Search PubMed⌕ Search

Biomedical subjects

Thomas G Brott

Publications and source records attributed to Thomas G Brott.

At least 19 recordsLinked to original sources

Modern treatment options for intracerebral hemorrhage.

Spontaneous intracerebral hemorrhage (ICH) is a devastating neurological event with a 30-day mortality of approximately 40%. Recent research provides new insights into the pathophysiology of ICH-associated edema, with potential molecular and cellular targets for future therapy. Neuroimaging techniques such as gradient echo MRI are yielding insights into cerebral microbleeds and the microangiopathies associated with hypertension and cerebral amyloid angiopathy. Recent literature provides new medical treatment strategies for fever, acute hypertension, and perihematomal edema, and methods of reducing intracranial pressure. Two randomized controlled trials have provided crucial evidence regarding surgical and medical intervention for acute ICH intervention. Recombinant factor VIIa appears to lessen growth of ICH when administered within 4 hours of ictus. Further study of potential efficacy and safety is underway in an international phase III trial. In addition, the Surgical Trial in Intracerebral Hemorrhage reported results from an international randomized trial of 1033 patients who did not show benefit for surgical evacuation of ICH, compared with medical therapy alone. Less invasive surgical methods for hematoma evacuation, studied previously over the past decade, continue to be investigated.

Journal Article↗

Carotid artery stenting versus carotid endarterectomy: current status.

As operator experience and device technology continue to improve, the theoretic advantages of endovascular approaches to treat carotid occlusive disease may be closer to realization. Currently, data from controlled trials of CAS is minimal, but several multicenter RCTs comparing CAS to CEA are recruiting patients actively and preliminary results show procedural morbidity and mortality rates for CAS that compare favorably to CEA. Community-based experience with CAS continues to grow and further refinements in patient selection based on plaque morphology and other variables offer further hope that endovascular approaches to carotid occlusive disease may benefit selected patients. Given the proved efficacy and durability of CEA for treatment of extracranial carotid stenosis, surgical revascularization remains the recommended standard of care for most patients. CAS will have to be proved equivalent or superior to surgery and as cost-effective to facilitate its widespread acceptance as a treatment alternative for carotid occlusive disease.

Angioplasty↗

Aging is neuroprotective during global ischemia but leads to increased caspase-3 and apoptotic activity in hippocampal neurons.

Previously, we found a significantly greater number of surviving CA1 neurons to global ischemia in the aged (24-month-old) F344 rats than in young (4-month-old) rats. The present study tests the hypothesis that aging retards neuronal death in the hippocampal CA1 region following cerebral ischemia. The CA1 "living cell ratio" was significantly greater in aged than in young rats at three days (62+/-8% vs. 30+/-8%) and at eight days (36+/-6% vs. 17+/-5%), but not at 14 days (15+/-12% vs. 18+/-12%) following ischemia. The number of the CA1 cells exhibiting co-localized TdT-mediated X-dUTP nick end labeling reaction and caspase-3 active peptide (C3AP) immunoreactivity was greater in aged than young animals at three and eight days following ischemia (36+/-8/mm vs. 3+/-1/mm and 36+/-14 vs. 0+/-0, p<0.05 respectively). Also, the total number of C3AP-positive cells in the CA1 region in the aged group was significantly greater than in the young group at three and eight days post-ischemia (p<0.05). Aging appears to delay caspase-3-dependent apoptotic cell death induced by global ischemia in the CA1 region of the hippocampus, consistent with an age-induced neuroprotective process.

Aging↗

The Siblings With Ischemic Stroke Study (SWISS): a progress report.

