Stroke Scale Items Associated with Neurologic Deterioration within 24 Hours after Recombinant Tissue Plasminogen Activator Therapy

Stroke Scale Items Associated with Neurologic Deterioration within 24 Hours after Recombinant Tissue Plasminogen Activator Therapy Yusuke Nanri, MD,* Yusuke Yakushiji, MD, PhD,* Megumi Hara, MD, PhD,† Makoto Eriguchi, MD, PhD,* Ryuichirou Okada, MD,* Motohiro Yukitake, MD, PhD,* and Hideo Hara, MD, PhD*

It is unclear when and which neurologic deficits should be examined within 24 hours after intravenous recombinant tissue plasminogen activator (rt-PA) therapy for acute ischemic stroke. Relationships between serial changes in National Institutes of Health Stroke Scale (NIHSS) subscores and neurologic deterioration (ND) within the first 24 hours after therapy were investigated in 43 consecutive patients. The NIHSS score was measured by neurologists 28 times within 24 hours after therapy. Assessments of subscores associated with ND, defined as the first change 4 or more points from baseline, were performed at 15 minutes (most frequent time of the first ND), 120 minutes (median time of the first ND), and 24 hours after therapy. Seventeen of 43 patients (age range, 5594 years) showed ND. Of the NIHSS subscores, increases in scores for loss of consciousness (15 minutes, P 5 .001; 120 minutes, P 5 .026; 24 hours, P 5 .018) and motor limbs total (15 minutes, P 5 .014; 120 minutes, P 5 .031) were related to deterioration. Items such as questions, gaze, visual fields, ataxia, language, dysarthria, and extinction/inattention were not related to deterioration at any time. In conclusion, ND of ischemic stroke patients treated with intravenous rt-PA therapy was frequently seen within 120 minutes after therapy. Items such as loss of consciousness and motor limbs total may be considered indices for monitoring neurologic deficits after therapy. Key Words: Intravenous recombinant tissue plasminogen activator therapy—acute ischemic stroke—National Institutes of Health Stroke Scale—neurologic deterioration. Ó 2013 by National Stroke Association

Introduction Intravenous administration of recombinant tissue plasminogen activator (rt-PA) is generally accepted as firstFrom the *Division of Neurology, Department of Internal Medicine; and †Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan. Received May 21, 2012; revision received September 28, 2012; accepted October 1, 2012. Grant support: None. Address correspondence to Yusuke Nanri, MD, Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga 849-8501, Japan. E-mail: nanriyu@cc. saga-u.ac.jp. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2012.10.006

line treatment for acute ischemic stroke within 3 hours of onset; however, such therapy causes 10 times the incidence of intracranial hemorrhage (ICH) compared with placebo.1 Because most symptomatic ICHs (sICHs) occur within the first 24 hours after the start of rt-PA therapy,2-4 repetitive neurologic and physiological monitoring of patients during this period is critical.5,6 The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study1 and the Japan Alteplase Clinical Trial (J-ACT)4 demonstrated the efficacy of intravenous rt-PA therapy for acute ischemic stroke within 3 hours of onset. Both studies used the National Institutes of Health Stroke Scale (NIHSS) to evaluate neurologic deterioration (ND). However, only the results of total score changes between baseline and 24 hours after stroke onset were reported in these studies. In the NINDS

Journal of Stroke and Cerebrovascular Diseases, Vol. 22, No. 7 (October), 2013: pp 1117-1124

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Y. NANRI ET AL.

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rt-PA study, repetitive neurologic evaluations after rt-PA therapy initiation were performed using the abbreviated NIHSS. During these repetitive assessments, a nurse evaluated the level of consciousness (LOC), extremity strength, and designated cardinal signs for each patient (such as language). A decline of 2 points in the total abbreviated NIHSS score indicates the need for reassessment with the complete NIHSS.7 In a subgroup analysis of the NINDS rt-PA study that assessed clinical variables associated with ICH, the complete NIHSS score was obtained 5 times, that is, at baseline, 2 hours after therapy, and 24 hours, 7-10 days, and 3 months after therapy.2 However, when and how neurologic deficits should be assessed within 24 hours after intravenous rt-PA therapy for acute ischemic stroke is not well known. To develop evidence-based protocols for management of ND after rt-PA therapy for acute ischemic stroke, relationships between serial changes in complete NIHSS subscores and ND within the first 24 hours after the start of rt-PA therapy for acute ischemic stroke were examined.

