Him ORIGINAL CONTRIBUTION Lack of Improvement in Patients With Acute Stroke After Treatment With Thrombolytic Therapy Predictors and Association With Outcome Gustavo Saposnik, MD Context ‘The focus of thrombolytic therapy in acute stroke has been on favorable MD outcome at 3 months. Few studies have analyzed outcome at 24 hours. An early and cr MD. reliable prediction of poor outcome has implications for clinical management and dis- Inia Di Legge, MD charge planning es Objective To evaluate predictors oflack of improvernent at 24 hours after receiving Bryan Yo ii Fiona Webster, MA alteplse and their relationship with poor outcome at 3 months Vain Beleteky, MD Design, Setting, and Participants Prospective cohort of consecutive patients with Vivek Jain, MD acute stoke who received altepase and were admitted toa university hospital from ai _anuary 1999 to March 2003. Participants were reruted from 2 academic centers in Yongchai Nilnont MD. a major city in Ontario and 33 affilated hospitals from 7 counties. ‘Main Outcome Measures Lack of improvement defined asa difference between TECOMBINANT TISUEPLASMING. the Nationa Institutes of Health Stroke Scale score at baseline and at 24 hours of 3 points or les. Poor outcome at 3 months defined by a modified Rankin Scale score of 3 to5 or death Results Among 216 patents with acute stroke who were treated with alteplase, 111 tients, Nine yeare-fer te approval, ine 1-49) had alack of mproverent at 24 hours. After adjusting forage, sex, and stroke Maree ee aclce conte be the verity, baseline glucose level on admission (odd ratio [OR] 2.89; 95% confidence in- i ras continues tobe the terval [Ci] 1.40-5.99 fora glucose evel >144 mg/dl [>8 mmol/L), cortical involve- cenly approved thrombolytic therapy for rent (GR, 2 66, 95% Cl, 136-5.20), and time to treatment (OR, 1.01; 95% Cl, 1.0- patients within 3 hours of an acute {s- 4.9 for each 1 minute increase in time to treatment) were independent predictors of chemic stroke.' However, several is- lack of improvement. At 3 months, 43 patents (20.2%) had died, of the 170 survivors, stues remain regarding its use. For ex- 75 patient (44%) had poor outcomes. After adjusting forage, sex, and stoke severity, ample, there was no significant lack of improvement at 24 hours was an independent predictor of poor outcome (OR, difference in recovery measured by >4 12.9; 95%CI, 57-29.) and death (OR, 75; 95% Cl, 2.9-19.6). Patients with alack of points improvementon the National In- improvement had longer lengths of hospitalization (145 vs 9.6 days; P=.02). stitutes of Health Stroke Scale [NIHSS}) Conelusions Among patients with acute stroke treated with thrombolytic therapy, at 24 hours between the alteplase and lack ofimprovementat 24 hoursis associated wth poor outcome and death at 3 months. lacebo groups in the National Insti--_ Elevated glucose level, time to thrombolytic therapy, and cortical involvement were Prot Rew predictor oflackof improvement. JAMA, 2008252 1839-1544 vwwama.com gen activator (alteplase) is one of the most elficacious treat ‘ments for ischemic stroke pa- tute of Neurological Disorders and stroke (NINDS) alteplase study (A greater outstanding issue was the ‘dentification of accurate predictors of 5 saomhs.>* Other recent studies ana- ‘Author Affiliations: Stroke Program, Department of Cini outcome.” Age, sex, mean arterial jvoed predictors for dramatic recovery SNswoogs Scenes London Hel Scena Cen Blood presse, NIISS score and =U redcon for deat recovery Ge Gey of ic Oxo computed tomographic (CT) findings 34 ore afer receiving alteplase.?"" Pocus ade Webs na Depart teu have been identified as independent rs after receiving ‘gy Hey Ford spa Ce ach (Se redictors of good clinical outcome at_ Nevertheless, the lack of improve- conesponding Author Gustavo Saposnit, MD, Stoke Pp Be ment at 24 hours after receiving. Senice London Heath Sciences Cente, Unversity of iit Got 35 Vine fhe stele snot been studi ystem- pr, NASR ose aia oo For editorial comment see p 7 (©2004 American Medical Assoc ton, Al rights reserved. (Reprinted) AMA, Oe‘THROMBOLYTIC THERAPY AND STROKE OUTCOMES Many predictors have a univariate re lationship with