Anti-adrenergic medications and edema development after intracerebral hemorrhage.

BACKGROUND: Use of antihypertensive medications is common after intracerebral hemorrhage (ICH). Medications that block adrenergic activation (e.g., beta-blockers and the alpha(2)-agonist, clonidine) may reduce the inflammatory response and therefore have secondary benefit after ICH. METHODS: The patients with acute ICH enrolled in the placebo arm of the CHANT trial were included. Univariate and multivariate analyses were undertaken for factors associated with blood pressure medication use, edema at 72 h, and clinical outcome at 90 days. RESULTS: Of the 303 patients, 87.8% received some antihypertensive treatment during the first 72 h of hospitalization. Edema volume on neuroimaging at 72 h was independently associated with clinical outcome. Use of anti-adrenergic medications was associated with less edema after controlling for hemorrhage volume and blood pressure. CONCLUSIONS: Antihypertensive medications that antagonize the sympathetic nervous system may reduce perihematomal edema after ICH.

Real-time cerebral angiography: sensitivity of a new contrast-specific ultrasound technique.

BACKGROUND AND PURPOSE: To test a new contrast-specific sonography imaging method that offers visualization of the intracranial vasculature in a manner similar to that seen on angiography. MATERIALS AND METHODS: Thirty patients (35 sonography studies total) were included in the study after they provided written informed consent. The patients were scanned through the temporal bone window from both sides after intravenous injection of an ultrasound contrast agent (UCA; perflexane lipid microspheres [Imagent]). The goal was to visualize the intracranial arteries, including the middle (M1-M3), anterior (A1 and A2), and posterior (P1-P3) cerebral arteries, using an axial scanning plane. The studies were performed using a contrast-specific imaging mode, based on a phase inversion technique (transcranial ultrasound angiography [tUSA]). For sensitivity, the results were compared with x-ray angiography as the "gold standard." For interobserver reliability, 24 of 35 sonography studies were evaluated by 2 physicians with little training in transcranial sonography and by a seasoned sonographer. RESULTS: The sensitivity of tUSA ranged between 0.778 (95% confidence interval [CI] of 0.577-0.914) and 0.963 (95% CI of 0.810-0.999). The sensitivities were similar among physicians with little training in transcranial sonography and the seasoned sonographer, indicating high inter-rater reliability. Overall, tUSA provided high anatomic resolution and vascular delineation even of small vessels in the millimeter range. At peak intensity, no UCA-related artifacts were observed. CONCLUSION: tUSA provides images of the intracranial arteries similar to those obtained at angiography with high anatomic resolution, reasonable sensitivity, and interobserver reliability.

An analysis of ischemic stroke in an urban southern California population. The University of California, San Diego, Stroke Data Bank.

BACKGROUND: Stroke databanks may provide important information regarding regional and temporal variations in the causes of stroke. METHODS: Five hundred consecutive patients presenting to the University of California, San Diego, stroke services with acute ischemic stroke were evaluated prospectively. A specific cause of stroke was assigned in each case according to predetermined diagnostic criteria. RESULTS: Relative incidences of ischemic stroke causes were as follows: lacunar, 27%; unknown cause, 23%; cardioembolic, 22%; large-vessel atherothrombotic/embolic, 18%; and miscellaneous, 10%. CONCLUSIONS: These relatively high rates of lacunar stroke and stroke of unknown cause are similar to those from other recent surveys and may reflect an important shift in the pathophysiologic mechanisms that underlie ischemic stroke.

A modified National Institutes of Health Stroke Scale for use in stroke clinical trials: preliminary reliability and validity.

BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) is accepted widely for measuring acute stroke deficits in clinical trials, but it contains items that exhibit poor reliability or do not contribute meaningful information. To improve the scale for use in clinical research, we used formal clinimetric analyses to derive a modified version, the mNIHSS. We then sought to demonstrate the validity and reliability of the new mNIHSS. METHODS: The mNIHSS was derived from our prior clinimetric studies of the NIHSS by deleting poorly reproducible or redundant items (level of consciousness, face weakness, ataxia, dysarthria) and collapsing the sensory item into 2 responses. Reliability of the mNIHSS was assessed with the certification data originally collected to assess the reliability of investigators in the National Institute of Neurological Disorders and Stroke (NINDS) rtPA (recombinant tissue plasminogen activator) Stroke TRIAL: Validity of the mNIHSS was assessed with the outcome results of the NINDS rtPA Stroke Trial: RESULTS: Reliability was improved with the mNIHSS: the number of scale items with poor kappa coefficients on either of the certification tapes decreased from 8 (20%) to 3 (14%) with the mNIHSS. With the use of factor analysis, the structure underlying the mNIHSS was found identical to the original scale. On serial use of the scale, goodness of fit coefficients were higher with the mNIHSS. With data from part I of the trial data, the proportion of patients who improved >/=4 points within 24 hours after treatment was statistically significantly increased by tPA (odds ratio, 1.3; 95% confidence limits, 1.0, 1.8; P=0.05). Likewise, the odds ratio for complete/nearly complete resolution of stroke symptoms 3 months after treatment was 1.7 (95% confidence limits, 1.2, 2.6) with the mNIHSS. Other outcomes showed the same agreement when the mNIHSS was compared with the original scale. The mNIHSS showed good responsiveness, ie, was useful in differentiating patients likely to hemorrhage or have a good outcome after stroke. CONCLUSIONS: The mNIHSS appears to be identical clinimetrically to the original NIHSS when the same data are used for validation and reliability. Power appears to be greater with the mNIHSS with the use of 24-hour end points, suggesting the need for fewer patients in trials designed to detect treatment effects comparable to rtPA. The mNIHSS contains fewer items and might be simpler to use in clinical research trials. Prospective analysis of reliability and validity, with the use of an independently collected cohort, must be obtained before the mNIHSS is used in a research setting.

Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial.

BACKGROUND AND PURPOSE: Little is known in regard to cerebral arterial reocclusion after successful thrombolysis. In the absence of arteriographic information, the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial investigators prospectively identified clinical deterioration following improvement (DFI) as a possible surrogate marker of cerebral arterial reocclusion after rt-PA-induced recanalization. Also, we identified any significant clinical deterioration (CD) even if not preceded by improvement. This observational analysis was designed to determine the incidence of DFI and CD in each treatment group, to identify baseline or posttreatment variables predictive of DFI or CD, and to determine any relationship between DFI, CD, and clinical outcome. METHODS: DFI was defined as any 2-point deterioration on the NIH Stroke Scale after an initial 2-point improvement after treatment. CD was defined as any 4-point worsening after treatment compared with baseline. All data were collected prospectively by investigators blinded to treatment allocation. A noncontrast brain CT was mandated when a 2-point deterioration occurred. All cases were validated by a central review committee. RESULTS: DFI was identified in 81 of the 624 patients (13%); 44 were treated with rt-PA and 37 were treated with placebo (P:=0.48). DFI occurred more often in patients with a higher baseline NIH Stroke Scale score. CD within the first 24 hours occurred in 98 patients (16% of all patients); 43 were given rt-PA and 55 were given placebo (P:=0.19). Baseline variables associated with CD included a less frequent use of prestroke aspirin and a higher incidence of early CT changes of edema or mass effect or dense middle cerebral artery sign. Patients with CD had higher rates of increased serum glucose and fibrin degradation products, and they also had higher rates of symptomatic intracranial hemorrhage and death. Patients who experienced either DFI or CD were less likely to have a 3-month favorable outcome. CONCLUSIONS: We found no association between DFI, CD, and rt-PA treatment, and no clinical evidence to suggest reocclusion. Deterioration was strongly associated with stroke severity and poor outcome and was less frequent in patients whose stroke occurred while they were on aspirin.

Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA stroke trial.

BACKGROUND AND PURPOSE: We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. METHODS: Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of "early activity" of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and "efficacy" and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. RESULTS: Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score

Delayed emergence of striatal dopaminergic hyperactivity after anterolateral ischemic cortical lesions in humans; evidence from turning behavior.

To test the hypothesis that striatal dopaminergic hyperactivity in humans may be an aftermath of anterior cortical ischemic insults, we utilized earlier observations that in several species, including humans with hemiparkinson's disease, asymmetric striatal dopaminergic activity results in spontaneous asymmetric turning away from the hemisphere with higher dopaminergic activity. In this study, electronic monitoring showed that, compared to normal controls, outpatients with old frontal and inferior-parietal cortical strokes exhibit a marked tendency to turn away from the side of the lesion. This delayed ipsilateral neglect suggests a delayed emergence of lasting ipsilateral striatal dopaminergic hyperactivity after unilateral anterolateral cortical insult in humans. Old ischemic insults to anterolateral cortical areas could be one etiological mechanism in human brain disorders that are associated with cortical dysfunction and delayed subcortical dopamine hyperactivity.

