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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. 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. 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. 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.

Evidence linking changes in calcium/calmodulin-dependent protein kinase II activity with ischemic cell death has been reported in animal models of global ischemia. The purpose of this study was to delineate the course of these changes after focal ischemia and to clarify the relation of changes in activity of calcium/calmodulin-dependent protein kinase II to the process of ischemic cell death. Change in calcium/calmodulin-dependent protein kinase II activity was evaluated in a rat model of focal ischemia after 5 minutes, 30 minutes, and 1 hour of tandem middle cerebral artery and common carotid artery occlusion both with and without reperfusion. Calcium/calmodulin-dependent protein kinase II activity was significantly decreased after all three durations of ischemia followed by immediate decapitation compared with sham-operated animals, in both ischemic core and border-zone regions (P < .05 for all groups). Depression of activity occurred in a regionally graded fashion, with the most severe decrease in infarct core and progressively smaller decreases in samples moving out from the center, corresponding to the severity of histological injury later detected in infarct core and border-zone regions. There were only minor differences between the three durations of ischemia in the degree of enzyme depression noted in the more peripheral regions, indicating that the initial decrease in calcium/calmodulin-dependent protein kinase II activity is an early, sensitive marker for an ischemic insult. After reperfusion, the differences between the 5-minute group and longer periods of ischemia widened because of an increase toward baseline in the 5-minute group and a trend toward further decrease in the 30- and 60-minute groups. The extreme sensitivity of calcium/calmodulin-dependent protein kinase II to focal ischemia and the parallel temporal and regional changes in its activity to those of more delayed cell injury point to a potential role for this enzyme in the process of excitotoxic injury.

Criteria for selecting patients for possible surgery in the management of intracerebral hemorrhage (ICH) are needed to plan a prospective therapeutic evaluation of surgical intervention. This study specifically addressed patients seen in the emergency room within a few hours of the ictus, many of whom were still awake, to identify and subsequently exclude from surgical procedure those expected to recover completely and those expected to die regardless of treatment. We retrospectively studied 75 patients evaluated at a mean time of 3 hours and 37 minutes after hemispheric ICH to determine factors that would predict both good and poor outcomes at the time of discharge. Eighty percent of our patients presented within 6 hours of symptom onset. These patients were younger and had more severe lesions than did those presenting later, yet most were still awake (mean admission Glasgow Coma Scale [GCS] score = 11.0). Using multivariate regression, we created two models. The first model predicts independent outcome, ie, Rankin 0 to 2, of all patients with a GCS score greater than 9 on admission who do not undergo surgery. The significant factors in this model were hemorrhage diameter, intraventricular extension, and age. The second model predicts poor outcome, ie, Rankin 5 and death, of all patients. GCS score, hemorrhage volume, age, and gender were the important factors in this model. We conclude that ICH patients presenting early to the emergency room have more severe lesions radiologically, although their initial clinical status may not be different from those seen late. Our models should identify and thus exclude those with very good and very poor prognoses from future randomized surgical trials.

What we need to carry out in the laboratory and at the bedside are experiments. If our experiments have been positive in the laboratory but negative at the bedside, it is logical to me that at the bedside we need to better emulate the conditions under which the laboratory experiment turns out positive; in other words, we need to do the “rat experiment” in man. Those clinical studies that have adhered to this dictum1–3 have been the only positive clinical trials to date. Figure 1 depicts the general design of the rat transient middle cerebral artery occlusion model that is most often used to test neuroprotective drugs. It also depicts the general design of the sort of clinical trial that I postulate must be done to get positive results in stroke patients. There are 4 main areas where clinical trials have departed most from this model. In rats, we take pains to produce lesions of standardized severity in order to better detect a treatment effect; we start by giving the drug soon after the onset of stroke and then determine how much this time to treatment (TTT) can be lengthened; we use models of temporary rather than permanent arterial occlusion; and we increase doses of drug until we see a therapeutic effect. Figure 1. Proposed algorithm for studying neuroprotective drugs in laboratory animals and human stroke patients. These factors must all be addressed in the design of future clinical trials, and they are listed in Figure 2 along with …

New therapeutic interventions for acute ischemic stroke are aimed at improving cerebral blood flow in the first 3 to 6 hours after symptom onset. Single-photon emission-computed tomography (SPECT) performed in the setting of clinical therapeutic trials may give us a better understanding of the physiological response to new forms of treatment and could impact acute management decisions. We prospectively studied 15 patients with hemispheric ischemic stroke with SPECT within 6 hours of symptom onset and again at 24 hours. The ischemic defect was assessed in a semiquantitative manner that used computer-generated regions of interest (SPECT graded scale). This measure was correlated with clinical presentation (National Institutes of Health [NIH] Stroke Scale), initial clinical course (change in NIH Stroke Scale), long-term outcome (Barthel Index at 3 months), and complications of cerebral hemorrhage and edema. The severity of the SPECT graded scale on the admission scan correlated with the severity of neurological deficit (admission NIH Stroke Scale) (P < .05) and was positively associated with poor long-term outcome as measured with the Barthel Index (P < .001) and the complications of cerebral hemorrhage and massive cerebral edema (P < .005). In fact, there was a threshold value for the SPECT graded scale above which all patients suffered poor long-term outcome and the complications of cerebral hemorrhage and edema. The measurement of an ischemic defect using SPECT is a valid assessment of hemispheric stroke severity in the hyperacute setting and may be useful for selecting or stratifying patients in clinical therapeutic trials.

