. Recent discoveries in stroke genetics involve the genetic basis of monogenic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and sickle cell disease. Reproducing similar advances in other forms of cerebrovascular disease and stroke will be more difficult because their inheritance is complex, multigenic, and heterogeneous. However, the future is promising with the application of molecular genetic approaches such as linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses as well as the transmission/disequilibrium test--a statistical method for detection of linkage between a marker and a disease-susceptibility locus.

Gamma radiation effect on vascular smooth muscle cells in culture.

PURPOSE: Prior work in our laboratory demonstrated that external gamma irradiation administered within 48 h following balloon catheter carotid artery injury in rats produced a marked inhibition of intimal hyperplasia and restenosis. The current study used smooth muscle cells (SMC) in vitro to examine the radiation dose response and to investigate the cellular mechanism by which radiation inhibits SMC proliferation. METHODS AND MATERIALS: Quiescent rat aortic SMC in plasma were refed with whole blood serum to stimulate synchronous proliferation and immediately irradiated with single fraction doses of 1.25-20 Gy. RESULTS: Comparison between a micronucleus assay and a clonogenic assay indicated a dose-dependent inhibition of SMC growth, with an ED50 at 2-3 Gy. The micronucleus assay also demonstrated a dose-dependent increase in apparent chromosomal damage at 72 h after irradiation. Inhibition of SMC growth by radiation did not correlate with changes in intracellular or released mitogenic activity. Furthermore, there was no evidence of apoptosis in irradiated SMC up to 96 h after treatment. CONCLUSION: Radiation likely inhibits SMC proliferation after arterial injury by a dose-dependent mechanism of lethal and/or sublethal cellular injury leading to clonogenic cell death.

The potential role of external beam radiation in preventing restenosis after coronary angioplasty.

The potential role of radiation in the prevention of coronary artery restenosis after angioplasty has generated much recent interest. Animal research and pilot clinical efforts have focused primarily on intraluminal methods of radiation delivery. This article reviews the experience to date with external beam radiation in restenosis prevention and suggests issues that should be considered from the standpoint of both external beam and intravascular radiotherapy. External beam radiation can certainly play an effective role in clinical studies of coronary artery restenosis, and a multicenter randomized trial of external beam radiation after coronary angioplasty has been initiated.

Inhibition of rat smooth muscle proliferation by radiation after arterial injury: temporal characteristics in vivo and in vitro.

Although several studies have suggested that inhibition of arterial narrowing by radiation after angioplasty is dependent on both time and dose, little is known regarding the temporal aspects of this effect and the mechanisms by which radiation affects the response of smooth muscle cells to injury. To determine the time course of inhibition of intimal hyperplasia by radiation, 135 rats were given single-fraction external gamma irradiation (1-10 Gy) to one carotid artery at intervals from 5 days before to 5 days after bilateral carotid artery balloon catheter injury, and intimal cross-sectional area was determined from histological sections at 20 days after injury. There was a prominent time- and dose-dependent inhibition of intimal hyperplasia by radiation when it was administered before or after balloon injury, with the greatest effect noted within 24 h before or after injury. To investigate the effect of radiation on smooth muscle cell growth (by cell counting) and proliferation, cell cycle kinetics (by BrdU incorporation), and cell killing (by clonogenic assay), smooth muscle cell cultures derived from rat aortic explants were seeded in equine plasma to induce quiescence, and radiation (2.5-10 Gy) was administered at various intervals before or after synchronous growth stimulation by 10% whole blood serum. A similar time and dose dependence was noted in growth kinetics, BrdU incorporation and cell killing for smooth muscle cells irradiated in vitro; in each case, the effect was most prominent for radiation administered in temporal proximity to stimulation with whole blood serum. By Western blot analysis, cultured smooth muscle cells showed a rapid time-dependent increase in Cdkn1a (formerly known as p21) protein expression, followed by a delayed increase in Tp53 (formerly known as p53) expression after irradiation. Activation of intracellular caspases, manifest by proteolytic poly(ADP-ribose) polymerase (PARP) cleavage, was not detected in smooth muscle cell cultures after irradiation. These observations suggest that radiation limits intimal hyperplasia in vivo by a transient, reversible process. Although apparent cytotoxic injury occurs in vitro, apoptosis of smooth muscle cells is not apparent. Both inhibition of proliferation of smooth muscle cells and cell cycle delay may contribute to inhibition of intimal hyperplasia in vivo by radiation.