poor outcome," but in multivariate analysis the relationship is less clear. Mdentlying predictors of lack of improvement may improve unde standing of the clinical factors that in- Mluence the acute recovery and clinical response to alteplase. This perspective can help predict poor outcome eatier (24 hours after receiving alteplase) than at 3 months, An early and reliable predic- lion of poor outcome has important im- plications for clinical management and Tor discharge planning, We hypothesized that baseline clint- cal, imaging, or laboratory factors are associated with lack of improvement at 24 hours; that these factors are diffe cent [rom those previously described ‘with poor outcome at 3 months or ma- jor neurological improvement (NIHSS 8 points) within 24 hours; and that lack of improvement at 24 hours isan independent predictor of poor out- ccome at 3 months, METHODS: We analyzed consecutive patients with acute stroke who received alteplase. All patients were admitted to the unive sity campus of the London Health Sei- ences Center (London, Ontario) from January 1999 10 March 2003, London is the largest city in south- western Ontario with a population of 336540 (452450 in the metropolitan area). Ithas 2 academic medical cen- ters with 24-hour access to CT and. magnetic resonance imaging, These aca demic hospitals are a relertal center for a large part of Ontario, In addition to serving the local population, the Health Sciences Centre receives acute stroke refertals from 33 rural hospitals from. 7 counties. This catchment area cov cers 7800 square miles and serves a population of 1.5 million." Details eon- cerning hospital characteristics and clinical assessment were outlined in 2 previous articles." Patients with suspected ischemic stroke were seen within 3 houts of symp- tom onset at the Health Seiences Cen- tre. Demographic variables, evaluation and treatment times, admission, and 24- $840 JAMA October 20,2004 Vol 292, No 15 Reprinted hour NIHSS scores and outcomes were entered into a database by stroke fe lows. The fellows were trained and ce Lied in administering the NIHSS, For all patients, ime of symptom onset was de- fined by the time when they were “last seen to be well.” Time of treatment with alteplase was obtained from the nurs- ing records as onset to needle time for the alteplase infusion. Time to alteplase was caleulated from these data The decision to treat with alteplase was made according to the NINDS pro- tocol.! Informed consent was given by the patient or his/her relatives. The eth- {es review board at the University of Western Ontario in London deter mined that approval was not required because there was no intervention and the study only observed outcomes part of standard care at this institution. Inclusion and exclusion criteria were applied with one major difference from NINDS: patients with involvement of more than one third of the middle ce- rebral artery territory on the baseline CT scan were excluded. Management after alteplase infusion followed the published guidelines." A control CT scan was performed at 24 hours to de- termine the presence of new infarc tion, cortical involvement, and exten- sion of the ischemic lesion. The neuroradiologist who interpreted the CT scans was blinded to the neurologi- cal status of the patient. ‘A rouline evaluation was performed todetermine the stroke mechanism and stroke subtype in all patients, which in- cluded routine laboratory tests electro cardiogram, transthoracic echocardio- gram, and carotid ultrasound. Magnetic resonance imaging, magnetic reso- nance angiography, CT angiography. transesophageal echocardiogram, or con- ventional angiography were performed when appropriate Definition of Vari Demographic, clinical, routine labora ory, and hemodynamic variables were recorded at admission. Data on his- tory of risk factors were obtained from medical records, the patient, or his/ her family. Stroke subtype (lacunar vs nonlacunar) was based on presenting symptoms, physical examination, and neuroimaging, The presence of corti- cal involvement, new infarction, or hemorrhagic transformation was es- lablished according to the neuroradio- logical