One explanation for inconclusive results with calcium channel blockers in human acute stroke trials may be incomplete information about the time course of calcium-mediated ischemic neuronal injury. This study explores the temporal relation between duration of focal ischemia and the functional activity of increased intracellular calcium as measured by calcium-calmodulin binding. Calcium-calmodulin binding, determined by immunohistochemical assay of free calmodulin, was measured in 60 male spontaneously hypertensive rats after 2 minutes and after 1, 2, 4, and 24 hours of permanent tandem common carotid and middle cerebral artery occlusion, and after 1 and 2 hours of reversible middle cerebral artery occlusion followed by 1 and 22 hours of reperfusion, respectively. Light microscopic histological damage was measured after 1 hour of occlusion with 23 hours of reperfusion and after 24 hours of occlusion. Significant loss of calmodulin staining in the core of the infarction was noted by 1 hour and became maximal after 4 hours of ischemia. No reversal of calmodulin staining loss was noted after reperfusion following 1 and 2 hours of ischemia. Cortical necrosis seen by light microscopy correlated well with the area of maximal calcium-calmodulin binding. The border zone area, represented by a mild loss of calmodulin staining surrounding the central core of maximal binding, gradually decreased in size and became incorporated into the central core after 4 hours of ischemia; it may represent an area of reversible ischemia. Calcium-calmodulin binding correlates with duration of focal ischemia, and histological neuronal necrosis corresponds to the cortical areas displaying a significant loss of calmodulin staining. Inasmuch as loss of calmodulin staining represents a marker for calcium-mediated activity after ischemia, it suggests a window of opportunity within 4 hours after acute stroke for therapeutic intervention with calcium antagonists.

This study analyzed the ability of the N-methyl-d-aspartate receptor antagonist dextrorphan (DX) to prevent neuronal degeneration (analyzed by light microscopy), calmodulin (CaM) redistribution (analyzed by immunocytochemistry) and changes in activity of two major Ca2+-dependent protein kinases—calcium/calmodulin-dependent protein kinase II (CaM-KII) and protein kinase C (PKC) (analyzed by specific substrate phosphorylation) after 20 min of global ischemia (four-vessel occlusion model) in rats. DX treatment before and after ischemia significantly protected hippocampal and cortical neurons from neurodegeneration whereas DX posttreatment alone did not have any effect on preservation of neuronal morphology as compared with placebo treatment analyzed 72 h after 20 min of ischemia. Similarly to histological changes, DX exhibited protection against redistribution of CaM observed after ischemia. These changes were detected both in hippocampus as well as in cerebral cortex. Finally, DX administered before ligation of the carotid arteries reduced loss in both CaM-KII and PKC activity evoked by ischemia.

However, there is a pathological process, namely, emboli-zation, that leads to arterial occlusion in the cerebral circula-tion much more frequently than in the coronary bed. Conse-quently, the detection and prevention of embolic events iscritical to reducing the burden of stroke. Emboli may causeeither large disabling strokes or small subclinical events,depending on the size and eventual location of the embolus.Emboli generated from the chambers or valves of the heart orfrom atherosclerotic plaques in the arteries of the neck arevariable in their size and consistency. When the cardiacchambers are dyskinetic or fibrillating, leading to stasis andthe formation of thrombus, distal emboli are usually large,they lodge in the initial branches of the circle of Willis, andthe resultant strokes are devastating. The posterior wall of themost proximal portion of the internal carotid artery just distalto the bifurcation is a common site of atherosclerosis becauseof the unique hemodynamic effects caused by the flowdivider. Emboli from such large-artery atheroma may consistof a thrombus or pieces of calcified plaque, but they may alsobe microscopic if composed only of fibrin-platelet material. Ifsuch “microemboli” are ,0.1 mm in diameter, they mightpass into the small arteriolar branches. There they may belysed by endogenous protective hemostatic defenses, or theymay cause areas of microinfarction.Much has been learned about the clinical consequences andprevention of large emboli. Because such strokes are theleading cause of disability among US adults, multicenter,randomized, clinical stroke prevention trials have been orga-nized to reduce clinically apparent strokes as the primary endpoint. These have conclusively demonstrated that antiplatelettherapy reduces the incidence of recurrent stroke by ’20% to25%

P43 BACKGROUND: The increased prevalence of patent foramen ovale (PFO) in patients with cryptogenic stroke suggests the occurrence of paradoxical embolism. Previous studies have found paradoxical embolism to be uncommon in stroke, but few have focussed on patients with cryptogenic stroke. We therefore evaluated pelvic veins and leg veins in this population. METHODS: Eighteen patients (median age 45 years) with a cryptogenic brain ischemic event (stroke 16, TIA 2) underwent magnetic resonance venography (MRV). Evaluation consisted of time-of-flight (TOF) and phase contrast images through the pelvis. A positive MRV was defined as an intravascular decrease in signal intensity at least 15 millimeters (mm) in length contacting the wall of a vein and showing matching abnormalities on both pulse sequences. Lower extremity venous duplex examination was also performed in 17/18. RESULTS: All patients had normal cranial arteries, apart from the artery referable to the index stroke. A right-to-left intracardiac shunt was identified in 16/18. MRV was performed a median of 22 days (range, 2–416) post-event. In three patients, only the TOF was performed (all negative studies). There were three patients who had evidence for paradoxical embolism. Patient 1 had sickle cell disease and two small cortical emboli, a PFO, a 30 mm left external iliac vein clot three days post-stroke, and a right calf vein clot diagnosed 23 days post-stroke. Patient 2 had a history of right knee injury and surgery, top of the basilar embolus, a PFO, and a chronic clot in the distal right popliteal vein. Patient 3 had several hours of sudden dysarthria and confusion after pelvic surgery, a PFO, and a right calf vein clot two days post-TIA. One patient had a basilar artery embolus and a 20 mm right external iliac vein clot, but no PFO. Another patient had no DVT day 2 post-stroke, but bilateral calf vein DVT on day 10. CONCLUSIONS: Pelvic MRV has diagnostic utility in the evaluation of patients with cryptogenic stroke. Pelvic vein and calf vein thrombosis are a source of paradoxical embolism in some patients with cryptogenic stroke. The incidence of thrombus in these two sites requires further evaluation in this population.