There is increasing evidence that genetic factors are associated with ischemic stroke, including multiple recent reports of association with the gene PDE4D, encoding phosphodiesterase 4D, on chromosome 5q12. Genetic studies of stroke are important but can be logistically difficult to perform. This article reviews the design of the Siblings With Ischemic Stroke Study (SWISS) and discusses problems in performing a sibling-based pedigree study where proband-initiated consent is used to enroll pedigree members. Proband-initiated enrollment optimizes privacy protections for family members, but it is associated with a substantial pedigree non-completion rate such that 3 to 4 probands must be identified to obtain one completed sibling pedigree. This report updates the progress of enrollment in the SWISS protocol, discusses barriers to pedigree completion and describes innovative approaches used by the SWISS investigators to enhance enrollment.

3',5'-Cyclic-AMP Phosphodiesterases↗

Spanish cross-cultural adaptation and validation of the National Institutes of Health Stroke Scale.

OBJECTIVES: To adapt and validate a Spanish-language version (SV) of the National Institutes of Health Stroke Scale (NIHSS) to facilitate its use in Spanish-speaking contexts. PATIENTS AND METHODS: The methods recommended by the International Quality of Life Assessment Project were followed. Two forward translations and 1 back translation of the NIHSS were developed to ensure lingual and cultural equivalence. A final revised SV-NIHSS was administered by 8 physicians to patients with stroke in 3 clinics in Buenos Aires, Argentina, from September 2003 to December 2003. RESULTS: The study included 102 patients (mean +/- SD age, 73.3+/-6.5 years; 56% women) with stroke (86% ischemic). The SV-NIHSS mean baseline score was 9.78+/-7.04. Interrater reliability was Independently evaluated for 98 patients, showing a high agreement: kappa, 0.77 to 0.99 for the 15 items; interrater correlation coefficient, 0.991 (95% confidence Interval, 0.987-0.994). Intrarater reliability was excellent: kappa, 0.86 to 1.00 for the 15 items; mean intrarater correlation coefficient, 0.994 (95% confidence interval, 0.991-0.996). Construct validity was also adequate; the SV-NIHSS had a negative correlation with baseline Glasgow Coma Scale (Spearman coefficient = -0.574, P < .001) and with Barthel index at 3 months (Spearman coefficient = -0.658, P < .001). Patients with different Rankin scores at 3 months also had significantly different baseline SV-NIHSS scores, from a mean of 4.29+/-2.21 for Rankin score of 0 to a mean of 29.40+/-3.97 for Rankin score of 6 (P < .001). CONCLUSION: This study shows that a Spanish-language version of the NIHSS developed with internationally recommended methods is reliable and valid when applied in a Spanish-speaking setting.

Aged↗

Hippocampal progenitor cells express nestin following cerebral ischemia in rats.

This study addresses whether hippocampal progenitor cells express nestin following cerebral ischemia in rats. Cell counts within the hippocampal hilus were significantly greater following severe (eight-vessel occlusion) ischemia than following intermediate (four-vessel occlusion) ischemia (1527+/-87/mm2 vs. 918+/-71/mm2). Bromedeoxyuridine-positive cell counts were significantly higher with severe ischemia than with intermediate ischemia or in sham-operated animals, respectively (368+/-45, 43+/-14 and 7+/-1/mm2). In the eight-vessel occlusion group, 47+/-8/mm2 bromedeoxyuridine-labeled cells expressed nestin, significantly higher than in the four-vessel occlusion group and sham-operated animals (1+/-1 and 1+/-0/mm2, P<0.01 vs. eight-vessel occlusion, respectively). Confocal microscopy verified that a subset of the bromedeoxyuridine-positive cells expressed nestin. In conclusion, severe ischemia elicits nestin expression in hippocampal progenitor cells in rats.

Analysis of Variance↗

A survey of the SWISS researchers on the impact of sibling privacy protections on pedigree recruitment.

To understand the perceptions and attitudes about privacy safeguards in research and investigate the impact of letter-based proband-initiated contact on recruitment, we surveyed researchers in the Siblings With Ischemic Stroke Study (SWISS). All 49 actively recruiting sites provided at least 1 response, and 61% reported that potential probands were enthusiastic. Although 66% of researchers valued proband-initiated contact, only 23% said that probands viewed this strategy as important to protecting the privacy of siblings. A substantial minority of researchers (37%) said the strategy impeded enrollment, and 44% said it was overly burdensome to probands.

