Original Paper Received: July 4, 2014 Accepted: January 12, 2015 Published online: March 14, 2015
Cerebrovasc Dis 2015;39:209–215 DOI: 10.1159/000375151
Defining Minor Symptoms in Acute Ischemic Stroke Davide Strambo a Alberto A. Zambon a Luisa Roveri a Giacomo Giacalone a Giovanni Di Maggio a Luca Peruzzotti-Jametti b Sara La Gioia a Sebastiano Galantucci a Giancarlo Comi a Maria Sessa a
a
San Raffaele Scientific Institute-Institute of Experimental Neurology, Stroke Unit-Department of Neurology and Neurophysiology, Milan, Italy; b Department of Clinical Neurosciences and Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
Abstract Background: Thrombolysis is often withheld from acute ischemic stroke patients presenting with mild symptoms; however, up to 40% of these patients end up with a poor outcome when left untreated. Since there is lack of consensus on the definition of minor symptoms, we aimed at addressing this issue by looking for features that would better predict functional outcomes at 3 months. Methods: Among all acute ischemic stroke patients admitted to our Stroke Unit (n = 1,229), we selected a cohort of patients who arrived within 24 hours from symptoms onset, with baseline NIHSS ≤6, not treated with thrombolysis (n = 304). Epidemiological data, comorbidities, radiological features and clinical presentation (NIHSS items) were collected to identify predictors of outcome. Our cohort was tested against minor stroke definitions selected from the literature and a newly proposed one. Results: Three months after stroke onset, 97 patients (31.9%) had mRS ≥2. Independent predictors of poor outcome were age (OR 0.97 [95% CI 0.95–9.99]) and baseline NIHSS score (OR 0.79 [95% CI 0.67–0.94]), while cardioembolic aetiology was negatively associated (OR 3.29 [95% CI 1.51–7.14]). Items of NIHSS associated with poor outcome
© 2015 S. Karger AG, Basel 1015–9770/15/0394–0209$39.50/0 E-Mail [email protected] www.karger.com/ced
were impairment of right motor arm (OR 0.49 [95% CI 0.27– 0.91]) or the involvement of any of the motor items (OR 0.69 [95% CI 0.48–0.99]). The definition of minor stroke as NIHSS ≤3 and the new proposed definition had the highest sensitivity and accuracy and were independent predictors of outcome. Conclusions: Our study confirmed that in spite of a low NIHSS score, one third of patients had poor outcome. As already described, age and NIHSS score remained independent predictors of poor outcome even in mild stroke. Also, motor impairment appeared a major determinant of poor outcome. The new proposed definition of minor stroke featured the NIHSS score and the NIHSS items that better predicted functional outcome. Awareness that even minor stroke can yield to poor outcome should sensitize patients to arrive early to the ED and neurologists to administer rt-PA. © 2015 S. Karger AG, Basel
Introduction
Patients with acute ischemic stroke presenting with low baseline NIHSS score are often referred to as ‘minor stroke’. While some minor stroke patients have minor non-disabling symptoms, a proportion of them (up to
D.S. and A.A.Z. contributed equally to this work.
Dr. Davide Strambo San Raffaele Scientific Institute-Institute of Experimental Neurology Stroke Unit-Department of Neurology and Neurophysiology Via Olgettina 58, IT–20132 Milan (Italy) E-Mail strambo.davide @ hsr.it
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Key Words Minor stroke · Minor symptoms · Stroke · Prognosis · Acute stroke outcome
Methods From our stroke database, we identified all patients with acute ischemic stroke consecutively admitted to our emergency department between January 2009 and January 2013. After excluding patients with final diagnosis of transient ischemic attack (TIA) [11] and patients treated with rTPA, we included in our cohort patients who satisfied both these criteria: onset to door time less than 24 hours and baseline NIHSS ≤6. For each patient we collected the following: demographic data, vascular risk factors, blood glucose and blood pressure measured in the Emergency Department (ED), onset to door time (OTD), baseline and discharge NIHSS score (total and individual item score), the Oxford clinical scale [12, 13] (OCSP, derived from the first neurological examination in the ED) and the Trial of Org 10172 in Acute Stroke Treatment classification [14, 15] (TOAST, upon extensive diagnostic workup). Neurological improvement or deterioration was measured as ΔNIHSS between discharge and baseline (ΔNIHSS 0: deterioration). Neurological evaluations were performed by trained neurologists with a valid certification to administer the NIH Stroke Scale. Favorable outcome was defined as lack of disability, quantified as mRS score ≤1, at three months followup. The mRS is a universally accepted method to evaluate the presence of disability after stroke and it was obtained either at outpatient visits or by telephone interview performed by certified medical personnel [16, 17]. Ischemic lesions on imaging were classified into lacunar sovratentorial lesions, non-lacunar sovratentorial lesions, infratentorial lesions, multiple lesions and negative imaging. Hemorrhagic transformation of ischemic lesion was classified as hemorrhagic infarction (HI1 and HI2) or parenchymal hematoma (PH1 and PH2) according to the criteria used in ECASS trials [18]. Minor Symptoms Definitions We performed a literature search for minor stroke definitions and selected the following definitions of minor symptoms: (1) NINDS-TPA trials definition [19, 20]: deficit not measurable on the NIHSS, pure sensory stroke, isolated ataxia, isolated dysarthria, or isolated facial weakness; (NIHSS range 0–3)
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(2) Park et al. definition [5]: deficit not measurable on the NIHSS or a deficit resulting in total NIHSS score = 1 with the point assigned in the level of consciousness (LOC), gaze, facial palsy, sensory, or dysarthria; (NIHSS range 0–1) (3) NIHSS ≤3 [4]: any neurological deficit resulting in baseline NIHSS score ≤3; (NIHSS range 0–3) (4) New proposed definition: NIHSS ≤6 with preservation of LOC items, score ≤1 in cortical (language and visual field) and motor items (limbs and speech), score 0 in the motor item of dominant arm and any score in the remaining items; (NIHSS range 0–6) The NINDS rt-PA Study Group tested other five definitions of minor stroke in a post-hoc analysis [19]. The functional outcome was similar for all five types of minor stroke definitions. However, each of the definitions proposed by the NINDS rt-PA study group allows a maximum total NIHSS score greater than the cut-off score of 6 that we used to select our study cohort. For this reason, we couldn’t apply these definitions to our population. Statistical Analysis Descriptive statistics were calculated for patient demographics, risk factors, baseline NIHSS score, onset-to-door time, imaging data, OXFORD and TOAST classification, comparing patients with favorable outcome (mRS score 0–1) to those with unfavorable outcome (mRS score 2–6). Counts and percentage proportions were displayed for categorical variables, while medians and interquartile range were calculated for continuous variables. The significance of differences between the two groups was evaluated using the Mann-Whitney test for continuous variables and Pearson Chi-square test for categorical variables. Variables showing association with outcome at the p < 0.10 level in the univariate analysis were included in the multivariate logistic regression model with dichotomized 3 months-mRS as dependent variable. Variables significant at p < 0.05 level in this analysis were considered independent predictors of outcome. The definitions of minor symptoms were applied to our cohort and, for each definition, patients were classified in the minor symptoms or in the non-minor-symptoms group. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Odds Ratio for 3-month favorable outcome (with 95% CI) were derived for each definition of minor symptoms. Chisquare test was used to compare the proportion of patients with good outcome in the four group of minor stroke identified using the different definitions. The Bonferroni method was used to adjust the p values of pairwise comparison. The distribution of single NIHSS items in the two outcome groups was analyzed with the Pearson Chi-square test. SPSS 13.0 software (SPSS Inc., Chicago, Ill., USA) was used for all statistical analyses.