Worldwide, CT scanning is by far the most available early CT changes, and both are correlated with worse imaging modality for evaluating acute stroke patients, and outcome. Whether the presence of early CT changes adds we have more data about the reliability and utility of CT in substantially more certainty about outcome than what we this setting than for any other imaging technique. Drs can conclude simply from a carefully quantitated neuroFiorelli and colleagues have added to our database by their logical exam (for instance by using the National Institutes evaluation of baseline CT scans in 158 patients with of Health Stroke Scale) requires careful statistical analysis suspected anterior circulation ischemia [1]. They found and remains, in my mind, uncertain. To make matters even that CT is reasonably sensitive to tissue damage since early more uncertain, recent studies have shown that abnorchanges of ischemia were detected in 49% of patients malities on diffusion-weighted MRI can be reversed by imaged within 5 h of symptom onset. They also found that reperfusion [2]. No such studies are available for early CT CT was reasonably accurate since the detected abnorchanges of ischemia, but if the same were true, early CT malities were almost always predictive of the ultimate changes might mislead the clinician into assuming (premainfarction except when early changes were limited only to turely) that the prognosis is poor. subcortical structures; of 27 such scans, infarction ultiA second problem is the reliability in recognizing and mately evolved to include both subcortical and cortical quantitating early CT changes of ischemia. The NINDS structures in 15. Finally, they found that the presence of group has recently published their data showing that interearly CT abnormalities were predictive of worse outcome. observor agreement was only ‘fair’ in detecting and Although the exact percentages differ somewhat from quantitating hypoattentuation of the CT signal on scans other studies, these findings are consistent with previous obtained within 3 h of stroke onset [3]. While others have studies and clinical experience. shown better agreement, and while it may be easier to Although such data are reassuring, we must not overagree on scans obtained later in the course after the state the information that CT provides, rely too heavily on changes are more obvious, uncertainly will undoubtedly the ‘shadows’ that we perceive on the CT images, nor remain about interpretation of individual CT scans. For should we jump to conclusions when applying this ininstance, when I looked at Fig. 1a, without reading the formation to clinical decision-making. figure legend, I would have said that in addition to First, it is still uncertain that early CT changes tell us subcortical changes, there is also effacement of cortical substantially more about long term clinical outcome than sulci, especially in the peri-sylvian region. If indeed CT is does simply quantitating the severity of the initial neuroimportant in decision-making, we need to make our logical deficit. The authors state that they adjusted for identification and quantitation of early CT changes more clinical severity on admission in their analysis finding that objective and reliable. more patients with CT changes died or were left disabled, Finally, it is extremely important to recognize that we but it is not clear how they determined baseline stroke still do not know the extent (if any) of early CT changes of severity or how it was factored into the analysis. Patients ischemia which should preclude administration of thromwith worse neurological deficit have a higher incidence of bolytic therapy if the patient otherwise qualifies. At least in the U.S. and Canada, the only approved use of thrombolysis is intravenous rtPA given within 3 h of stroke *Tel.: 11-713-500-7100 (x7092); fax: 11-713-500-7090 or 7019. E-mail address: jgrotta@neuro.med.uth.tmc.edu (J. Grotta) symptom onset, based on results of the NINDS rtPA Stroke

Background and Purpose— Enrollment in acute stroke trials at a stroke center with multiple study protocols may delay the initiation of intravenous thrombolytics in patients who present within 3 hours of symptom onset. Methods— We studied all patients presenting with acute ischemic stroke over the past 3.5 years who qualified for thrombolysis within 3 hours of symptom onset. We collected demographics, baseline National Institutes of Health Stroke Scale scores, CT findings, and arrival-to-treatment times and compared patients treated with intravenous thrombolytics in a clinical trial with patients who received standard of care intravenous tissue plasminogen activator. Results— Of 290 treated patients, 19 were enrolled in prelytic studies, 46 were enrolled in postlytic studies, and 225 were treated with standard intravenous tissue plasminogen activator. There was no significant difference in age, gender, National Institutes of Health Stroke Scale score, admission glucose, or changes on CT. There was no difference in onset-to-arrival time or arrival-to-treatment time between patients enrolled in clinical studies and those who received standard treatment. However, among study patients, prelytic randomization led to a significantly longer arrival-to-treatment time by 13 minutes ( P =0.028). Conclusion— We found that trials requiring prethrombolytic randomization can lead to a delay in the initiation of treatment. Future studies are needed to determine if such a delay is clinically significant and can be shortened by improved enrollment strategies.

Calcium antagonists may be useful for certain cerebrovascular conditions. In addition to producing a variable amount of cerebral vascular relaxation, high doses of some of these drugs may block calcium entry into neurons. Clinical trials in patients with vasospasm have clearly shown that calcium antagonists can improve outcome. Clinical trials in patients with acute stroke have been inconclusive, and have been flawed by delayed patient entry. Cardiovascular side effects may limit the safety and efficacy of calcium antagonists in acute stroke patients. Further investigation of early treatment with cerebroselective agents, possibly in conjunction with complementary therapies, is needed.