Angiogenesis after stroke is correlated with increased numbers of macrophages: the clean-up hypothesis.

Brain cells manufacture and secrete angiogenic peptides after focal cerebral ischemia, but the purpose of this angiogenic response is unknown. Because the maximum possible regional cerebral blood flow is determined by the quantity of microvessels in each unit volume, it is possible that angiogenic peptides are secreted to generate new collateral channels; other possibilities include neuroprotection, recovery/regeneration, and removal of necrotic debris. If the brain attempts to create new collaterals, microvessel density should increase significantly after ischemia. Conversely, if angiogenic-signaling molecules serve some other purpose, microvessel densities may increase slightly or not at all. To clarify, the authors measured microvessel densities with quantitative morphometry. Left middle cerebral arteries of adult male Sprague-Dawley rats were occluded with intraluminal nylon suture for 4 hours followed by 7, 14, 19, or 30 days of reperfusion. Controls received no surgery or suture occlusion. Changes in microvessel density and macrophage numbers were measured by light microscopic morphometry using semiautomated stereologic methods. Microvessel density increased only in the ischemic margin adjacent to areas of pannecrosis and was always associated with increased numbers of macrophages. Ischemic brain areas without macrophages displayed no vascularity changes compared with normal animals. These data suggest that ischemia-induced microvessels are formed to facilitate macrophage infiltration and removal of necrotic brain.

Glutamate antagonist therapy reduces neurologic deficits produced by focal central nervous system ischemia.

Ischemia may increase synaptic concentrations of glutamate, which may cause neuronal damage. Drugs that antagonize glutamate's effects may reduce this type of damage. MK-801, an N-methyl-D-aspartate receptor antagonist that readily enters the central nervous system, was evaluated in two focal central nervous system ischemia models: a multiple cerebral embolic model and a rabbit spinal cord ischemia model. When animals were treated five minutes after the onset of injury, MK-801 was effective in reducing ischemic damage in both models. In the multiple cerebral embolic model, the average dose of microspheres trapped in the brain increased from 344.8 +/- 51.4 micrograms (n = 29) in controls to 534 +/- 41.4 micrograms (n = 17) in the MK-801-treated group. Similarly, in the rabbit spinal cord ischemia model, the average ischemia duration increased from 28.9 +/- 1.7 minutes (n = 52) in controls to 50.6 +/- 3.9 minutes (n = 12) in the MK-801-treated group. These results suggest that this glutamate antagonist should be useful for the treatment of stroke.

Migrainous stroke.

Twenty-two patients with acute migraine-associated stroke were prospectively evaluated; 91% were female, and 23% had a prior history of presumed migrainous stroke. The incidences of major stroke risk factors and mitral valve prolapse were no higher for the study group than for the general population of similar age. Computed tomography, magnetic resonance imaging, or radionucleotide scanning of the brain was performed on all patients, and demonstrated ischemic or hemorrhagic infarction in 12 (55%). Cerebral arteriography revealed abnormalities related to the acute stroke in five (42%) of 12 cases overall, and in four (67%) of six studies performed within 72 hours of stroke onset; one patient (8%) suffered significant complications from arteriography. Although a variety of processes, alone or in combination, may contribute to migrainous stroke, extracranial and/or intracranial vasospasm appears to play a major role in at least some cases.

Intracerebral hemorrhage after experimental embolic infarction. Anticoagulation.

Embolic stroke was induced in rabbits using autologous blood clot. One hour after stroke, animals received heparin anticoagulation (AC) for five hours (acute AC) or five days (chronic AC). Animals received excessive AC (partial thromboplastin time greater than 3.0 times control), adequate AC (partial thromboplastin time, 1.2 to 2.5 times control), or saline. After the animals were killed, the brains were examined for macroscopic evidence of intracerebral hemorrhage. There was no significant increase over control in the incidence or severity of hemorrhage in any of the four treatment groups. The data suggest that heparin AC does not promote intracerebral hemorrhage after experimental embolic stroke.

Tissue plasminogen activator. Reduction of neurologic damage after experimental embolic stroke.

Tissue plasminogen activator (tPA) has become available for pharmacologic use, and it appears to produce relatively fewer hemorrhagic complications than the previously available, less specific thrombolytic agents. We tested the effects of tPA in several models of embolic stroke and found that neurologic damage was reduced when the drug was administered as late as 45 minutes after cerebral embolic occlusion. The mechanism of therapeutic efficacy of tPA was probably thrombolysis. Drug-induced hemorrhages did not occur when therapy was started within four hours after the onset of vascular occlusion. These results suggest that tPA may be useful for thrombolytic therapy of embolic stroke if the drug is administered rapidly after the onset of vascular occlusion.

