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Background and Purpose: Using newly developed computerized image analysis, we studied the heterogeneity of apparent diffusion coefficient of water (ADCw) values in human ischemic stroke within 10 hours of onset., Methods: Echo-planar trace diffusion-weighted images from 9 patients with focal cortical ischemic stroke were obtained within 10 hours of symptom onset. An Iterative Self-Organizing Data Analysis (ISODATA) clustering algorithm was implemented to segment different tissue types with a series of DW images. ADCw maps were calculated from 4 DW images on a pixel-by-pixel basis. The segmented zones within the lesion were characterized as low, pseudonormal, or high, expressed as a ratio of the mean+/-SD of ADCw of contralateral noninvolved tissue., Results: The average ADCW in the ischemic stroke region within 10 hours of onset was significantly depressed compared with homologous contralateral tissue (626.6+/-76.8 versus 842.9+/-60.4x10(-6) mm2/s; P<0.0001). Nevertheless, ISODATA segmentation yielded multiple zones within the stroke region that were characterized as low, pseudonormal, and high. The mean proportion of low:pseudonormal:high was 72%:20%:8%., Conclusions: Despite low average ADCW, computer-assisted segmentation of DW MRI detected heterogeneous zones within ischemic lesions corresponding to low, pseudonormal, and high ADCw not visible to the human eye. This supports acute elevation of ADCw in human ischemic stroke and, accordingly, different temporal rates of tissue evolution toward infarction.

We evaluated the ability of an MR signature model (SM) of cerebral ischemic injury to stage the evolution of cellular damage in human stroke. In 19 patients with ischemic stroke of presumed embolic or non-embolic cause we carried out diffusion-weighted and T2-weighted MR imaging within 48 h of onset, and obtained apparent diffusion coefficient of water (ADCw), and T2 weighted images. We used the signatures obtained from these ADCw/T2 maps to formulate two patterns of damage signifying accelerated or non-accelerated progression of cellular death after stroke onset. Those patients with the accelerated pattern corresponded to those with the neuroradiological (NRC) and clinical diagnosis (TOAST.1 and TOAST.2) of presumed embolic stroke, with clinical diagnosis performed blinded both to NRC and to SM. Agreement between the SM and NRC was substantial (kappa=0.62), moderate (0.60

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.

Background and Purpose: We sought to identify MRI measures that have high probability in a short acquisition time to predict, at early time points after onset of ischemia, the eventual development of cerebral infarction in clinical patients who suffer occlusion of a cerebral artery., Methods: We developed an MR tissue signature model based on experimentally derived relationships of the apparent diffusion coefficient of water (ADCw) and T2 to ischemic brain tissue histopathology. In eight stroke patients we measured ADCw and T2 intensity using diffusion-weighted echo-planar imaging (DW-EPI). Tissue signature regions were defined, and theme maps of the ischemic focus at subacute time points after stroke onset were generated., Results: Five MR signatures were identified in human stroke foci: two that may predict either cell recovery or progression to necrosis, one that may mark the transition to cell necrosis, and two that may be markers of established cell necrosis., Conclusions: An MR tissue signature model of ischemic histopathology using ADCw and T2 can now be tested for its potential to predict reversible and identify irreversible cellular damage in human ischemic brain regions.

Leukocytes may have an important role in the pathogenesis of brain injury after ischemia. Expression of adhesion molecules on leukocytes and/or endothelia is needed for leukocytes to adhere to endothelia and infiltrate into the injured brain. The purpose of the present pilot study is to delineate whether the expression of leukocyte adhesion molecules, CD11a and CD18, are upregulated in patients with ischemic stroke and transient ischemic attack. Ten patients with ischemic stroke, 6 with transient ischemic attack (TIA), and 11 age and risk factor matched controls were studied. Using immunofluorescence phenotyping and flow cytometry, leukocyte membrane expression of CD11a and CD18 were measured within 72 h after onset of ischemia. Follow-up measurements were performed at 5-7 days after ictus in 6 patients with stroke, and at 3-5 days after ictus in 3 patients with TIA. CD11a immunofluorescence (IF) was significantly increased within 72 h after onset of symptoms in patients with stroke as well as TIA compared with the control group (p < 0.017). IF of CD18 also increased in both patient groups, but significance was reached only in the TIA group (p < 0.05). No difference of CD11a and CD18 IF was detected between stroke and TIA groups. Follow-up measurement of CD11a and CD18 showed a trend of decrease, but CD11a IF remained significantly elevated compared with the control group (p < 0.017). Expression of leukocyte adhesion molecules CD11a, and CD18 are upregulated in patients with ischemic stroke and TIA. Although these data are preliminary, our data suggest that these molecules are associated with cerebrovascular disorders including ischemic stroke and TIA.