Activation of N-methyl-D-aspartate (NMDA) receptors by ischemia-induced glutamate release results in the entry of ionic calcium into neurons, followed by progressive neuronal damage by calcium-activated enzyme systems and delayed cell death. Earlier studies using excitatory neurotransmitter antagonists have demonstrated neuronal protection against ischemia, raising the possibility that these drugs can be used effectively in the therapy of acute stroke. When evaluating the effectiveness of a drug for use in cases of acute stroke however, it is important to demonstrate functional as well as histological improvement.

Background Most patients with cardioembolic stroke require long-term anticoagulation. Still, uncertainty exists regarding the best mode of starting long-term anticoagulation. Design, Setting, and Patients We conducted a retrospective review of all patients with cardioembolic stroke admitted to our center from April 1, 2004, to June 30, 2006, and not treated with tissue plasminogen activator. Patients were grouped by treatment: no treatment, aspirin only, aspirin followed by warfarin sodium, intravenous heparin sodium in the acute phase followed by warfarin (heparin bridging), and full-dose enoxaparin sodium combined with warfarin (enoxaparin bridging). Outcome measures and adverse events were collected prospectively. Laboratory values were captured from the records. Main Outcome Measures Symptomatic hemorrhagic transformation, stroke progression, and discharge modified Rankin Scale score. Results Two hundred four patients were analyzed. Recurrent stroke occurred in 2 patients (1%). Progressive stroke was the most frequent serious adverse event, seen in 11 patients (5%). Hemorrhagic transformation occurred in a bimodal distribution—an early benign hemorrhagic transformation and a late symptomatic hemorrhagic transformation. All of the symptomatic hemorrhagic transformation cases were in the enoxaparin bridging group (10%) ( P = .003). Systemic bleeding occurred in 2 patients (1%) and was associated with heparin bridging ( P = .04). Conclusions Anticoagulation of patients with cardioembolic stroke can be safely started with warfarin shortly after stroke. Heparin bridging and enoxaparin bridging increase the risk for serious bleeding. Published online July 14, 2008 (doi:10.1001/archneur.65.9.noc70105).

Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.

Background The ultimate test of an educational intervention is the sustainability of the effect after the intervention ceases. Methods The TLL Temple Foundation Stroke Project was a quasi-experimental study aimed at increasing Food and Drug Administration–approved acute stroke therapy in a nonurban community in east Texas. During the intensive community and professional intervention (phase 2), significantly more patients with acute stroke received intravenous tissue plasminogen activator (tPA) compared with the preintervention period (phase 1). In the comparison community, no change was noted. We present the results of tPA treatment in the 6 months after the intervention ended (phase 3). Results Two hundred thirty-eight patients had a validated stroke during phase 3. Among patients who experienced an ischemic stroke, 11.2% in the intervention group received intravenous tPA compared with 2.2% in phase 1 ( P = .007). In the comparison group, 1.4% received intravenous tPA in phase 3 compared with 0.7% in phase 1 ( P >.99). Among eligible candidates for treatment, 69.2% were treated in phase 3 in the intervention community compared with 13.6% in phase 1 ( P = .002). In the comparison group, 20.0% were treated in phase 3 compared with 6.7% in phase 1 ( P = .45). There was 1 protocol violation among the 9 patients treated in the intervention community in phase 3. Conclusions There was a sustained benefit of the intervention in increasing tPA treatments in the intervention community even after cessation of the educational effort. Treatments in the control community remained few through all 3 phases of the study. A carefully planned multilevel intervention can improve community stroke treatments even in a nonurban community.

ContextThe prevalence and clinical significance of early ischemic changes (EICs) on baseline computed tomography (CT) scan of the head obtained within 3 hours of ischemic stroke are not established.ObjectiveTo determine the frequency and significance of EIC on baseline head CT scans in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA (recombinant tissue plasminogen activator) Stroke Trial.Design and SettingThe original study, a randomized controlled trial, took place from January 1991 through October 1994 at 43 sites, during which CT images were obtained within 3 hours of symptom onset and prior to the initiation of rt-PA or placebo. For the current analysis, detailed reevaluation was undertaken after October 1994 of all baseline head CT scans with clinical data available pretreatment (blinded to treatment arm).PatientsOf 624 patients enrolled in the trial, baseline CT scans were retrieved and reviewed for 616 (99%).Main Outcome MeasuresFrequency of EICs on baseline CT scans; association of EIC with other baseline variables; effect of EICs on deterioration at 24 hours (≥4 points increase from the baseline National Institutes of Health Stroke Scale [NIHSS] score); clinical outcome (measured by 4 clinical scales) at 3 months, CT lesion volume at 3 months, death at 90 days; and symptomatic intracranial hemorrhage (ICH) within 36 hours of treatment.ResultsThe prevalence of EIC on baseline CT in the combined rt-PA and placebo groups was 31% (n = 194). The EIC was significantly associated with baseline NIHSS score (ρ = 0.23; P

