Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis.

BACKGROUND: Endarterectomy reduces risk of stroke in certain patients with recently symptomatic internal carotid stenosis. However, investigators have made different recommendations about the degree of stenosis above which surgery is effective, partly because of differences between trials in the methods of measurement of stenosis. To accurately assess the overall effect of surgery, and to increase power for secondary analyses, we pooled trial data and reassessed carotid angiograms. METHODS: We pooled data from the European Carotid Surgery Trial (ECST), North American Symptomatic Carotid Endarterectomy Trial, and Veterans Affairs trial 309 from the original electronic data files. Outcome events were re-defined, if necessary, to achieve comparability. Pre-randomisation carotid angiograms from ECST were re-measured by the method used in the other two trials. RESULTS: Risks of main outcomes in both treatment groups and effects of surgery did not differ between trials. Data for 6092 patients, with 35000 patient-years of follow-up, were therefore pooled. Surgery increased the 5-year risk of ipsilateral ischaemic stroke in patients with less than 30% stenosis (n=1746, absolute risk reduction -2.2%, p=0.05), had no effect in patients with 30-49% stenosis (1429, 3.2%, p=0.6), was of marginal benefit in those with 50-69% stenosis (1549, 4.6%, p=0.04), and was highly beneficial in those with 70% stenosis or greater without near-occlusion (1095, 16.0%, p<0.001). There was a trend towards benefit from surgery in patients with near-occlusion at 2 years' follow-up (262, 5.6%, p=0.19), but no benefit at 5 years (-1.7%, p=0.9). INTERPRETATION: Re-analysis of the trials with the same measurements and definitions yielded highly consistent results. Surgery is of some benefit for patients with 50-69% symptomatic stenosis, and highly beneficial for those with 70% symptomatic stenosis or greater but without near-occlusion. Benefit in patients with carotid near-occlusion is marginal in the short-term and uncertain in the long-term.

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.

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.

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.

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.

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.

Expression of endothelial nitric oxide synthase after exposure to perivascular blood.

OBJECTIVE: Although nitric oxide (NO) has been implicated in the development of vasospasm after subarachnoid hemorrhage, little is known regarding the time course of NO synthesis in vessel wall after exposure to perivascular blood. This study measures temporal characteristics of changes in vessel wall NO synthesis. METHODS: Rat femoral arteries exposed to perivascular blood for 3, 5, or 7 days were assayed for the endothelial isoform of NO synthase (eNOS) by Western blot testing. Additionally, rat femoral arteries exposed to perivascular blood for intervals from 3 to 14 days were analyzed by means of immunohistochemistry for eNOS. RESULTS: Semiquantitative densitometry of femoral artery Western blots demonstrated a biphasic pattern of eNOS expression after exposure to perivascular blood. Compared with control arteries, eNOS expression increased at 3 days (53 +/- 36%), normalized at 5 days (-6 +/- 7%), and decreased by 7 days (-39 +/- 15%). Immunohistochemistry confirmed the changes in expression of immunoreactive eNOS in femoral endothelium during the first week after chronic perivascular blood exposure and apparent reduced eNOS immunostaining, which persisted up to 14 days after application of blood. CONCLUSION: The expression of endothelial-derived NO in rat femoral artery exposed to perivascular whole blood does not directly correlate with changes in vessel caliber during this interval. The biphasic expression of eNOS observed in these experiments highlights the complexity of processes occurring in the vicinity of the vessel wall during vasospasm and may be related to several mechanisms that modulate vessel tone and response to injury.

Gamma knife radiosurgery in the management of patients with acromegaly: a review.