Results
A total of 1,299 patients with acute ischemic stroke were admitted to our emergency department between January 1st 2009 and January 1st 2013. We excluded 554 patients with NIHSS >6, 157 patients with a final diagnosis of TIA, 128 patients arrived beyond 24 h from sympStrambo et al.
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40%) develops significant long-term disability [1–3]. In addition, the definition of minor symptoms is still a matter of debate [4, 5], leaving uncertainties in everyday clinical practice [6–8]. Indeed, according to AHA guidelines for acute ischemic stroke treatment, the presence of minor symptoms at the onset of acute ischemic stroke is indicated as a relative exclusion criterion to IV thrombolysis [9, 10]. The aim of this study is to assess the capability of different definitions of minor symptoms to predict favorable outcome in patients with acute ischemic stroke and low baseline NIHSS score (NIHSS ≤6). This could help to increase the confidence with decision of withhold or administer thrombolysis in minor stroke patients.
n = 1,299 patients with cerebrovascular ischemic event n = 554 patients with baseline NIHSS >6 n = 745 patients n = 157 patients with final diagnosis of TIA n = 588 patients n = 128 patients arrived to the ED 24 h after symptoms onset n = 460 patients n = 61 patients with no follow-up + n = 51 with pre-stroke mRS >1 348 patients
Fig. 1. Process to select eligible patients for
44 patients treated with rt-PA
304 selected patients
toms onset, 61 patients with missing follow-up, 51 patients with pre-stroke mRS >1 and 44 patients who had received rtPA. At the end, 304 satisfied the inclusion criteria of this study (fig. 1). The median age of the study population was 73 years (IQR 15 years), 60% were male, median baseline NIHSS was 2 (IQR 2) and the median OTD was 4 h (IQR 9 h). All patients underwent baseline CT scan and Magnetic Resonance Imaging was performed in 164 (53.9%). At three months follow-up, 207 patients (68.1%) had slight or no disability (mRS ≤1). Baseline features according to the outcome group are shown in table 1. Patients with favorable outcome were younger, had lower baseline NIHSS scores and lower systolic blood pressure at admission to the ED. Independent predictors of poor outcome were age (OR 0.97 [95% CI 0.95–9.99]) and baseline NIHSS score (OR 0.79 [95% CI 0.67–0.94]), while cardioembolic etiology was an independent predictor of good outcome (OR 3.29 [95% CI 1.51–7.14]). Accordingly, in this study cohort, cardioembolic strokes compared to stroke of other etiologies featured a higher proportion of small cortical lesions (48.5 vs. 23.5%, p 0.001), PACS clinical presentation (39.4 vs. 22.7%, p 0.006) and neurological improvement (62.5 vs. 48.7%, p 0.051), in spite of similar baseline NIHSS (median [IQR]: 3 [2] vs. 3 [2], p 0.661).
Hemorrhagic transformation of ischemic lesion occurred in 10 (3.2%) patients (n = 5 with HI-1, n = 4 with HI-2 and n = 1 with PH-1). Among them, two patients (1 HI-1 and 1 HI-2) experienced worsening of initial neurological deficit, which yielded to poor outcome in one case. Instead, 2 out of 8 patients with asymptomatic hemorrhagic transformation had poor outcomes. Overall, neurological deterioration (mean increase in NIHSS 2.2, range 1–13) occurred in 51 patients of whom 28 (54.9%) had poor outcomes. Patients who experienced neurological worsening had more frequently a history of hypertension (84.3 vs. 66.4%, p 0.011), higher systolic blood pressure at baseline (164 vs. 154 mm Hg, p 0.047), lower baseline NIHSS (median [IQR]: 3 [2] vs. 2 [1], p 0.000), higher proportion of infratentorial lesions (29.4 vs. 11.3%, p 0.009) and a low rate of PACS clinical presentation (15.7 vs. 29.2%, p 0.048). The rate of favorable outcome in minor and non-minor symptoms groups according to each definition is shown in table 2. In the minor symptoms group, the proportion of patients with good outcome was comparable across all the definitions tested (p 0.942), while higher variability emerged in the non-minor symptoms groups (p 0.001), with significant difference between definitions 1 and 4 (p 0.016) and between definitions 2 and 4 (p 0.015). The proportion of patients with good outcome
Defining Minor Symptoms in Acute Ischemic Stroke
Cerebrovasc Dis 2015;39:209–215 DOI: 10.1159/000375151
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the study.