Patients and Methods Patients Forty-five consecutive patients admitted to our division and treated with intravenous rt-PA for acute ischemic stroke within 3 hours of onset between May 1, 2006 and January 31, 2011 were considered potential subjects for this study. Intravenous rt-PA therapy was done with a single dose of alteplase (.6 mg/kg; not exceeding 60 mg), with 10% given as a bolus, followed by continuous infusion of the remaining dose over 1 hour, according to the J-ACT study.4 The inclusion and exclusion criteria for intravenous rt-PA therapy were the same as in the J-ACT study4 and matched the guidelines for intravenous use of rt-PA (alteplase) in Japan.6 In brief, in addition to the inclusion and exclusion criteria of the NINDS study, patients with an NIHSS score 4 or less and who demonstrated early ischemic changes on computed tomography (CT) affecting more than one third of the middle cerebral artery territory were excluded. Two patients were excluded as they could not be assessed because of clinical circumstances (one had adult respiratory distress syndrome, and the other had hematemesis from advanced gastric cancer). In both cases, they developed coma, and because of treatment for acute respiratory distress syndrome or hematemesis, NIHSS evaluations could not be performed. In both cases, the patients’ outcomes 3 months after rt-PA therapy were modified Rankin scale8 (mRS) scores of 5. Thus, 43 patients were studied prospectively. Informed consent was not obtained from the patients because the data needed for this study were collected while patients were treated according to the guidelines for intravenous use of rt-PA (alteplase) in Japan6 without additional invasive examinations or treatments. Instead, our intention to use data from patients who were treated was posted on the hos-

pital’s Web site between October 4, 2010 and February 28, 2011. All protocols were approved by the institutional review board on October 4, 2010 (approval number: 2010-10-02).

Neurologic Assessments The NIHSS has established reliability and validity for use in prospective clinical research, predictive validity for longterm stroke outcome,9-11 and appears to be the most sensitive way to detect changes associated with acute stroke.12 Thus, in this study, neurologic examination was assessed by the complete NIHSS, which consists of the following 15 items: 1A, LOC; 1B, questions; 1C, commands; 2, gaze; 3, visual fields; 4, facial palsy; 5a, motor left arm; 5b, motor right arm; 6a, motor left leg; 6b, motor right leg; 7, limb ataxia; 8, sensory; 9, language; 10, dysarthria; and 11, extinction/inattention. In each patient, the complete NIHSS was measured a total of 28 times by neurologists as follows: pre–rt-PA (baseline) and post–rt-PA at 15, 30, 45 minutes, and every hour from 1 to 24 hours. The neurologist in charge of NIHSS measurements rotated every 4 or 5 hours within 24 hours after the start of rt-PA therapy. The interrater variability for each NIHSS item score measured using the NIHSS training and demonstration digital video disk,13 expressed as Cohen k, was as follows: 1A, .64; 1B, .64-.82; 1C, 1.00; 2, .68; 3, .75; 4, .03-.21; 5a, .40-.62; 5b, .79-1.00; 6a, .36-.63; 6b, .35-.48; 7, 2.10; 8, .56-.89; 9, .73-1.82; 10, .71-.90; and 11, 1.41-1.73. Of the 1204 NIHSS measurements (43 subjects 3 28 examinations as planned), 54 (4.5%) NIHSS evaluations could not be performed because of the following: head magnetic resonance imaging or CT examination, 13 times; operation for hemorrhagic infarction, 4; treatment for nasal hemorrhage, 1; medical care for other patients, 4; transfer to general medical ward, 1; and unknown, 31. Thus, the data of 1150 NIHSS total scores and subscores were used for the analysis. Based on previous studies,14-17 ND was defined as an increase of 4 or more points from the baseline NIHSS score. No change or improvement was defined as an increase of less than 4 points. sICH was defined as CT evidence of ICH accompanied by apparent ND, defined as conditions that could be documented objectively or an increase of 4 or more points from the last NIHSS score.16 Recurrence of infarction was diagnosed when there was both clinical and imaging evidence of ischemic stroke in an independent arterial territory, so as to exclude deficits explainable by arterial reocclusion, proximal extension, or distal embolism of the original thrombus.18 Early ND of the original cerebral infarction (CI) was defined as an increase of 4 or more points from the baseline NIHSS score without sICH or recurrent infarction. Activities of daily living of each patient were assessed before and 3 months after rt-PA therapy using the mRS.8