Background and Purpose: Despite the frequent use of clinical rating scales in multicenter therapeutic stroke trials, no generally acceptable method exists to train and certify investigators to use the instrument consistently. We desired to train investigators to use the National Institutes of Health Stroke Scale in a study of acute stroke therapy so that all examiners rated patients comparably., Methods: We devised a two-camera videotape method that optimizes the visual presentation of examination findings. We then measured the effectiveness of the training by asking each investigator to evaluate a set of 11 patients, also on videotape. We tabulated the evaluations, devised a scoring system, and calculated measures of interobserver agreement among the participants in this study., Results: We trained and certified 162 investigators. We found moderate to excellent agreement on most Stroke Scale items (unweighted kappa > 0.60). Two items, facial paresis and ataxia, exhibited poor agreement (unweighted kappa < 0.40) and should be revised in future editions of the scale. Performance improved with video training compared with previous studies. Inclusion of the motor rating of the unaffected limbs in the total score did not affect reliability., Conclusions: Video training and certification is a practical and effective method to standardize the use of examination scales. Two cameras must be used during the taping of patients to accurately present the clinical findings. This method is easily adapted to any study in which a large number of investigators will be enrolling patients at multiple clinical centers.

The epidemiology of migraine-related stroke is reviewed. The International Headache Society classification of "migrainous cerebral infarction" is further categorized according to defined diagnostic criteria. Migraine-induced stroke is one of a number of migraine-related stroke syndromes.

We report clinical and angiographic features of accelerated intracranial occlusive disease resembling moyamoya vasculopathy in five young women who used oral contraceptives (OCs) and smoked cigarettes, but generally had no other obvious risk factors for cerebrovascular disease. Three women had been on OCs for at least 4 years, one woman each had been on OCs for 3 months and for 2 weeks. All five women had smoked cigarettes for at least eight pack-years. Intermittent and progressive multifocal cognitive, visual, motor, or sensory hemispheric symptoms and signs developed in all. All patients developed strokes, four preceded by transient ischemic attacks. Cerebral angiography demonstrated bilateral supraclinoid internal carotid artery stenosis in four patients and proximal posterior cerebral artery stenosis in one. Additional features included rete mirabile, telangiectasias, prominent lenticulostriate collaterals, and multifocal distal cerebral branch occlusions. Three had mild abnormalities of serum fibrinogen, antinuclear antibody, erythrocyte sedimentation rate, or CSF IgG. After discontinuing OCs and reducing cigarette use, four women have not had further strokes over a mean follow-up of approximately 5 years. In certain young women, clinical and angiographic features resembling moyamoya may develop with the use of OCs and cigarettes. We speculate that an immunologically mediated vasculopathy may explain, in part, this unusual cerebrovascular syndrome in otherwise healthy young women.

Background and Purpose: This study sought to determine the degree of agreement between asymmetries of neuropsychological functioning and nine methods of quantifying asymmetries of regional cerebral blood flow., Methods: The regional cerebral blood flow methods combined three markers of cerebral blood flow asymmetry (percent hemispheric difference, maximum percent probe-pair asymmetry, and number of probe-pair asymmetries) with three indexes of regional cerebral blood flow (fast compartment flow, initial slope index, and initial slope). Eleven patients with left hemispheric ischemic strokes and 13 with right hemispheric ischemic strokes were studied with the xenon-133 inhalation technique and neuropsychological tests., Results: Blind clinical judgments of neuropsychological asymmetry significantly correlated with all nine methods of cerebral blood flow asymmetry determination; correlations ranged from -0.42 to -0.77. Clinical judgment of asymmetry of neuropsychological functioning accurately predicted the hemisphere of lower flow in 71-92% of cases, depending on the method of cerebral blood flow asymmetry determination. Agreement between cerebral blood flow and neurobehavioral signs of asymmetry was greater for initial slope and initial slope index than for the fast flow index. The initial slope and initial slope index showed equally good agreement. The use of the number of asymmetrical probe pairs to detect cerebral blood flow asymmetries agreed less well with neurobehavioral asymmetry than did the other two markers studied., Conclusions: Both the initial slope index and the initial slope measures of cerebral blood flow are useful in predicting neuropsychological asymmetries, especially when the magnitude of the asymmetry is taken into account.