Attitude of Health Personnel↗

Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke.

Risk for ischemic stroke is mediated by both environmental and genetic factors. Although several environmental exposures have been implicated, relatively little is known about the genetic basis of predisposition to this disease. Recent studies in Iceland identified risk polymorphisms in two putative candidate genes for ischemic stroke: phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP). A collection of North American sibling pairs concordant for ischemic stroke and two cohorts of prospectively ascertained North American ischemic stroke cases and control subjects were used for evaluation of PDE4D and ALOX5AP. Although no evidence supported linkage of ischemic stroke with either of the two candidate genes, single-nucleotide polymorphisms and haplotypic associations were observed between PDE4D and ischemic stroke. There was no evidence of association between variants of ALOX5AP and ischemic stroke. These data suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations.

3',5'-Cyclic-AMP Phosphodiesterases↗

Genetics of cerebrovascular disorders.

Physicians must be able to recognize stroke caused by a mendelian or mitochondrial disorder. Some genetic disorders such as sickle cell anemia and Fabry disease have proven disease-specific treatments, whereas others have no effective treatment, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Proper diagnosis of a genetic disorder has prognostic value and prevents patient exposure to unnecessary and potentially harmful therapeutic agents and diagnostic tests. This article reviews the clinical and genetic features of some mendellan and mitochondrial disorders associated with ischemic stroke, hemorrhagic stroke, and cerebrovascular malformations.

Acidosis, Lactic↗

Aging blunts ischemic-preconditioning-induced neuroprotection following transient global ischemia in rats.

The present study examines the hypothesis that aging defined by the 50% survival age compromises neuroprotection afforded by ischemic preconditioning (IPC). Sixty-four male F344 rats aged 4- and 24-months, respectively, were subjected to IPC, (3-min ischemia) or sham-surgery followed by 10-min (full) ischemia or sham-surgery 2 days later. There were 4 groups at each age: sham-surgery-sham-surgery (SS), preconditioning-sham-surgery (PS), preconditioning-ischemia (PI) and sham-surgery-ischemia (SI) groups. Assessments of histology and immunoreactivities of N-methyl-D-aspartic acid receptor 1 (NMDAr1) and caspase-3 active peptide (C3AP) in the hippocampal CA1 region were performed 8 days after full ischemia. The CA1 "living cell ratio" was greater in the aged SI group than in the young SI group (32+/-6% vs. 17+/-5%, p<0.05), whereas the degree of protection against full ischemia afforded by IPC was reduced in the aged compared with the young (53+/-17% vs. 241+/-25%, P<0.0001). The basal level of NMDAr1 immunofluorescence was significantly higher in young animals, while the numbers of C3AP-positive cells were greater in all three aged ischemic groups as compared to respective young groups (p<0.01, p=0.055 and p<0.05). A fourth method of assessing cell damage using Fluoro Jade C labeled degenerating neurons that were also intensively eosinophilic. Counts of Fluoro Jade C-positive cells were higher in the young SI group than in the aged SI group (P<0.05), suggesting that mechanisms of ischemic cell death may change with aging. In conclusion, aging alters mechanisms of ischemic cell death in CA1 neurons and ischemic tolerance mechanisms are blunted by aging.

Aging↗

Beyond subgroup analysis: improving the clinical interpretation of treatment effects in stroke research.

