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the Stroke Unit (S.D.L.), Stroke Unit, Universita di Tor Vergata, Rome, Italy
the Department of Clinical Neurological Sciences (G.S., V.H.), London Health Science Centre, University of Western Ontario, London, Ontario, Canada
the Division of Neurology (Y.N.), Siriraj Hospital, Mahidol University Bangkok, Thailand
the Stroke Research Program (G.S.), Department of Medicine, St. Michael’s Hospital, University of Toronto, Ontario, Canada.
Abstract
Background and Purpose— Patients with right hemispheric strokes (RHSs) present later to an emergency department, have a lower chance to receive intravenous recombinant tissue plasminogen activator (IV rt-PA), and have worse clinical outcomes than do patients with left hemispheric strokes (LHSs). We analyzed outcomes after IV rt-PA with respect to the side of the affected hemisphere.
Methods— A prospective cohort of acute stroke patients was treated with IV rt-PA at the London Health Sciences Centre (December 1998 to March 2003). Differences between patients with RHS and LHS were identified by univariate analysis. Logistic-regression analysis was used to determine a subset of variables independently associated with major neurological improvement at 24 hours and good outcome at 3 months after treatment.
Results— Of 219 stroke patients who received IV rt-PA, 165 had hemispheric strokes (68 RHSs and 97 LHSs). Patients with RHSs were less hypertensive (P=0.001) and had lower pretreatment National Institutes of Health Stroke Scale (NIHSS) scores (P=0.005). LHS (odds ratio [OR], 2.29; 95% CI, 1.14 to 4.59; P=0.019), age (OR, 0.96; 95% CI, 0.93 to 0.99; P=0.012), and pretreatment NIHSS (OR, 0.83; 95% CI, 0.78 to 0.89; P<0.0001) were independent predictors of 3-month outcome. Female sex (OR, 3; 95% CI, 1.53 to 5.90; P=0.001) and LHS (OR, 2.07; 95% CI, 1.05 to 4.08; P=0.03) were independent predictors of major neurological improvement at 24 hours after IV rt-PA.
Conclusions— Despite higher pretreatment NIHSS, patients with LHSs have a 2-fold increased chance of a good outcome 3 months after rt-PA treatment compared with patients with RHSs. This gain can be clinically detected at 24 hours after treatment. These results need to be coupled with neuroimaging and hemodynamic characteristics known to influence stroke outcome.
Key Words: acute stroke outcome thrombolysis
Introduction
Interesting and consistent data are emerging on barriers preventing the successful administration of thrombolytic therapy to patients who experience an acute ischemic stroke. In particular, these barriers seem to be applicable to patients with right hemispheric strokes (RHSs). Two studies have shown that patients with RHSs present later to an emergency department1,2 and are less frequently diagnosed as having had a stroke.1 Our group previously observed that patients with RHS are 45% less likely to receive intravenous recombinant tissue plasminogen activator (IV rt-PA) compared with patients with left hemispheric strokes (LHSs).2 Neuroimaging studies have shown that the National Institutes of Health Stroke Scale (NIHSS) is underpowered for assessing the severity of right hemisphere damage in the acute phase of stroke.3,4 As a consequence, under current guidelines, patients with RHS are at risk of not being properly assessed or treated with IV thrombolysis. Outcome studies have also shown that patients with RHS have a worse functional recovery compared with LHS patients.5,6 Whether the administration of IV rt-PA can reverse this pattern has not been specifically investigated. Our aim was to investigate whether the affected hemisphere is (1) predictor of neurological improvement at 24 hours and (2) a determinant of good outcome at 3 months after IV administration of rt-PA.
