Warren R. Selman

Recommendations for Comprehensive Stroke Centers: A Consensus Statement From the Brain Attack Coalition

Background and Purpose— To develop recommendations for the establishment of comprehensive stroke centers capable of delivering the full spectrum of care to seriously ill patients with stroke and cerebrovascular disease. Recommendations were developed by members of the Brain Attack Coalition (BAC), which is a multidisciplinary group of members from major professional organizations involved with the care of patients with stroke and cerebrovascular disease. Summary of Review— A comprehensive literature search was conducted from 1966 through December 2004 using Medline and Pub Med. Articles with information about clinical trials, meta-analyses, care guidelines, scientific guidelines, and other relevant clinical and research reports were examined and graded using established evidence-based medicine approaches for therapeutic and diagnostic modalities. Evidence was also obtained from a questionnaire survey sent to leaders in cerebrovascular disease. Members of BAC reviewed literature related to their field and graded the scientific evidence on the various diagnostic and treatment modalities for stroke. Input was obtained from the organizations represented by BAC. BAC met on several occasions to review each specific recommendation and reach a consensus about its importance in light of other medical, logistical, and financial factors. Conclusions— There are a number of key areas supported by evidence-based medicine that are important for a comprehensive stroke center and its ability to deliver the wide variety of specialized care needed by patients with serious cerebrovascular disease. These areas include: (1) health care personnel with specific expertise in a number of disciplines, including neurosurgery and vascular neurology; (2) advanced neuroimaging capabilities such as MRI and various types of cerebral angiography; (3) surgical and endovascular techniques, including clipping and coiling of intracranial aneurysms, carotid endarterectomy, and intra-arterial thrombolytic therapy; and (4) other specific infrastructure and programmatic elements such as an intensive care unit and a stroke registry. Integration of these elements into a coordinated hospital-based program or system is likely to improve outcomes of patients with strokes and complex cerebrovascular disease who require the services of a comprehensive stroke center.

Length of stay and mortality in neurocritically ill patients: impact of a specialized neurocritical care team.

Objective:To determine predictors of in-hospital and long-term mortality and length of stay in patients admitted to the neurosciences critical care unit. Design:Retrospective analysis of a prospectively collected database. Setting:Neurosciences critical care unit of a large academic tertiary care hospital. Patients:Adult patients (n = 2381) admitted to our neurosciences critical care unit from January 1997 to April 2000. Interventions:Introduction of a specialized neurocritical care team. Measurements and Main Results:Data obtained from the database included demographics, admission source, length of stay, neurosciences critical care unit and hospital disposition, admission Acute Physiology and Chronic Health Evaluation (APACHE) III score, and principal and secondary diagnoses. The introduction of a neurocritical care team in September 1998 was also collected, as was death at 1 yr after admission. Univariate analysis was carried out using Student’s t-test, Mann-Whitney U test, or chi-square test (significance, p < .05). A logistic regression model was used to create a prediction model for in-hospital and long-term mortality. A general linear model was used to determine predictors of length of stay (after log transformation). Independent predictors of in-hospital mortality included APACHE III (odds ratio, 1.07 [1.06–1.08]) and admission from another intensive care unit (odds ratio, 2.9 [1.4–6.2]). The presence of a neurocritical care team was an independent predictor of decreased mortality (odds ratio, 0.7 [0.5–1.0], p = .044). Admission after the neurocritical care team was implemented was associated with reduced length of stay in both the neurosciences critical care unit (4.2 ± 4.0 vs. 3.7 ± 3.4, p < .001) and the hospital (9.9 ± 8.0 vs. 8.4 ± 6.9, p < .0001). There was no difference in readmission rates to the intensive care unit or discharge disposition to home before and after the neurocritical care team was established. The availability of the neurocritical care team was not associated with significant changes in long-term mortality. Factors independently associated with long-term mortality included female gender, admission from another intensive care unit, APACHE III score, and being moderately disabled before admission. Conclusion:Introduction of a neurocritical care team, including a full-time neurointensivist who coordinated care, was associated with significantly reduced in-hospital mortality and length of stay without changes in readmission rates or long-term mortality.