Statistics Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL)

NIHSS ITEMS AND DETERIORATION AFTER rt-PA

version 11.0. The times at which the NIHSS subscore was associated with a substantial degree of ND were determined at 3 time points: (1) the most frequent time for the first ND time after the start of rt-PA therapy; (2) the median time of the first ND time after the start of rt-PA therapy; and (3) 24 hours after the start of rt-PA therapy. Changes in NIHSS total score, subscores, and total score of items 1A, B, and C (LOC total), and total score of items 5 and 6 (motor limbs total) between those obtained at baseline and at the 3 times listed previously were calculated. The Mann-Whitney U test was used to compare changes in these scores between patients with and without ND at each time point. Logistic regression analyses of each score associated with ND at the 3 times were also performed. Because there were interactions between each NIHSS item, in these analyses, nonadjusted odds ratios (not adjusted for age, sex, and the other subscore changes) were evaluated with univariate logistic regression analyses. P , .05 was considered significant.

Results Thirty-six of 43 patients (23 men, 20 women; mean age, 75.0 6 10.1 years; age range, 55-94 years) had infarcts in the anterior circulation (AC) territory, 6 had infarcts in the posterior circulation (PC) territory, and 1 had infarcts in both areas. Based on the criteria of the Classification of Cerebrovascular Diseases III,19 stroke subtype was atherothrombotic brain infarction in 8 patients, cardioembolic infarction in 31 patients, lacunar infarction in 0 patients, and other type of infarctions in 4 patients. The median baseline NIHSS score was 16 (range, 5-37). The distribution of patients’ mRS scores before stroke onset was as follows: 0-1, 26 patients; 2-3, 15 patients; and 4-5, 2 patients. Patient outcomes 3 months after rt-PA therapy were as follows: mRS score of 0-1, 10 patients; 2-3, 12 patients; 45, 19 patients; and 6, 2 patients. Of the 26 patients with no or trivial pre-existing disability, corresponding to an mRS score of 0 or 1 before stroke onset, 10 (38.5%) had a favorable outcome (mRS score of 0-1) 3 months after rt-PA therapy. Overall, 17 patients (39.5%) had at least one episode of ND within 24 hours after rt-PA therapy (Table 1). The median baseline NIHSS score of these patients was 13. The median score change was 5 (range, 4-13). In these patients, infarction developed in the AC territory in 15 patients and PC territory in 2 patients. The main causes of deterioration were as follows: early ND of the original CI (15 patients, 34.9%); sICH (1, 2.3%); and recurrent infarction (1, 2.3%). A total of 8 patients developed ICH with an increase of 4 points or less from the baseline NIHSS score. The first ND was most frequently seen at 15 minutes after rt-PA administration (16.3%), and the median time to first ND was 120 minutes after the start of rt-PA therapy. Thus, the analysis examining which NIHSS subscores were associated with a substantial de-

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gree of ND was performed using data from 15 minutes, 120 minutes, and 24 hours after the start of rt-PA therapy. Changes in NIHSS total scores and subscores, which were calculated as the score at each time point (15 minutes, 120 minutes, and 24 hours after therapy) minus the baseline score, were compared between patients with and without ND (Table 2). At 15 minutes, score changes of items 1A (P , .001), LOC total (P , .001), 5a (P 5 .004), motor limbs total (P , .001), and 8 (sensory) (P 5 .009) were significantly higher in patients with deterioration (n 5 7) than in patients without deterioration (n 5 33). At 120 minutes, score changes of items 1A (P 5 .043), 1B (P 5 .012), LOC total (P , .001), 6b (P 5 .043), and motor limbs total (P 5 .014) were significantly higher in patients with deterioration (n 5 5) than in patients without deterioration (n 5 34). At 24 hours, score changes of items 1A (P 5 .017), 1C (P 5 .019), LOC total (P 5 .002), 4 (P 5 .045), 5a (P 5 .006), 5b (P , .001), 6a (P 5 .001), 6b (P , .001), motor limbs total (,.001), and 9 (P 5 .003) were significantly higher in patients with deterioration (n 5 7) than in patients without deterioration (n 5 35). Results of univariate logistic regression analyses of each NIHSS subscore change relevant to ND at 15 minutes, 120 minutes, and 24 hours after the start of rt-PA therapy are shown in Table 3. For items such as questions, gaze, visual fields, ataxia, language, dysarthria, and extinction/inattention, there were no significant relationships between the subscore changes and ND at any time after the start of rt-PA therapy. The increased scores for 1A, 1C, LOC total, 4, 5a, 5b, 6a, 6b, motor limbs total, and 8 were significantly correlated with ND at 1 or more time points. Of these subscores, the increased scores for 1A, LOC total, 5a, 6b, and motor limbs total were related to ND on logistic regression analysis at 2 or more time points.