Total quality improvement method for reduction of delays between emergency department admission and treatment of acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.

OBJECTIVE: To develop an approach for reducing time between emergency department (ED) admission and treatment in patients with acute ischemic stroke to meet the challenge of providing tissue plasminogen activator treatment within 180 minutes. DESIGN: An observational study. SETTING: Forty trial-affiliated hospitals, including 30 community hospitals. PARTICIPANTS: A total of 17,324 consecutive patients admitted to trial-affiliated hospital EDs within 24 hours of possible stroke, from January 1991 through October 1994. INTERVENTION: Appraisal of the process of triage, evaluation, diagnosis, and treatment by means of total quality improvement techniques in each hospital. Staff participating in the process identified sources of variation and modifications by flow charting the process. MAIN OUTCOME MEASURE: Time between ED admission and treatment with study medication. RESULTS: Total quality improvement methods identified hospital-specific process improvements. Many improvements were administrative, requiring no additional resources. More than 50% of screened patients arrived too late to be treated. Only 1268 patients were admitted between 0 and 125 minutes from stroke onset with no other trial exclusion criteria; 48% were treated. Of 243 patients admitted between 126 and 170 minutes from stroke onset with no exclusion criteria, 4% were treated. Mean time from ED admission to treatment was similar in teaching and community hospitals. CONCLUSIONS: Total quality improvement methods identified ED-specific sources of process variability and reduced time between ED admission and treatment. Therefore, these methods should be considered in developing and monitoring emergent stroke treatment protocols.

Ischemic stroke associated with methamphetamine inhalation.

Intracranial hemorrhage and ischemic stroke have been reported to complicate oral or intravenous use of methamphetamine. We report three cases of ischemic stroke following methamphetamine inhalation.

'Crescendo' transient ischemic attacks: clinical and angiographic correlations.

Forty-seven consecutive patients presenting acutely with repetitive symptoms indicative of anterior circulation ischemia ("crescendo" transient ischemic attacks) were evaluated to identify clinical features that might reliably predict the presence of significant stenosis, ulceration, or both in the presumably symptomatic internal carotid artery. Angiographic or intraoperative correlation was obtained in all patients, and 26 (55%) were found to have anatomically significant disease. Of 20 patients with signs or symptoms suggestive of cortical ischemia, amaurosis fugax, or both, 17 (85%) had "positive" angiograms; of 18 with numbness/weakness only, 9 (50%) had positive angiograms; of 9 whose symptoms suggested lacunar ischemia, none had positive angiograms.

Tissue plasminogen activator-mediated thrombolysis of cerebral emboli and its effect on hemorrhagic infarction in rabbits.

Tissue plasminogen activator (tPA) dissolves intravascular thrombus and restores blood flow after thromboembolic vascular occlusion. The utility of this agent for treatment of stroke in humans may be limited by post-reperfusion hemorrhagic complications. We studied tPA-mediated thrombolysis in an animal model of cerebrovascular occlusion in order to determine what factors, if any, predispose tPA-treated animals to suffer hemorrhage. Small blood clot emboli were injected into the internal carotid arteries of rabbits. Angiograms confirmed occlusion of the middle cerebral artery or internal carotid artery in 100% of subjects. tPA or saline was administered as a 30-minute infusion at various times after embolization. Hemorrhage rates were similar in all groups regardless of treatment. tPA increased the prothrombin time and the thrombin time but not the partial thromboplastin time. There was no correlation between these changes in blood coagulation and the finding of cerebral hemorrhage. We observed a significant association between stroke severity and cerebral hemorrhage. We conclude that tPA treatment successfully causes thrombolysis of cerebral emboli without causing an increase in the incidence of cerebral hemorrhage in rabbits.

Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial.