Intraventricular thrombolysis speeds blood clot resolution: Results of a pilot, prospective, randomized, double-blind, controlled trial

OBJECTIVEAnimal models and clinical studies suggest that intraventricular thrombolysis improves clot resolution and clinical outcomes among patients with intraventricular hemorrhage. However, this intervention may increase the rates of rebleeding and infection. To assess the safety and efficacy of intraventricular thrombolysis, we conducted a pilot, randomized, double-blind, controlled, multicenter study. METHODSPatients with intraventricular hemorrhage requiring ventriculostomy were randomized to receive intraventricular injections of normal saline solution or urokinase (25,000 international units) at 12-hour intervals. Injections continued until ventricular drainage was discontinued according to prespecified clinical criteria. Head computed tomographic scans were obtained daily, for quantitative determinations of intraventricular hemorrhage volumes. The rate of clot resolution was estimated for each group. RESULTSTwelve subjects were enrolled (urokinase, seven patients; placebo, five patients). Commercial withdrawal of urokinase precluded additional enrollment. The urokinase and placebo groups were similar with respect to age (49.6 versus 55.2 yr, P = 0.43) and presenting Glasgow Coma Scale scores (7.14 versus 8.00, P = 0.72). Randomization to the urokinase treatment arm (P = 0.02) and female sex (P = 0.008) favorably affected the clot resolution rate. The sex-adjusted clot half-life for the urokinase-treated group was reduced 44.6%, compared with the value for the placebo group (4.69 versus 8.48 d). CONCLUSIONIntraventricular thrombolysis with urokinase speeds the resolution of intraventricular blood clots, compared with treatment with ventricular drainage alone.

Multimodality treatment of giant intracranial arteriovenous malformations

OBJECTIVE Giant arteriovenous malformations (AVMs) (i.e., those greater than 6 cm at maximum diameter) are difficult to treat and often carry higher treatment morbidity and mortality rates than do smaller AVMs. In this study, we reviewed the treatment, angiographic results, and clinical outcomes in 53 patients with giant AVMs who were treated at Stanford between 1987 and 2001. METHODS The patients selected included 20 males (38%) and 33 females (62%). Their presenting symptoms were hemorrhage (n = 20; 38%), seizures (n = 18; 34%), headaches (n = 8; 15%), and progressive neurological deficits (n = 7; 13%). One patient was in Spetzler-Martin Grade III, 9 were in Spetzler-Martin Grade IV, and 43 were in Spetzler-Martin Grade V. The mean AVM size was 6.8 cm (range, 6-15 cm). AVM venous drainage was superficial (n = 7), deep (n = 20), or both (n = 26). At presentation, 31 patients (58%) were graded in excellent neurological condition, 17 were graded good (32%), and 5 were graded poor (9%). RESULTS The patients were treated with surgery (n = 27; 51%), embolization (n = 52; 98%), and/or radiosurgery (n = 47; 89%). Most patients received multimodality treatment with embolization followed by surgery (n = 5), embolization followed by radiosurgery (n = 23), or embolization, radiosurgery, and surgery (n = 23). Nineteen patients (36%) were completely cured of their giant AVMs, 90% obliteration was achieved in 4 patients (8%), less than 90% obliteration was achieved in 29 patients (55%) who had residual AVMs even after multimodality therapy, and 1 patient was lost to follow-up. Of the 33 patients who either completed treatment or were alive more than 3 years after undergoing their most recent radiosurgery, 19 patients (58%) were cured of their AVMs. The long-term treatment-related morbidity rate was 15%. The clinical results after mean follow-up of 37 months were 27 excellent (51%), 15 good (28%), 3 poor (6%), and 8 dead (15%). CONCLUSION The results in this series of patients with giant AVMs, which represents the largest series reported to date, suggest that selected symptomatic patients with giant AVMs can be treated successfully with good outcomes and acceptable risk. Multimodality treatment is usually necessary to achieve AVM obliteration.

Interleukin-1β messenger ribonucleic acid and protein levels after fluid-percussion brain injury in rats: Importance of injury severity and brain temperature

OBJECTIVE Posttraumatic temperature manipulations have been reported to significantly influence the inflammatory response to traumatic brain injury (TBI). The purpose of this study was to determine the temporal and regional profiles of messenger ribonucleic acid (mRNA) expression and protein levels for the proinflammatory cytokine interleukin-1&bgr; (IL-1&bgr;), after moderate or severe TBI. The effects of posttraumatic hypothermia (33°C) or hyperthermia (39.5°C) on these consequences of TBI were then determined. METHODS Male Sprague-Dawley rats underwent fluid-percussion brain injury. In the first phase of the study, rats were killed 15 minutes or 1, 3, or 24 hours after moderate TBI (1.8–2.2 atmospheres), for reverse transcription-polymerase chain reaction analysis. Other groups of rats were killed 1, 3, 24, or 72 hours after moderate or severe TBI (2.4–2.7 atmospheres), for protein analysis. In the second phase, rats underwent moderate fluid-percussion brain injury, followed immediately by 3 hours of posttraumatic normothermia (37°C), hyperthermia (39.5°C), or hypothermia (33°C), and were then killed, for analyses of protein levels and mRNA expression. Brain samples, including cerebral cortex, hippocampus, thalamus, and cerebellum, were dissected and stored at −80°C until analyzed. RESULTS The findings indicated that mRNA levels were increased (P < 0.05) as early as 1 hour after TBI and remained elevated up to 3 hours after moderate TBI. Although both moderate and severe TBI induced increased levels of IL-1&bgr; (P < 0.05), increased protein levels were also noted in remote brain structures after severe TBI. Posttraumatic hypothermia attenuated IL-1&bgr; protein levels, compared with normothermia (P < 0.05), although the levels remained elevated in comparison with sham values. In contrast, hyperthermia had no significant effect on IL-1&bgr; levels, compared with normothermic values. Posttraumatic temperature manipulations had no significant effect on IL-1&bgr; mRNA levels. CONCLUSION Injury severity determines the degree of IL-1&bgr; protein level elevation after TBI. The effects of posttraumatic hypothermia on IL-1&bgr; protein levels (an important mediator of neurodegeneration after TBI) may partly explain the established effects of posttraumatic temperature manipulations on inflammatory processes after TBI.

Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema.

OBJECTIVE Therapeutic cerebral angiogenesis, i.e., using angiogenic factors to enhance collateral vessel formation within the central nervous system, is a potential method for cerebral revascularization. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that also increases capillary permeability, particularly in ischemic tissue. The purpose of this study was to assess the angiogenic and capillary permeability effects of chronic intraventricular infusion of exogenous VEGF in nonischemic brain tissue, because many patients with impaired cerebrovascular reserve do not exhibit chronic cerebral ischemia. METHODS Recombinant human VEGF165 was infused into the right lateral ventricle of rats at a rate of 1 &mgr;l/h for 7 days, at concentrations of 1 to 25 &mgr;g/ml, with osmotic minipumps. Control animals received vehicle only. Vessels were identified in laminin immunohistochemical analyses. Capillary permeability and brain edema were assessed with Evans blue extravasation, [3H]inulin permeability, and brain water content measurements. RESULTS Vessel density was dose-dependently increased by VEGF165 infusions, with significant increases occurring in animals treated with 5 or 25 &mgr;g/ml, compared with control animals (P < 0.01). Significant enlargement of the lateral ventricles was observed for the highest-dose group but not for animals treated with other doses. Capillary permeability was assessed in animals treated with a dose of 5 &mgr;g/ml. An increase in capillary permeability in the diencephalon was identified with Evans blue extravasation and [3H]inulin permeability assessments; however, the brain water content was not significantly increased. CONCLUSION Chronic intraventricular infusions of VEGF165 increased vascular density in a dose-dependent manner. There seems to be a therapeutic window, because infusion of VEGF165 at a concentration of 5 &mgr;g/ml resulted in a significant increase in vessel density with minimal associated brain edema and no ventriculomegaly.

Steal Affecting the Central Nervous System

STEAL IS A pathophysiological process in which increased blood flow through a low-resistance vascular bed is sufficient to divert flow away from a region of the central nervous system. Three disease states in which steal may cause neurological deficits due to central nervous system ischemia are reviewed. Subclavian steal occurs when stenosis of the subclavian artery proximal to the vertebral origin causes retrograde flow in the left vertebral artery. Patients with anatomic subclavian steal usually do not develop neurological symptoms but may rarely present with posterior circulation ischemia.Arteriovenous malformations alter cerebral blood flow patterns and regional perfusion pressure. It has been hypothesized that cerebral arteriovenous malformations may cause neurological deficits due to steal and that these deficits may be cured with arteriovenous malformation treatment. Intra-arterial pressure measurements and transcranial velocity studies show regional hemodynamic alterations. However, these changes have not been correlated with presenting symptoms. Evidence from single-photon emission computed tomography does suggest a relationship between regional hypoperfusion and neurological deficits.Coarctation of the aorta may divert flow from the spinal cord circulation through intercostal arteries distal to the stenosis. This is a possible but unproven mechanism of myelopathology.Steal syndromes may be amenable to treatment by open surgical or endovascular approaches. Experimental studies of the pathophysiology of steal are strengthened by precise definitions of the measured parameters and innovative applications of technology.