Table 1. Patient characteristics according to outcome groups at 3 months from stroke onset
Total
mRS at 3 months from stroke 0–1 (n = 207)
Demographics Age, years Male sex, n (%) Vascular risk factors, n (%) Hypertension Diabetes Smoke Hypercholesterolemia Atrial fibrillation SBP at ED, mm Hg DBP at ED, mm Hg Glycemia at ED, mmol/l Stroke subtype, n (%) Cardioembolic Large vessels Small vessels Other or undetermined OCSP classification, n (%) PACS LACS POCS Not classified OTD, h NIHSS at baseline ΔNIHSS (NIHSS at discharge – NIHSS at baseline) ΔNIHSS 0 (mean ΔNIHSS +2.2) Ischemic lesion localization, n (%) Sovratentorial, lacunar Sovratentorial, non-lacunar Infratentorial Multiple lesions Negative imaging
p value
≥2 (n = 97)
73 (15) 183 (60.2)
72 (15) 129 (62.32)
77 (17) 54 (55.67)
0.001 0.270
213 (70.07) 74 (24.34) 73 (24.01) 67 (22.04) 47 (15.46) 155 (30) 80 (20) 116 (41)
142 (68.6) 45 (21.74) 57 (27.54) 44 (21.26) 32 (15.46) 150 (32) 80 (20) 114 (42)
71 (73.2) 29 (29.9) 16 (16.49) 23 (23.71) 15 (15.46) 160 (40) 80 (20) 126 (48)
0.415 0.122 0.036 0.630 0.999 0.014 0.691 0.090
66 (21.71) 55 (18.09) 80 (26.32) 103 (33.88)
53 (25.6) 33 (15.94) 53 (25.6) 68 (32.85)
13 (13.4) 22 (22.68) 27 (27.84) 35 (36.08)
0.016 0.155 0.680 0.579
113 (37.17) 80 (26.32) 80 (26.32) 31 (10.2) 4 (9) 2 (2)
77 (37.2) 56 (27.05) 53 (25.6) 21 (10.14) 4 (10) 2 (1)
36 (37.11) 24 (24.74) 27 (27.84) 10 (10.31) 4 (8) 3 (2)
0.989 0.670 0.680 0.965 0.712 0.005
39 (40.2) 28 (28.9) 28 (28.9)
0.008 0.379 0.000
19 (19.59) 27 (27.84) 17 (17.53) 9 (9.28) 25 (25.77)
0.887 0.770 0.300 0.403 0.831
154 (50.7) 93 (30.6) 51 (16.8) 61 (20.07) 88 (28.95) 44 (14.47) 35 (11.51) 76 (25)
115 (55.6) 65 (31.4) 23 (11.1) 42 (20.29) 61 (29.47) 27 (13.04) 26 (12.56) 51 (24.64)
Medians and interquartile range displayed for continuous variables, counts and percentage proportions for categorical variables. TIA = Transitory ischemic attack; SBP = systolic blood pressure; DBP = diastolic blood pressure; ED = emergency department; mRS = modified Rankin scale; OCSP = Oxford community stroke project classification; OTD = onset to door.
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In patients with impairment of any of the motor items, those with good and bad outcomes had similar baseline NIHSS (median [IQR]: 3 [2] vs. 4 [3], p 0.110) and number of other items involved (median [IQR]: 3 [1] vs. 3 [2], p 0.595), while there was a significant difference in the score of single motor items (median [IQR]: 1 [1] vs. 2 [1], p 0.021). Among patients classified as minor according to definition 3, the rate of good outcome differed between patients with and without motor impairment of the dominant arm (respectively 14/24 – 58.3% – vs. 134/174 – Strambo et al.
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was significantly different between the minor and nonminor symptoms groups classified according to definition 3 (adjusted OR 3.04 [95% CI 1.02–9.09]) and definition 4 (adjusted OR 3.11 [95% CI 1.65–5.86]). Overall, definition 3 and definition 4 had greater NPV, moderate specificity, higher accuracy and sensitivity. The relationship between NIHSS items and outcome is shown in table 3. Impairment of any motor item is significantly associated with poor outcome (adjusted OR 0.69 [95% CI 0.48–0.99]) as well as impairment of right motor arm (adjusted OR 0.49 [95% CI 0.27–0.91]).
Table 2. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and odds ratio of minor stroke for favorable outcome according to each minor stroke definition
a Rate of good outcome
Definition 1a (NINDS-TPA trials) Definition 2b (Park et al. [5]) Definition 3 (NIHSS ≤3) Definition 4a, b (new proposed definition)
Minor (%)
Non minor (%)
p
OR (95% CI)
Adj. OR (95% CI)
46/60 (76.67) 40/52 (76.92) 158/211 (74.88) 161/208 (77.4)
161/244 (65.98) 167/252 (66.27) 49/93 (52.69) 46/96 (47.92)
n.s. n.s. * *
1.69 (0.88–3.26) 1.7 (0.85–3.4) 2.68 (1.6–4.47) 3.72 (2.22–6.24)
0.81 (0.34–1.9) 0.69 (0.27–1.73) 3.04 (1.02–9.09) 3.11 (1.65–5.86)
b Statistics
Definition 1 Definition 2 Definition 3 Definition 4
Sensitivity
Specificity
PPV
NPV
Accuracy
22.2 (20–25) 19.3 (17–22) 76.3 (74–79) 77.8 (75–80)
85.6 (84–88) 87.6 (86–90) 45.4 (43–48) 51.5 (49–54)
76.7 (74–79) 76.9 (75–79) 74.9 (72–77) 77.4 (75–80)
34 (31–37) 33.7 (31–36) 47.3 (44–50) 52.1 (49–55)
42.4 41.1 66.4 69.4
* p < 0.05; n.s. = non significant. Adj. OR = OR adjusted for age, current smoking, NIHSS score at admission, systolic BP and glycemic levels in ED and cardioembolic etiology. a Proportion of patients with good outcome in non-minor stroke groups significantly different between definition 1 and 4. b Proportion of patients with good outcome in non-minor stroke groups significantly different between definition 2 and 4.