Cocaine, especially in its alkaloidal or "crack" form, has been increasingly associated with cerebrovascular disease. Before the crack epidemic, cocaine hydrochloride (HCl) was also implicated as a cause of stroke. However, less is known about the differences in stroke subtypes, age at stroke onset, or presence of underlying structural cerebrovascular disease with different forms of cocaine use. We compared 26 patients (previously reported) from our four institutions plus 16 cases reported in the literature of stroke associated with alkaloidal cocaine to 63 (57 reported in the literature and six not previously reported from our four institutions) cases of stroke associated with cocaine HCl. Ischemic and hemorrhagic strokes are equally likely after alkaloidal cocaine use, whereas cocaine HCl is more likely (approximately 80% of the time) to cause hemorrhagic stroke, with approximately half the intracranial hemorrhages occurring from ruptured cerebral saccular aneurysms or vascular malformations. The presence of an underlying cerebral aneurysm was more common among patients with cocaine HCl-associated strokes than alkaloidal cocaine-associated strokes. Cerebral infarction was significantly more common among the alkaloidal cocaine users than in all the cocaine HCl users, and this was also true when alkaloidal cocaine users were compared with parenteral cocaine HCl (intravenous and intramuscular) users. Only hemorrhagic stroke has been reported with intravenous cocaine HCl use. We conclude that the pathogenesis of cocaine-related stroke is heterogeneous, and depends, in part, on the form of cocaine used.

The effect of chronic antiplatelet treatment on PAF--induced platelet aggregation, ATP--release, and cytoplasmic ionized calcium was studied in 20 acute ischemic stroke patients. Chronic antiplatelet treatment failed to suppress these PAF--induced platelet responses. We speculate that selective PAF antagonists may be useful in suppressing PAF--induced platelet activation, and thereby possibly improve the treatment of stroke.

The diagnosis of migraine-related stroke is reviewed and illustrative case histories are provided. The International Headache Society classification of "migrainous cerebral infarction" is amplified and further categorized using strictly defined diagnostic criteria. True migraine-induced stroke is revealed as only one of a number of migraine-related stroke syndromes.

To study the pathogenesis of platelet activation in ischemic stroke, ionized calcium ([Cai2+]) was measured in aequorin-loaded gel-filtered platelets in the basal and stimulated state. Basal [Cai2+] was increased in stroke patients maximally 36-72 hours after onset. The increase in [Cai2+] after stimulation with thrombin, collagen, and platelet-activating factor were also greater in stroke patients, but the profiles of these [Cai2+] changes were parallel to control. Cross incubation of control platelets with plasma from stroke patients resulted in raised basal [Cai2+] and caused the release of serotonin from platelets. These results indicate that the higher platelet basal [Cai2+] in stroke patients represents a lowered threshold for activation and that this may be due to a plasmatic factor rather than a primary platelet defect.

Lupus anticoagulants and anticardiolipin antibodies, known collectively as antiphospholipid antibodies, are becoming established as markers for increased risk of thrombosis, including ischemic cerebrovascular disease. In this brief review, we highlight evidence for and against a pathogenetic role of these antibodies in ischemic brain disease and comment on currently available laboratory studies to detect them. Future research on the association of antiphospholipid antibodies with neurological disease should focus on establishing the pathogenicity of these antibodies, identifying groups at high risk for recurrent ischemic cerebrovascular events, and initiating prospective multicenter natural history and treatment protocols.

The effect of intravenous infusion of 10 per cent glycerol on regional cerebral blood flow (using hydrogen bolus and Xenon-133 (133Xe) clearance methods) and metabolism was investigated in 57 patients with recent cerebral infarction. Hemispheric blood flow (HBF) increased, together with increase in regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV), in foci of brain ischemia. Hemispheric oxygen consumption (HMIO2) decreased together with hemispheric respiratory quotient. Systemic blood levels of glucose, lactate, pyruvate, and triglycerides also increased after glycerol while free fatty acids (FFA) and inorganic phosphate (Pi) decreased. Hemispheric glucose consumption was unaltered after glycerol so that hemispheric glucose to oxygen ratio tended to rise. Pyruvate and lactate production by brain was unchanged. Glycerol moved across the blood brain barrier into brain and cerebrospinal fluid (CSF). Release of FFA and Pi from infarcted brain was reversed by glycerol. Total phosphate balance was maintained actoss brain both before and after glycerol infusion. Triglycerides increased in CSF after glycerol, originating either from cerebral blood or as a result of lipogenesis in cerebral tissue. The EEG Recording and neurological status of the patients improved despite decreased brain oxygen consumption. Results of this study suggest that after intravenous infusion of 10 per cent glycerol in patients with recent cerebral infarction, glycerol rapidly enters the CSF and brain compartments and favorably affects the stroke process in two ways: first, by redistribution of cerebral blood flow with increase in rCBF and rCBV in ischemic brain secondary to reduction in focal cerebral edema; and second glycerol may become an alternative source of energy either by being directly metabolized by the brain, or indirectly, by enhancing lipogenesis, or by both processes. Involvement of glycerol in lipogenesis with esterification to accumulated FFA might lead to improved coupling of oxidative phosphorylation, a hypothesis that fits the finding of improved neuronal function despite further decrease in cerebral hemispheric oxygen consumption.