Discussion Most studies of rt-PA therapy for acute ischemic stroke that performed neurologic assessments using some stroke or function scale restricted findings to changes that occurred between baseline and 24 hours or 3 months after therapy. Few studies have assessed ICH in association with rt-PA or examined serial fluctuations of neurologic scale scores. However, neurologic symptoms often change dynamically immediately after rt-PA therapy, especially within the first 24 hours. Thus, it might be helpful for medical staff on a stroke care unit to know which neurologic symptoms are associated with substantial ND within 24 hours after rt-PA therapy. To the best of our knowledge, this is the first study to analyze the relationship between serial changes of NIHSS subscores and ND within the first 24 hours after the start of rt-PA therapy for acute ischemic stroke. The strengths of the present study include its prospective design, inclusion of consecutive ischemic stroke patients treated with rt-PA, use of

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Table 1. Features of patients with ND within 24 hours after rt-PA therapy Patients

NIHSS score change

Baseline

No

Age

Sex

NIHSS score

Territory of CI

First ND time (min)

Total

Item (score change)

Cause of ND

1

74

M

13

AC

15

113

Early ND of the original CI

2

71

F

21

AC

720

16

3 4

89 79

F M

10 9

AC AC

120 480

15 112

5 6 7 8 9 10 11 12 13 14 15 16 17 Median

90 84 60 83 56 85 78 94 84 88 70 78 83 83

F F M M M F F F M F F M M —

21 6 25 6 5 23 11 17 16 18 13 30 12 13

AC PC AC AC AC AC AC AC AC PC AC PC AC —

420 15 900 45 120 720 15 960 15 15 15 780 15 120

14 14 17 14 14 14 14 16 15 17 16 15 113 15

1A (11); 1B (11); 1C (11); 5a (13); 6a (13); 6b (11); 9 (12); 11 (11) 1A (12); 1C (11); 2 (11); 3 (11); 4 (11); 5a (12); 6a (11); 9 (21); 10 (22) 1B (11); 1C (11); 2 (21); 5a (11); 5b (11); 6a (11); 6b (11) 1A (11); 1C (11); 3 (12); 4 (11); 5b (13); 6a (12); 6b (11); 7 (22); 8 (11); 9 (2) 1A (11); 1C (11); 4 (11); 6a (21); 6b (11); 8 (11) 1A (11); 1B (12); 5b (11); 6b (21); 8 (11) 1A (12); 5a (12); 6a (12); 8 (11) 3 (11); 4 (11); 11 (12) 1B (11); 5a (11); 7 (11); 11 (11) 1A (11); 1C (11); 5b (2); 6b (1); 8 (21) 1A (11); 4 (11); 5a (11); 6a (11) 1A (22); 4 (11); 5b (12); 6b (11); 8 (11); 9 (11); 11 (12) 1A (11); 1C (11); 5a (11); 6a (11); 9 (11) 1C (11); 4 (11); 6b (11); 8 (12); 9 (11); 10 (11) 1A (11); 1B (11); 3 (12); 5a (11); 8 (11) 2 (12); 3 (13); 4 (12); 5a (21); 5b (21) 1A (11); 3 (11); 5b (14); 6b (13); 8 (11); 10 (11); 11 (12) —

Early ND of the original CI Early ND of the original CI Recurrence of infarction Early ND of the original CI Early ND of the original CI sICH Early ND of the original CI Early ND of the original CI Early ND of the original CI Early ND of the original CI Early ND of the original CI Early ND of the original CI Early ND of the original CI Early ND of the original CI Early ND of the original CI Early ND of the original CI —

Y. NANRI ET AL.

Abbreviations: AC, anterior circulation; CI, cerebral infarction; F, female; M, male; ND, neurologic deterioration; NIHSS, National Institutes of Health Stroke Scale; PC, posterior circulation; rt-PA, recombinant tissue plasminogen activator; sICH, symptomatic intracerebral hemorrhage; 1A, Level of consciousness; 1B, Questions; 1C, Commands; 2, Gaze; 3, Visual fields; 4, Facial palsy; 5, Motor arm—a. Left and b. Right; 6, Motor leg—a. Left and b. Right; 7, Ataxia; 8, Sensory; 9, Language; 10, Dysarthria; 11, Extinction/inattention.