Table 3. Presence of deficit in each NIHSS item (absolute and percent values) in the two outcome groups at 3 months
NIHSS items
Level of consciousness 1a 1b 1c (2) Gaze (3) Visual field (4) Facial palsy Any motor item (5) Right motor arm (5) Left motor arm (6) Right motor leg (6) Left motor leg (7) Limb ataxia (8) Sensory (9) Language (10) Speech (11) Inattention
mRS at 3 months from stroke 0–1 (n^ = 432), %
≥2 (n^ = 237), %
1 (0.23) 10 (2.31) 1 (0.23) 13 (3.01) 11 (2.55) 134 (31.02) 110 (25.46) 25 (5.79) 24 (5.56) 35 (8.1) 26 (6.02) 21 (4.86) 31 (7.18) 27 (6.25) 69 (15.97) 4 (0.93)
0 (0) 11 (4.64) 1 (0.42) 5 (2.11) 9 (3.8) 60 (25.32) 83 (35.02) 26 (10.97) 16 (6.75) 26 (10.97) 15 (6.33) 5 (2.11) 17 (7.17) 12 (5.06) 33 (13.92) 1 (0.42)
p value
Adjusted OR*
0.459 0.099 0.666 0.492 0.363 0.120 0.009 0.016 0.533 0.218 0.873 0.078 0.999 0.531 0.481 0.469
– 0.62 (0.25–1.57) 0.43 (0.03–7.08) 1.46 (0.48–4.5) 0.66 (0.24–1.82) 1.33 (0.91–1.94) 0.69 (0.48–1) 0.49 (0.27–0.91) 0.91 (0.46–1.81) 0.77 (0.44–1.35) 1.05 (0.53–2.08) 2.29 (0.82–6.38) 0.72 (0.37–1.39) 1.16 (0.55–2.43) 1.16 (0.73–1.86) 2.22 (0.22–22.46)
(1)
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* Adjusted for good outcome in presence vs. absence of deficit, adjusted for age and NIHSS score at admission. ^ Total number of NIHSS items with score >0.
Discussion
Similar to data of previous studies [21, 22], in our whole cohort, the proportion of patients with low baseline NIHSS ≤6 was 57% (745/1,299). Stroke etiology in the study cohort was also comparable to epidemiological records [23]. Our findings confirm that 32% of patients with low NIHSS scores (≤6) had unfavorable outcome (mRS ≥2) [2]. Age and total NIHSS score were associated to poor prognosis. The positive correlation with good outcome in patients with cardioembolic stroke might be explained by the prevalence of small subcortical lesions and the high rate of neurological improvement. Looking at the definitions of minor stroke, the main distinctive feature is the high proportion of good outcome (66%) in patients classified as non-minor according to definitions 1 and 2. In addition, for these definitions, the proportion of good outcome was similar in minor and non-minor groups. Instead, as previously reported [4], the two groups of patients with total NIHSS respectively from 0 to 3 and from 4 to 6 clearly had a different outcome. The choice of a cut point to define minor stroke is supported by the observation that increasing NIHSS scores is inversely correlated to the chance of good outcome [24]. However, any definition of minor stroke that does not account for NIHSS items will assume that a severe deficit in one NIHSS item would be comparable to a mild deficit in more than one item. Intuitively we can imagine that not every item has the same impact on outcome. In this study cohort, our proposed definition, which takes into account the quality of neurological deficit performed well in predicting outcome, with good specificity and accuracy. This finding suggests that, in patients with mild symptoms, there is more to outcome than the NIHSS score [1, 6, 25]. Indeed, in addition to neurological deterioration, which accounted for 28.8% of patients with poor outcome, our proposed definition of minor symptoms picked up the items that better estimate 3 months disability. In our cohort, high blood pressure and infratentorial localization of ischemic stroke were risk factors for neurological deterioration, but we still lack strong predictors to identify patients who are most likely to experience poor outcome. The question whether or not to treat with thrombolysis patients with low NIHSS score is beyond the purpose 214
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of this paper [26–29]. A recent case-control study based on the Austrian Stroke Unit registry demonstrated the efficacy of thrombolytic treatment in a cohort of patients with NIHSS ≤5 [30]. However, they couldn’t find a significant effect of rt-PA treatment on outcome for patients with baseline NIHSS ≤3. A refined definition of minor stroke that also accounts NIHSS items could enrich this population and improve patients’ selection candidate to thrombolysis. Advanced neuroimaging techniques might represent a possible way to identify these subgroups of patients [31]. Our study had limitations. First, this was a monocentric cohort study, which limited the generalization of findings. Second, the proposed minor symptoms definition was built on clinical experience and will therefore have to be validated on a larger population of stroke patients. Third, a proportion of patients, although small, with significant distal motor impairment, not measured by NIHSS, yielding a significant functional impairment could have been misclassified within the minor stroke group. However, the rate of false negative was 2.1% (1 out of 47) that confirm a low impact of this event.
Conclusion
A widely accepted definition of minor symptoms is needed both for research and clinical practice. It appears that this new definition of minor stroke based on the NIHSS score as well as quality of neurological symptoms was able to select patients with non-disabling symptoms and favorable outcome. In addition, the newly proposed definition of minor stroke is easy to apply in everyday clinical practice, foremost in the setting of ED where the faster we act, the better we are able to treat stroke patients. Our results suggest that although baseline NIHSS ≤3 might be a good criterion to define minor symptoms, taking into account the type of neurological deficit may strengthen prognostic assessment. A low NIHSS score is not necessarily associated with favorable outcome; therefore, IV thrombolysis should not be withheld on this ground. Awareness that even minor stroke can yield to poor outcome should sensitize patients to arrive early to the ED and neurologists to administer rt-PA.
Disclosures The authors declare that they have no conflicts of interest.
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77% –, p 0.048). The difference was non-significant in non-minor patients (rate of good outcome 38/66 – 57.58% – vs. 11/27 – 40.74% –, p 0.140).