P172 Background: Dramatic recovery (DR) during TPA infusion is not well described. Methods: We compared clinical patterns and time course in patients with DR to Non-DR. We prospectively captured acute MCA strokes treated with standard NINDS IV-TPA protocols and performed serial NIHSS exams. DR was defined as a decrease by ≥ 10 NIHSS points or total score of ≤3 by end of TPA infusion.Intracranial flow signals were graded using the Thrombolysis in Brain Ischemia (TIBI) scale. Results: From 9/98–6/00, DR was observed in 12/53 patients(Table). With DR, there was a consistent pattern and time course of recovery: Gaze preference recovered first (8/11 complete; 2/11 partial; 1/11 none); followed by Sensory (4/7 complete; 3/7 partial recovery; 0/7 none) and Leg Strength (8/10 complete; 1/10 partial; 1/10 none). Arm Strength followed next, but was often incomplete (5/12 complete; 6/12 partial;1/12 none) Certain findings had partial improvement later during infusion: Facial strength (3/12 complete; 7/12 partial; 1/12 none);Aphasia (2/7 complete; 4/7 partial; 1/7 none). Dysarthria tended not to improve during infusion(2/7 complete; 0/7 partial; 5/7 none). DR was observed in 22% of patients during IV-TPA infusion and was sustained at 24 hours. The stroke severity and timing to bolus was similiar between DR and Non-DR groups. Early recanalization was the only noted difference. Conclusion: The clinical pattern of DR may result from reperfusion of the white matter tracts supplied by MCA perforators or improved collateral flow. With clot lysis, the observed recovery pattern is referable to vessel anatomy. How DR occurs and why some clinical deficits have delayed recovery needs further study.

P187 BACKGROUND: Recanalization precedes clinical improvement in patients treated with IV TPA. Transcranial Doppler (TCD) can assess the timing and degree of recanalization. We studied how the degree of recanalization and the NIH stroke scale (NIHSS) at the end of infusion correlated with short-term clinical improvement at 24 hours. Subjects and Methods: We evaluated consecutive IV TPA treated patients with anterior circulation ischemic symptoms, TCD evidence of occlusion, and serial NIHSS assessments (baseline, end of infusion, 24 hours post infusion). TCD was interpreted at the end of infusion using validated criteria for degree of recanalization. Changes in the NIHSS were defined as improvement (≥4 point improvement or complete resolution)or deterioration(decline of ≥2). Results: 52 patients met the criteria for inclusion (baseline NIHSS 17±6, median 18, range 5–29). By the end of infusion, NIHSS scores improved in 26 patients (50%). From the end of infusion to 24 hours, subsequent improvement by ≥4 points occurred in another 9 patients (17%), mostly in patients with partial recanalization (56%). NIHSS at end infusion correlated with NIHSS at 24 hrs in all patients (Adjusted R 2 =0.74). In patients with no recanalization, end-of-infusion NIHSS most highly predicted 24 hour scores (Adj.R 2 =.89) while correlation was less significant with partial(Adj.R 2 =.61) and complete(Adj.R 2 =.66) recanalization(all pConclusions: In patients with MCA occlusion, end of TPA infusion NIHSS scores accurately predict scores at 24 hours, especially in patients without vascular recanalization. This suggests that a majority of short term improvement occurs by the end of infusion. In patients without hemorrhagic transformation, deterioration of the NIHSS after infusion occurs mostly due to reocclusion.

40 Background: Implementation of intravenous (IV) tissue plasminogen activator (TPA) therapy with the NINDS protocol has been reported with variable safety. Our center has an experienced stroke team of fellows and stroke faculty servicing one University hospital and three community hospitals. Methods: We report our experience in the treatment of 269 consecutive patients with ischemic stroke within the first 3 hours after symptom onset with 0.9 mg/kg IV TPA according to the NINDS protocol. Results: A total of 269 patients were treated between 1/96 and 6/00: median age 69 (range 24–93 years, females 48%). Pre-treatment NIHSS was 14±6 (median 14, range 4–33 points). TPA bolus was given at 137 min (range 30–180 minutes) with 28% of patients treated within 2 hours. Median door-to-needle time was 68 minutes (range 10–129 minutes). Overall symptomatic ICH rate was 4.5% (range 2.6% - 8.7% between hospitals, ns), with a decline noted from 1996 to 2000 (Table). Protocol violations (excessive blood pressure, seizure at onset) were found in 13% of all patients and symptomatic ICH rate in these patients was 15%. At 24 hours NIHSS score was 9±8 (median 8, range 0–36 points). In hospital mortality was 15% and discharge NIHSS score was 6±7 (median 3, range 0–36). Long-term follow-up will be reported. Conclusions: Intravenous TPA in a dose of 0.9 mg/kg can be given with a risk of symptomatic ICH lower than previously reported. Safety of TPA improved from 1996 to 2000. We conclude that the safety of TPA therapy depends more on the expertise of the treating team than the type of the hospital.