Age, y, mean (SD) Male, n (%) Score changes (SD) NIHSS total 1A) LOC 1B) LOC questions 1C) LOC commands LOC total 2) Gaze 3) Visual fields 4) Facial palsy 5) Motor arm a. Left b. Right 6) Motor leg a. Left b. Right Motor limbs total 7) Ataxia 8) Sensory 9) Language 10) Dysarthria 11) Extinction/inattention

15 min*

120 miny

24 hz

Deterioration

Deterioration

Deterioration

Without (n 5 33)

With (n 5 7)

73.9 (10.8) 19 (56)

80.1 (6.4) 3 (43)

2.71 (2.64) 2.06 (.42) 2.15 (.74) .00 (.70) 2.21 (1.10) 2.09 (.62) 2.03 (.80) 2.09 (.38)

P

Without (n 5 34)

With (n 5 5)

P

Without (n 5 35)

.148 .529

75.4 (10.1) 18 (53)

76.4 (13.4) 3 (60)

.689 .77

73.5 (10.2) 19 (54)

17.43 (3.95) 1.86 (.38) 1.57 (.79) 1.43 (.54) 11.86 (.90) .00 (.00) 1.43 (.79) 1.29 (.49)

— ,.001 .063 .154 ,.001 .722 .224 .164

22.50 (4.45) 2.12 (.64) 2.35 (.73) .00 (.49) 2.47 (1.13) 2.15 (.66) 2.21 (1.04) 2.06 (.74)

16.00 (3.39) 1.60 (.55) 1.60 (.55) 1.40 (.55) 11.60 (.55) 2.20 (.45) 1.60 (.89) .00 (.00)

— .043 .012 .223 ,.001 .919 .139 .919

2.26 (.51) 2.21 (.77)

1.86 (1.07) 1.71 (1.45)

.004 .125

2.35 (.95) 2.12 (1.20)

1.40 (.55) 11.20 (1.64)

1.06 (.65) 2.24 (.65) 2.62 (1.39) 1.18 (.63) 2.18 (.52) .00 (.25) 1.15 (.44) 1.21 (.64)

1.71 (1.11) 1.57 (1.27) 12.86 (2.91) .00 (.00) 1.71 (.76) 1.57 (.79) 1.29 (.49) 1.43 (.79)

.154 .116 ,.001 .722 .009 .087 .599 .599

2.26 (.93) 2.44 (.93) 21.18 (2.63) 2.03 (.72) 2.15 (.66) 2.18 (.39) 2.03 (.52) 2.06 (.65)

1.20 (.84) 1.60 (.89) 12.40 (2.51) 1.20 (.45) 1.40 (.55) 1.20 (.45) 1.20 (.45) 1.60 (.89)

With (n 5 7)

P

84.6 (5.6) 3 (43)

.007 .585

25.34 (4.77) 2.14 (.73) 2.20 (.76) 2.09 (.61) 2.43 (1.29) 2.31 (.72) 2.34 (.97) 2.29 (.93)

18.71 (4.35) 1.71 (.76) .00 (.58) 1.86 (.90) 11.57 (1.27) .00 (.58) .00 (1.29) 1.57 (.98)

— .017 .716 .019 .002 .319 .466 .045

.089 .081

2.74 (1.27) 2.71 (1.27)

1.71 (.95) 12.00 (1.29)

.006 ,.001

.314 .043 .014 .5 .128 .239 .5 .178

2.49 (1.01) 2.89 (1.16) 22.83 (2.67) 2.06 (.73) 2.37 (.77) 2.34 (.68) 2.14 (.60) 2.23 (.65)

1.71 (.49) 11.57 (1.40) 15.00 (1.83) 2.29 (.76) 1.14 (.90) 1.86 (.90) 1.43 (.54) 1.43 (1.13)

.001 ,.001 ,.001 .741 .181 .003 .058 .181

NIHSS ITEMS AND DETERIORATION AFTER rt-PA

Table 2. Comparisons of NIHSS subscore changes between patients with and without ND at each time point after rt-PA therapy