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Defining Minor Symptoms in Acute Ischemic Stroke
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1 Balucani C, Levine SR: Mild stroke and rapidly improving symptoms: it’s not always a happy ending. Stroke 2011;42:3005–3007. 2 Leira EC, Ludwig BR, Gurol ME, Torner JC, Adams HP Jr: The types of neurological deficits might not justify withholding treatment in patients with low total national institutes of health stroke scale scores. Stroke 2012; 43: 782–786. 3 Nedeltchev K, Schwegler B, Haefeli T, Brekenfeld C, Gralla J, Fischer U, Arnold M, Remonda L, Schroth G, Mattle HP: Outcome of stroke with mild or rapidly improving symptoms. Stroke 2007;38:2531–2535. 4 Fischer U, Baumgartner A, Arnold M, Nedeltchev K, Gralla J, De Marchis GM, Kappeler L, Mono ML, Brekenfeld C, Schroth G, Mattle HP: What is a minor stroke? Stroke 2010; 41: 661–666. 5 Park TH, Hong KS, Choi JC, Song P, Lee JS, Lee J, Park JM, Kang K, Lee KB, Cho YJ, Saposnik G, Han MK, Bae HJ: Validation of minor stroke definitions for thrombolysis decision making. J Stroke Cerebrovasc Dis 2013; 22:482–490. 6 Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM: Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2001;56:1015–1020. 7 Smith EE, Abdullah AR, Petkovska I, Rosenthal E, Koroshetz WJ, Schwamm LH: Poor outcomes in patients who do not receive intravenous tissue plasminogen activator because of mild or improving ischemic stroke. Stroke 2005;36:2497–2499. 8 Smith EE, Fonarow GC, Reeves MJ, Cox M, Olson DM, Hernandez AF, Schwamm LH: Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from get with the guidelines-stroke. Stroke 2011;42:3110–3115. 9 European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee: Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457–507. 10 Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology: Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American heart association/American stroke association. Stroke 2013;44:870–947.
Cerebrovasc Dis 2015;39:209–215 DOI: 10.1159/000375151
Defining Minor Symptoms in Acute Ischemic Stroke Davide Strambo a Alberto A. Zambon a Luisa Roveri a Giacomo Giacalone a Giovanni Di Maggio a Luca Peruzzotti-Jametti b Sara La Gioia a Sebastiano Galantucci a Giancarlo Comi a Maria Sessa a
a
San Raffaele Scientific Institute-Institute of Experimental Neurology, Stroke Unit-Department of Neurology and Neurophysiology, Milan, Italy; b Department of Clinical Neurosciences and Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
Abstract Background: Thrombolysis is often withheld from acute ischemic stroke patients presenting with mild symptoms; however, up to 40% of these patients end up with a poor outcome when left untreated. Since there is lack of consensus on the definition of minor symptoms, we aimed at addressing this issue by looking for features that would better predict functional outcomes at 3 months. Methods: Among all acute ischemic stroke patients admitted to our Stroke Unit (n = 1,229), we selected a cohort of patients who arrived within 24 hours from symptoms onset, with baseline NIHSS ≤6, not treated with thrombolysis (n = 304). Epidemiological data, comorbidities, radiological features and clinical presentation (NIHSS items) were collected to identify predictors of outcome. Our cohort was tested against minor stroke definitions selected from the literature and a newly proposed one. Results: Three months after stroke onset, 97 patients (31.9%) had mRS ≥2. Independent predictors of poor outcome were age (OR 0.97 [95% CI 0.95–9.99]) and baseline NIHSS score (OR 0.79 [95% CI 0.67–0.94]), while cardioembolic aetiology was negatively associated (OR 3.29 [95% CI 1.51–7.14]). Items of NIHSS associated with poor outcome
© 2015 S. Karger AG, Basel 1015–9770/15/0394–0209$39.50/0 E-Mail [email protected] www.karger.com/ced
were impairment of right motor arm (OR 0.49 [95% CI 0.27– 0.91]) or the involvement of any of the motor items (OR 0.69 [95% CI 0.48–0.99]). The definition of minor stroke as NIHSS ≤3 and the new proposed definition had the highest sensitivity and accuracy and were independent predictors of outcome. Conclusions: Our study confirmed that in spite of a low NIHSS score, one third of patients had poor outcome. As already described, age and NIHSS score remained independent predictors of poor outcome even in mild stroke. Also, motor impairment appeared a major determinant of poor outcome. The new proposed definition of minor stroke featured the NIHSS score and the NIHSS items that better predicted functional outcome. Awareness that even minor stroke can yield to poor outcome should sensitize patients to arrive early to the ED and neurologists to administer rt-PA. © 2015 S. Karger AG, Basel
Introduction
Patients with acute ischemic stroke presenting with low baseline NIHSS score are often referred to as ‘minor stroke’. While some minor stroke patients have minor non-disabling symptoms, a proportion of them (up to
D.S. and A.A.Z. contributed equally to this work.
Dr. Davide Strambo San Raffaele Scientific Institute-Institute of Experimental Neurology Stroke Unit-Department of Neurology and Neurophysiology Via Olgettina 58, IT–20132 Milan (Italy) E-Mail strambo.davide @ hsr.it
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Key Words Minor stroke · Minor symptoms · Stroke · Prognosis · Acute stroke outcome
Methods From our stroke database, we identified all patients with acute ischemic stroke consecutively admitted to our emergency department between January 2009 and January 2013. After excluding patients with final diagnosis of transient ischemic attack (TIA) [11] and patients treated with rTPA, we included in our cohort patients who satisfied both these criteria: onset to door time less than 24 hours and baseline NIHSS ≤6. For each patient we collected the following: demographic data, vascular risk factors, blood glucose and blood pressure measured in the Emergency Department (ED), onset to door time (OTD), baseline and discharge NIHSS score (total and individual item score), the Oxford clinical scale [12, 13] (OCSP, derived from the first neurological examination in the ED) and the Trial of Org 10172 in Acute Stroke Treatment classification [14, 15] (TOAST, upon extensive diagnostic workup). Neurological improvement or deterioration was measured as ΔNIHSS between discharge and baseline (ΔNIHSS 0: deterioration). Neurological evaluations were performed by trained neurologists with a valid certification to administer the NIH Stroke Scale. Favorable outcome was defined as lack of disability, quantified as mRS score ≤1, at three months followup. The mRS is a universally accepted method to evaluate the presence of disability after stroke and it was obtained either at outpatient visits or by telephone interview performed by certified medical personnel [16, 17]. Ischemic lesions on imaging were classified into lacunar sovratentorial lesions, non-lacunar sovratentorial lesions, infratentorial lesions, multiple lesions and negative imaging. Hemorrhagic transformation of ischemic lesion was classified as hemorrhagic infarction (HI1 and HI2) or parenchymal hematoma (PH1 and PH2) according to the criteria used in ECASS trials [18]. Minor Symptoms Definitions We performed a literature search for minor stroke definitions and selected the following definitions of minor symptoms: (1) NINDS-TPA trials definition [19, 20]: deficit not measurable on the NIHSS, pure sensory stroke, isolated ataxia, isolated dysarthria, or isolated facial weakness; (NIHSS range 0–3)