Methods
Data from consecutive stroke patients treated with IV rt-PA at the London Health Sciences Centre, University Campus in London, Ontario, were collected prospectively. The hospital category, size of the population served, and catchment area have been described.7 For all patients, the time of symptom onset was defined by the time they were "last seen to be well." The onset-to-door, onset-to—computed tomography (CT) scan of the brain, and onset-to-needle time were obtained from nursing records. Data were entered into a database by stroke Fellows, all of whom were certified in administering the NIHSS. Collected information included demographics (age, sex, handedness), evaluation and treatment time, admission and 24-hour NIHSS scores, side of the affected brain area, and 3-month outcome. Handedness was recorded as part of the routine neurological examination. History of coronary artery disease, atrial fibrillation, heart failure, transient ischemic attack or stroke, hypertension, diabetes mellitus, hypercholesterolemia, smoking, and alcohol consumption was obtained through self-report and supported by hospital records or lists of medications taken and defined according to Canadian standards. Excessive alcohol consumption was defined as any daily intake >50 g.8 During admission, all patients underwent a stroke diagnostic work-up, consisting of blood cell count, metabolic panel, ECG, transthoracic echocardiogram, and carotid ultrasound. Magnetic resonance imaging (MRI), magnetic resonance and CT angiography, transesophageal echocardiography, and conventional angiography were preformed when appropriate. Stroke subtypes were recorded as lacunar and nonlacunar infarcts. Administration of IV rt-PA followed the National Institute of Neurological Disorders and Stroke protocol,9 except for the exclusion of patients with involvement of more than one third of the middle cerebral artery territory on the baseline CT scan. The acute stroke protocol adopted in our institution has been described.2,7,10,11 We retrospectively analyzed the distribution of all variables by both graphic and analytical methods (frequency distribution by quartiles or quintiles). When the relation between a continuous variable and the primary outcome was linear, it was kept continuous. When the relation suggested a cut-off, the variable was categorized. When there was no clear relation, we used clinical criteria to analyze the variable. Age, baseline NIHSS, time from stroke onset to treatment, and total rt-PA dose were considered continuous. A major neurological improvement (MNI) was defined as an NIHSS score equal to 0 or 1 at 24 hours or an improvement 8 points compared with baseline, according to the definition of Brown and colleagues.12 Three-month outcome was analyzed by the modified Rankin Scale (mRS).13
Statistical Analysis
Differences between patients were identified by univariate analysis. Logistic-regression analysis was used to determine a subset of variables independently associated with good outcome at the 3-month follow-up (ie, mRS 0 to 1) and MNI at 24 hours after treatment. Discrimination of the model was assessed by the area under the receiver operating characteristic curve, and calibration was assessed with a goodness-of-fit test. Statistical analysis was performed with a commercially available software package (STATA, version 7.0, Stata Corp LP). Probability values <0.05 were considered significant.
Results
Two-hundred nineteen ischemic stroke patients received rt-PA at the London Health Sciences Centre between January 1999 and March 2003. Demographic and clinical characteristics of this cohort have been presented.11 They were 111 (51%) males, and the mean (SD) age was 71.5 (12) years, with 178 (81%) of the patients being >60 years old. London was the city of onset in 129 (59%) patients, their median NIHSS (SD) was 13 (6), and 195 (89%) had a nonlacunar stroke. From this initial cohort, patients with brainstem or cerebellar infarcts, unknown side of the affected hemisphere, and lack of follow-up data were excluded. One hundred sixty-five patients were eligible for this analysis. Of them, 97 (59%) patients had LHS and 68 (41%) patients had RHS. Patients with LHS were more hypertensive (P=0.001) and had higher NIHSS (P=0.005) (Table 1).
Logistic-regression analysis for good outcome at 3 months (mRS 0–1) and infarct side showed that LHS independently predicted good outcome at 3 months (odds ratio [OR], 2.29; 95% CI, 1.14 to 4.59), after adjusting for age, sex, hypertension, and baseline NIHSS. Age (OR, 0.96; 95%, CI 0.93 to 0.99; P=0.012) and pretreatment NIHSS (OR, 0.83; 95% CI, 0.78 to 0.89; P<0.0001) were also negative predictors of good outcome at 3 months (Table 2).
Logistic-regression analysis for MNI at 24 hours after the IV rt-PA infusion and infarct side showed that female sex (OR, 3.00; 95% CI, 1.53 to 5.90; P=0.001) and LHS (OR, 2.07; 95% CI, 1.05 to 4.08; P=0.03) were independent predictors of MNI after adjusting for age, hypertension, and baseline NIHSS (Table 3).
Discussion
In this cohort of patients with acute ischemic strokes, we observed that patients with LHS had significantly higher NIHSS scores on admission and were more frequently hypertensive compared with RHS patients. Older age and higher NIHSS scores on admission were found to be independent predictors of poor outcome at 3 months, whereas patients with LHS had a higher chance of good outcome at 3 months compared with RHS patients. Female sex and LHS also predicted MNI at 24 hours after IV rt-PA administration.