We present three cases of "crack" cocaine-associated stroke, together with a review of cocaine-associated cerebrovascular complications. Unlike previously reported cases tentatively associating ischemic stroke with cocaine, our patients had no other potential causes for their strokes. Although the exact mechanism of cocaine-related stroke remains uncertain, both disordered neurogenic control of the cerebral circulation as well as systemic factors (ie, acute hypertension) may play a role.

Platelet activating factor, a potent inducer of in vivo platelet activation and thrombosis, has been shown to be excessively active in acute ischemic stroke patients. Therefore, we studied the effect of aspirin/dipyridamole therapy in inhibiting platelet activating factor-induced platelet activation in acute ischemic stroke patients, 23 taking aspirin/dipyridamole and 21 untreated. Aspirin/dipyridamole-treated patients failed to show suppression of platelet activating factor-induced platelet aggregation even though collagen-induced activation was inhibited, suggesting that platelet activating factor acts by cyclooxygenase-independent mechanisms. Failure to suppress cyclooxygenase-independent mechanisms of platelet activation may explain the limited usefulness of current antiplatelet therapy, aspirin in particular, in stroke prevention. The role of selective platelet activating factor antagonists both in isolation and combined with aspirin needs to be investigated for their usefulness in the treatment and prevention of ischemic stroke.

Cerebral hemispheric blood flow and metabolism were measured before and after therapy with intracarotid infusion of combined PBZ and PPL in 15 patients with recent cerebral infarction. HBF was unaltered despite decrease in cerebral perfusion pressure. Cerebral hemispheric oxygen comsumption and carbon dioxide production decreased while cerebral hemispheric lactate production increased. Biphasic cerebral uptake of tyrosine was observed during and immediately after PBZ and PPL infusion. CSF HVA increased, indicating altered DA turnover. CSF 5HIAA levels also increased, suggesting altered 5HT turnover after PBZ and PPL. Release of cyclic AMP from ischemic brain into cerebral venous blood seen in the steady state was abolished after therapy. Cerebral hemodynamic studies suggest a functional balance between monaminergic neurogenic influences in the control of cerebral circulation. Imbalance of such controlling factors in ischemic brain may lead to paradoxical vascular responses to induced hypertension and hypotension. PBZ and PPL enhance such responses perhaps by increasing central neurotransmitter turnover and release. Further shift toward cerebral anaerobic metabolism may occur in ischemic brain following the use of phenoxybenzamine and propranolol. Worsening of neurological deficit occurred in four cases. Combined therapy with PBZ and PPL does not appear beneficial in the therapy of patients with recent stroke.

We studied platelet function in whole blood, a situation that better reflects the in vivo state, from 85 patients with acute ischemic stroke and from 19 healthy controls. Patients receiving no antithrombotic drugs demonstrated increased platelet dense body secretion without an associated increase in platelet aggregation, thus raising the possibility that dense body secretion may be of separate importance in cerebral infarction. Our results also suggest that dense body secretion may occur independently of aggregation. Heparin and heparin plus warfarin were ineffective in reducing the high level of dense body secretion seen in acute cerebral infarction, whereas treatment with aspirin plus dipyridamole inhibited both dense body secretion and platelet aggregation. It seems worthwhile to investigate the usefulness of antiplatelet drugs in the treatment of acute ischemic stroke wherein clinical outcome is correlated with the extent of suppression of platelet dense body secretion.