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(2) Park et al. definition [5]: deficit not measurable on the NIHSS or a deficit resulting in total NIHSS score = 1 with the point assigned in the level of consciousness (LOC), gaze, facial palsy, sensory, or dysarthria; (NIHSS range 0–1) (3) NIHSS ≤3 [4]: any neurological deficit resulting in baseline NIHSS score ≤3; (NIHSS range 0–3) (4) New proposed definition: NIHSS ≤6 with preservation of LOC items, score ≤1 in cortical (language and visual field) and motor items (limbs and speech), score 0 in the motor item of dominant arm and any score in the remaining items; (NIHSS range 0–6) The NINDS rt-PA Study Group tested other five definitions of minor stroke in a post-hoc analysis [19]. The functional outcome was similar for all five types of minor stroke definitions. However, each of the definitions proposed by the NINDS rt-PA study group allows a maximum total NIHSS score greater than the cut-off score of 6 that we used to select our study cohort. For this reason, we couldn’t apply these definitions to our population. Statistical Analysis Descriptive statistics were calculated for patient demographics, risk factors, baseline NIHSS score, onset-to-door time, imaging data, OXFORD and TOAST classification, comparing patients with favorable outcome (mRS score 0–1) to those with unfavorable outcome (mRS score 2–6). Counts and percentage proportions were displayed for categorical variables, while medians and interquartile range were calculated for continuous variables. The significance of differences between the two groups was evaluated using the Mann-Whitney test for continuous variables and Pearson Chi-square test for categorical variables. Variables showing association with outcome at the p < 0.10 level in the univariate analysis were included in the multivariate logistic regression model with dichotomized 3 months-mRS as dependent variable. Variables significant at p < 0.05 level in this analysis were considered independent predictors of outcome. The definitions of minor symptoms were applied to our cohort and, for each definition, patients were classified in the minor symptoms or in the non-minor-symptoms group. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Odds Ratio for 3-month favorable outcome (with 95% CI) were derived for each definition of minor symptoms. Chisquare test was used to compare the proportion of patients with good outcome in the four group of minor stroke identified using the different definitions. The Bonferroni method was used to adjust the p values of pairwise comparison. The distribution of single NIHSS items in the two outcome groups was analyzed with the Pearson Chi-square test. SPSS 13.0 software (SPSS Inc., Chicago, Ill., USA) was used for all statistical analyses.
Results
A total of 1,299 patients with acute ischemic stroke were admitted to our emergency department between January 1st 2009 and January 1st 2013. We excluded 554 patients with NIHSS >6, 157 patients with a final diagnosis of TIA, 128 patients arrived beyond 24 h from sympStrambo et al.
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40%) develops significant long-term disability [1–3]. In addition, the definition of minor symptoms is still a matter of debate [4, 5], leaving uncertainties in everyday clinical practice [6–8]. Indeed, according to AHA guidelines for acute ischemic stroke treatment, the presence of minor symptoms at the onset of acute ischemic stroke is indicated as a relative exclusion criterion to IV thrombolysis [9, 10]. The aim of this study is to assess the capability of different definitions of minor symptoms to predict favorable outcome in patients with acute ischemic stroke and low baseline NIHSS score (NIHSS ≤6). This could help to increase the confidence with decision of withhold or administer thrombolysis in minor stroke patients.
n = 1,299 patients with cerebrovascular ischemic event n = 554 patients with baseline NIHSS >6 n = 745 patients n = 157 patients with final diagnosis of TIA n = 588 patients n = 128 patients arrived to the ED 24 h after symptoms onset n = 460 patients n = 61 patients with no follow-up + n = 51 with pre-stroke mRS >1 348 patients
Fig. 1. Process to select eligible patients for
44 patients treated with rt-PA
304 selected patients
toms onset, 61 patients with missing follow-up, 51 patients with pre-stroke mRS >1 and 44 patients who had received rtPA. At the end, 304 satisfied the inclusion criteria of this study (fig. 1). The median age of the study population was 73 years (IQR 15 years), 60% were male, median baseline NIHSS was 2 (IQR 2) and the median OTD was 4 h (IQR 9 h). All patients underwent baseline CT scan and Magnetic Resonance Imaging was performed in 164 (53.9%). At three months follow-up, 207 patients (68.1%) had slight or no disability (mRS ≤1). Baseline features according to the outcome group are shown in table 1. Patients with favorable outcome were younger, had lower baseline NIHSS scores and lower systolic blood pressure at admission to the ED. Independent predictors of poor outcome were age (OR 0.97 [95% CI 0.95–9.99]) and baseline NIHSS score (OR 0.79 [95% CI 0.67–0.94]), while cardioembolic etiology was an independent predictor of good outcome (OR 3.29 [95% CI 1.51–7.14]). Accordingly, in this study cohort, cardioembolic strokes compared to stroke of other etiologies featured a higher proportion of small cortical lesions (48.5 vs. 23.5%, p 0.001), PACS clinical presentation (39.4 vs. 22.7%, p 0.006) and neurological improvement (62.5 vs. 48.7%, p 0.051), in spite of similar baseline NIHSS (median [IQR]: 3 [2] vs. 3 [2], p 0.661).
Hemorrhagic transformation of ischemic lesion occurred in 10 (3.2%) patients (n = 5 with HI-1, n = 4 with HI-2 and n = 1 with PH-1). Among them, two patients (1 HI-1 and 1 HI-2) experienced worsening of initial neurological deficit, which yielded to poor outcome in one case. Instead, 2 out of 8 patients with asymptomatic hemorrhagic transformation had poor outcomes. Overall, neurological deterioration (mean increase in NIHSS 2.2, range 1–13) occurred in 51 patients of whom 28 (54.9%) had poor outcomes. Patients who experienced neurological worsening had more frequently a history of hypertension (84.3 vs. 66.4%, p 0.011), higher systolic blood pressure at baseline (164 vs. 154 mm Hg, p 0.047), lower baseline NIHSS (median [IQR]: 3 [2] vs. 2 [1], p 0.000), higher proportion of infratentorial lesions (29.4 vs. 11.3%, p 0.009) and a low rate of PACS clinical presentation (15.7 vs. 29.2%, p 0.048). The rate of favorable outcome in minor and non-minor symptoms groups according to each definition is shown in table 2. In the minor symptoms group, the proportion of patients with good outcome was comparable across all the definitions tested (p 0.942), while higher variability emerged in the non-minor symptoms groups (p 0.001), with significant difference between definitions 1 and 4 (p 0.016) and between definitions 2 and 4 (p 0.015). The proportion of patients with good outcome
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the study.