P175 Background: Paramedic diagnostic accuracy in stroke and designation of stroke centers may improve treatment of acute stroke. We studied patients transported from the scene by paramedics with suspected acute stroke to 6 hospital candidate “ stroke center” sites in Houston as part of pre-intervention data collection for a study funded by the American Stroke Association aimed at increasing the number of patients that receive effective urgent stroke therapy. Methods: Candidate sites consisted of 2 university affiliated tertiary care and 4 community hospitals. Total time from suspected symptom onset to arrival in a study site emergency center, patient demographics, definitive diagnosis, and use of thrombolytic therapy were collected prospectively from September 1999 through March 2000. Results: The sample consisted of 446 patients with a paramedic diagnosis of acute stroke. Patient distribution to study sites was as follows: Hospital 1, n=153 (34.3%); Hospital 2, n=71 (15.9%); Hospital 3, n=72 (16.1%); Hospital 4, n=59 (13.2%); Hospital 5, n=64 (14.3%); Hospital 6, n=27 (6.1%). Average time from onset of symptoms suggestive of stroke to arrival in the emergency center was 226 minutes + 348 minutes (median 95 minutes; 234 patients (52%) arrived within 150 minutes of stroke symptom onset. Definitive stroke diagnosis was confirmed in 321 (72%) EMS transported cases; in 125 cases (28%) EMS misdiagnosed stroke for seizures, altered mental status, headache and syncope. Of valid stroke cases, 260 (81%) were ischemic and 61 (19%) were hemorrhagic. Total time from symptom onset to arrival in the emergency center was 196 ±240 minutes with a median of 90 minutes for ischemics, and 154 ±171 minutes with a median of 90 minutes for hemorrhages. Of this group, 216 (71%) of ischemic, and 43 (70%) hemorrhages arrived within 150 minutes of stroke symptom onset. A total of 21 (8%) patients received thrombolysis. Conclusions: Paramedic accuracy in diagnosing stroke is reasonable. Community and paramedic awareness of stroke and stroke-like symptoms in Houston already leads to over half of stroke patients arriving within the window for thrombolysis. An ongoing study will try to improve these statistics.

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.

46 Background: In acute stroke, few tools are readily available to determine clot presence and location before thrombolysis, nor whether occlusion persists after intravenous TPA. Because the NIH Stroke Scale (NIHSS) is easily obtained in the Emergency Department, we correlated sequential NIHSS scores and arterial occlusion in prospective candidates for IV TPA. Methods: Potential thrombolysis patients evaluated with transcranial Doppler (TCD) ultrasound and the NIHSS at the time of presentation were studied. TCD was performed using previously validated criteria for clot detection, localization, and subsequent degree of recanalization after thrombolysis. In patients treated at Results: 119 ischemic stroke patients met inclusion criteria (age 68±15, NIHSS 15±7, median 14, range 2–36), with 83% having occlusion consistent with symptoms. Occlusion was present in all patients with NIHSS ≥22, none with NIHSS Conclusions: Baseline NIHSS accurately predicts clot presence with increasing scores corresponding to increasing clot burden. However, NIHSS becomes less predictive of clot persistence at the end of TPA infusion and may less accurately identify patients for further revascularization efforts.

47 Background: Arterial recanalization precedes clinical improvement in ischemic stroke. However sudden reperfusion may increase the chance of edema or hemorrhage. Methods: Consecutive patients given intravenous TPA were monitored using transcranial Doppler (TCD). The NIH Stroke Scale (NIHSS) was performed before bolus and at 24 hours. Patients with complete or partial recanalization according to validated criteria were analysed. Duration of recanalization was classified a priori as sudden (abrupt appearance of a normal or stenotic low resistance signal), stepwise (flow improvement over 1–29 minutes), and slow (30–60 minutes). Results: Recanalization occurred in 43 patients (age 68±17 years, NIHSS 16.8±6, median 15 points, TPA bolus at 135±61 minutes after onset). Recanalization began at 23±19 min (median 17) and completed at 42±23 min (median 35) after bolus. Duration of recanalization was 23±16 min (median 17 min). Recanalization was sudden in 5, stepwise in 23, and slow in 14 patients. Faster recanalization predicted better short term improvement (Table, p=0.03). Symptomatic hemorrhage occurred in 1 patient with stepwise recanalization at 5.5 hours after onset. Slow and/or partial recanalization with dampened flow signal was found in 53% of patients with NIHSS ≥ 10 points at 24 hours (p=0.01). Conclusions: Short duration of recanalization is associated with better short-term improvement mostly likely due to faster clot break-up and low resistance of the distal circulatory bed. Slow flow improvement and dampened flow signal are poor prognostic signs that may be useful in patient selection for interventional treatment.

This pastyear has been particularly important for researchers and clinicians dedicated to acute stroke therapy. The publication of results from the first large randomized clinical trials of intravenous thrombolytic therapy1,2has finally demonstrated unequivocally that human ischemic stroke is a treatable disease. This momentous event has implications for all members of the stroke community, including patients, health care planners, and all clinical health professionals, especially neurologists and those involved in emergency patient care. These results are also of critical interest to laboratory and clinical investigators. Over the past 5 years a healthy debate has developed in the stroke research community about the relevance of animal models to human stroke. The similarities and differences between stroke in patients vs rats, and between designing human clinical trials vs rodent experiments, have been discussed in detail3-6and do not need to be repeated here. What lessons can we learn from