report of the control CT sean We analyzed the distribution ofall variables by both graphic and analytic methods (requency distnbution by quar- tiles or quintiles). Ifthe relationship be- tween a continuous variable and the pri- mary outcome (lack of improvement, modified Rankin Seale score, or death) ‘was linear, iL was kept as continuous, If the relationship suggested a cutoff, the variable was categorized. When there was no clear relationship, we used elinial cri- teria to analyze the variable. According to theaforementioned analysis, glucose ‘on admission was dichotomized as less than, greater than, or equal to 144 mg/dl. (SmmoV/L).Inouranalysis, age, weight, baseline NIHSS, creatinine levels, he- matoctit, white blood cell count, time from stroke onset to treatment (al- teplase), and total alteplase dose wer continuous variables, ‘Outcome Measures including the NINDS alteplase stroke trial, used a difference ‘of 4 points or more on the NIHSS to fleet a clinically significant improve- ment beyond interrater variability!" Other studies showed a good inter- rater agreement when examiners did not differ in the total scares by 3 points ‘or more." We defined lack of tm- provement as less than of equal to a S-point difference between the base- line and 24-hour NIHSS score, Out- come measures were evaluated using the modified Rankin Seale score at 3 months, which is a commonly used riod in studies of thrombolysis for acute stroke. Poor outcome was defined as a modified Rankin Scale score greater than oF equal to 3 or death, Previous studies Statistical Analysis Two exploratory analyses were per- formed. Pirst, predictors of lack of im- provement at 24 hours were identified, The association between demographic (©2004 American Medical Association, All rights reserved.characteristics, clinical and hemody- namic variables, and lack of improve- ment was examined using univariate lo- istic regression, We also retrospes performed survival analyses to repre- sent the number of patients at risk and the cumulative proportion of patients ‘with lack of improvement by the ime to Second, lack of improvernent at 24 hours was evaluated as an indepen- dent predictor of poor outcome (modi- fied Rankin Seale score, 3-5 or death) C3 months in a multivariate analysis, Step-wise multivariate logistic regres sion, allowing for entry at the 15 level of significance based on the score sla- listic, was used to determine a subset ‘of these variables independently asso- ciated with lack of improvement. Co- variates were checked for collinearit and interaction effects. Diserimina- lion of the model was assessed by the area under the receiver operating char- acteristic curve and calibration Was as- sessed using the goodness of fi test. No adjustment was made for multiple test- ing. Analysis was performed using STATA statistical software (version 7.0, STATA Corp, College Station, Tex), P<.05 was considered significant RESULTS tient Characteristics rom January 1999 to March 2003, 1214 patients with acute stroke were admi ted to the Health Sciences Center. Dur- ing that period, 219 patients (18%) were treated with intravenous lt patients were excluded because of miss- ing 24-hour outcome data. OF the 216 remaining patients, 111 (51.4%) had lack. ‘of improvernent at 24 hours after rec ing alteplase (TaBLe 1). Three patients (1.49%) were lost to follow-up. There were no statistically signili- ccant differences in demographic vari- ables, geographic location of symptom ‘onset (London vsother),rsk factors, pre- vious medication, baseline NIHSS score, and alteplase dose between both groups (lack of tmprovernent vs improvement; Table 1). There was no statistically sig- nificant difference NIHSS score as a categorical variable ase. Three ween the baseline (©2004 American Medical Assoc tion. Al rights reserved. Reprinted) JAMA, Oxobe THROMBOLYTIC THERAPY AND STROKE OUTCOMES (based on clinical categories 0-6, 7-15, minutes of stroke onset. The overall 16) and lack of improvement. Me- asymptomatic and symptomatic hemor- dian change in the NIHSS score was 7in rhage rates at 36 hours were 104% and. the group with improvementand I inthe 4.1%, respectively. Five