In large clinical trials designed to determine efficacy of an experimental treatment, patients are enrolled with presence or absence of various risk factors, such as diabetes or history of atrial fibrillation. A treatment-by-risk factor interaction indicates that the treatment effect may depend on the risk factor presence or absence. It is important to identify such interaction, since a treatment may fail or cause adverse events in the presence of the risk. Although statistical methods exist to identify such interaction, they are underutilized in clinical stroke research. This paper reviews the notion of treatment-by-risk factor interaction and identifies two types of interaction, quantitative and qualitative, using a graphical technique and statistical testing. We illustrate how to avoid drawing the erroneous conclusions regarding the treatment effect on subgroups when failing to detect an interaction, and provide rigorous tools to estimate the treatment effect on subgroups when an interaction is observed. Applications are presented using the data collected from the NINDS t-PA stroke studies. In stroke clinical trials, a treatment-by-risk factor interaction must be considered if the data permit. The graphical approach provides a heuristic illustration of interactions. Qualitative interactions are more important than quantitative interactions on therapeutic conclusion. Results of NINDS t-PA stroke studies confirmed our previous conclusions on the treatment t-PA benefit within 3-h therapeutic window. No subgroup of patients would lead a physician to withhold the t-PA treatment.

Algorithms↗

Credentialing of surgeons as interventionalists for carotid artery stenting: experience from the lead-in phase of CREST.

BACKGROUND: Credentialing of vascular surgeons to perform carotid artery stenting (CAS) continues to be a major issue confronting the specialty of Vascular Surgery. Cannulation of aortic arch branches, and placement of carotid antiembolic devices and stents constitute the major technical challenges to vascular surgeons becoming credentialed to perform CAS. The multicenter Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), supported by the National Institute of Neurological Disorders and Stroke, National Institute of Health, reviews credentials of interventionalists, including surgeons, for the trial's "lead-in" phase of CAS to treat symptomatic (>50% stenosis) and asymptomatic (>70% stenosis). METHODS: Vascular surgeons requesting participation in CREST must have achieved basic interventional credentialing criteria as recommended by the Society of Vascular Surgery. Each interventionalist is asked to submit notes and narrative summaries from a series of 10 to 30 CAS procedures for review by a multi-specialty review committee before being approved to participate in CREST. Thereafter, during the lead-in phase of CREST, each approved interventionalist is asked to perform CAS procedures using the study devices in as many as 20 patients. In this interim report from the CREST lead-phase, the association of specialty of operator (vascular surgeon, neurosurgeon, other specialist) and periprocedural stroke and death rate was examined in patients undergoing CAS. In addition, current enrollment volume in the lead-in phase by specialty of the principal investigator was examined. RESULTS: Thirty-two of 134 (23.9%) CREST-credentialed interventionalists are vascular surgeons (n = 22; 16.4%) or neurosurgeons (n = 10; 7.5%). For events monitored through March 31, 2004, 789 patients had undergone CAS procedures performed by these 134 specialists. Thirty-day stroke and death rate was 4.6%, and myocardial infarction was observed in 1.1% of patients. Serious adverse events have not been clustered at individual institutions, and no significant differences have been observed between vascular surgeons or neurosurgeons and other credentialed specialists. CONCLUSIONS: Vascular surgeons with basic catheter and guide wire skills, particularly those who have incorporated diagnostic cerebral angiography into their practice, can be credentialed to perform CAS. Individuals or groups should devote a number of cases (n = 10-30 per surgeon) to CAS to accomplish this goal. Pending US Food and Drug Administration approval of devices and Center for Medicaid and Medicare Services reimbursement, institutional financial support for the performance of these procedures must be secured. The learning curve for CAS should not be considered so formidable as to discourage surgeons from adding these techniques of CAS to their procedural inventory.

Angioplasty, Balloon↗

Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase.

