Marc R. Mayberg

Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veterans Affairs Cooperative Studies Program 309 Trialist Group

OBJECTIVEnTo determine whether carotid endarterectomy provides protection against subsequent cerebral ischemia in men with ischemic symptoms in the distribution of significant (greater than 50%) ipsilateral internal carotid artery stenosis.nnnDESIGNnProspective, randomized, multicenter trial.nnnSETTINGnSixteen university-affiliated Veterans Affairs medical centers.nnnPATIENTSnMen who presented within 120 days of onset of symptoms that were consistent with transient ischemic attacks, transient monocular blindness, or recent small completed strokes between July 1988 and February 1991. Among 5000 patients screened, 189 individuals were randomized with angiographic internal carotid artery stenosis greater than 50% ipsilateral to the presenting symptoms. Forty-eight eligible patients who refused entry were followed up outside of the trial.nnnOUTCOME MEASURESnCerebral infarction or crescendo transient ischemic attacks in the vascular distribution of the original symptoms or death within 30 days of randomization.nnnINTERVENTIONnCarotid endarterectomy plus the best medical care (n = 91) vs the best medical care alone (n = 98).nnnRESULTSnAt a mean follow-up of 11.9 months, there was a significant reduction in stroke or crescendo transient ischemic attacks in patients who received carotid endarterectomy (7.7%) compared with nonsurgical patients (19.4%), or an absolute risk reduction of 11.7% (P = .011). The benefit of surgery was more profound in patients with internal carotid artery stenosis greater than 70% (absolute risk reduction, 17.7%; P = .004). The benefit of surgery was apparent within 2 months after randomization, and only one stroke was noted in the surgical group beyond the 30-day perioperative period.nnnCONCLUSIONSnFor a selected cohort of men with symptoms of cerebral or retinal ischemia in the distribution of a high-grade internal carotid artery stenosis, carotid endarterectomy can effectively reduce the risk of subsequent ipsilateral cerebral ischemia. The risk of cerebral ischemia in this subgroup of patients is considerably higher than previously estimated.

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°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.

Overexpression of Multiple Drug Resistance Genes in Endothelial Cells from Patients with Refractory Epilepsy

Summary: u2002Purpose: 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.

Serum S-100β as a possible marker of blood–brain barrier disruption

Two brain-specific proteins, S-100β and neuron-specific enolase (NSE), are released systemically after cerebral lesions, but S-100β levels sometimes rise in the absence of neuronal damage. We hypothesized that S-100β 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-100β increased significantly after mannitol infusion (P<0.05) while NSE did not. This suggests that S-100β is an early marker of BBB opening that is not necessarily related to neuronal damage.

Serum S100β: A noninvasive marker of blood-brain barrier function and brain lesions

S100β protein is expressed constitutively by brain astrocytes. Elevated S100β levels in cerebrospinal fluid and serum reported after head trauma, subarachnoid hemorrhage, and stroke were correlated with the extent of brain damage. Because elevated serum S100β also was shown to indicate blood‐brain barrier (BBB) dysfunction in the absence of apparent brain injury, it remains unclear whether elevation of serum levels of S100β reflect BBB dysfunction, parenchymal damage, or both.

Outcome after the Treatment of Spinal Dural Arteriovenous Fistulae: A Contemporary Single-institution Series and Meta-analysis