BACKGROUND: Hyperglycemia during acute ischemic stroke may augment brain injury, predispose to intracerebral hemorrhage (ICH), or both. METHOD: To analyze the relationship between admission glucose level and clinical outcomes from acute ischemic stroke, the authors performed multivariate regression analysis with the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial data. Neurologic improvement was defined as improvement on the NIH Stroke Scale by 4 or more points from baseline to 3 months, or a final score of zero. Favorable outcome was defined as both Glasgow Outcome score of 1 and Barthel Index 95 to 100 at 3 months. Symptomatic ICH was defined as CT-documented hemorrhage temporally related to clinical deterioration within 36 hours of treatment. Potential confounding factors were controlled, including acute treatment (rt-PA or placebo), age, baseline NIH Stroke Scale score, history of diabetes mellitus, stroke subtype, and admission blood pressure. RESULTS: There were 624 patients enrolled within 3 hours after stroke onset. As admission glucose increased, the odds for neurologic improvement decreased (odds ratio [OR] = 0.76 per 100 mg/dL increase in admission glucose, 95% CI 0.61 to 0.95, p = 0.01). The relation between admission glucose and favorable outcome depended on admission mean blood pressure (MBP): as admission MBP increased, the odds for favorable outcome related to increasing admission glucose levels progressively decreased (p = 0.02). As admission glucose increased, the odds for symptomatic ICH also increased (OR = 1.75 per 100 mg/dL increase in admission glucose, 95% CI 1.11 to 2.78, p = 0.02). Admission glucose level was not associated with altered effectiveness of rt-PA. CONCLUSIONS: In patients with acute ischemic stroke, higher admission glucose levels are associated with significantly lower odds for desirable clinical outcomes and significantly higher odds for symptomatic ICH, regardless of rt-PA treatment. Whether this represents a cause and effect relationship remains to be determined.

Effect of ischemic cerebral volume changes on behavior.

Ischemia causes long-term effects on brain volume and neurologic function but the relationship between the two is poorly characterized. We studied the relationships between brain volume and three measures of rodent behavior after cerebral ischemia was induced by injecting several thousand microspheres into the internal carotid arteries of rats. Forty eight hours later, each subject was rated using a global neurologic rating scale. Several weeks later, the subjects were tested for open field activity and visual spatial learning. Post-mortem we measured the volume of the cerebral hemispheres and estimated the volume densities of cortex, white matter, hippocampus, basal ganglia, thalamus, ventricle, and visible infarction. Ischemia caused significant impairment, as measured by the global rating scale; the probability of an abnormal rating was correlated with the number of microspheres trapped in the brains. Visual spatial learning was significantly impaired by ischemia, but this deficit was independent of the count of microspheres, whether the subject was abnormal at 48 h, and whether the left or right hemisphere was embolized. Cerebral hemisphere volume was reduced from 430 mm3 to 376 mm3 (P < 0.05). The cortex was reduced from 22 to 19% of cerebrum (P < 0.05) and the white matter compartment was reduced to similar degree. The lesion volume was 6% of cerebrum, comparable to that seen with other ischemia methods. The global outcome rating was significantly related to total cerebral volume, but not to volume changes in any single compartment. On the other hand, visual spatial learning was significantly influenced by volume changes in the cortex and white matter, but not by the topography of the visible infarctions. Open field activity was not altered by infarction. Our data suggests that the total volume of brain tissue lost to infarction may partially determine global neurological rating independently of the topography of the volume loss. Integrative functions such as learning may depend more on the integrity of specific compartments and less on the total volume of intact brain. The volume of visible cystic infarction was not related to long term behavioral outcome. These results should be confirmed using another method of inducing ischemia.

A model for quantitative evaluation of embolic stroke therapy.

We developed a small animal embolic stroke model for pharmacological screening trials. Microspheres are injected into the carotid circulations and group embolus dose-response relationships are calculated. Emboli quantity is related to neurologic injury, and small changes in neurologic function are detectable. Rabbits tolerated twice as many microspheres when cyproheptadine-treated after embolization. This demonstrated both the sensitivity of the model and the value of serotonin antagonists in reducing neurological injury.

Dialysis dysequilibrium syndrome in neurosurgical patients.

Four neurosurgical patients with acute renal failure are presented. Intracranial pressure (ICP), cerebrospinal fluid (CSF) osmolality, and plasma osmolality were measured before, during, and after hemodialysis. There was an increase in ICP during all six hemodialyses performed on these patients. An osmolality gradient was established between the plasma and the CSF during four hemodialyses performed on two patients but not during one hemodialysis on one other patient. Continuous ventricular drainage and ICP monitoring were simple and effective clinical methods to avoid irreversible herniation during hemodialysis in these patients. A review of the literature on, proposed pathogenesis of, and prophylactic possibilities for dialysis dysequilibrium syndrome in neurosurgical patients is presented.