Table 1. Patient characteristics according to outcome groups at 3 months from stroke onset
Total
mRS at 3 months from stroke 0–1 (n = 207)
Demographics Age, years Male sex, n (%) Vascular risk factors, n (%) Hypertension Diabetes Smoke Hypercholesterolemia Atrial fibrillation SBP at ED, mm Hg DBP at ED, mm Hg Glycemia at ED, mmol/l Stroke subtype, n (%) Cardioembolic Large vessels Small vessels Other or undetermined OCSP classification, n (%) PACS LACS POCS Not classified OTD, h NIHSS at baseline ΔNIHSS (NIHSS at discharge – NIHSS at baseline) ΔNIHSS 0 (mean ΔNIHSS +2.2) Ischemic lesion localization, n (%) Sovratentorial, lacunar Sovratentorial, non-lacunar Infratentorial Multiple lesions Negative imaging
p value
≥2 (n = 97)
73 (15) 183 (60.2)
72 (15) 129 (62.32)
77 (17) 54 (55.67)
0.001 0.270
213 (70.07) 74 (24.34) 73 (24.01) 67 (22.04) 47 (15.46) 155 (30) 80 (20) 116 (41)
142 (68.6) 45 (21.74) 57 (27.54) 44 (21.26) 32 (15.46) 150 (32) 80 (20) 114 (42)
71 (73.2) 29 (29.9) 16 (16.49) 23 (23.71) 15 (15.46) 160 (40) 80 (20) 126 (48)
0.415 0.122 0.036 0.630 0.999 0.014 0.691 0.090
66 (21.71) 55 (18.09) 80 (26.32) 103 (33.88)
53 (25.6) 33 (15.94) 53 (25.6) 68 (32.85)
13 (13.4) 22 (22.68) 27 (27.84) 35 (36.08)
0.016 0.155 0.680 0.579
113 (37.17) 80 (26.32) 80 (26.32) 31 (10.2) 4 (9) 2 (2)
77 (37.2) 56 (27.05) 53 (25.6) 21 (10.14) 4 (10) 2 (1)
36 (37.11) 24 (24.74) 27 (27.84) 10 (10.31) 4 (8) 3 (2)
0.989 0.670 0.680 0.965 0.712 0.005
39 (40.2) 28 (28.9) 28 (28.9)
0.008 0.379 0.000
19 (19.59) 27 (27.84) 17 (17.53) 9 (9.28) 25 (25.77)
0.887 0.770 0.300 0.403 0.831
154 (50.7) 93 (30.6) 51 (16.8) 61 (20.07) 88 (28.95) 44 (14.47) 35 (11.51) 76 (25)
115 (55.6) 65 (31.4) 23 (11.1) 42 (20.29) 61 (29.47) 27 (13.04) 26 (12.56) 51 (24.64)
Medians and interquartile range displayed for continuous variables, counts and percentage proportions for categorical variables. TIA = Transitory ischemic attack; SBP = systolic blood pressure; DBP = diastolic blood pressure; ED = emergency department; mRS = modified Rankin scale; OCSP = Oxford community stroke project classification; OTD = onset to door.
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In patients with impairment of any of the motor items, those with good and bad outcomes had similar baseline NIHSS (median [IQR]: 3 [2] vs. 4 [3], p 0.110) and number of other items involved (median [IQR]: 3 [1] vs. 3 [2], p 0.595), while there was a significant difference in the score of single motor items (median [IQR]: 1 [1] vs. 2 [1], p 0.021). Among patients classified as minor according to definition 3, the rate of good outcome differed between patients with and without motor impairment of the dominant arm (respectively 14/24 – 58.3% – vs. 134/174 – Strambo et al.
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was significantly different between the minor and nonminor symptoms groups classified according to definition 3 (adjusted OR 3.04 [95% CI 1.02–9.09]) and definition 4 (adjusted OR 3.11 [95% CI 1.65–5.86]). Overall, definition 3 and definition 4 had greater NPV, moderate specificity, higher accuracy and sensitivity. The relationship between NIHSS items and outcome is shown in table 3. Impairment of any motor item is significantly associated with poor outcome (adjusted OR 0.69 [95% CI 0.48–0.99]) as well as impairment of right motor arm (adjusted OR 0.49 [95% CI 0.27–0.91]).
Table 2. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and odds ratio of minor stroke for favorable outcome according to each minor stroke definition
a Rate of good outcome
Definition 1a (NINDS-TPA trials) Definition 2b (Park et al. [5]) Definition 3 (NIHSS ≤3) Definition 4a, b (new proposed definition)
Minor (%)
Non minor (%)
p
OR (95% CI)
Adj. OR (95% CI)
46/60 (76.67) 40/52 (76.92) 158/211 (74.88) 161/208 (77.4)
161/244 (65.98) 167/252 (66.27) 49/93 (52.69) 46/96 (47.92)
n.s. n.s. * *
1.69 (0.88–3.26) 1.7 (0.85–3.4) 2.68 (1.6–4.47) 3.72 (2.22–6.24)
0.81 (0.34–1.9) 0.69 (0.27–1.73) 3.04 (1.02–9.09) 3.11 (1.65–5.86)
b Statistics
Definition 1 Definition 2 Definition 3 Definition 4
Sensitivity
Specificity
PPV
NPV
Accuracy
22.2 (20–25) 19.3 (17–22) 76.3 (74–79) 77.8 (75–80)
85.6 (84–88) 87.6 (86–90) 45.4 (43–48) 51.5 (49–54)
76.7 (74–79) 76.9 (75–79) 74.9 (72–77) 77.4 (75–80)
34 (31–37) 33.7 (31–36) 47.3 (44–50) 52.1 (49–55)
42.4 41.1 66.4 69.4
* p < 0.05; n.s. = non significant. Adj. OR = OR adjusted for age, current smoking, NIHSS score at admission, systolic BP and glycemic levels in ED and cardioembolic etiology. a Proportion of patients with good outcome in non-minor stroke groups significantly different between definition 1 and 4. b Proportion of patients with good outcome in non-minor stroke groups significantly different between definition 2 and 4.