Although acromegaly is a rare disease, the need for an effective treatment that is able to induce biochemical cure is an extremely important issue. Unsuccessfully treated acromegaly is associated with increased morbidity and an age-corrected mortality so that early and aggressive therapy to normalize hormonal levels should be instituted at diagnosis. Ideally, the growth hormone-secreting adenoma should be completely resected, with preservation or subsequent restoration of pituitary function. Patients with recurrence or failure after surgery are treated with a second surgery, medical, radiation treatment, or combined modality treatment. Steotactic radiosurgery with gamma knife allows the delivery of focused radiation in a single session to the pituitary tumor that delivers a more biologically effective dose to the tumor than fractionated radiotherapy. Its use as a primary or adjuvant treatment for acromegalics may be more cost effective than medical treatment in these patients. Although it seems to be very effective in controlling growth and secretion of the growth hormone-secreting pituitary adenomas, there is a chance that some major risks from gamma knife radiosurgery might occur. This article will review the role that gamma knife radiosurgery might have in patients with acromegaly.

Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy.

PURPOSE: It has been suggested that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). To test this hypothesis further, we measured multiple drug resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue. METHODS: cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data. RESULTS: We found overexpression of selected MDR and significantly higher P-glycoprotein levels in "epileptic" versus "control" ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin resistance--associated protein (hCRA-alpha) also was overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue. CONCLUSIONS: Complex MDR expression changes may play a role in AEDs pharmacoresistance by altering the permeability of AEDs across the BBB.

Recommendations for the establishment of primary stroke centers. Brain Attack Coalition.

OBJECTIVE: To develop recommendations for the establishment and operation of primary stroke centers as an approach to improve the medical care of patients with stroke. PARTICIPANTS: Members of the Brain Attack Coalition (BAC), a multidisciplinary group of representatives from major professional organizations involved with delivering stroke care. Supplemental input was obtained from other experts involved in acute stroke care. EVIDENCE: A review of literature published from 1966 to March 2000 was performed using MEDLINE. More than 600 English-language articles that had evidence from randomized clinical trials, meta-analyses, care guidelines, or other appropriate methods supporting specific care recommendations for patients with acute stroke that could be incorporated into a stroke center model were selected. CONSENSUS PROCESS: Articles were reviewed initially by 1 author (M.J.A.). Members of the BAC reviewed each recommendation in the context of current practice parameters, with special attention to improving the delivery of care to patients with acute stroke, cost-effectiveness, and logistical issues related to the establishment of primary stroke centers. Consensus was reached among all BAC participants before an element was added to the list of recommendations. CONCLUSIONS: Randomized clinical trials and observational studies suggest that several elements of a stroke center would improve patient care and outcomes. Key elements of primary stroke centers include acute stroke teams, stroke units, written care protocols, and an integrated emergency response system. Important support services include availability and interpretation of computed tomography scans 24 hours everyday and rapid laboratory testing. Administrative support, strong leadership, and continuing education are also important elements for stroke centers. Adoption of these recommendations may increase the use of appropriate diagnostic and therapeutic modalities and reduce peristroke complications. The establishment of primary stroke centers has the potential to improve the care of patients with stroke. JAMA. 2000.

Prospective randomized studies for carotid endarterectomy.

The clinical trial has become the standard method used to evaluate surgical procedures. Regarding carotid endarterectomy, clinical trials have reformed the indications for surgery as a means of decreasing the risk of stroke. The methodology and results from significant trials for the symptomatic and asymptomatic patient with carotid stenosis are described. Critical evaluation of these trials is necessary for the discerning surgeon to form a rational approach to clinical practice in carotid disease.

Effects of radiation on cerebral vasculature: a review.

Radiation therapy plays a critical role in the treatment of central nervous system neoplasms and cerebral arteriovenous malformations. The deleterious effects of radiation on cerebral arteries may be the primary limitation to these treatment methods, as radiation may cause a variety of cerebrovascular injuries and hemodynamic changes. Radiation-induced changes in the cerebral arterial wall are determined by a number of cellular processes in endothelium and smooth muscle cells that modulate differences in radiosensitivity and phenotypic expression. The histopathological findings in arterial radiation injury include vessel wall thickening, thrombosis, luminal occlusion, and occasional telangiectases. Mechanisms for radiation injury to blood vessels include phenotypic changes in normal vessel wall cells (especially endothelium) manifested by the expression or suppression of specific gene and protein products that affect cell cycle progression or cellular proliferation or demise via cytotoxic injury or apoptosis. This review describes the molecular and cellular events involved in the systemic and cerebral vascular response to radiation and the potential means by which these responses may be influenced to augment the therapeutic effects of radiation while minimizing the untoward consequences.