patients (2.3%) group with lack of improvement. ‘with symptomatic intracranial hemor- TThe mean time [rom symptom onset rhage died. Forty patients (18%) wet to arrival in the emergency department treated outside the 3-hour vas 83 minutes (median, 70 minutes). dow. There was no statistically signif The mean time from symptom onset to cant difference between the presence of treatment was 157 minutes median, 160 intracranial hemorrhage and the time minutes). In the overall sample, only window (within or outside 180 min- 4.196 of patients were treated within 90 utes of symptom onset; P=.56). ‘Table 1. Comparson of Cimen Charactensier and Univariate Anaya According fo Unek of Improvement at 24 Hourst improvement n= 101)" Valuet aS Patents aged <00y Nien Tea ren SOS Symptom ongetn Londen, Oras FHSS score, mean SO) Fis factors Fiperchoesteoeria ‘Sure among ‘ira fora “leche us ‘Crary ee a aan, ean OT “Gucoes, ma reatrine wnat, ‘ite tod oat oar TOTAL Fematoet ‘Compute tomographic Tangs 358 28) Fight so of bran rclved 24 Tew ntact a ‘Coral vob mr Femoragis tansiorraon 1019) 20 Sree air Nesacar 10592) 85/85) a Taearar TS) a ‘Riapase, mean Fist eaten min (82) Total daa, ma Br (Te) 5 1081‘THROMBOLYTIC THERAPY AND STROKE, ‘OUTCOMES Dr Lagutic Regression Mage for Lack of Improvement Unadjusted Model ‘Adjusted Mode Cae ee aN SEAL (OR (05% CP Value’ OR(@5% CHP Value Ey SaaS OT Oar EETIEEEEE 2000 OT (00-102) ToT 0-10) TOT (057-705) TT eee 0.0 0.96107), Tom 6-101) a Basaina NSS aoe Tas 008-280) TOO 95-1106) 98 Figure, Cumulative Proportion of Patents With Lack of Improvement by Time From Symptom Onset to Treatment With Thrombolytic Thera one of the patients ceived apse prot 60 mites ale sympiom ons Predictors of Lack of Improvement The presence of hyperglycemia (glu- cose level >144 mg/dl. [> mmoVL]), new infarction, cortical involvement, and lime to treatment with alteplase were in dependent predictors of lack of improv ment in the univariate analysis (Table 1). In logistic regression analysis, glucose level (odds ratio [OR], 2.89; 95% con- fidence interval [CI], 1-40-5.99), pres cence of cortical involvement (OR, 2.66; 95% Cl, 1.36-5.20), and time to treat- ment with alteplase (OR, 1.01; 95% Cl 1.00-1.02 per L-minute increase) we independent predictorsalter adjusting for age, sex, and stroke severity (TABLE 2) For each mimute increase: ment, the OR for lack of improvement is 1.01, The longer the time to treat ment, the higher the probability of lack of improvement (FIGURE). 4842 JAMA occa 20,2004 ol 282, No 15 Reprinted) Lack of improvement was present in allo patients with symptomatic intracra- nial hemorrhage. In this small group, it ‘sdilficulttodeterminetflackofimprove- ‘ment was present before orafter the de- velopment of theintrseranial hemorrhage. Therefore, the clinical deterioration se ondary tothe intracranial hemorrhageand concomitant lack of improvement were probably nonindependent events, There was not a statistically significant diffe ence in the presence ofasymptomaticin- tuacranial hemorthage or hemorrhagic ransformation between patients withand \withoutlackofimproverent (0% vs 12% P=.50). Patients with lack of improve ‘ment had longer lengths of hospitaliza- tion (mean length, 14.5 vs 0.6 days; P=.02).Foreach 5-minute increase, the chance oflackofimproverent increased by 50% The goodness of fit and Hosmer Lemeshow tests used to evaluate the e not sig- 7; Hoste calibration of the model wer nificant (goodness of fit P= Lemeshow P=.13), indicating ad- ‘equate fitness, There was no evidence of collinearity in inspection of tolerance ‘warnings, SEs, and correlation matrix. Interaction was explored between age, sex, NIHSS score, and risk factors, but none achieved statistical significance, The model in its entirety was an ad- equate predictor of lack of improve- ment with anarea under the receiver op- crating characteristic curve of 0.73, Lack of Improvement as a Predictor of 3-Month Outcomes (Overall in-hospital mortality rate was 12.0% forall stroke admissions, includ- ing 28 deaths among those who re- ceived alteplase and 146 deaths among those not treated with alteplase. Among 213 patients evaluated at 00 days, 43 (20.2%) died. Among the same 43 who dled, 5 patients (12%) died within 24 hours afer receiving alteplase, while 23 died (53%) at 30 days. Lack of improvement at 4 hours was significantly more likely in patients who died at 3 months (35/43 [8196] com- pared with 79/170 [46%]; P<.001). Lack of improvement at 24 hours was fan independent predictor of death al- ter adjusting forage, sex, and stroke verity (OR, 7.5; 95% Cl, 20-196). Of the 170 patients who survived to 90 days, 75 (44%) had poor outcome (modified Rankin Seale score, 3-5). Lack of improvement was also signifi- cantly more likely in patients who had poor outcome (49/75 [65%] com- pared with 30/95 [3296]; P<.001). Lack ‘of improvement at 24 hours was an in- dependent predictor of poor outcome after adjusting for age, sex, and stroke severity (OR, 12.9; 95% CI, 5.7-29.6). COMMENT The benefit of intravenous alteplase has been demonstrated in randomized clini- cal rialssince 1995." Lis one of the most cllicacious therapies to date for stroke with « number needed to treat of only 822 We examined the clinical rel- (©2004 American Medical Association, All rights reserved.cevance of lack of improvement ina pro- spective cohort of patients with acute stroke who received alteplase. We found that the presence of cortical involve- ment, hyperglycemia, and time to treat- ment with alteplase were associated in dependently with lack of improvement. Age, baseline NIHSS score, presence of carotid stenosis, prior medication use, presence ofvascularrisk factors, or stroke subtype were not associated with lack of improvement at 24 hours. Alternately, lack of improvement at 24 hours was independently and strongly associated with an increased likelihood of poor outcome (modified Rankin Seale score, 3-5) and death at 3 monthsafter stroke. Lack of improve- ment at 24 hours increased the risk of poor outcome or death at 3 months 10 more than 7-fold alter adjusting forage, sex, and stroke severity. In addition, pa- tients with lack of improvement had a longer period of hospitalization, which isa major factor in determining cost.” Several studies identified predictors of ‘good or poor outcome at 3 months alter thrombolytic therapy; butonlyafewans- lyzed outcome at 24 hours aller treat- that baseline NIHSS score, age, mean ate rial blood pressure, no history of dia tes, hyperglycemia, anda normal CT are independent predictors of good out- come (modified Rankin Sealescore, 0-1) aL3 months." To the best of our knowl edge, lack of improvement at 24 hours, its predictors and prognostic value, has, not been analyzed previously. This infor mation may be useful for managing patient and family expectations as well as [or organizing the health care system. In the NINDS cohort, Brown et al reported major neurological improve- ment (NIHSS score >8) 24 hours af- ler receiving alteplase. Age and time to treatment with alteplase were associ- ated with major neurological improve- ment in a logistic regression model, which showed a moderate predictive value of 0.66 under the receiver ope ‘ling curve area. Grotta etal investi- gated the rate of clinical deterioration Following improvement in the NINDS alteplase tial. The rate of clinical de- 2" These studies have shown (©2004 American Medical Assoc 1, All rights reserved. THROMBOLYTIC THERAPY AND STROKE OUTCOMES: {crioration following improvement was defined by a 2-point increase in the NIHSS score, To address the relation- ship between recanalization/reoccl- sion and the clinical course, Grotia et al mainly used single positron emi sion tomographic scan of cerebral per- fusion. Ten percent of patients in the alteplase group had a rate of clinical de- {crioration following improvement at 24 hours with no statistical difference compared with the placebo group— although neurological worsening did not suggest reocclusion.” However, the cutoff used in the NIHSS score cannot be specific enouigh for reflecting the pa renchyma damage to the brain, which fs probably related to additional con- ditions (such as fluctuations in blood pressure or concurrent medications). More convincingly, an early clinical improvement correlated with recanali- zation assessed