Training, competency, and credentialing standards for diagnostic cervicocerebral angiography, carotid stenting, and cerebrovascular intervention A Joint Statement from the American Academy of Neurology, the American Association of Neurological Surgeons, the American Society of Interventional and Therapeutic Neuroradiology, the American Society of Neuroradiology, the Congress of Neurological Surgeons, the AANS/CNS Cerebrovascular Section, and the Society of Interventional Radiology*

Appropriate and adequate cognitive and technical training, proficiency and experience are essential for the safe performance of procedures that confer significant risk to patient well-being. This principle is the foundation of all medical education and is especially important when considering the cerebral vasculature, for which stroke is a defined risk for every endovascular procedure. Despite recent advances in noninvasive diagnostic neuroimaging, diagnostic cervicocerebral angiography remains the cornerstone and “gold standard” for the evaluation and treatment of patients with cerebrovascular disease.1 In addition to a high level of technical expertise, performance and interpretation of diagnostic cervicocerebral angiography requires in-depth cognitive knowledge of related neurological pathophysiology, neurovascular anatomy and pathology, and an understanding of the full range of neurodiagnostic possibilities. Expert diagnostic cervicocerebral angiography is the foundation for safe and successful cervicocerebral endovascular intervention, including carotid artery angioplasty and stenting for atherosclerosis, interventional stroke therapy, intracranial angioplasty and stenting, and embolization of cerebral aneurysms, epistaxis and vascular malformations. All of these procedures are increasing in volume and complexity with recent technological advances that further mandate the need for adequate cognitive acumen and technical skills. To ensure proper outcomes, formal neuroscience training, adequate procedural training and sufficient experience are all essential for competency in diagnostic cervicocerebral angiography and interventional procedures, including carotid stenting. These concepts have been delineated in training requirements by the Accreditation Council for Graduate Medical Education (ACGME) and by previously published official society statements. The purpose of this document is to define the minimum training and experience necessary to provide adequate quality of patient care for extracranial cerebrovascular interventions, particularly carotid artery stenting. Hospital credentialing is the mechanism by which competence is ensured. ### Risks of diagnostic cervicocerebral angiography. Stroke is recognized as the most disabling and costly of all medical conditions.2 Stroke is also the most feared of all iatrogenic medical and procedural …

Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat.

The endoplasmic reticulum (ER) is emerging as a contributory component of cell death after ischemia. Since caspase-12 has been localized to the ER and is a novel signal for apoptosis, we examined the message levels and protein expression of caspase-12 after cerebral ischemia in vivo. Animals underwent permanent middle cerebral artery occlusion (MCAO) and were sacrificed 24 h after ischemia. Protein analysis revealed a significant increase in caspase-12 and a corresponding up-regulation of caspase-12 mRNA in the ischemia group compared with that in the sham group. Immunohistochemical analysis revealed diffuse positive immunostaining of caspase-12 throughout the striatum and cerebral cortex in animals that underwent ischemia, with more intense caspase-12 immunostaining in the striatum than in the cortex after ischemia. These results demonstrate that cerebral ischemia initiates an ER-based stress response that results in the transcriptional up-regulation and corresponding increased expression of caspase-12 protein, and may provide a new area for therapeutic intervention to ameliorate outcomes following stroke.

Apoplexy of a pituitary adenoma after dynamic testing with gonadotropin-releasing hormone

Pituitary tumor apoplexy is a rare clinical syndrome characterized by hemorrhagic infarction of a pre-existing adenoma followed by the acute onset of headache, vomiting, visual disturbances, and sometimes alteration in the level of consciousness [l-3]. Although the pathophysiology of its development is not known, there are some apparent precipitating factors as recently summarized by Ebersold et al [4]. A few recent reports described the occurrence of apoplexy after dynamic testing of anterior pituitary function [5-71. In all of these instances, the apoplectic episode occurred after the combined administration of thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH), insulin, or glucagon. Although GnRH is commonly used in the dynamic testing of pituitary gonadotropin secretion, there are, to our knowledge, no known serious neurologic complications associated with its use. Apoplexy has never been reported to occur after the single injection of this hypothalamic-releasing factor. In this report, we describe a patient with hyperprolactinemia in association with a pituitary macroadenoma who developed hemorrhagic infarction of the adenoma following the intravenous administration of GnRH. The patient had an uneventful recovery after transsphenoidal removal of the necrotic tumor. CASE REPORT A 41-year-old woman presented with a five-year history of amenorrhea. Three years before admission, she had an elevated serum prolactin level to 75 ng/mL and a demonstrable pituitary adenoma on computed tomography. No treatment was given at that time and the patient was next seen by us for endocrine evaluation. She had remained amenorrheic, but exhibited no findings to suggest hypopituitarism, and had no visual disturbances or headaches. Except for a minimal clear discharge from both breasts, results of physical examination were unremarkable. Initial studies showed elevated serum prolactin and follicle-stimulating hormone (FSH) levels (Table I). Magnetic resonance imaging (MRI) of the sella turcica showed a macroadenoma with extension into the suprasellar region and superior displacement of the optic chiasm. Determination of the gonadotropin responses of GnRH was planned in view of the known elevation of the basal FSH level. Approximately 60 minutes after the administration of GnRH (100 pg intravenously), the patient noted the sudden onset of headache, which