BACKGROUND: A heightened risk of stroke and death among octogenarians undergoing carotid artery stenting (CAS) has been reported. The multicenter Carotid Revascularization Endarterectomy vs. Stent Trial (CREST) supported by the National Institute of Neurological Disorders, National Institutes of Health, compares the efficacy of carotid endarterectomy (CEA) and CAS in an ongoing clinical trial. This effort also includes a "lead-in" phase of symptomatic (>50% stenosis) and asymptomatic (>70% stenosis) patients. The protocol calls for patients to receive aspirin and clopidogrel before and 30-days after CAS and to be examined by a study neurologist preprocedure, at 24-hours, and at 30-day. The occurrence of stroke and death was reviewed by an independent clinical events committee. METHODS: The association of age and periprocedural stroke and death was examined in 749 lead-in patients undergoing CAS (30.7% symptomatic, 69.3% asymptomatic). Patients were separated into four age categories: less than 60, 60 to 69, 70 to 79, and 80 years or older, and the proportion of patients with stroke and death during the 30-day periprocedural period was calculated for each category. RESULTS: An increasing proportion of patients suffered stroke and death with increasing age (P = .0006); 2 (1.7%) of 120 patients under age 60, 3 (1.3%) of 229 aged 60 to 69, 16 (5.3%) of 301 aged 70 to 79, and 12 (12.1%) of 99 patients aged 80 years and older. These increasingly high complication rates at older ages were not mediated by adjustment for symptomatic status, use of antiembolic devices, gender, percentage of carotid stenosis, or the presence of distal arterial tortuosity. CONCLUSIONS: Interim results from the lead-in phase of CREST show that the periprocedural risk of stroke and death after CAS increases with age in the course of a credentialing registry. This effect is not mediated by potential confounding factors. Randomized trial data are needed to compare the CAS versus CEA periprocedural risk of stroke and death by age. Pending results from randomized studies, care should be taken when CAS is performed in older patient populations.

Adult↗

Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in acute ischaemic stroke: scientific rationale and available evidence.

Acute ischaemic stroke is the result of an abrupt interruption of focal cerebral blood flow. In the majority of cases, this interruption is caused by an acute thromboembolism. Based on clinical experience in the treatment of acute coronary syndromes, platelet glycoprotein (GP) IIb/IIIa receptor antagonists alone, in combination with reduced doses of thrombolytic agents, or as complementary therapy for short-term mechanical interventions merit consideration as a class of agents with potential use in ischaemic stroke. Research to date and extrapolation from the cardiac literature suggest significant, but as yet unproven, potential for the use of GP IIb/IIIa receptor antagonists in the treatment of acute ischaemic stroke. This potential exists both at the site of the thromboembolic occlusion and at the distal microvascular level. This article reviews the scientific rationale and available evidence for the potential use of platelet GP IIb/IIIa receptor antagonists in acute ischaemic stroke.

Acute Disease↗

Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage.

OBJECTIVE: To assess the effects of recombinant factor VIIa (rFVIIa) on hemorrhage volume and functional outcomes in warfarin-related acute intracranial hemorrhage (ICH), which has a 30-day mortality of more than 50%. PATIENTS AND METHODS: We reviewed the clinical, laboratory, and radiographic features of a consecutive series of 7 patients (median age, 87 years; 5 women) with symptomatic, nontraumatic warfarin-related acute ICH treated with intravenous rFVIIa at St. Luke's Hospital in Jacksonville, Fla, between December 2002 and September 2003. Prestroke baseline functional status was assessed with the modified Rankin Scale. Outcome was assessed with the Glasgow Outcome Scale. RESULTS: The international normalized ratio decreased from a mean of 2.7 before administration of rFVIIa to 1.08 after administration of rFVIIa. The median prestroke score on the modified Rankin Scale was zero. The median presenting score on the Glasgow Coma Scale was 14 (range, 4-15). The mean time from onset to treatment was 6.2 hours. The mean initial dose of rFVIIa was 62.1 microg/kg. One patient underwent placement of an external ventricular drain, and another underwent craniotomy and hematoma evacuation. Five of the 7 patients survived and were dismissed from the hospital with severe disability (Glasgow Outcome Scale, 3); 2 patients died during hospitalization. CONCLUSIONS: Intravenous bolus administration of rFVIIa can rapidly lower the international normalized ratio and appears to be safe for patients with warfarin-related ICH. Prospective controlled studies are needed to determine whether rFVIIa can prevent hematoma expansion and improve neurologic outcomes in patients with warfarin-related ICH.

Acute Disease↗