Seizure activity as a component of the ischemic process possibly responsible for monoamine changes described in the gerbil stroke model was the subject of this study. Abnormal motor activity suggestive of seizures developed one to three hours after unilateral ligation of the common carotid artery in approximately 50% of gerbils that exhibited signs of stroke. Reduction of cortical levels of dopamine and norepinephrine was observed only when seizures occurred in association with stroke. The levels of 5-hydroxytryptamine were reduced bilaterally in animals with and without signs of stroke and were reduced further in animals with stroke plus seizures. Further study is needed to establish whether the catecholamine changes associated with ischemia-induced seizures are primary and causative or secondary to seizure activity itself. In the ischemic brain, 5-hydroxytryptamine metabolism appears disordered independent of seizure activity. Seizure activity must be taken into account when the mechanisms of disordered monoamine metabolism are being examined in the gerbil stroke model.

We studied 15 patients with angiographically documented intraluminal clot in the vertebrobasilar (VB) circulation and ischemic stroke. Progressive brainstem signs were the most common presentation; the neurologic deficit was maximum at stroke onset in 4. Seven experienced their first symptoms during sedentary activities. Thirteen of the initial 15 CTs revealed infarcts in the VB territory, 7 with multiple foci. Intraluminal clot was present in the vertebral artery in 7 patients (2 bilateral), basilar artery in 7, posterior cerebral artery in 5, and superior cerebellar artery in 1. Multiple clots were seen in 5 patients. Stroke risk factors were present in the majority of cases. Although cardiac source embolism was the most common single etiology (4 patients), most patients had other causes including migraine, coagulopathy associated with malignancy and nephrotic syndrome in systemic lupus erythematosus, vertebral artery dissection with local embolism, delayed irradiation arteriopathy, and a fusiform, ectatic basilar artery. Six (40%) died within 5 months of follow-up. Intraluminal clot in the posterior circulation is a marker for multiple stroke mechanisms, not all of which are embolic. Intraluminal clot should prompt investigations into occult risk factors when no cause appears obvious.

We report a young migraine sufferer who developed bilateral posterior cerebral artery territory infarcts during the course of his classic migraines, the second of which was associated with intraluminal clot in the posterior cerebral artery. To our knowledge, bilateral posterior cerebral artery stroke from spontaneous migraine has not been reported. Head computed tomographic, magnetic resonance imaging, and angiographic correlation is presented. The mechanism of migrainous infarction may be in part explained by caliber changes in arterioles and capillaries leading to flow reduction in the more proximal conduit arteries combined with the associated coagulopathy that has been previously documented during migraine attacks.

Cerebral hemispheric blood flow (HBF) and metabolism were measured before and after withdrawal of 20 to 30 ml of cerebrospinal fluid (CSF) over a 10-minute interval in eight patients with recent cerebral infarction and in four patients with Alzheimer's disease (AD). Immediately after CSF removal HBF decreased significantly in the AD group (-14%) but showed no significant change in the stroke group (-5%). There was rapid reduction in cerebral venous O2 content and some increase in cerebral venous PCO2 appearing within 60 seconds of CSF withdrawal, interpreted as a rapid reduction of cerebral blood flow (CBF) as judged by cerebral A-VO2 differences. The reduction in CBF was confirmed by the hydrogen clearance method. Reduction of CBF in response to lowering CSF pressure is presumably of neurogenic origin since it was rapid and occurred without changes in PaCO2 or MABP. Furthermore, measurement of HBF demonstrated that cerebral metabolism constant after CSF removal. It is postulated that in AD, reduction of HBF following CSF withdrawal is mediated by a disordered neurogenic veno-arterial vasoconstriction reflex which is stimulated by rapid reduction in CSF pressure (CSFP). In patients with stroke, when cerebral perfusion pressure is increased by lowering CSFP, CBF is maintained constant most likely by a physiological cerebral veno-arterial vasoconstrictive reflex. Apparently, this vasocontrictive reflex becomes excessive in Alzheimer's disease, possibly due to cerebral neurogenic imbalance.

Twenty-four neurologically normal subjects, 12 in their twenties and 12 in their sixties, were included in a protocol that studied the relationship of resting cerebral blood flow and cerebral blood flow activation by neuropsychological testing to age and stroke risk factors. Both age and a stroke risk index were predictive of a reduced resting cerebral blood flow. Despite this, cerebral blood flow activation relative to resting flow was preserved. Subclinical lesions of deep white matter are proposed to explain the apparently paradoxical result that resting cerebral blood flow is decreased by factors that damage cerebral vessels, while cerebral vascular reactivity is unimpaired.