Dr. Pfausler and colleagues report in this issue of Journal of Travel Medicine a series of patients with an interesting and potentially fatal neurovascular disorder; they raise the question, is this condition more frequent in travelers? Over a period of 18 months, Dr. Pfausler and colleagues identified five of fifteen consecutive patients presenting with occlusion of the cerebral veins who had been traveling on long distance flights. Some of these patients also had a history of diarrhea, and exposure to heat or dehydration associated with their air travel. It is important to note that their air travel experience was also associated with other precipitating factors in several of the cases. One patient had been mountaineering at high altitude and also had donated plasma. Another had severe diarrhea. A third patient was taking oral contraceptives. Whereas more than a coincidental link appears to be related to air travel, some of the authors' statements implying causality should be qualified in the absence of a larger, more formal, epidemiologic analysis. How might air travel lead to cerebral venous thrombosis? In clinical practice, thrombosis of the cerebral veins most commonly occurs after trauma or infection of the head and neck. However, thrombosis is also seen in conditions of heightened coagulability or viscosity. One could conjecture that prolonged air travel in a cabin, pressurized to the equivalent of high altitude, might lead to compensatory hemoconcentration and heightened blood viscosity, which could be aggravated further by other conditions such as diarrhea or oral contraceptive use. A critical point made by the authors is that the clinical presentation of cerebral venous thrombosis differs from that of conventional stroke. Patients with venous occlusion often present with headache and behavioral abnormalities, which often lead to a mistaken diagnosis of psychogenic illness before seizures or signs of increased intracranial pressure become obvious. Neurologists are trained to have a high index of suspicion for this condition in patients with trauma, infection, or in the peri-partal period. If the observations of Pfausler et al are confirmed, we should add prolonged air travel to the list of predisposing conditions. Cerebral venous thrombosis is a very treatable type of stroke. Major morbidity is due to increased intracranial pressure, which can be relieved by steroids or dehydrating agents. Treatment of underlying infection or hypercoagulability is critical. In the past, most patients were given anticoagulants, despite the risk of hemorrhage into a venous infarct. If the major draining veins of the brain are affected - in particular, the sagittal sinus - a malignant form of increasing intracranial pressure with high morbidity ensues. Recently, direct infusion of thrombolytic agents in the venous sinuses through a retrograde placed catheter has been used in patients with this condition. Cerebral venous thrombosis can be diagnosed readily with magnetic resonance imaging and angiography, which have largely replaced conventional angiography in suspected cases. The development of thrombolytic therapy for acute occlusive stroke and the demonstration of its efficacy and relative safety in carefully selected patients1 have focused attention on the need for ultra-fast recognition and treatment of cerebrovascular disease. As stroke enters the era of emergency therapy, all health professionals, including those who care for air travelers, should be aware of the various presentations of stroke syndromes and the need for urgent therapy.

To the Editor: I have read with great interest Caplan's excellent review of Binswanger's disease. [1] I am particularly interested in the author's point that conditions other than hypertension might be related to the genesis of this disorder. To date, most authors and clinicians have given excessive weight to hypertension as both an etiologic factor and a diagnostic feature of Binswanger's disease. Caplan reviews very well the …

We examined the baseline characteristics of patients in the Ticlopidine Aspirin Stroke Study (TASS) to determine if the effects of the two treatments in preventing stroke differed in various subgroups. Patients with the following characteristics did less well on aspirin: elevated creatinine, hypertension or diabetes requiring treatment, or treatment with anticoagulant or antiplatelet drugs prior to their qualifying TIA or stroke. Women and patients with vertebrobasilar symptoms did particularly well on ticlopidine. We performed arteriography in 1,188 patients with carotid qualifying events. The frequency of stroke in patients with abnormal arteriograms ipsilateral to their symptoms was slightly higher than in those with normal carotid arteries. Ticlopidine was more effective in patients without carotid stenosis. Ticlopidine is more effective than aspirin in preventing strokes in patients having warning TIAs. The patients who benefit most from ticlopidine may be women, those who have vertebrobasilar symptoms, those with cerebral ischemic symptoms while on aspirin or anticoagulant therapy, and patients with diffuse atherosclerotic disease rather than high-grade carotid stenosis.

This study examines the effect of fibrinogen and consequent blood viscosity reduction on cerebral blood flow and cellular injury following severe cerebral ischemia for 30 minutes in 78 Wistar rats. In half of these rats 10 to 15 cc's of blood was removed and replaced with a mixture of 5% albumin and autologous red blood cells maintaining a constant hematocrit but resulting in a 30% decrease in fibrinogen and corresponding reduction in viscosity. Fibrinogen reduction in a slight increase in baseline CBF and the elimination of post-ischemic hyperemia at 24 hours. Both study and control animals showed a similar decrease in CBF at 30 minutes and 2 hours. There was no significant difference in the severity of ischemic cellular change between the fibrinogen reduction group and controls, although there was a significant inverse relationship between the amount of viscosity change and severity of cellular injury within the treatment group. Fibrinogen reduction alone cannot significantly ameliorate ischemic injury in this model. Viscosity reduction therapy should include reduction of hematocrit and alteration of red cell deformability.

Dihydropyridine calcium channel blockers such as nicardipine are under evaluation for treating acute cerebral ischemia because they may increase cerebral blood flow by causing vasodilation and because they may be cytoprotective in part by limiting production of arachidonic acid metabolites. We demonstrated in a previous study that nicardipine improves postischemic neuronal function, as measured by somatosensory evoked potentials, without reducing the extent of light-microscopic CA-1 hippocampal histologic damage. To characterize further the effect of nicardipine on global ischemic injury, we administered the drug beginning 24 hours before 30 minutes of four-vessel ischemia in Wistar rats. We then measured hippocampal ATP, phosphocreatine, and glucose contents immediately and 2 hours after ischemia, and measured learning ability (working and reference errors) on an eight-arm radial maze beginning 30 days after ischemia. To gain insight into the possible mechanism of action, we measured production of arachidonic acid metabolites (eicosanoids: TXB2 and 6-keto-PGF1 alpha) and hemispheric and hippocampal cerebral blood flow by the [14C]butanol indicator fractionation technique immediately and 2 hours after ischemia. Nicardipine was associated with fewer working errors (p less than 0.02) but no difference in reference errors. The drug had no effect on energy metabolites, cerebral blood flow, or eicosanoids immediately after ischemia, but ATP, phosphocreatine, and cerebral blood flow all returned to normal levels significantly more rapidly during reperfusion in treated rats. Nicardipine improves behavioral, electrophysiologic, and mitochondrial function after ischemia without preventing cellular damage and improves postischemic reperfusion. The drug's positive effect appears to occur during reperfusion.