OBJECTIVE:Spinal dural arteriovenous fistulae (Type I spinal AVMs) are the most common type of spinal vascular malformations. The optimal treatment strategy has yet to be defined, and endovascular embolization is being offered with increasing frequency. A 7-year single-institution retrospective review of outcome with surgical management of Type I spinal AVMs is presented along with a meta-analysis of existing literature. METHODS:For the institutional analysis, a retrospective review of all patients who underwent treatment at our institution for Type I spinal AVMs was performed. Between 1995 and the present (the time frame during which endovascular treatments were available), 19 consecutive patients were treated. Follow-up was performed by clinical examination or telephone interview, and functional status was measured by use of the Aminoff-Logue score. For the meta-analysis, a MEDLINE search between 1966 and the present was performed for surgical, endovascular, or combined treatment of spinal dural arteriovenous fistula. These series were included in a meta-analysis to evaluate success and failure rates, complications, and functional outcome. Specifically, embolization and microsurgery were compared. RESULTS:For the institutional analysis, 18 of 19 patients were available for long-term follow-up after surgery. There were no surgical failures, but one complication was seen. Patients demonstrated a statistically significant improvement in gait and bladder function after surgery. For the meta-analysis, 98% of those patients treated with microsurgery had their dural arteriovenous fistulae successfully obliterated after the initial treatment, compared with only 46% with embolization, as judged by radiographic or clinical follow-up. 89% percent of patients demonstrated improvement or stabilization in neurological symptoms after surgical treatment. Few complications were demonstrated with either surgery or embolization. CONCLUSION:At this point, surgery seems to be superior to embolization for the management of spinal dural arteriovenous fistula. The fistula is usually obliterated after the initial treatment, with few clinical or radiographic recurrences. The majority of patients either improve or stabilize after treatment. Few worsen, and the morbidity is minimal. It is reasonable to attempt initial embolization, especially at the time of the initial diagnostic spinal angiogram. The treating physicians and patients should be aware of the high chance of recurrence, and patients may ultimately require surgery or repeat embolization. After endovascular therapy, patients are committed to repeat angiography and probably embolization. For these reasons, it is the authors’ opinion that surgery should be used as the first-line therapy for spinal dural arteriovenous fistulae.

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.

A new dynamic in vitro model for the multidimensional study of astrocyte-endothelial cell interactions at the blood-brain barrier.

Blood-brain barrier endothelial cells are characterized by the presence of tight intercellular junctions, the absence of fenestrations, and a paucity of pinocytotic vesicles. The in vitro study of the BBB has progressed rapidly over the past several years as new cell culture techniques and improved technologies to monitor BBB function became available. Studies carried out on viable in vitro models are set to accelerate the design of drugs that selectively and aggressively can target the CNS. Several systems in vitro attempt to reproduce the physical and biochemical behavior of intact BBB, but most fail to reproduce the three-dimensional nature of the in vivo barrier and do not allow concomitant exposure of endothelial cells to abluminal (glia) and lumenal (flow) influences. For this purpose, we have developed a new dynamic in vitro BBB model (NDIV-BBB) designed to allow for extensive pharmacological, morphological and physiological studies. Bovine aortic endothelial cells (BAEC) developed robust growth and differentiation when co-cultured alone. In the presence of glial cells, BAEC developed elevated Trans-Endothelial Electrical Resistance (TEER). Excision of individual capillaries proportionally decreased TEER; the remaining bundles were populated with healthy cells. Flow played an essential role in EC differentiation by decreasing cell division. In conclusion, this new dynamic model of the BBB allows for longitudinal studies of the effects of flow and co-culture in a controlled and fully recyclable environment that also permits visual inspection of the abluminal compartment and manipulation of individual capillaries.

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.

The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology.

Abstract It is widely accepted that vascular mechanisms are involved in the genesis of many neurological disorders. In particular, blood–brain barrier (BBB) dysfunction has been related to the severity of Alzheimers disease, encephalopathy due to meningitis, multiple sclerosis, HIV-associated encephalopathy, epilepsy, gliomas and metastatic brain tumors. The BBB may constitute an important therapeutic target to protect neurons after CNS diseases. Both in vivo and in vitro, the functional phenotype of vascular endothelium is dynamically responsive to circulating cytokines, growth factors and puslatile blood flow (shear stress). Shear stress can play a critical role in vascular homeostasis and pathophysiology; it is a major regulator of remodeling in developed blood vessels and in blood vessels affected by atherosclerotic lesions. The physiological fluid mechanic stimulus, shear stress, could be considered to be an important differentiative stimulus capable of modulating endothelial phenotype in vivo. Endothelial cells undergo cell cycle arrest after exposure to physiological levels of shear stress. As for mature endothelial cells, in which flow mediated shear stress may play a role in the induction, progression and/or prevention of atherosclerosis by changing their function, stress may play a role in endothelial cell differentiation from hemopoietic stem cells and/or from embryonic stem cells. Stem cells may be used to repair vascular damage, including loss of EC, due to a variety of diseases (e.g. myocardial neovascularization by adult bone marrow derived angioblasts). In the brain, it was proposed that neuron-producing stem cells may be used to treat Alzheimers disease, paralysis, etc. Surprisingly, very few investigators are exploring the use of endothelial precursors to revert or prevent cerebrovascular disease. This review summarizes the most recent data related to cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in blood–brain barrier homeostasis and pathophysiology.