Abbreviations: LOC, level of consciousness; ND, neurologic deterioration; NIHSS, National Institutes of Health Stroke Scale; rt-PA, recombinant tissue plasminogen activator; SD, standard deviation. Patients’ numbers of each evaluation were not total to 43. The reasons that NIHSS evaluations could not be performed were as follows: *Examination of head magnetic resonance imaging or computed tomography, 1 time; and unknown, 2. yExamination of head magnetic resonance imaging or computed tomography, 2 times; treatment for nasal hemorrhage, 1; and unknown, 1. zOperation for hemorrhagic infarction, 1. 1121

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Table 3. Results of univariate logistic regression analysis of each NIHSS subscore change associated with ND at 15 min, 120 min, and 24 h after the start of rt-PA therapy 15 min

120 min

24 h

Score changes

OR

P

OR

P

OR

P

1A) LOC 1B) Questions 1C) Commands 1A, B, C total (LOC total) 2) Gaze 3) Visual fields 4) Facial palsy 5) Motor arm a. Left b. Right 6) Motor leg a. Left b. Right 5, 6 total (motor limbs total) 7) Ataxia 8) Sensory 9) Language 10) Dysarthria 11) Extinction/ inattention

84.33 (6.58-1080.19) * * 8.23 (1.90-35.61)

.001 * * .005

9.44 (1.31-67.91) 116011.78 (0.00-3.53 3 1050) * 15.57 (1.76-137.83)

.026 .827 * .014

5.15 (1.32-20.10) * 9.63 (1.80-51.70) 4.07 (1.54-10.79)

.018 * .008 .005

* * *

* * *

* * *

* * *

* * 2.61 (1.02-6.63)

* * .045

25.57 (2.21-296.08) *

.009 *

* *

* *

4.12 (1.32-12.86) 20.60 (2.15-197.59)

.015 .009

* * 6.05 (1.45-25.2)

* * .014

* 5.56 (1.14-27.10) 2.29 (1.08-4.89)

* .034 .031

8.91 (1.67-47.48) 65.90 (3.51-1238.74) 2.11 3 1013 (.00-y)

.01 .005 .989

* 14.44 (2.07-100.89) * * *

* .007 * * *

* * * * *

* * * * *

* * 40610.10 (.00-7.78 3 1044) * *

* * .823 * *

Abbreviations: LOC, level of consciousness; ND, neurologic deterioration; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; rt-PA, recombinant tissue plasminogen activator. *Not examined because there were no significant differences in score changes between patients with and without deterioration. yCould not calculate.

repetitive neurologic assessments performed by a neurologist (28 times per 24 hours), and consistent use of the complete NIHSS. The European Cooperative Acute Stroke Study (ECASS) I and the NINDS rt-PA Stroke Study20,21 used different assessments to investigate serial changes of stroke scale scores within 24 hours after rt-PA therapy. The secondary analysis of the ECASS I,20 a doubleblind, randomized, multicenter trial, assessed the efficacy of intravenous rt-PA (1.1 mg/kg) therapy for acute ischemic hemispheric stroke within 6 hours after onset using the Scandinavian Stroke Scale at baseline and 120 minutes, 8 hours, and 24 hours after treatment. Of all ECASS I subjects (rt-PA group and placebo group), substantial ND was seen within 120 minutes after treatment in 23%, within 8 hours after treatment in 32%, and within 24 hours after treatment in 38%. These findings were consistent with the present results of 23% (n 5 10) within 120 minutes, 28% (n 5 12) within 8 hours, and 40% (n 5 17) within 24 hours (data not shown). The secondary analysis of the NINDS rt-PA study,21 a double-blind, randomized, multicenter trial, evaluated the efficacy of intravenous rtPA (.9 mg/kg) therapy for acute ischemic stroke within 3

hours after onset, using the NIHSS at baseline. A substantial ND, defined as any increase in 4 or more points compared with baseline within 24 hours after treatment, was seen in 18% of patients in the placebo group and 14% of patients in the rt-PA group, with no significant difference between the groups. The reason for the substantial difference in the prevalence of ND within 24 hours after rt-PA therapy between the NINDS rt-PA study and the present study is unclear, but it might be mainly caused by differences between a clinical trial and the real world. However, the prevalence of patients with favorable outcomes 3 months after rt-PA therapy was similar in both studies. The main mechanism by which ND was frequently observed within 120 minutes after rt-PA therapy in this study may have been early ND of the original CI. In fact, 10 patients had ND within 120 minutes after rt-PA therapy, of whom 7 had ND within 15 minutes of the therapy. Of these 10 patients, none had sICH. In the present study, 7 items, including questions, gaze, visual fields, ataxia, language, dysarthria, and extinction/ inattention, were not significantly related to ND at any time after the start of rt-PA therapy. These findings might result from the low reliability of all 7 items, but