by transcranial Dop- pler-*” In these studies, dramatic recov- ery Was defined as a total NIHSS score of 0 to 3 points and early recovery was defined as an improvement of 10 points for more at 2 hours alter eatment with alteplase. Both clinical conditions were present in 22% of patients—75% of whom had good outcomes at 3 months. Therefore, detection of eatly collateral flow oF restoration of flow in the pen- ctratingartery territory assessed by rans- cranial Doppler seems to bea predictor of dramatic o early recovery alter treat- ‘ment with alteplase. Recently, the same group studied the clinical response alter carly recanalization, which wasassessed by transcranial Doppler in 120 stroke patients following treatment with alteplase, They found that 37%of patients with early recanalization did not expe- rience clinical changes or worsening 24 hours following treatment withalteplase and one third achieved a good outcome a3 months. The authors theorized that a “stunned brain syndrome” explained the delayed recovery.® These studies dh {er from ours in that they analyzed net ther clinical predictors oflack of improve- mental 24hoursnor the prognosti vale of ack of improvernent at 3 months, ‘We observed that the presence of cor- tical involvement as detected by imag- ing of the brain obtained 24 hours after treatment with alteplase isa predictor of lack of improvement at 24 hours. Few studies identified the prognosis of cor- Lical involvement in patients with acute stroke” The cerebral cortex is ust- ally affected in patients with seve strokes; persistence of cortical signs isa marker of recanalization in the occluded. vessels orabsence ofcollateal flow *? The presence of cortical signs, such as apha- sia, negleet, and anosognosia, has been associated with poor long-term fune- tional recovery and outeome.2 Although the present study did not pro- Vide direct evidence on vessel state, the ‘observation that cortical involvement is an independent contributing factor of lack of improvement can be explained tosome extent by the absence ofrecana- lization or poor collateral flow. Imour study, the benefit of treatment with alteplase was demonstrated with similar results as the original NINDS trial"? Acute stroke management re- quires certain degree of expertise. Only 4 few institutions are sophisticated enough to provide highly specialized eare for patents with acute stroke, sueh as 24- hour availability of transcranial dop- pler, difusion-perfusion imaging, oren- dovascular therapy." Many of the current stroke units and hospitals, espe- cially in developing countries, have only essential personnel and structure (CT sean ofthe head, carotid ultrasound, and basic routine laboratory) required to manage patients with acute stroke."*# These centers need to use a straightfor- ‘ward approach by extracting the most uselal elinial information for acute man- agement (eg, hyperglycemia, acute is- chemic changes on CT sean, ete). Some carly prediction rules of stroke recov- ery have been validated, but they re- quite diffusion in weight imaging." Cr study adds a useful perspective concerning early predietion of outcome by introducing a elinical variable (lack ‘ofimprovement) that ean be easily sured, Its recognition can contribute to the management of patients with stroke after thrombolytic therapy with alteplase in terms of early prediction of outcome. ‘Our report contains exploratory analy- (Reprinted) JAMA, Cx 20,2004 Not 292, No, 15. 1848‘THROMBOLYTIC THERAPY AND STROKE OUTCOMES ses: predictors of lack of improvement a12+hours and whether lack of mprove- ment at 24 hours is a predictor of poor ‘outcome a3 months, Exploratory analy- ses are useful for generating hypoth- cess, However, an external validation in a large cohort of patients may be neces- sary to createa predictivescore. tis pos- sible that the stnall number and spuri- ‘ous associations of the sample may lit the generalizability of our findings. On the other hand, the present study corroborates previous findings on the deleterious effect of hyperglycemia in acutestroke patients,**and reinforces the ‘concept that the timely administration of alteplase is conditional factor