Radiation inhibition of intimal hyperplasia after arterial injury.

To demonstrate the effect of gamma radiation on proliferating smooth muscle cells in vivo, a standardized bilateral carotid balloon catheter arterial injury was produced in 45 rats and doses from 0-20 Gy were delivered to the right carotid artery at 24 h after injury. At 20 days after injury, cross-sectional area of intima was determined from axial histological sections. Compared to contralateral, nonirradiated balloon-injured arteries, radiation produced a significant dose-dependent reduction in intimal cross-sectional area, with a 50% decrease at 5-7.5 Gy. To determine the effect of timing of irradiation on intimal hyperplasia, 30 rats with bilateral carotid injury received unilateral cervical irradiation at doses of 1, 5 or 10 Gy administered at either 1, 3 or 5 days after injury. The radiation dose (P = 0.0002), timing of irradiation (P = 0.003) and an interaction between timing and dose (P = 0.0278) were significantly associated with reduction in neointimal cross-sectional area. To determine the effects of radiation on intimal hyperplasia at later intervals, rats irradiated with 15 (n = 5) or 20 Gy (n = 5) were euthanized at 3 months after injury. A significant persistent reduction in intimal cross-sectional area for irradiated arteries at 3 months was associated with minimal apparent radiation effects upon adjacent tissue. These data suggest that external gamma irradiation at the single doses used effectively inhibits smooth muscle proliferation and intimal hyperplasia in the rat balloon catheter injury model in a time- and dose-dependent manner.

Induction of a senescence-like phenotype in bovine aortic endothelial cells by ionizing radiation.

Treatment of confluent monolayers of bovine aortic endothelial cells (BAEC) with gamma rays resulted in the delayed appearance of cells with an enlarged surface area that were morphologically similar to senescent cells. The majority of these cells stained positively for senescence-associated beta-galactosidase (SA-beta-gal), indicating that these cells are biochemically similar to senescent cells. The incidence of the senescence-like phenotype increased with dose (5-15 Gy) and time after irradiation. Cells with a senescence-like phenotype began to appear in the monolayer several days after irradiation. The onset of the appearance of this phenotype was accelerated by subculturing 24 h after irradiation. This acceleration was not entirely due to stimulation of progression through the cell cycle, since a high percentage of the senescent-like cells that appeared after subculture were not labeled with BrdUrd during the period after subculture. Prolonged up-regulation of expression of CDKN1A (also known as p21(CIP1/WAF1)) after irradiation was noted by Western blot analysis, again suggesting a similarity to natural senescence. Phenotypically altered endothelial cells were present in the irradiated monolayers as long as 20 weeks after irradiation, suggesting that a subpopulation of altered endothelial cells that might be functionally deficient could persist in the vasculature of irradiated tissue for a prolonged period after irradiation.

Reduction of free water clearance with cephalic venous hypertension.

A laboratory model was developed in the dog to quantitate the effects of cerebral venous hypertension on inappropriate antidiuretic hormone (ADH) secretion. When cerebral venous pressure was abruptly increased during continuous water loading, there was a sharp rise in urine osmolality within 30 minutes. Urine osmolality continued to increase during, and ten minutes after, the period of hypertension. On lowering cerebral venous pressure, the osmolality returned to baseline within 60 minutes. The effects could be extended for at least three hours and presumably longer. A 50% response threshold for this ADH effect occurred at a cerebral venous pressure between 18 and 19 cm of water. The effect correlated with plasma ADH levels. The study paralled documented clinical observations. The results are discussed in light of the recognition and management of surgical states where increased cerebral venous pressure might produce a severe antidiuretic effect.