NIHSS ITEMS AND DETERIORATION AFTER rt-PA

‘‘questions,’’ as consistently demonstrated in previous studies.9,11,22-24 Such low reliability of these items may lead to random noise resulting from variable inter-rater scoring because the neurologist in charge of NIHSS measurements rotated every 4 or 5 hours within 24 hours after the start of rt-PA therapy in the present study. Results of this study showing that an increased LOC score was associated with ND are inconsistent with other studies, which have shown that LOC has low reliability.9,11,22,23 However, the NIHSS measurement depends mostly on the patient’s responsiveness, and it appears to be common knowledge that the total NIHSS score is well correlated with consciousness level. Therefore, the present results might partially demonstrate the validity of such common sense. Furthermore, because the scoring of the LOC is almost the same as the score for ‘‘eye opening’’ on the Glasgow Coma Scale, which is traditionally used in many hospitals,25 this demonstration of the efficacy of the LOC measurement for acute ischemic stroke patients might be acceptable for medical staff on a stroke care unit. Interestingly, the present results demonstrated that an increased LOC score (1A), and the motor limbs total score, was significantly associated with ND within 24 hours after rt-PA therapy, supporting the appropriateness of the adoption of the ‘‘abbreviated NIHSS’’ of the NINDS rt-PA stroke; this abbreviated score consists mainly of assessments of LOC and extremity strength.9 As for the reason of significant association between NDs and LOC (1A), LOC total, or motor limbs total, the disparity in the distribution of the score for each items should also be considered. Their subscores have more wide ranges (0-3, 0-7, and 0-16, respectively) than almost of the others. Thus, such wide-ranged subscores might have relatively strong influence to a substantial degree of the deterioration. The present study had several limitations. First, this study included a small number of subjects, and ND associated with ICH within 24 hours after rt-PA therapy occurred in only 1 patient (2.3%). Such a weakness made it difficult to examine which factors represented highrisk neurologic deficits after rt-PA therapy. Second, the difference in the predictive utility of the NIHSS between AC stroke patients and PC stroke patients should be considered because the NIHSS appears to have limitations when comparing the neurologic severity of PC and AC strokes.26 The cutoff score for the baseline NIHSS score for favorable chronic outcome seems to be relatively low in patients with PC stroke compared with patients with AC stroke.26 The present study primarily included patients with AC stroke. Therefore, further study is required to determine if the present results apply to patients with PC stroke. Third, the statistical difficulty that arose from interactions among individual NIHSS items should be considered. In fact, the multiple logistic regression analysis, which included NIHSS items associated with ND at each time point with a significant difference be-

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tween groups on univariate analysis (Mann-Whitney U test), showed no significant differences in any items between groups with and without ND. Thus, significant findings were only shown on univariate analysis. Fourth, the association between ND and hyperperfusion syndrome (HPS) should be discussed. HPS is thought to be caused by an acute excessive increase in cerebral blood flow into an area of previous hypoperfusion.27,28 The pathophysiology of HPS is defined by the clinical triad of ipsilateral headache, seizures, and ICH. To assess brain perfusion, single-photon emission computerized tomography scanning, transcranial Doppler, perfusion CT, and so on have been used. Clinically, patients with early ND did not have ipsilateral headache or seizures. As stated previously, 8 patients developed ICH with an increase of less than 4 points from the baseline NIHSS score. Their minor deteriorations might be interpreted as caused by HPS, clinically. However, unfortunately, pre–rt-PA and post–rt-PA cerebral blood flow could not be performed in these patients. Thus, HPS could not be definitely diagnosed with diagnostic imaging, and this is a limitation of the present study. In conclusion, a substantial degree of ND was frequently seen in ischemic stroke patients treated with rtPA therapy within 120 minutes after the start of therapy. This study offers the first evidence that the scores of NIHSS items, such as LOC, LOC total, motor limbs, and motor limbs total, had reproducible associations with ND within 24 hours after rt-PA therapy. These items could be considered indices for monitoring neurologic deficits after rt-PA therapy.

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