Reperfusion of ischemic brain is associated with production of thromboxane A2 (TXA2), a proaggregatory vasoconstrictor. We used an animal model of transient forebrain ischemia to study the effects of 1-benzylimidazole (1-BI), a selective inhibitor of thromboxane synthase, upon cerebral eicosanoid levels and cerebral blood flow. Male Wistar rats were subjected to 30 minutes of four-vessel occlusion. The mean +/- SEM brain level of TXB2, the stable metabolite of TXA2, determined after 60 minutes of reperfusion was 101 +/- 20 pg/mg brain protein in five ischemic control rats. Infusion of 10 micrograms/g 1-BI reduced mean +/- SEM cerebral TXB2 concentration to 11 +/- 3 pg/mg brain protein in five rats (p less than or equal to 0.002). Mean +/- SEM hemispheric cerebral blood flow measured in four ischemic control rats after 60 minutes of reperfusion was 42 +/- 9 ml/100 g brain/min compared with 104 +/- 13 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.001). Mean +/- SEM hippocampal blood flow in four ischemic control rats after 60 minutes of reperfusion was 51 +/- 14 ml/100 g brain/min compared with 125 +/- 25 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.04). We conclude that selective inhibition of thromboxane synthase may alleviate ischemic brain damage by reducing cerebral TXA2 concentrations and elevating cerebral blood flow.

• Four patients had involvement of the anterior visual pathway by sarcoidosis. In two cases recognition of the systemic disease was delayed because only visual symptoms were present. Three cases had evidence of hypothalamic-pituitary axis dysfunction, with histologically proved granulomatous infiltration of this region. The chiasmal syndrome in sarcoidosis is characterized by a pattern of blindness in one eye, atrophy of the optic discs, and temporal visual field loss in the contralateral eye with variable degrees of pituitary dysfunction. The condition is medically treatable and simulates the clinical and even the roentgenographic appearance of a pituitary tumor.

THE past several years have witnessed a flurry of prospective clinical trials of new treatments for transient ischemic attack, cerebral infarction, and cerebral hemorrhage, and the results have markedly altered our management of these conditions (Table 1). Furthermore, another generation of Phase II and controlled prospective studies (based on pilot studies) are planned or under way (Table 2). This survey will briefly review these studies in the context of current therapy for the following: prevention of stroke after transient ischemic attack or stroke, acute cerebral infarction and progressing stroke, cardiogenic embolism to the brain, cerebral arteritis, intracerebral hematoma, arteriovenous malformation, . . .

The selective vulnerability of pyramidal neurons in the CA1 hippocampal region in ischemic rat brain may be preceded by regional alterations of energy metabolism during early reperfusion. We measured ATP, phosphocreatine (PCr), and glucose in paramedian and lateral CA1 and in an area showing little postischemic cell loss, CA2. ATP levels in paramedian CA1 were depressed immediately after 30 min of ischemia (P less than or equal to 0.02) and remained abnormal after 2 hr of reperfusion (P less than or equal to 0.05). PCr was reduced substantially in both subdivisions of CA1 immediately after ischemia (P less than or equal to 0.04) but returned to normal levels after 2 hr. Glucose levels were depressed in paramedian CA1 and CA2 after ischemia (P less than or equal to 0.02) but corrected with reperfusion. We determined approximately P, the sum of ATP and PCr, in separate experiments investigating regional differences in consumption of high-energy phosphate metabolites during complete ischemia. The approximately P levels of rats subjected to 30 min of reversible ischemia followed by 2 hr of reperfusion showed a different pattern of regional differences from those seen in sham-ischemic animals (P less than or equal to 0.01), indicating a persistent depression of metabolic rate in CA1 during reperfusion. We conclude that regional depletion of high-energy phosphates and alteration of metabolic rate may contribute to the selective vulnerability of the CA1 region during brain ischemia.

A 59-year-old man presented with jugular foramen syndrome caused by a mass with roentgenographic and histologic features highly suggestive of a glomus jugulare tumor. However, electron microscopic examination of the surgical specimen revealed features diagnostic of a previously unsuspected renal cell carcinoma. Because primary tumors of the glomus jugulare and metastatic renal cell carcinoma may present with the same clinical and roentgenographic findings and look similar histologically, careful electron microscopic examination of the tumor and urologic screening should be performed in suspected cases of glomus jugulare tumors.

A retrospective study of 910 patients surviving at least five years after cervical irradiation for Hodgkin's disease, non-Hodgkin's lymphoma, or primary head an neck neoplasms showed the incidence of stroke following cervical irradiation was 63 of 910 patients (6.3%) during a mean period of observation of nine years. This represents a trend toward an increased risk for this population observed over the same period of time (p = 0.39). A prospective study of 118 similar patients currently living five years after cervical radiotherapy was performed to determine the incidence of carotid artery disease occurring as a consequence of neck irradiation. Abnormal carotid phonangiograms (CPA) were found in 25% of the patients and abnormal oculoplethysmographs (OPG) were found in 17%. These studies represent significant carotid lesions that are not expected in such a population. It is concluded that the carotid stenoses demonstrated are most likely a consequence of prior irradiation. Patients that are five-year survivors of cervical irradiation should have noninvasive vascular laboratory studies performed as part of their routine follow-up examinations in order to detect these carotid lesions while they are occult.