Serum S-100beta as a possible marker of blood-brain barrier disruption.

Two brain-specific proteins, S-100beta and neuron-specific enolase (NSE), are released systemically after cerebral lesions, but S-100beta levels sometimes rise in the absence of neuronal damage. We hypothesized that S-100beta is a marker of blood-brain barrier (BBB) leakage rather than of neuronal damage. We measured both proteins in the plasma of patients undergoing iatrogenic BBB disruption with mannitol, followed by chemotherapy. Serum S-100beta increased significantly after mannitol infusion (P<0.05) while NSE did not. This suggests that S-100beta is an early marker of BBB opening that is not necessarily related to neuronal damage.

Mechanisms of glucose transport at the blood-brain barrier: an in vitro study.

How the brain meets its continuous high metabolic demand in light of varying plasma glucose levels and a functional blood-brain barrier (BBB) is poorly understood. GLUT-1, found in high density at the BBB appears to maintain the continuous shuttling of glucose across the blood-brain barrier irrespective of the plasma concentration. We examined the process of glucose transport across a quasi-physiological in vitro blood-brain barrier model. Radiolabeled tracer permeability studies revealed a concentration ratio of abluminal to luminal glucose in this blood-brain barrier model of approximately 0.85. Under conditions where [glucose](lumen) was higher than [glucose](ablumen), influx of radiolabeled 2-deoxyglucose from lumen to the abluminal compartment was approximately 35% higher than efflux from the abluminal side to the lumen. However, when compartmental [glucose] were maintained equal, a reversal of this trend was seen (approximately 19% higher efflux towards the lumen), favoring establishment of a luminal to abluminal concentration gradient. Immunocytochemical experiments revealed that in addition to segregation of GLUT-1 (luminal>abluminal), the intracellular enzyme hexokinase was also asymmetrically distributed (abluminal>luminal). We conclude that glucose transport at the CNS/blood interface appears to be dependent on and regulated by a serial chain of membrane-bound and intracellular transporters and enzymes.

Perivascular delivery of heparin for the reduction of smooth muscle cell proliferation after endothelial injury.

Thin flexible sheets composed of poly(lactic acid) (PLA) laminated polyanhydride, poly(erucic acid dimer-sebacic anhydride) (P(EAD-SA)), loaded with heparin were evaluated in vitro and in vivo. PLA was used for coating the polyanhydride to improve the release profile and improve the strength of the films. Heparin was released constantly for 20 days from PLA-coated 2% loaded P(EAD-SA). The uncoated film of P(EAD-SA) released heparin for only 4 days. The localized delivery of heparin around the carotid artery was investigated by implanting polymer loaded with [3H]heparin around the carotid artery of rats and the heparin release and tissue distribution was monitored. The maximum heparin concentration in the artery exposed to the drug was on day 4 for the P(EAD-SA) uncoated device (fast releasing system) and day 11 for the coated devices. The control artery, the uncovered segments of the artery, and the surrounding tissue contained negligible amounts of radioactivity. These data confirm that heparin was delivered locally without systemic exposure. Two independent animal studies were conducted to evaluate the effectiveness of these heparin-releasing devices. In both studies the balloon catheter injury in a rat model was used. After inflicting an injury to the common carotid, a matrix oriented with its long axis along the artery was placed under the injured portion of the vessel. In both studies the treated rats showed a very thin layer of neointima where the control group showed a significant reduction of the artery internal diameter with SMC neointima ratio greater than 1.

Effects of irradiation geometry on treatment plan optimization with linac-based radiosurgery.