A negative effect of age on patient outcome after IV thrombolysis has been described,12 whereas data on the impact of initial stroke severity as measured by the NIHSS on patient outcome are controversial.11,12,14 We discovered that, after correction for initial stroke severity, patients with LHS had a 2-fold increased likelihood of a good outcome at 3 months after IV thrombolysis than did patients with RHS. Left hemispheric damage and female sex also conferred a higher chance of MNI at 24 hours, which is an indicator of recanalization15,16 and a predictor of excellent outcome at 3 months.11,12,17 Although women have more severe strokes and worse outcomes than men,18 women seem to benefit more from IV thrombolysis than men.11,19 Right hemispheric damage has been also associated with poor outcome.5,6 Owing to a combination of underdiagnosis, delayed arrival to an emergency department, and consolidated use of stroke severity scales biased toward left hemisphere damage, patients with RHS are less likely to be treated with rt-PA compared with those with LHS.1,2 However, we previously observed that the presence of visuospatial neglect on admission confers a 2-fold increased probability of receiving IV rt-PA,2 meaning that patients with RHS are adequately treated if symptoms are severe enough to be recognized.
The reasons why patients with RHS should benefit less than those with LHS from IV thrombolysis are not clear. One possibility is that the available stroke assessment tools may be inherently poor at correctly measuring RHS function, and this limitation may have confounded our findings. For instance, a 1-point NIHSS improvement in the language item (ie, from severe to moderate aphasia) can reflect changes in other items, eg, the level of consciousness questions and commands. Conversely, the clinical spectrum of the neglect syndrome can be defined only within a narrow score, and for the most severe neglect, no fixed rules are applied to other items such as gaze preference, visual field, and level of consciousness. Neurological improvement might be "magnified" by the structure of the NIHSS for patients with damage in the left hemisphere. Alternatively, physiological and cellular differences between the brain hemispheres might differently influence blood flow and thus, neuronal functional recovery after an ischemic injury. The notion of "competition" between the hemispheres and the negative influence of activity in the intact hemisphere are emerging from functional MRI studies as important principles for understanding recovery.20 In our cohort, patients with LHS were more frequently hypertensive before the stroke compared with patients with RHS. Although this might be explained by the small sample size, cerebral asymmetry in sympathetic and cardiac autonomic control has been demonstrated,21,22 and a possible role of these variables on patient outcome deserves further investigation.
Factors other than those reported might account for the better outcome we observed in the left hemispheric group. Differences between the 2 groups in terms of stroke subtype, site of arterial occlusion, or the presence of a diffusion-perfusion mismatch on MRI might have influenced our results. Although no differences were found in stroke etiology between the 2 groups, the site of occlusion and the presence of mismatch were not evaluated before IV rt-PA administration, with the exception of a very few selected cases. Furthermore, early ischemic changes on baseline CT were not entered into our rt-PA database in a standardized fashion. On the basis of the information available in this study, we cannot provide definite evidence that the 2 groups were well matched for those hemodynamic and neuroimaging characteristics (ie, site of arterial occlusion, presence of diffusion-perfusion mismatch) known to strongly influence outcome. Unfortunately, previous studies aimed at investigating predictors of outcome after IV thrombolysis in patients with documented middle cerebral artery occlusion or aimed at correlating stroke subtypes with different patterns of perfusion-diffusion MRI mismatch have not looked at hemispherical differences.23–25
Summary
We speculate that some patients with RHS may be less likely to benefit from IV rt-PA administration than patients with LHS, even if the former are promptly recognized and adequately treated. The bias introduced by the NIHSS in evaluating stroke severity in patients with RHS can hamper proper evaluation of the clinical gain in these patients: language improvement is reflected by changes in several items on the NIHSS, whereas the score for neglect only allows a narrow range of changes. The observed results need to be confirmed by studies coupling clinical information with those hemodynamic and MRI characteristics that are strong determinants of patient outcome.
Acknowledgments
The authors thank the Stroke fellows and the Stroke research nurses at the LHSC for their help in assessing patients and collecting data.
Disclosures
None.
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