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.

Destructive tophaceous calcium hydroxyapatite tumor of the infratemporal fossa. Case report and review of the literature.

Tophaceous pseudogout is one of the rarest forms of crystal deposition disease, typically presenting as a destructive and invasive mass involving the temporomandibular joint or the infratemporal fossa region in the absence of any other articular manifestations. Previous cases have been assumed to be caused by calcium pyrophosphate dihydrate (CPPD) crystal deposition, based on finding weakly birefringent crystals in the involved tissues. The authors present the unique case of a 65-year-old woman with a destructive and invasive facial mass extending to the middle cranial fossa with microscopic and clinical features consistent with tophaceous pseudogout. High-resolution x-ray crystallographic powder diffraction and Fourier transformed infrared spectroscopy subsequently revealed that the crystals were composed of calcium hydroxyapatite without CPPD. The patient was later found to have primary hyperparathyroidism and mild hypercalcemia. This case demonstrates that tissue deposits of calcium hydroxyapatite can cause a destructive and invasive mass containing weakly birefringent crystals and raises the question of whether previous cases attributed to tophaceous pseudogout resulting from CPPD actually were composed of birefringent calcium hydroxyapatite.

Complex right hemisphere developmental venous anomaly associated with multiple facial hemangiomas. Case report.

Complex developmental venous anomalies (DVAs) represent variations of normal cerebral venous drainage and consist of dilation of the superficial and/or deep venous system. These rare anomalies can occur unilaterally or bilaterally, supratentorially or infratentorially, focally or they can affect the entire hemisphere. Some DVAs are associated with cervicofacial venous malformations or facial lymphatic malformations. Anomalies of this type are generally clinically silent, and cerebral dysfunction is usually absent. Symptoms, when they occur, are most commonly headache or mild seizure disorders. The angiographic findings are striking, with well-formed but enlarged transcerebral medullary and deep and/or superficial cortical veins. Opacification of these venous structures occurs within the same time frame as a normal angiographic venous phase. The authors report the case of a 33-year-old man in whom a large inoperable arteriovenous malformation had been previously diagnosed and who presented with seizures. Repeated magnetic resonance imaging and angiography demonstrated abnormally dilated transcerebral, superficial, and deep venous structures involving the entire right hemisphere with no identifiable nidus. Additionally, multiple bilateral benign facial hemangiomas were present in this patient. It is important to recognize this rare venous appearance as a developmental variant and not mistake it for an arteriovenous malformation or a partially thrombosed vein of Galen malformation. Because these venous anomalies are extreme variants of the normal venous system, hemorrhage rarely, if ever, occurs and the patient can be reassured that no interventional or surgical therapy is necessary or warranted.

Traumatic leptomeningeal cyst in an adult: a case report and review of the literature.

BACKGROUND: Traumatic leptomeningeal cyst as a complication of skull fractures was initially thought to occur primarily in the pediatric population. The occurrence of a traumatic leptomeningeal cyst in the adult population is rare. CASE DESCRIPTION: A lump in the right parietal region of this 53-year-old man prompted a computed tomography (CT) scan. The patient denied any symptoms and was in good health. Examination confirmed a firm, nontender, nonpulsatile mass in the right parietal region of the skull. The CT scan demonstrated a 4 x 3 cm area of irregular bone destruction involving both the inner and outer table of the skull. At operation a distinctly raised paper-thin outer table was noted, and underneath was a soft, tan-colored mass, which measured approximately 2 x 2 cm and was connected to the underlying brain through a 1 cm dural defect. The extradural portion of the mass was amputated, the dura repaired with a pericranium patch, the skull defect was repaired with a split thickness bone graft, and the final pathology was congruent with gliotic brain. CONCLUSION: Although rare, this case demonstrates a traumatic leptomeningeal cyst in an adult.