A comparison was made of different treatment plans to determine the effect on the three-dimensional dose distributions of varying the allowed parameters in linac-based stereotactic radiosurgery with circular collimators; these parameters are arc position, length, and weighting, and collimator diameter. For the class of eccentrically shaped target volumes that are not so irregular as to require several separate isocenters, it was found that superior dose distributions could be achieved by varying arc length, arc position, arc weighting, and collimator diameter. An analysis of the results achieved with an automated planning program indicates that, in general, the variables of arc position and arc length are of greater importance than collimator size or beam weighting. However, there are cases where varying these latter two parameters does result in markedly better dose distributions. A deeper investigation into the effects of multiple collimators on the dose distribution in the area of steepest gradient demonstrated that multiple collimator sizes do not significantly degrade the dose falloff, which is in fact mostly determined by the effects of intersecting arcs.

Risks of anticoagulation therapy after experimental corticectomy in the rat.

To determine the optimal postoperative interval after which heparin therapy can be safely initiated, a rat model for experimental craniotomy and corticectomy was developed. In 50 rats (100 lesions), heparin therapy was initiated 1, 2, 3, 5, or 7 days after standardized bilateral frontal corticectomy and was continued for 7 days. Intraperitoneally administered heparin, 75 to 100 U/kg.h, was continuously given to maintain the activated partial thromboplastin time in one of two ranges: therapeutic (1.5-3 times control) or supratherapeutic (> 3 times control). The size of intracranial hemorrhage was determined from coronal brain sections by automated image analysis. No significant hemorrhage was observed in control (saline infusion) animals or in rats receiving therapeutic doses of heparin beginning more than 24 hours after surgery. Small (10-50 mm3) and large (> 50 mm3) hemorrhages were frequent at all intervals up to 5 days in animals with supratherapeutic activated partial thromboplastin time (P < 0.01). Judicious heparin therapy may be safely initiated at 48 hours after craniotomy and corticectomy in rats, whereas supratherapeutic anticoagulation is associated with intracranial hemorrhage at intervals of up to 5 days.

Localized release of perivascular heparin inhibits intimal proliferation after endothelial injury without systemic anticoagulation.

Segmental endothelial desquamation of the common carotid artery was produced in 30 rats using a balloon catheter technique which produces consistent proliferation of intimal smooth muscle cells from 5 to 20 days after injury. Immediately after endothelial injury, 15 animals were treated with periadventitial application of heparin contained in a continuous-release drug-delivery system using the polymer polyvinyl alcohol (PVA) and PVA alone applied in a similar fashion to 15 control rats. Animals were killed at 5, 10 and 20 days, respectively, after surgery by intracardiac perfusion-fixation, and vessels were prepared for light microscopy, scanning electron microscopy, and immunohistochemistry with antibodies directed against actin. At all time periods, there was a significant reduction in intimal cross-sectional area in heparin/PVA-treated vessels compared to control vessels. Scanning electron microscopy showed complete absence of endothelial cells from the luminal surface in both control and treated arteries at all time periods without evidence of significant platelet aggregation. Immunohistochemistry demonstrated the presence of immunoreactive actin in the proliferating myointimal cells. Femoral venous prothrombin time and partial thromboplastin time were unchanged in heparin/PVA-treated animals compared to controls at 1, 5, and 10 days. Continuous-release polymer drug delivery can be used to apply heparin selectively to the adventitial surface of vessels and effect changes in the vessel wall over periods of up to 3 weeks. By this means, smooth muscle proliferation and subsequent vessel narrowing after endothelial injury were inhibited without systemic anticoagulation. This technique may be applicable to both clinical and research applications related to the pathophysiology of arterial injury.

Progressive aneurysmal degeneration of cortical venous drainage of dural arteriovenous malformations: case report.

OBJECTIVE AND IMPORTANCE: The development of a venous aneurysm associated with dural arteriovenous malformations rarely has been documented in the literature. CLINICAL PRESENTATION: A 64-year-old man with known dural arteriovenous malformations developed a venous aneurysms, as shown on sequential angiograms obtained during 2 years. INTERVENTION: The dural arteriovenous malformations were treated with neuroendovascular embolization and then surgical excision. CONCLUSION: The clinical presentation, diagnosis, and treatment of this unusual case are presented.