Table 3. Presence of deficit in each NIHSS item (absolute and percent values) in the two outcome groups at 3 months
NIHSS items
Level of consciousness 1a 1b 1c (2) Gaze (3) Visual field (4) Facial palsy Any motor item (5) Right motor arm (5) Left motor arm (6) Right motor leg (6) Left motor leg (7) Limb ataxia (8) Sensory (9) Language (10) Speech (11) Inattention
mRS at 3 months from stroke 0–1 (n^ = 432), %
≥2 (n^ = 237), %
1 (0.23) 10 (2.31) 1 (0.23) 13 (3.01) 11 (2.55) 134 (31.02) 110 (25.46) 25 (5.79) 24 (5.56) 35 (8.1) 26 (6.02) 21 (4.86) 31 (7.18) 27 (6.25) 69 (15.97) 4 (0.93)
0 (0) 11 (4.64) 1 (0.42) 5 (2.11) 9 (3.8) 60 (25.32) 83 (35.02) 26 (10.97) 16 (6.75) 26 (10.97) 15 (6.33) 5 (2.11) 17 (7.17) 12 (5.06) 33 (13.92) 1 (0.42)
p value
Adjusted OR*
0.459 0.099 0.666 0.492 0.363 0.120 0.009 0.016 0.533 0.218 0.873 0.078 0.999 0.531 0.481 0.469
– 0.62 (0.25–1.57) 0.43 (0.03–7.08) 1.46 (0.48–4.5) 0.66 (0.24–1.82) 1.33 (0.91–1.94) 0.69 (0.48–1) 0.49 (0.27–0.91) 0.91 (0.46–1.81) 0.77 (0.44–1.35) 1.05 (0.53–2.08) 2.29 (0.82–6.38) 0.72 (0.37–1.39) 1.16 (0.55–2.43) 1.16 (0.73–1.86) 2.22 (0.22–22.46)
(1)
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* Adjusted for good outcome in presence vs. absence of deficit, adjusted for age and NIHSS score at admission. ^ Total number of NIHSS items with score >0.
Discussion
Similar to data of previous studies [21, 22], in our whole cohort, the proportion of patients with low baseline NIHSS ≤6 was 57% (745/1,299). Stroke etiology in the study cohort was also comparable to epidemiological records [23]. Our findings confirm that 32% of patients with low NIHSS scores (≤6) had unfavorable outcome (mRS ≥2) [2]. Age and total NIHSS score were associated to poor prognosis. The positive correlation with good outcome in patients with cardioembolic stroke might be explained by the prevalence of small subcortical lesions and the high rate of neurological improvement. Looking at the definitions of minor stroke, the main distinctive feature is the high proportion of good outcome (66%) in patients classified as non-minor according to definitions 1 and 2. In addition, for these definitions, the proportion of good outcome was similar in minor and non-minor groups. Instead, as previously reported [4], the two groups of patients with total NIHSS respectively from 0 to 3 and from 4 to 6 clearly had a different outcome. The choice of a cut point to define minor stroke is supported by the observation that increasing NIHSS scores is inversely correlated to the chance of good outcome [24]. However, any definition of minor stroke that does not account for NIHSS items will assume that a severe deficit in one NIHSS item would be comparable to a mild deficit in more than one item. Intuitively we can imagine that not every item has the same impact on outcome. In this study cohort, our proposed definition, which takes into account the quality of neurological deficit performed well in predicting outcome, with good specificity and accuracy. This finding suggests that, in patients with mild symptoms, there is more to outcome than the NIHSS score [1, 6, 25]. Indeed, in addition to neurological deterioration, which accounted for 28.8% of patients with poor outcome, our proposed definition of minor symptoms picked up the items that better estimate 3 months disability. In our cohort, high blood pressure and infratentorial localization of ischemic stroke were risk factors for neurological deterioration, but we still lack strong predictors to identify patients who are most likely to experience poor outcome. The question whether or not to treat with thrombolysis patients with low NIHSS score is beyond the purpose 214
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of this paper [26–29]. A recent case-control study based on the Austrian Stroke Unit registry demonstrated the efficacy of thrombolytic treatment in a cohort of patients with NIHSS ≤5 [30]. However, they couldn’t find a significant effect of rt-PA treatment on outcome for patients with baseline NIHSS ≤3. A refined definition of minor stroke that also accounts NIHSS items could enrich this population and improve patients’ selection candidate to thrombolysis. Advanced neuroimaging techniques might represent a possible way to identify these subgroups of patients [31]. Our study had limitations. First, this was a monocentric cohort study, which limited the generalization of findings. Second, the proposed minor symptoms definition was built on clinical experience and will therefore have to be validated on a larger population of stroke patients. Third, a proportion of patients, although small, with significant distal motor impairment, not measured by NIHSS, yielding a significant functional impairment could have been misclassified within the minor stroke group. However, the rate of false negative was 2.1% (1 out of 47) that confirm a low impact of this event.
Conclusion
A widely accepted definition of minor symptoms is needed both for research and clinical practice. It appears that this new definition of minor stroke based on the NIHSS score as well as quality of neurological symptoms was able to select patients with non-disabling symptoms and favorable outcome. In addition, the newly proposed definition of minor stroke is easy to apply in everyday clinical practice, foremost in the setting of ED where the faster we act, the better we are able to treat stroke patients. Our results suggest that although baseline NIHSS ≤3 might be a good criterion to define minor symptoms, taking into account the type of neurological deficit may strengthen prognostic assessment. A low NIHSS score is not necessarily associated with favorable outcome; therefore, IV thrombolysis should not be withheld on this ground. Awareness that even minor stroke can yield to poor outcome should sensitize patients to arrive early to the ED and neurologists to administer rt-PA.
Disclosures The authors declare that they have no conflicts of interest.
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77% –, p 0.048). The difference was non-significant in non-minor patients (rate of good outcome 38/66 – 57.58% – vs. 11/27 – 40.74% –, p 0.140).
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Defining Minor Symptoms in Acute Ischemic Stroke
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