for suc- cessful treatment of acute stroke, These data are not useful for making deci- sions about treatment with alteplase or ‘withholding care for those with lack of improvement at 24 hours. Guidelines from the American Heart Association for the management of patients with acute ischemic stroke should be followed.” In summary, the results of our study. suggest that lack of improvement at 24 |houtrsisan independent predictor of poor ‘outcome and death at 3 months. Time to treatment with alteplase, glucose level ‘on admission, and cortical involvement ‘were independent predictors of lack of improvement. The identification of these clinical variables at 24 hours after treat- ment with alteplase may improve early prediction of outcome at 3 months ‘Author Contribution: Saposnic had fl aces to ‘Setthe tant say anaes sponsor ‘icity of ead ies fe as ass Sd concept and design Saposnic. Youn Aegon te Soin, Ser ibe ees, ‘a Nisront ‘nai anditepetaton of dt: Sapos eg. Nast Dating ofthe manuscrit: Saposrik, Di Lege, aca Cia revision of te manus fr important in {elect content Sos oung Sve DiLeee, Webster, lett, Nant, Hach, Satta ana posi Obtained nde Hacisk ‘aminnstrative technieaor material suppor: ‘Sos Sie, Di Legge Webster, Bly, Jan, Nabront Hac Study spe: Young. Hahn Funding Support These nas suppatedin part Byant fem he Heat Ste Fondo of Canada Evento Sapam The gant was ebaesbsed En compete appear folowing ubleton of fontasversements $844 JAMA Ccioher 20,2004 Vol 292, No 15 Reprinted ‘Downloaded From: https:/jamanetwork.com/ on 02/26/2022 Role ofthe Sponsor: Theinvesiatrs acd as thespor sashes. The Heat Stoke Fourdabon of are Faro inputon the dese, acess tothe dats, analy se iferetaton or publcation of the sty. ‘Adsowledgment We tank Demaeschk, MD, Bain Fel: MD, sé G. Merno, MD, Fa Poncha, IMO, Arturo Tamay, MD, and Edward Wong. MO, {er thar contin in coecing cata. Wea ap preci the dina nda upper Cs Orcataghan, chery Mayer, Connie Frank, Kener ley Hesse. 4a Newhouse, and May Ke a heLon- ‘on Heath Scenes Centre London, Ona. TaN 4. National niu of Neurological Diodes and Sire Pa 'Suoke Stuy Group. Tisue pasmine [enacvatorfor acute chee sole fg) Md. fs05 333 1581-1897 2. da Zoppo Gl Trombotss: tom the experimen {artist the ciel practice. Cerebrovasc Ds OOH Tapp 14182 3 Cenerazedetacy of PA for acute stoke: ‘Boup aaiasel te NINDS UPAStoke Tra Stoke iso zeatisaias, 4, Derchuk AM, Tanne D Hil MD, eta. Preto good outers afer ravenous PA To act ‘hem stoke, Neurology 200157474480, $5 Trouls,eghownosian Deres etl To Boys with nvaveneus EPA nase of TOD cases fact att ttn stoke determination of to lope opoespi andradlopel oteme factors ‘oe. 199628 2529-2540 {6 Maver Rey BC, LUM tal Ea stoke beat. tet ssc thet oicome the NINDS PA Stroke Study: Nevolgy. 200095. 1689-165. 7. Deak A Burg WS, Cnisiou a Tor Boys in Ban schema (TD: transcranial Doppler ‘ow gadepredet cnc sever eu recover and moti in patents Weated win vavenus sue Bsrnogen actuator stoke 200132 89.53, 48 Faber RA. Okon Nets A Burgin WS, Gita Alranio AVE camate recover dur ing itavenoustisue plasminogen activator if Stonccliseal pattem andouteamen cue mae ce fear stoke, Svoke 200233-1301-1307 2. Labebe La Alera F, Wojer AW, Gata, Nakot M Aesandroy AV. ete bene of ate ‘alain sstaned a 3 months? aprospedtneco. fort stay stoke 2003:321695-658 40. Brow DL, Jonson KC, Wagner DP Hak EC Preacing miornurlapes imoroveent thn {even conbrart ue pasagen scar tetnetof trae, Stoke 200835147190 1 Aver Sabin] Moteg CA, Montane) eta Et {ects of admisonhypergycemaon stoke outcome in vepertuse tue plasminogen activator vealed patents Soke 2005 3412351281 4. Kags Koen Eke 8 et a Colater c- ‘lat an inepencet googie pacer of ou ome ser tomo in acute behaemi stoke, ‘Netoraioloy. 200325: -18 42: Mena Lue DN, Grier FG, Shah Ak, ‘heer Basle computed tomotrphy changes ndinea outcome afer thomahse th eco Finatfsue plasminogen activator in acute ehemc stoke J Nevrmazing, 20011: 101-108 4: Saisie Canada. Population and demography (aia tales Avalable Nips /vanw 12tatean ca Teneihers pres tadar/pepdwel aes Cm Accessed August 20,2004 15 Merino IG Siver 8. 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